CN110878052A - FXR agonist-containing compound and preparation method and application thereof - Google Patents

FXR agonist-containing compound and preparation method and application thereof Download PDF

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CN110878052A
CN110878052A CN201911264964.6A CN201911264964A CN110878052A CN 110878052 A CN110878052 A CN 110878052A CN 201911264964 A CN201911264964 A CN 201911264964A CN 110878052 A CN110878052 A CN 110878052A
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朱元菊
方浩
杨新颖
李丽
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to FXR agonist-containing compounds shown in general formula (I) or pharmaceutically acceptable salts thereof, preparation methods of the compounds, pharmaceutical compositions and pharmaceutical preparations containing the compounds, and applications of the compounds in preparation of medicines for treating and/or preventing FXR mediated diseases, wherein R in the formula (I)1、R2、R3、R4、m、n、p、q、T、L1‑L2Ring A or ring B are as defined in the specification.

Description

FXR agonist-containing compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to FXR agonist-containing compounds or pharmaceutically acceptable salts thereof, preparation methods of the compounds, pharmaceutical compositions and pharmaceutical preparations containing the compounds, and applications of the compounds in preparation of medicines for treating and/or preventing FXR mediated diseases.
Background
Farnesoid X Receptor (FXR) was discovered in 1995 as an orphan nuclear receptor, the nomenclature of which stems from the fact that this receptor can be activated by farnesoid at a supraphysiological level. FXR belongs to a member of the nuclear receptor family and is now collectively designated NR1H4(nuclear receptor subunit family 1, group H, member 4). FXR is distributed mainly in tissues and organs such as liver, small intestine, kidney, and adrenal gland.
In 1999, 3 groups independently discovered bile acids (bile acids) simultaneously and at physiological concentrations that activated FXR, thus demonstrating that FXR is a bile acid receptor. Bile acid has multiple physiological functions and plays an important role in the processes of absorption, transportation, distribution, dynamic balance of cholesterol and the like of fat and fat-soluble vitamins. FXR acts as a bile acid receptor and maintains bile acid homeostasis by regulating the expression of genes involved in bile acid. FXR has also been found to play an important role in glucose homeostasis and insulin resistance, among other things. Therefore, the FXR is expected to provide a new direction for treating diseases such as hypercholesterolemia, cholelithiasis, hypertriglyceridemia, cholestatic liver disease and diabetes.
In 2002, Pellicori et al (6 α -Ethyl-chenodeoxycholic acid (6 ECDCCA), a patent and selective FXR aggregated controlled with pharmacological activity. J Med Chem,2002,45: 3569. sup. 72.) reported the first synthetic high-activity steroid FXR ligand, 6-Ethyl chenodeoxycholic acid (6 ECDCCA) in 9.2019, and Intercept Pharmaceuticals published a commercial application for Obeticholic acid (6 ECCA) to treat liver fibrosis caused by non-alcoholic hepatitis (NASH).
In 2000, Maloney et al (Identification of a chemical tool for the organic and non-steroidal agonist FXR. J. Med Chem,2000,43: 2971-. Although GW4064 has very high FXR agonistic activity both at the extracellular and cellular level, its structure contains stilbene groups and is potentially toxic. In recent years, several derivatives have been reported in succession in order to optimize GW4064. Akwabi et al (formatting constrained disease X Receptor agents: Nanphatotic-based analytes of GW4064.Bloorq Med Chem Lett 2008,18, 4339-.
Figure BDA0002312565780000021
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a compound containing FXR agonist, and further provides a pharmaceutical composition and medical application of the compound.
The specific technical scheme is as follows:
compound containing FXR agonist
A compound comprising an FXR agonist, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (i):
Figure BDA0002312565780000022
wherein R is1Is hydrogen, halogen, cyano, amino, C1-6Alkyl radical, C3-8Cycloalkyl radical, C4-8Alkylcycloalkyl or C1-6Alkoxy radical, wherein C1-6Alkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxy or C1-6The group of the alkoxy group is substituted,
R2is hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A halogenated alkoxy group,
t is-O-, -S-、-C(R5)(R6) -or-N (R)5)-，R5And R6Independently of each other are hydrogen and C1-6Alkyl or C3-8Cycloalkyl, wherein said alkyl or cycloalkyl may be substituted by 1 to 5 fluorine atoms,
the A ring and the B ring are respectively and independently 6-14-membered aryl, 5-14-membered heteroaryl, 3-14-membered cycloalkyl or 3-14-membered heterocyclyl,
L1-L2is-C (R)8)＝C(R8)-、-R7-、-N(R8)-R7-、-R7-N(R8)-、-N(R8)C(O)-R7-、-N(R8)C(O)N(R8)-、-C(O)N(R8)-、-C(O)R7N(R8)-、-OR7-、-R7O-、-C(O)-R7-、-S-R7-、-R7-S-、-S(O)f-R7-、-R-S(O)f-、-S(O)fN(R8)-,-S(O)fR7N(R8R)-、-N(R8)S(O)f-, wherein R7And R8Each independently selected from hydrogen or C1-6Alkyl, f is an integer of 0 to 2,
R3is hydrogen, halogen, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylaminocarbonyl, hydroxy C1-6Alkyl, cyano, nitro, azido, carboxyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkyl, halo C1-6Alkyl, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-6Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6alkylene-R12、SO2-C1-6Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-5.
The technical scheme of the invention is preferably as follows:
wherein R is1Is hydrogen, C1-6Alkyl or C3-8A cycloalkyl group,
R2is hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A halogenated alkoxy group,
t is-O-,
the A ring and the B ring are respectively and independently 6-14-membered aryl, 5-14-membered heteroaryl, 3-14-membered cycloalkyl or 3-14-membered heterocyclyl,
L1-L2is-C (R)8)＝C(R8)-、-N(R8)-R7-、-R7-N(R8)-、-N(R8)C(O)-R7-、-N(R8)C(O)N(R8)-、-C(O)N(R8)-、-C(O)R7N(R8)-、-C(O)-R7-, wherein R7And R8Each independently selected from hydrogen or C1-6An alkyl group, a carboxyl group,
R3is hydrogen, halogen, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylaminocarbonyl, hydroxy C1-6Alkyl, cyano, nitro, azido, carboxyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkyl, halo C1-6Alkyl, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-6Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6alkylene-R12、SO2-C1-6Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-5.
The technical scheme of the invention is further preferably as follows:
wherein R is1Is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group,
R2is hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A halogenated alkoxy group,
the A ring and the B ring are respectively and independently cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, azetidine, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 4-thiadiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, 1,2, 4-oxadiazole, benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, Pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
L1-L2is-C (R)8)＝C(R8) -or-N (R)8)-R7-, wherein R7And R8Each independently selected from hydrogen or C1-4An alkyl group, a carboxyl group,
R3is hydrogen, halogen, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkylaminocarbonyl, hydroxy C1-4Alkyl, cyano, nitro, azido, carboxyl, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, halo C1-4Alkyl, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl orC1-4An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-4Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-4Alkyl radical, C1-4Haloalkyl, C1-4alkylene-R12、SO2-C1-4Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-3.
The technical scheme of the invention is still further preferable:
wherein R is1Is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group,
R2is hydrogen, halogen, C1-4Alkyl radical, C1-4A halogenated alkyl group,
the A ring and the B ring are respectively and independently a benzene ring, pyridine, cyclohexane, cyclopentane, piperidine, tetrahydropyrrole, azetidine, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, 1,2, 4-thiadiazole, tetrahydrofuran, furan, isoxazole, 1,2, 4-oxadiazole or piperazine,
L1-L2is-CH ═ CH-, -NHCH2-or-N (CH)3)CH2-，
R3Is hydrogen, halogen, C1-4Alkyl, or halo C1-4An alkyl group, a carboxyl group,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-4Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy or C1-4An alkyl group, a carboxyl group,
m, n, p and q are respectively independent integers of 0-2.
The technical scheme of the invention is further preferable:
wherein R is1Is C1-3Alkyl radical, C3-6A cycloalkyl group,
R2is hydrogen, halogen or C1-3An alkyl group, a carboxyl group,
the ring A is a benzene ring or a pyridine ring,
the ring B is a benzene ring,
L1-L2is-CH-or-N (CH)3)CH2-，
R3Is hydrogen, halogen, C1-3Alkyl, or halo C1-3An alkyl group, a carboxyl group,
R4is hydrogen, halogen, COOH, CONHOH or tetrazolyl,
m is a number of 0, and m is,
n is a number of 2 and is,
p is 0 or 1, and p is,
q is 0, 1 or 2.
The technical scheme of the invention is particularly preferably as follows:
wherein R is1Is an isopropyl group or a cyclopropyl group,
R2is a hydrogen atom or a chlorine atom,
the ring A is a benzene ring or a pyridine ring,
the ring B is a benzene ring,
L1-L2is-CH-or-N (CH)3)CH2-，
R3Is a hydrogen atom, a chlorine atom or a trifluoromethyl group,
R4is a hydrogen atom or-COOH,
m is a number of 0, and m is,
n is a number of 2 and is,
p is 1, and p is a group of,
q is 1.
Detailed Description
The "halogen" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like. Fluorine atom and chlorine atom are preferred.
The term "halo" as used herein means that any atom in the group which can be substituted is substituted by halogen, and can be perhalogenated, i.e., the halogen atom is substituted at all positions in the group which can be substituted.
Said "C" of the present invention1-6Alkyl "denotes straight-chain or branched alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, n-propyl, i-propylPropyl, 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. Preferably C1-3An alkyl group. Said "C" of the present invention1-3Alkyl "refers to the above examples containing 1 to 3 carbon atoms.
Said "C" of the present invention2-6The alkenyl group "means a straight chain or branched alkenyl group having 2 to 6 carbon atoms containing a double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-1-propenyl, 2-methyl-2-butenyl, 2-methyl-propenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2-methyl-3-pentenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 1-methyl-pentenyl, 2-methyl-2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 2-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1,1, 2-dimethyl-2-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenylButenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-butadienyl, 1, 3-pentadienyl, 1, 4-pentadienyl, 2, 4-pentadienyl, 1, 4-hexadienyl, 1-ethyl-2-methyl-2-propenyl, 1, 3-pentadienyl, 1, 4-hexadienyl, 2, 4-hexadienyl, and the like. The double bond may optionally be cis and trans.
Said "C" of the present invention2-6Alkynyl "means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and having a triple bond, such as ethynyl, 1-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, etc, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and the like.
Said "C" of the present invention1-6Alkoxy "means" C1-6Alkyl "a group bonded to another structure through an oxygen atom, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1-dimethylethoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropyloxy, 1, 2-dimethylpropyloxy, 2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy, 1-dimethylbutyloxy, 1, 2-dimethylbutyloxy, 1, 3-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 2-dimethylbutyloxy, 1-methylpropyloxy, 1-dimethylbutyloxy, 1-methylpropyloxy, 2, 3-dimethylbutyloxy group, 3-dimethylbutyloxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1, 2-trimethylpropoxy group, 1,2,2-Trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. The term "C1-3The "alkoxy group" refers to a specific example containing 1 to 3 carbon atoms among the above examples.
Said "C" of the present invention1-6Alkylcarbonyl "refers to the term" C1-6Alkyl "a group attached to another structure through a carbonyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, and the like.
Said "C" of the present invention1-6Alkylamino "refers to the term" C1-6Alkyl "a group attached to another structure through an amine group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino, and the like.
Said "C" of the present invention1-6Alkylcarbonyloxy "refers to the term" C1-6Alkyl "a group bonded to another structure through a carbonyloxy group, such as methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, sec-butylcarbonyloxy, pentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy and the like.
Said "C" of the present invention1-6Haloalkyl "means the term" C1-6The hydrogen atoms of the alkyl groups "are substituted with one or more halogen atoms, the halogens being as described above.
Said "C" of the present invention1-6Haloalkoxy "refers to the term" C1-6The hydrogen atom of alkoxy "is substituted with one or more halogen atoms, the halogens being as described above.
The "3-to 14-membered cycloalkyl" as used herein means a cyclic alkyl group derived from an alkane moiety of 3 to 14 carbon atoms by removing one hydrogen atom, and includes a 3-to 8-membered monocyclic cycloalkyl group, a 6-to 14-membered fused cycloalkyl group, a 7-to 12-membered bridged cyclic group and a 7-to 12-membered spiro cyclic group. Preferably C3-8Cycloalkyl radical, C3-6Cycloalkyl and C5-6A cycloalkyl group. The term "C3-8A cycloalkyl group“C3-6Cycloalkyl group "," C5-6Cycloalkyl "is a specific example containing 3 to 8, 3 to 6, and 5 to 6 carbon atoms in the following examples, respectively.
3-8 membered monocyclic cycloalkyl groups, including 3-8 membered saturated monocyclic cycloalkyl groups and 3-8 membered partially saturated monocyclic cycloalkyl groups. 3-8 membered saturated monocyclic cycloalkyl, meaning that the monocyclic ring is fully saturated carbocyclic, examples of which include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopropane, dimethylcyclopropane, methylcyclobutane, dimethylcyclobutane, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, dimethylcyclohexane, etc. 3-8 membered partially saturated monocyclic cycloalkyl, meaning that the monocyclic ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like;
6-14 membered fused ring group means a 6-14 membered cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other, and includes a 6-14 membered saturated fused ring group and a 6-14 membered partially saturated fused ring group. 6-to 12-membered fused ring group, 6-to 10-membered fused ring group are preferred. 6-14 membered saturated fused cycloalkyl, meaning that the fused ring group is a fully saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hexanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.0] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.2.0] octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthryl and the like. A 6-14 membered partially saturated fused cycloalkyl group, meaning that at least one ring in the fused ring is a partially saturated carbocyclic ring, examples of which include, but are not limited to: bicyclo [3.1.0] hex-2-enyl, bicyclo [4.1.0] hept-3-enyl, bicyclo [3.2.0] hept-3-enyl, bicyclo [4.2.0] oct-3-enyl, 1,2,3,3 a-tetrahydropentalenyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8 a-octahydronaphthyl, 1,2,4a,5,6,8 a-hexahydronaphthyl, 1,2,3,4,5,6,7,8,9, 10-decahydrophenanthryl and the like;
the 7-12-membered bridged ring group refers to a structure containing 5-12 carbon atoms formed by two atoms which are not directly connected and are shared by any two rings, and the 5-12-membered bridged ring comprises a 5-12-membered saturated bridged ring group and a 5-12-membered partially saturated bridged ring group. 5-12 membered saturated bridged ring group, preferably 6-10 membered saturated bridged ring group, including but not limited to bicyclo [2.1.1] hexanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.2.1] heptanyl, bicyclo [2.2.2] octanyl, bicyclo [3.2.1] octanyl, bicyclo [3.3.1] nonanyl, bicyclo [4.3.1] nonanyl, 4-azabicyclo [5.3.1] decanyl and the like. 7-12 membered partially saturated bridged ring group means a cyclic group in which at least one ring in the bridged ring is unsaturated, preferably 6-10 membered partially saturated bridged ring group, and specific examples include, but are not limited to, bicyclo [2.2.1] hept-5-enyl, bicyclo [3.2.1] oct-6-enyl, bicyclo [4.3.1] non-5-enyl, biscyclopentadienyl and the like;
7-12 membered spirocyclic groups refer to a class of 5-12 membered fused ring structures formed by at least two rings sharing an atom. 5-12 membered saturated spiro ring group means that all rings in the spiro ring group are saturated cyclic groups, specific examples include but are not limited to:
Figure BDA0002312565780000081
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 5-12 membered partially saturated spiro ring group means a cyclic group in which at least one ring of the spiro ring group is unsaturated, and specific examples include, but are not limited to:
Figure BDA0002312565780000082
Figure BDA0002312565780000083
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. Preferred are 7-to 10-membered spiro ring groups, including "7-to 10-membered saturated spiro ring groups" and "7-to 10-membered unsaturated spiro ring groups".
"C" according to the invention3-8Cycloalkoxy "refers to the term" C3-8Cycloalkyl "a group attached to another structure through an oxygen atom, e.g. cyclopropyloxy, cyclobutyloxy, 1-methylcyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxyOxy, and the like.
The "6-14 membered aryl" as referred to herein means a cyclic aromatic group having 6-14 membered carbon atoms as ring atoms, and includes 6-8 membered monocyclic aryl and 8-14 membered fused ring aryl. The 6-8 membered monocyclic aryl group means an all unsaturated aryl group such as phenyl, cyclooctatetraenyl and the like. The 8-to 14-membered fused ring aryl group means a cyclic group formed by two or more cyclic structures sharing two adjacent carbon atoms with each other and having at least one ring being an all unsaturated aromatic ring, and includes 8-to 14-membered all unsaturated fused ring aryl, naphthyl, anthryl, phenanthryl and the like, and also includes 8-to 14-membered partially saturated fused ring aryl groups such as benzo 3-to 8-membered saturated monocyclic cycloalkyl, benzo 3-to 8-membered partially saturated monocyclic cycloalkyl, and specific examples thereof are 2, 3-dihydro-1H-indenyl, 1,2,3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl and the like. Preferably 6-to 10-membered aryl, more preferably benzene or a benzo 3-to 8-membered saturated monocyclic cycloalkyl, a benzo 3-to 8-membered partially saturated monocyclic cycloalkyl. The term "6-to 10-membered aryl" refers to a specific example of the above-mentioned "aryl" having 6 to 10 ring atoms.
The "5-to 14-membered heteroaryl" includes one or more heteroatoms in addition to carbon atoms in the ring, including but not limited to oxygen, nitrogen, and sulfur atoms. Heteroaryl groups may be bonded through carbon or a heterocyclic atom. Including 5-8 membered monocyclic heteroaryl and 8-14 membered fused heterocyclic aryl. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, tetrazolyl, oxadiazolyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, isooxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like; 8-14 membered fused heterocyclic aryl groups include, but are not limited to, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, indolizinyl, indazolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzisoxazolyl, benzoxazinyl, benzimidazolyl, pyridopyridyl, pyrazolo [3,4-b ] pyridyl, purinyl, acridinyl, xanthenyl, and the like.
The term "3-14 membered heterocyclic group" as used herein means a 3-14 membered cyclic group containing one or more heteroatoms, wherein the "heteroatom" means N, S, O, SO and/or SO2And the like. Including saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO23-8 membered heteromonocyclic group and 5-14 membered heteromonocyclic group of the hetero atom of (a). Also included are the heteroaryl groups mentioned above and their dihydro and tetrahydro analogs. 5-14 membered diheterocyclyl includes saturated, partially saturated, unsaturated having 1-4 substituents selected from N, S, O, SO and/or SO2Fused, spiro, bridged rings of heteroatoms of (a). Preferred is a 3-to 8-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 3-to 8-membered heteromonocyclic group. More preferred is a 5-8-membered, 5-7-membered, 5-6-membered heterocyclic group, and further preferred is a saturated, partially saturated, unsaturated 5-8-membered, 5-7-membered, 5-6-membered heteromonocyclic group.
3-8 membered heteromonocyclic group means a monocyclic heterocyclic group containing 3 to 8 ring atoms (wherein at least one hetero atom is contained), and includes 3-8 membered unsaturated heteromonocyclic group, 3-8 membered partially saturated heteromonocyclic group, 3-8 membered saturated heteromonocyclic group. Preference is given to 5-7-membered unsaturated heteromonocyclic groups, 5-7-membered partially saturated heteromonocyclic groups, 5-7-membered saturated heteromonocyclic groups. 3-8 membered unsaturated Monoheterocyclyl, which means an aromatic heteroatom-containing cyclic group, specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, 2-pyridone, 4-pyridone, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, oxepitrienyl, thiepintrienyl, azepintrienyl, 1, 3-diazepitrienyl, azepinatetraenyl, and the like. 3-8 membered partially saturated monoheterocyclyl means a cyclic group containing a double bond, a heteroatom, and specific examples include, but are not limited to, 2, 5-dihydrothienyl, 4, 5-dihydropyrazolyl, 3, 4-dihydro-2H-pyranyl, 5, 6-dihydro-4H-1, 3-oxazinyl, and the like. 3-8 membered saturated monoheterocyclyl, refers to heteroatom-containing cyclic groups that are all saturated bonds, specific examples include, but are not limited to: aziridinyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, 1, 4-dioxanyl, 1, 3-dithianyl, morpholinyl, piperazinyl, and the like.
Said has 1-4 selected from N, S, O and/or SO2Is a fused, spiro or bridged ring of a heteroatom, in particular a fused, spiro or bridged ring in which one of the carbon atoms not shared by it is N, S, O and/or SO2The heteroatom(s) in place of the 6-to 14-membered heterocyclic group, 5-to 12-membered spiroheterocyclic group, 5-to 12-membered bridged heterocyclic group formed.
The 6-to 14-membered heterocyclic group means a heterocyclic ring structure having 6 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two adjacent atoms to each other, and includes a 6-to 14-membered unsaturated heterocyclic group, a 6-to 14-membered partially saturated heterocyclic group, and a 6-to 10-membered saturated heterocyclic group. 6-14 membered unsaturated heterocyclo means that all rings are unsaturated fused ring structures such as structures formed by benzo 3-8 membered unsaturated heteromonocyclic group, structures formed by 3-8 membered unsaturated heteromonocyclic group and 3-8 membered unsaturated heteromonocyclic group, and the like, and specific examples include, but are not limited to: benzofuranyl, benzisofuranyl, benzothienyl, indolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, isoquinolyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, indolyl, and mixtures thereof,
Figure BDA0002312565780000101
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 6-14 membered partially saturated heterocyclo, refers to fused ring structures containing at least one partially saturated ring, e.g. benzo 3Structures formed from 8-membered partially saturated heteromonocyclic groups, structures formed from 3-8-membered partially saturated heteromonocyclic groups and 3-8-membered partially saturated heteromonocyclic groups, and the like, specific examples include, but are not limited to: 1, 3-dihydrobenzofuranyl, benzo [ d ]][1.3]Dioxolyl, isoindolinyl, chromanyl, 1,2,3, 4-tetrahydropyrrolo [3,4-c ]]Pyrrole, pyrrole,
Figure BDA0002312565780000102
Figure BDA0002312565780000103
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure. 6-to 10-membered saturated and heterocyclic group means a fused ring structure in which all rings are saturated, such as a structure formed by a 3-to 8-membered saturated heteromonocyclic group and a 3-to 8-membered saturated heteromonocyclic group, and specific examples include, but are not limited to: cyclobutane tetrahydropyrrole, cyclopentane tetrahydropyrrole, azetidine imidazolidine radical,
Figure BDA0002312565780000111
And a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The 5-to 12-membered bridged heterocyclic group means a bridged ring structure formed by 5 to 12 ring atoms (containing at least one hetero atom). "5-12 membered bridged heterocyclic group" includes 5-12 membered saturated bridged heterocyclic group, 5-12 membered partially saturated bridged heterocyclic group.
5-12 membered saturated bridged heterocyclyl, meaning that all rings in the bridged heterocyclyl are saturated cyclic groups, preferably 7-8 membered saturated bridged heterocyclyl, specific examples include but are not limited to:
Figure BDA0002312565780000112
Figure BDA0002312565780000113
Figure BDA0002312565780000114
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-12 membered partially saturated bridged heterocyclyl means that there is a cyclic group in the bridged heterocyclyl in which at least one ring is unsaturated, preferably 7-8 membered partially saturated bridged heterocyclyl, specific examples include, but are not limited to:
Figure BDA0002312565780000115
Figure BDA0002312565780000116
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The 5-12 membered spiroheterocyclic group means a spiro ring structure formed from 5 to 12 ring atoms (containing at least one hetero atom). The 5-12 membered spiroheterocyclic group includes a 5-12 membered saturated spiroheterocyclic group, a 5-12 membered partially saturated spiroheterocyclic group.
5-12 membered saturated spiroheterocyclyl, meaning that all rings in the spiroheterocyclyl are saturated cyclic groups, specific examples include, but are not limited to:
Figure BDA0002312565780000117
Figure BDA0002312565780000118
Figure BDA0002312565780000121
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
5-12 membered partially saturated spiroheterocyclic group means a cyclic group in which at least one ring of the spiroheterocyclic group is unsaturated, and specific examples include, but are not limited to:
Figure BDA0002312565780000122
and a group formed by substituting an optionally substituted hydrogen atom with an isocyclic structure.
The terms 3-8 membered heterocyclic group, 5-7 membered heterocyclic group, 5-6 membered heterocyclic group mean specific examples in which the number of ring atoms in the above-mentioned "3-14 membered heterocyclic group" is 3-8, 5-7, 5-6 membered.
In the present invention, the term "3-14-membered cyclic group" means a 3-14-membered saturated or unsaturated carbocyclic group or a saturated or unsaturated heterocyclic group containing a heteroatom selected from N, O and S, and includes a 3-6-membered cyclic group, a 3-14-membered cycloalkyl group, a 6-14-membered aryl group, a 5-14-membered heteroaryl group and a 3-14-membered heterocyclic group.
Particularly preferred compounds of the invention include:
Figure BDA0002312565780000123
process for preparing FXR agonist-containing compounds
The above compounds of the present invention can be synthesized using the methods described in the schemes below and/or other techniques known to those of ordinary skill in the art, but are not limited to the methods below.
The reaction equation is as follows:
Figure BDA0002312565780000131
the reaction steps are as follows:
step 1: dissolving the raw material 1 in an ether solvent, adding lithium aluminum hydride under cooling, reacting at room temperature until the raw material disappears, quenching the reaction, and separating by a silica gel column to obtain an intermediate 1; or using an alcohol solvent, using sodium borohydride as a reducing agent, and heating to react at room temperature;
step 2: dissolving the intermediate 1 in an inert solvent, adding an excessive chlorinated reagent, stirring at room temperature until the raw materials disappear, and concentrating the system to obtain an intermediate 2;
and step 3: dissolving the intermediate 2 and the raw material 2 in a polar solvent, adding alkali and a catalytic amount to an equivalent amount of potassium iodide or sodium iodide, stirring at room temperature until the raw material disappears, adding water for quenching, extracting, and separating by a silica gel column to obtain an intermediate 3; or directly reacting the intermediate 1 with the raw material 2 under the Mitsunobu reaction condition to obtain an intermediate 3;
and 4, step 4: condition 1: and butting the intermediate 3 and the raw material 3 under the Horner-Wittig reaction condition to obtain the compound shown in the formula I.
Or condition 2: and butting the intermediate 3 and the raw material 3 under reducing-Amination reaction conditions to obtain the compound shown in the formula I.
In a preferred embodiment of the present invention,
the ether solvent in the step 1 is one or two of tetrahydrofuran or diethyl ether; the alcohol solvent is selected from one or two of methanol or ethanol.
The inert solvent in the step 2 is selected from one or more of dichloromethane, carbon tetrachloride or toluene; the chlorinating reagent is selected from one or more of thionyl chloride and phosphorus trichloride.
The polar solvent in the step 3 is selected from one or more of DMF, DMA and acetone; the alkali is potassium carbonate; the Mitsunobu reaction is a reaction for generating ester under the action of diethyl dicarboxylate (DEAD), triphenylphosphine (Ph3P) and benzoic acid.
The Horner-Wittig reaction in the step 4 is a reaction that carbanion stabilized by phosphine oxide is added with aldehyde to generate β -hydroxy phosphine oxide, and then the carbanion reacts with alkali to eliminate the generated olefin;
the reduction-Amination reaction is a reaction in which imine is formed and then reduced to amine.
The raw materials 1 and 2 in the above reaction equation are prepared by converting easily available raw materials through simple functional groups. R in the above reaction equation1、R2、R3、R4、T、m、n、p、q、L1-L2Ring a or ring B are as defined above.
The compounds of the present invention include compounds in any form, such as free forms, salt forms, solvate forms, and salt and solvate forms.
According to another aspect, the present invention provides a compound of the invention in the form of a salt and/or solvate.
The salts preferably include pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, for example, for purposes of preparation, isolation, purification.
Salts of the compounds of the present invention include base or acid addition salts. Pharmaceutically acceptable base salts include ammonium salts such as the tri ylammonium salt, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases including primary, secondary and tertiary amines such as isopropylamine, diethylamine, ethanolamine, tri amine, dicyclohexylamine and N-methyl-D-glucamine, preferably the sodium salt.
The acid addition salts may be pharmaceutically or non-pharmaceutically acceptable salts. When a non-pharmaceutically acceptable salt, it can be used to isolate and purify the compound of the invention or an intermediate thereof, and then converted into a pharmaceutically acceptable salt or a free base. Pharmaceutically acceptable acid addition salts include those described in journal of pharmaceutical sciences (j.pharm.sci), 1977, 66, 1-19. Such as fumaric acid, tartaric acid, ethane-1, 2-disulfonic acid, maleic acid, naphthalene-1, 5-sulfonic acid, acetic acid, maleic acid, succinic acid, salicylic acid, azelaic acid, 2- [ (2, 6-dichlorophenyl) amino ] phenylacetic acid, hydrochloric acid, deuterochloricaic acid; hydrochloric acid is preferred.
"pharmaceutically acceptable salts" of the compounds of the present invention refers to base addition salts or acid addition salts of the compounds of the present invention with pharmaceutically acceptable, non-toxic bases or acids, including organic acid salts, inorganic acid salts, organic base salts, inorganic base salts. The organic acid salt includes formate, acetate, propionate, benzenesulfonate, benzoate, p-toluenesulfonate, 2, 3-dihydroxysuccinate, camphorsulfonate, citrate, methanesulfonate, ethanesulfonate, propanesulfonate, fumarate, gluconate, glutamate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, succinate, tartrate and the like, and benzoate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, tartrate are particularly preferable. The inorganic acid salt includes hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate and the like, and the hydrochloride, hydrobromide, sulfate, phosphate are particularly preferable. Organic base salts include amine salts, including salts with primary, secondary and tertiary amines, cyclic amines and basic ion exchange resins, and may be selected from salts with the following organic bases: such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. The inorganic base salt includes salts with ammonia, alkali metals and alkaline earth metals, such as ammonium salts and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, copper, ferrous, manganese and manganous salts, with ammonium salts and sodium, potassium, calcium and magnesium salts being particularly preferred.
The compounds of the invention in free form can be converted to the corresponding compounds in salt form and vice versa. The compounds of the invention in free form or in salt form and/or solvate form can be converted into the corresponding compounds in non-solvate form, in free form or in salt form; and vice versa.
The compounds of the present invention may exist as isomers and mixtures thereof, such as optical isomers, diastereomers, cis/trans conformers. The compounds of the invention may, for example, contain asymmetric carbon atoms and may therefore exist as enantiomers (enatiomers) or diastereomers and mixtures thereof, e.g., racemates or diastereomeric mixtures. Any asymmetric carbon atom may be present in the (R) -, (S) -or (R, S) -configuration, preferably in the (R) -or (S) -configuration.
The compounds of the present invention contain one or more asymmetric centers and are thus useful as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The compounds of the present invention have asymmetric centers that each independently 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 present invention includes all stereoisomeric forms of these compounds.
The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified.
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. Each tautomer and mixtures thereof are included in the compounds of the invention.
The isomer mixtures can be separated as desired, for example, in analogy to conventional methods, to give the pure isomers. The present invention includes compounds of the present invention in any isomeric form and any isomeric mixture thereof. The present invention also includes tautomers of the compounds of the present invention, as long as tautomers can exist.
Application of FXR agonist-containing compound
The compounds of the present invention exhibit pharmacological activity and are therefore useful as pharmaceuticals.
For example, the compounds of the present invention exhibit excellent FXR agonism, and thus can be used for the preparation of drugs for the treatment and/or prevention of FXR-mediated diseases.
The compounds of the invention may be administered, for example, in the form of coated or uncoated tablets, capsules, injectable solutions or suspensions, for example in the form of ampoules, vials, emulsions, gels, pastes, inhalation powders, foams, tinctures, lipsticks, drops, sprays, or in the form of suppositories, for example in a form analogous to that of macrocyclic lactones, for example erythromycin, such as clarithromycin and azithromycin, by any conventional route, for example enterally, including, for example, nasal, buccal, rectal, oral administration; parenteral administration, including, for example, intravenous, intramuscular, subcutaneous administration; or topical administration, including, for example, transdermal, intranasal, intratracheal administration.
The compounds of the invention may be administered in the following forms: in the form of a pharmaceutically acceptable salt, for example an acid addition salt or a base addition salt such as a metal salt; or administered in free form; optionally in the form of a solvate. The compounds of the invention in salt form exhibit the same degree of activity as the compounds of the invention in free form, optionally in solvate form.
According to the present invention, the compounds of the present invention may be used in pharmaceutical therapy, either alone or in combination with one or more other pharmaceutically active agents. Such other pharmaceutically active agents include, for example, other FXR agonists.
The present invention provides a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form and/or solvate form; and at least one pharmaceutically acceptable excipient, such as a carrier or diluent, including, for example, fillers, binders, disintegrants, flow regulators, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting and/or emulsifying agents, solubilizers, salts for regulating osmotic pressure and/or buffering agents.
The pharmaceutical compositions may be manufactured, for example, in a manner similar to conventional methods, e.g., by mixing, granulating, coating, dissolving or lyophilizing processes. The unit dosage form may contain, for example, from about 0.5mg to about 2000mg, such as from 10mg to about 500mg, of the active ingredient.
The invention also provides application of the compound with the general formula (I) or pharmaceutically acceptable salt thereof in preparing medicines for treating and/or preventing FXR mediated diseases.
Experiments prove that the FXR agonist compound has good agonistic activity to a certain degree on an FXR receptor, and can be used for preparing a medicament for treating and/or preventing diseases mediated by FXR.
The beneficial effects of the compounds of the present invention are further illustrated below by antibacterial activity experiments, but this should not be understood as meaning that the compounds of the present invention have only the following beneficial effects.
Experimental example 1 in vitro pharmacological Activity of the Compound of the present invention
And (3) testing the sample: some of the compounds of the invention were prepared according to the methods of the examples.
The experimental method comprises the following steps: cytological experiments (cellular assay) assigned to Shanghai Ruizi chemical research, Inc.
Method for detecting report expression by adopting Cell-based transient transfection co-transfection reporter assay
The HEK293 cell line is adopted, the cell concentration is adjusted to 500,000/mL after being cultured for 24h, and the prepared cell transfection reagent (pBIND 50ng/well, pG5Luc50ng/well, FuGENE HD 0.3ul/well, No FBSmedia3.7 mu L/well) is added and distributed into a 96-well plateMedium 100. mu.L/well, 37 ℃, 5% CO2The culture was carried out at concentration for 24 h. Compounds were dissolved in DMSO and diluted to 21-fold final concentration, 3-fold dilution, and transferred to a 96-well plate containing transfected cells at 5. mu.L/well, 37 ℃ and 5% CO, respectively2And incubating for 18 h. After removing the cell culture medium, adding 20 mu L of lysate into each hole, and vortexing for 15 min; adding 30 mu L/hole of luciferase detection reagent II to detect luciferase signals; add stop reaction solution 30. mu.L/well and detect Renilla luciferase signal. The rate of activation was calculated by the following formula, and EC50 value was calculated using Prism 5.0.
Signal value luciferase signal/reninase signal
Activation% (compound signal value-background signal value)/(maximum signal value-background signal value) × 100%
The background signal value refers to the signal value of DMSO
Experimental results and conclusions:
TABLE 1% of the inventive Compounds on FXR Activation at Max Conc
Figure BDA0002312565780000171
And (4) conclusion: as can be seen from table 1, the compounds of the present invention have a certain degree of agonistic activity against the FXR receptor, and their agonistic activity against the FXR receptor is higher than that of GW4064.
Experimental example 2 pharmacological Activity of the Compound of the present invention in vivo
Experimental animals:
SPF grade C57BL/6 Male mice 31 weeks, 8-10 weeks old, from Beijing Wittingle laboratory animal technology Ltd
Experimental drugs and materials
Reagent 1: ConA, source: sigma; reagent 2: DPBS, source Invitrogen.
Experimental methods
Preparation of a reagent:
1) preparation of 20mg/mL ConA
Adding 100mg ConA in a 1-bottle, adding 5mL of DPBS into the bottle by using a pipette, dissolving, slightly mixing up and down, subpackaging in a 0.7mL centrifuge tube with specification of 420 and 320 mu L, and keeping at-80 ℃ in a dark place.
2)1.5mg/mL ConA preparation
In the test, 320. mu.L of ConA was dispensed from 1 bottle and dissolved when 1.5mg/mL of ConA was prepared. 3.7mL of DPBS was added to a 5mL centrifuge tube, and 300. mu.L of 20mg/mL ConA dissolved in the total volume of 4mL was put in the 5mL centrifuge tube and gently mixed up and down for use. The number of animals in the blank group of the three experiments is 5, the number of animals in the first experiment of the model group is 11, the number of animals in the second experiment and the third experiment are 10, the blank group is not administrated, the model group is administrated in an i.v., mode, the dosage of ConA is 15mg/kg, and the volume of ConA is 10 mL/kg.
3) Preparing the medicine:
the solvent is 0.5% Methyl Cellulose (MC), and is prepared into a solution with a concentration of 10mg/mL, and the volume of 0.5% MC is measured according to the purity and weight of the compound, which is shown in Table 2.
TABLE 2 pharmaceutical formulations
Figure BDA0002312565780000181
C57BL/6 is randomly divided into a corresponding blank group, a model group and an administration group according to the body weight after the SPF animal room is adapted for 1 week; before the experiment, a marker pen is adopted to mark the tail of the mouse, and the cage is marked with the experiment number, the group and the experiment date. In the model group, ConA was administered to the tail vein 30min after vehicle administration; ConA was administered to the tail vein 30min after administration of each administration group, and blood was collected 7h after ConA administration. The experimental groups and the mode of administration are shown in table 3.
TABLE 3 grouping and administration mode
Figure BDA0002312565780000182
Blood sample collection: mice are anesthetized by intraperitoneal injection of 45mg/kg pentobarbital sodium, 300 mu L of blood is taken from the angular sinus in the eye, the blood is placed in a 1.5mL centrifuge tube without anticoagulant, the centrifuge tube is kept still at room temperature for 1h, an eppendorf 5424R centrifuge is used for centrifuging at 3500rpm for 10min at 4 ℃, and 100 mu L of serum is extracted for ALT and AST measurement. All data were analyzed using One-wayanalysis of variation Test, followed later by Tukey's Multiple company Test.
Results of the experiment
The results are shown in Table 4
Table 4: changes in serum ALT and AST in mice of each group
Figure BDA0002312565780000183
As can be seen from Table 4, ALT was 9045U/L in the model group mice 7h (15mg/kg) after ConA administration in this experiment. After the compound 3 is administered, the serum average ALT value and the AST value of the mice are respectively reduced by 63 percent and 59 percent compared with the model group, and the ALT and the AST are both significantly different (P is less than 0.05) compared with the model group in the compound 3 group.
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(E) -3- (3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) Preparation of styryl) benzoic acid (Compound 1)
Figure BDA0002312565780000191
(1) Preparation of 1, 3-dichloro-2- (2-nitrovinyl) benzene
2, 6-Dichlorobenzaldehyde (10.0g,57.1mmol) was dissolved in 100mL of glacial acetic acid, and ammonium acetate (10.6g,137mmol) and nitromethane (21.2mL) were added in this order, followed by heating to 100 ℃ for 6 hours. Water was added, ethyl acetate was extracted twice, the organic phase was washed with saturated sodium bicarbonate solution, brine washed, dried over anhydrous sodium sulfate, and spin dried to give a yellow solid 8.6g, yield: and 69 percent.
(2) Preparation of 4- (2, 6-dichlorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester
1, 3-dichloro-2- (2-nitrovinyl) benzene (8.4g,38.5mmol) was dissolved in 50mL of dibutyl ether, and 90% ethyl diazoacetate in dichloromethane (4.88g,38.5mmol) was added thereto under ice-cooling, followed by reaction at room temperature for three hours and heating to 60 ℃ for 12 hours. A large amount of solid is separated out, filtered, and a filter cake is washed by petroleum ether and dried to obtain 6.6g of brown solid, the yield is as follows: 60 percent.
(3) Preparation of ethyl 4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole-5-carboxylate
Ethyl 4- (2, 6-dichlorophenyl) -1H-pyrazole-5-carboxylate (6.5g,22.8mmol) was dissolved in 50mL of acetonitrile, cesium carbonate (14.9g,45.7mmol) was added thereto, and after stirring at room temperature for ten minutes, 2-iodopropane (4.7g,27.6mmol) was added thereto, and the mixture was heated to 90 ℃ for reaction overnight. Water was added, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and column chromatography (PE: EA 15:1) was performed to obtain 3.2g of a colorless oily substance, yield: 42.9 percent.
(4) Preparation of (4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methanol
Ethyl 4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole-5-carboxylate (3.0g,9.17mmol) was dissolved in 30mL of tetrahydrofuran, and lithium aluminum hydride (700mg,18.4mmol) was slowly added under ice-bath, followed by stirring at room temperature for two hours. TLC monitoring the reaction was completed, and 5mL of water and sodium hydroxide (736mg,18.4mmol) were added to quench the reaction, ethyl acetate was extracted, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed (PE: EA ═ 10:1) to obtain 1.6g of colorless oil, yield: 61.2 percent.
(5) Preparation of 3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) benzaldehyde
(4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methanol (1.5g,5.26mmol), 3-chloro-4-hydroxybenzaldehyde (846mg,5.40mmol) and triphenylphosphine (1.70g,6.48mmol) were dissolved in 30mL of tetrahydrofuran, and DIAD (1.3g,6.43mmol) was slowly added under ice bath to complete the reaction at room temperature for 12 hours. The reaction solution was directly spin-dried and subjected to column chromatography (PE: EA ═ 20:1) to give 1.4g of a colorless oil, yield: 62.7 percent.
(6) Preparation of methyl (E) -3- (3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) styryl) benzoate
Methyl 3- ((diethoxyphosphoryl) methyl) benzoate (572mg,2.0mmol) was dissolved in 10mL of tetrahydrofuran, and 60% of NaH (88mg,2.2mmol) and 3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) benzaldehyde (423mg,1.0mmol) were added to the solution to react at room temperature for 2 hours. Adjusting pH to neutral with diluted hydrochloric acid in ice bath, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spin-drying, and performing column chromatography (PE: EA: 25:1) to obtain colorless oil 512mg, yield: 92.1 percent.
(7) Preparation of (E) -3- (3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) styryl) benzoic acid
Methyl (E) -3- (3-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) styryl) benzoate (501mg,0.9mmol) was dissolved in a mixed solution of 20mL of tetrahydrofuran and 5mL of water, and sodium hydroxide (360mg,9.0mmol) was added thereto, followed by stirring at 40 ℃ overnight. Adjusting pH to weak acidity with dilute hydrochloric acid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spin-drying, and performing column chromatography (PE: EA: 5:1) to obtain white solid 160mg, with yield: 32.8 percent.
The molecular formula is as follows: C28H23Cl3N2O3 molecular weight: 540.08, respectively; mass spectrum (M + H): 541.1
1H-NMR(DMSO-d6,400MHz)：13.09(1H,s),8.09(1H,s),7.88-7.80(2H,m),7.75(1H,d),7.59-7.46(4H,m),7.44-7.35(2H,m),7.25(1H,d),6.94(1H,d),6.84(1H,dd),5.08(2H,s),4.70(1H,septet),1.45(6H,d).
Example 23- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) Preparation of phenyl) (methyl) amino) methyl) benzoic acid (Compound 2)
Figure BDA0002312565780000211
(1) Preparation of methyl 3- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenylimino) methyl) benzoate
2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) aniline (240mg,0.58mmol) was dissolved in 5mL of DCE, methyl 3-formylbenzoate (285mg,1.74mmol) and acetic acid (209mg,3.48mmol) were added, the temperature was raised to 80 ℃ to react for 12 hours, and the reaction solution was cooled to room temperature and used directly in the next step.
(2) Preparation of methyl 3- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) anilino) methyl) benzoate
Adding sodium triacetoxyborohydride (1.23g,5.80mmol) into the reaction system in the last step, reacting at room temperature for 12 hours, spin-drying the solvent, and performing column chromatography (PE: EA is 5:1) to obtain 180mg of colorless oily substance, wherein the total yield of the two steps is 55.2%.
(3) Preparation of methyl 3- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) amino) methyl) benzoate
Methyl 3- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) anilino) methyl) benzoate (180mg,0.32mmol) was added to 10mL of an aqueous formaldehyde solution, 1mL of formic acid was added, the temperature was raised to 100 ℃ to react for 2 hours, most of the reaction solution was spun off, water was added, ethyl acetate was extracted, the organic phase was washed three times with a saturated sodium bicarbonate solution, washed with a saturated salt solution, dried, concentrated, and subjected to column chromatography (PE: EA ═ 5:1) to obtain 139mg of a white solid, the yield was 75.0%.
(4) Preparation of 3- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) amino) methyl) benzoic acid
Methyl 3- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) amino) methyl) benzoate (139mg,0.24mmol) was dissolved in 10mL of THF, 5mL of water and sodium hydroxide (96mg,2.40mmol) were added, the temperature was raised to 50 ℃ and the reaction was reacted for 2 hours, and the reaction was terminated by TLC. Adding water, extracting and washing an organic phase once by DCM, adjusting the pH value of a water phase to 3 by using 1N diluted hydrochloric acid, adding ethyl acetate for extraction, washing the organic phase by using saturated salt solution, drying by using anhydrous sodium sulfate, filtering, spin-drying, carrying out column chromatography (PE: EA is 5:1) to obtain a white solid, washing the white solid by using anhydrous ether, filtering, dissolving a filter cake into the ethyl acetate, washing twice by using water, washing once by using the saturated salt solution, drying by using the anhydrous sodium sulfate, filtering and concentrating to obtain 62mg of the white solid with the yield of 45.8%.
The molecular formula is as follows: C28H26Cl3N3O3 molecular weight: 557.1; mass spectrum (M + H): 558.1
1H-NMR(DMSO-d6,400MHz)：12.89(1H,br s),7.96(1H,s),7.80(1H,d),7.62-7.29(6H,m),7.08(1H,d),6.88(1H,d),6.72(1H,dd),4.97(2H,s),4.68(1H,septet),4.07(2H,s),2.51(3H,s),1.44(6H,d).
Example 3 3- (((6- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) -2- (tris) Preparation of fluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoic acid (Compound 3)
Figure BDA0002312565780000221
(1) Preparation of 5-amino-6- (trifluoromethyl) pyridin-2-ol
To a dry reaction flask, 5-nitro-6- (trifluoromethyl) pyridin-2-ol (5.88g, 28.3mmol) (see EP2128158 (2009)) was added and dissolved in 200mL of methanol, followed by addition of zinc powder (18.4g, 283mmol) in portions and addition of 2mL of acetic acid, and the reaction was allowed to warm to 50 ℃ overnight. And filtering the reaction solution, washing a filter cake by using methanol, and spin-drying the filtrate to obtain a yellow solid crude product.
(2) Preparation of methyl 3- ((6-hydroxy-2- (trifluoromethyl) pyridin-3-ylimino) methyl) benzoate
To a dry reaction flask, the crude product obtained in the above step and methyl 3-formylbenzoate (13.9g, 84.9mmol) were added, dissolved in 100mL of 1, 2-dichloroethane, and then 1mL of acetic acid was added, and the temperature was raised to 50 ℃ to react for 72 hours. The reaction solution was spin-dried and used directly for the next reaction.
(3) Preparation of methyl 3- ((6-hydroxy-2- (trifluoromethyl) pyridin-3-ylamino) methyl) benzoate
In a dry reaction flask, the crude product obtained in the above step was dissolved in 100mL of anhydrous methanol, and sodium cyanoborohydride (5.35g, 84.9mmol) was added portionwise at room temperature, and the reaction was allowed to warm to 50 ℃ for 12 hours. The reaction mixture was spin-dried and subjected to silica gel column chromatography (PE: EA ═ 10:1) to give 4.5g of a crude colorless oil.
(4) Preparation of methyl 3- (((6-hydroxy-2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate
To a dry reaction flask was added methyl 3- ((6-hydroxy-2- (trifluoromethyl) pyridin-3-ylamino) methyl) benzoate (4.5g crude), 100mL of aqueous formaldehyde was added, 2mL of formic acid was added, and the temperature was raised to 100 ℃ for 8 hours. After water was added to the system, extraction was performed with ethyl acetate, drying, concentration and silica gel column chromatography (PE: EA ═ 5:1) to obtain 3.00g of a white solid, with a yield of 31.2% in four steps.
(5) Preparation of 5- (chloromethyl) -4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole
(4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methanol (1.5g,5.3mmol) was dissolved in 30mL of dichloromethane, and thionyl chloride (1.3g,10.6mmol) was slowly added dropwise thereto, followed by reaction at room temperature for 2 hours. TLC monitoring the reaction was complete and the reaction solution was spin dried to give a pale yellow solid 1.5g, yield: 92.5 percent.
(6) Preparation of methyl 3- (((6- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate
5- (chloromethyl) -4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole (200mg,0.66mmol) was dissolved in 5mL of DMA, potassium carbonate (91mg,0.66mmol) was added, stirring was carried out for 10 minutes, methyl 3- (((6-hydroxy-2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate (225mg,0.66mmol) and sodium iodide (99mg,0.66mmol) were added, reaction was carried out at room temperature for 12 hours, water was added, ethyl acetate was extracted three times, the combined organic phases were washed with water once, concentrated, and column chromatography (PE: EA: 10:1) gave 335mg of a white solid in 83.3% yield.
(7) Preparation of 3- (((6- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoic acid
Methyl 3- (((6- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate (335mg,0.55mmol) was dissolved in 10mL of THF, 5mL of water and sodium hydroxide (220mg,5.50mmol) were added, the reaction was heated to 50 ℃ and reacted for 2 hours, and the reaction was terminated by TLC. Water was added and the aqueous phase was washed once with DCM, adjusted to pH3 with 1N dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give 210mg of a white solid with a yield of 63.6%.
The molecular formula is as follows: C28H25Cl2F3N4O3 molecular weight: 592.1, respectively; mass spectrum (M + H): 593.1
1H-NMR(DMSO-d6,400MHz)：12.89(1H,br s),8.05(1H,d),7.94(1H,s),7.81(1H,d),7.54(1H,d),7.49-7.40(4H,m),7.33(1H,dd),6.92(1H,d),5.32(2H,s),4.76(1H,septet),4.02(2H,s),2.47(3H,s),1.45(6H,d).
EXAMPLE 44- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) Preparation of methyl phenyl) (methyl) (amino) methyl) benzoate (Compound 4)
Figure BDA0002312565780000241
(1) Preparation of 3-chloro-4-nitrophenol
6.43g (50mmol) of m-chlorophenol was dissolved in 10mL of glacial acetic acid at-20 ℃ and 3.15g (50mmol) of fuming nitric acid was slowly added and the reaction was maintained at-20 ℃ for 1h after the addition was completed. Adding saturated solution of sodium carbonate, quenching, pouring into water, adjusting the sodium carbonate solid to be neutral, extracting with ethyl acetate, concentrating the organic phase, and performing column chromatography (PE: EA is 50:1-5:1) to obtain 2.2g of yellow solid with the yield of 25.4%.
(2) Preparation of 5- ((3-chloro-4-nitrophenoxy) methyl) -4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole
To a dried reaction flask, 3-chloro-4-nitrophenol (0.459g, 2.644mmol) and 5- (chloromethyl) -4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole (0.8g, 2.644mmol) were added and dissolved with 10mL of DMA, followed by addition of potassium carbonate (1.096g, 7.932mmol) and sodium iodide (0.396g, 2.644mmol), stirring at room temperature for 24H, water was added to the system, the aqueous phase was extracted with EA, the organic phase was dried and concentrated, and column chromatography (PE: EA ═ 20:1 to 5:1) gave 0.96g of the product in 82.4% yield.
(3) Preparation of 2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) aniline
Adding 5- ((3-chloro-4-nitrophenoxy) methyl) -4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazole (0.756g,1.715mmol) into 10mL of methanol, adding zinc powder (1.122g,17.15mmol), adding glacial acetic acid (0.514g,8.575mmol), stirring at room temperature for 16 hours, filtering to remove the zinc powder, collecting the filtrate, and spin-drying to obtain 0.68g of a product, wherein the yield is 96.6%.
(4) Preparation of methyl 4- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenylimino) methyl) benzoate
2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) aniline (0.36g,0.877mmol) and methyl p-formylbenzoate (0.432g,2.63mmol) were dissolved in 10mL of dichloromethane, and 0.315g of acetic acid was added to react at room temperature for 72 hours, followed by spin-drying, dissolution with ethyl acetate, washing with a sodium bicarbonate solution, drying, and spin-drying to obtain 0.54g of a crude product.
(5) Preparation of methyl 4- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) anilino) methyl) benzoate
To 0.27g of the crude product obtained in the previous step, 10mL of 1, 2-dichloroethane was added, sodium triacetoxyborohydride (0.514g,2.424mmol) was added, the mixture was reacted at room temperature for 2 hours, water was added, the organic phase was synthesized by extraction three times with ethyl acetate, dried over sodium sulfate, spin-dried, and subjected to column chromatography (PE: EA: 50:1-5:1) to obtain 0.2g of a product.
(6) Preparation of methyl 4- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) (amino) methyl) benzoate
In a reaction flask, methyl 4- ((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) anilino) methyl) benzoate (0.2g,0.358mmol) was added, 10mL of aqueous formaldehyde solution was added, 0.6mL of formic acid was added, the temperature was raised to 100 ℃ to react for 16 hours, sodium bicarbonate was adjusted to neutrality, ethyl acetate was extracted three times, the organic phase was dried, concentrated, and passed through a silica gel column (PE: EA ═ 50:1-1:1) to obtain 0.17g of a product, the yield was 82.9%.
(7) Preparation of methyl 4- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) (amino) methyl) benzoate
Methyl 4- (((2-chloro-4- ((4- (2, 6-dichlorophenyl) -1-isopropyl-1H-pyrazol-5-yl) methoxy) phenyl) (methyl) (amino) methyl) benzoate (0.14g,0.244mmol) was dissolved in 20mL of methanol, sodium hydroxide (98mg,2.44mmol) was added, 2mL of water was added, reaction was carried out at 40 ℃ for 5 hours, 50mL of water was added, most of the methanol was removed by rotation, pH was adjusted to 4.0 with 1N hydrochloric acid, extraction was carried out three times with ethyl acetate, the organic phase was separated, dried, and dried to give 112mg of a product, with a yield of 82.1%.
The molecular formula is as follows: C28H26Cl3N3O3 molecular weight: 557.1; mass spectrum (M + H): 558.1
1H-NMR(DMSO-d6,400MHz)：12.84(1H,br s),7.86(2H,d),7.53(2H,d),7.50-7.42(3H,m),7.38(1H,t),7.06(1H,d),6.88(1H,d),6.71(1H,dd),4.97(2H,s),4.68(1H,septet),4.09(2H,s),2.52(3H,s),1.44(6H,d).
Example 53- (((6- ((1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -2- (tris) Preparation of fluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoic acid (Compound 5)
Figure BDA0002312565780000261
(1) Preparation of 1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazole-5-carboxylic acid ethyl ester
Ethyl 4- (2, 6-dichlorophenyl) -1H-pyrazole-5-carboxylate (2.0g,7.01mmol), cyclopropylboronic acid (1.2g,13.95mmol) and sodium carbonate (1.5g,14.16mmol) were dissolved in dichloroethane (20mL), anhydrous copper acetate (1.3g,7.16mmol) and pyridine (1.1g,13.92mmol) were added thereto, the temperature was raised to 60 ℃ to react for 12 hours, the solid was filtered, washed with dichloromethane several times, the filtrate was concentrated and subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 15:1) to give 800mg of a white solid in 35.1% yield.
(2) Preparation of (1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methanol
Ethyl 1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazole-5-carboxylate (500mg,1.54mmol) was dissolved in 20mL of tetrahydrofuran, and lithium aluminum hydride (117mg,3.08mmol) was slowly added under ice-cooling, followed by stirring for 10 minutes. TLC monitoring the reaction was complete, water 5mL was added, the reaction was quenched with sodium hydroxide (123mg,3.08mmol), extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, spun dry, and column chromatographed (PE: EA ═ 10:1) to give 370mg of white solid, yield: 85.1 percent.
(3) Preparation of 5- (chloromethyl) -1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazole
(1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methanol (370mg,1.31mmol) was dissolved in DCM (10mL), thionyl chloride (312mg,2.62mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. TLC was used to monitor the completion of the reaction, and the reaction solution was spin-dried to obtain 347mg of a pale yellow solid. Yield: 87.8 percent.
(4) Preparation of methyl 3- (((6- ((1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate
Dissolving 5- (chloromethyl) -1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazole (200mg,0.66mmol) in 5mL of DMA, adding potassium carbonate (91mg,0.66mmol), stirring for 10 minutes, adding methyl 3- (((6-hydroxy-2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate (225mg,0.66mmol) and sodium iodide (99mg,0.66mmol), reacting at room temperature for 12 hours, adding water, extracting with ethyl acetate three times, washing the combined organic phases with water once, concentrating, and subjecting to column chromatography (PE: EA ═ 10:1) to obtain 352mg of a white solid with a yield of 87.9%
(5) Preparation of 3- (((6- ((1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoic acid
Methyl 3- (((6- ((1-cyclopropyl-4- (2, 6-dichlorophenyl) -1H-pyrazol-5-yl) methoxy) -2- (trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) benzoate (352mg,0.58mmol) was dissolved in THF (10mL), water (5mL) and sodium hydroxide (232mg,5.80mmol) were added, the temperature was raised to 50 ℃ and the reaction was allowed to react for 2 hours, and the TLC detection reaction was completed. Water was added and the organic phase was washed once with DCM, the pH of the aqueous phase was adjusted to 3 with 1N dilute hydrochloric acid, ethyl acetate was added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give 260mg of a white solid with a yield of 75.9%.
The molecular formula is as follows: molecular weight of C28H23Cl2F3N4O 3: 590.1, respectively; mass spectrum (M + H): 591.1
1H-NMR(DMSO-d6,400MHz)：12.88(1H,br s),8.04(1H,d),7.94(1H,s),7.81(1H,d),7.54(1H,d),7.50-7.28(5H,m),6.85(1H,d),5.43(2H,s),4.02(2H,s),3.77(1H,quintet),2.47(3H,s),1.18-1.00(4H,m).

Claims (10)

1. A compound comprising an FXR agonist or a pharmaceutically acceptable salt thereof, having a structure represented by formula (i):
Figure FDA0002312565770000011
wherein R is1Is hydrogen, halogen, cyano, amino, C1-6Alkyl radical, C3-8Cycloalkyl radical, C4-8Alkylcycloalkyl or C1-6Alkoxy radical, wherein C1-6Alkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxy or C1-6The group of the alkoxy group is substituted,
R2is hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A halogenated alkoxy group,
t is-O-, -S-, -C (R)5)(R6) -or-N (R)5)-，R5And R6Independently of each other are hydrogen and C1-6Alkyl or C3-8Cycloalkyl, wherein said alkyl or cycloalkyl may be substituted by 1 to 5 fluorine atoms,
the A ring and the B ring are respectively and independently 6-14-membered aryl, 5-14-membered heteroaryl, 3-14-membered cycloalkyl or 3-14-membered heterocyclyl,
L1-L2is-C (R)8)＝C(R8)-、-R7-、-N(R8)-R7-、-R7-N(R8)-、-N(R8)C(O)-R7-、-N(R8)C(O)N(R8)-、-C(O)N(R8)-、-C(O)R7N(R8)-、-OR7-、-R7O-、-C(O)-R7-、-S-R7-、-R7-S-、-S(O)f-R7-、-R-S(O)f-、-S(O)fN(R8)-,-S(O)fR7N(R8R)-、-N(R8)S(O)f-, wherein R7And R8Each independently selected from hydrogen or C1-6Alkyl, f is a whole number from 0 to 2The number of the first and second groups is,
R3is hydrogen, halogen, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylaminocarbonyl, hydroxy C1-6Alkyl, cyano, nitro, azido, carboxyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkyl, halo C1-6Alkyl, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-6Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6alkylene-R12、SO2-C1-6Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-5.
2. The FXR agonist-containing compound according to claim 1, wherein R is1Is hydrogen, C1-6Alkyl or C3-8A cycloalkyl group,
R2is hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6A halogenated alkoxy group,
t is-O-,
the A ring and the B ring are respectively and independently 6-14-membered aryl, 5-14-membered heteroaryl, 3-14-membered cycloalkyl or 3-14-membered heterocyclyl,
L1-L2is-C (R)8)＝C(R8)-、-N(R8)-R7-、-R7-N(R8)-、-N(R8)C(O)-R7-、-N(R8)C(O)N(R8)-、-C(O)N(R8)-、-C(O)R7N(R8)-、-C(O)-R7-, wherein R7And R8Each independently selected from hydrogen or C1-6An alkyl group, a carboxyl group,
R3is hydrogen, halogen, amino, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylaminocarbonyl, hydroxy C1-6Alkyl, cyano, nitro, azido, carboxyl, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, C1-6Alkyl, halo C1-6Alkyl, aminosulfonyl C1-6Alkyl, carbamoyl C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-6Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-6Alkyl radical, C1-6Haloalkyl, C1-6alkylene-R12、SO2-C1-6Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-5.
3. The FXR agonist-containing compound according to claim 2, wherein R is1Is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group,
R2is hydrogen, halogen, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A halogenated alkoxy group,
the A ring and the B ring are respectively and independently cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1, 3-cyclohexadiene, tetrahydropyrrole, 2, 3-dihydropyrrole, 2, 5-dihydropyrrole, pyrrole, azetidine, imidazole, 4, 5-dihydroimidazole, pyrazole, 4, 5-dihydropyrazole, 1,2, 3-triazole, tetrahydrothiophene, thiophene, 2, 3-dihydrothiophene, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 4-thiadiazole, tetrahydrofuran, 2, 3-dihydrofuran, furan, 4, 5-dihydrooxazole, oxazole, 4, 5-dihydroisoxazole, isoxazole, 1,2, 4-oxadiazole, benzene ring, 1,4,5, 6-tetrahydropyrimidine, 1, 6-dihydropyrimidine, 4, 5-dihydropyrimidine, Pyrimidine, 3, 6-dihydro-2H-pyran, piperidine, 1,2,3, 4-tetrahydropyridine, 1,2,3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1,2,3, 4-tetrahydropyrazine, 2, 3-dihydropyrazine or pyrazine,
L1-L2is-C (R)8)＝C(R8) -or-N (R)8)-R7-, wherein R7And R8Each independently selected from hydrogen or C1-4An alkyl group, a carboxyl group,
R3is hydrogen, halogen, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkylaminocarbonyl, hydroxy C1-4Alkyl, cyano, nitro, azido, carboxyl, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C3-6Cycloalkyl, halo C1-4Alkyl, aminosulfonyl C1-4Alkyl, carbamoyl C1-4Alkyl radical, C1-4Alkylcarbonyl or C1-4An alkyl-carbonyloxy group, or a salt thereof,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-4Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy, C1-4Alkyl radical, C1-4Haloalkyl, C1-4alkylene-R12、SO2-C1-4Alkyl radical, wherein R12Is COOH, OH or SO3H，
m, n, p and q are respectively independent integers of 0-3.
4. The FXR agonist-containing compound according to claim 3, wherein R is1Is hydrogen, C1-4Alkyl or C3-6A cycloalkyl group,
R2is hydrogen, halogen, C1-4Alkyl radical, C1-4A halogenated alkyl group,
the A ring and the B ring are respectively and independently a benzene ring, pyridine, cyclohexane, cyclopentane, piperidine, tetrahydropyrrole, azetidine, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, 1,2, 4-thiadiazole, tetrahydrofuran, furan, isoxazole, 1,2, 4-oxadiazole or piperazine,
L1-L2is-CH ═ CH-, -NHCH2-or-N (CH)3)CH2-，
R3Is hydrogen, halogen, C1-4Alkyl, or halo C1-4An alkyl group, a carboxyl group,
R4is hydrogen, halogen, COOR9、CONR10R11Or tetrazolyl, R9Is hydrogen or C1-4Alkyl radical, R10And R11Each independently selected from hydrogen, hydroxy or C1-4An alkyl group, a carboxyl group,
m, n, p and q are respectively independent integers of 0-2.
5. The FXR agonist-containing compound according to claim 4, wherein R is1Is C1-3Alkyl radical, C3-6A cycloalkyl group,
R2is hydrogen, halogen or C1-3An alkyl group, a carboxyl group,
the ring A is a benzene ring or a pyridine ring,
the ring B is a benzene ring,
L1-L2is-CH-or-N (CH)3)CH2-，
R3Is hydrogen, halogen, C1-3Alkyl, or halo C1-3An alkyl group, a carboxyl group,
R4is hydrogen, halogen, COOH, CONHOH or tetrazolyl,
m is a number of 0, and m is,
n is a number of 2 and is,
p is 0 or 1, and p is,
q is 0, 1 or 2.
6. The FXR agonist-containing compound according to claim 5, wherein R is1Is an isopropyl group or a cyclopropyl group,
R2is a hydrogen atom or a chlorine atom,
the ring A is a benzene ring or a pyridine ring,
the ring B is a benzene ring,
L1-L2is-CH-or-N (CH)3)CH2-，
R3Is a hydrogen atom, a chlorine atom or a trifluoromethyl group,
R4is a hydrogen atom or-COOH,
m is a number of 0, and m is,
n is a number of 2 and is,
p is 1, and p is a group of,
q is 1.
7. The FXR agonist-containing compound according to claim 6,
Figure FDA0002312565770000041
8. the process for the preparation of a compound containing an FXR agonist according to claim 1, characterized in that,
the reaction equation is as follows:
Figure FDA0002312565770000051
r in the above reaction equation1、R2、R3、R4、T、m、n、p、q、L1-L2Ring A or ring B is as defined in claim 1;
the reaction steps are as follows:
step 1: dissolving the raw material 1 in an ether solvent, adding lithium aluminum hydride under cooling, reacting at room temperature until the raw material disappears, quenching the reaction, and separating by a silica gel column to obtain an intermediate 1; or using an alcohol solvent, using sodium borohydride as a reducing agent, and heating to react at room temperature;
step 2: dissolving the intermediate 1 in an inert solvent, adding an excessive chlorinated reagent, stirring at room temperature until the raw materials disappear, and concentrating the system to obtain an intermediate 2;
and step 3: dissolving the intermediate 2 and the raw material 2 in a polar solvent, adding alkali and a catalytic amount to an equivalent amount of potassium iodide or sodium iodide, stirring at room temperature until the raw material disappears, adding water for quenching, extracting, and separating by a silica gel column to obtain an intermediate 3; or directly reacting the intermediate 1 with the raw material 2 under the Mitsunobu reaction condition to obtain an intermediate 3;
and 4, step 4: condition 1: butting the intermediate 3 and the raw material 3 under Horner-Wittig reaction conditions to obtain a compound shown in the formula I;
or condition 2: butting the intermediate 3 and the raw material 3 under reducing-Amination reaction conditions to obtain a compound shown in the formula I;
in accordance with a preferred aspect of the present invention,
the ether solvent in the step 1 is one or two of tetrahydrofuran or diethyl ether; the alcohol solvent is selected from one or two of methanol or ethanol;
the inert solvent in the step 2 is selected from one or more of dichloromethane, carbon tetrachloride or toluene; the chlorinating reagent is selected from one or more of thionyl chloride and phosphorus trichloride;
the polar solvent in the step 3 is selected from one or more of DMF, DMA and acetone; the alkali is potassium carbonate; the Mitsunobu reaction is a reaction for generating ester under the action of diethyl dicarboxylate (DEAD), triphenylphosphine (Ph3P) and benzoic acid;
the Horner-Wittig reaction in step 4 is a reaction in which carbanions stabilized by phosphine oxide are added with aldehyde to produce β -hydroxyphosphine oxide, which then reacts with alkali to eliminate the produced olefin.
9. Use of a compound containing an FXR agonist or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-7 for the manufacture of a medicament for the treatment and/or prevention of diseases mediated by FXR.
10. A pharmaceutical composition comprising a compound containing an FXR agonist or a pharmaceutically acceptable salt thereof according to any of claims 1-7 and one or more pharmaceutically acceptable carriers or excipients.
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