CN107021958A - FXR receptor stimulating agents - Google Patents

FXR receptor stimulating agents Download PDF

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Publication number
CN107021958A
CN107021958A CN201710045084.4A CN201710045084A CN107021958A CN 107021958 A CN107021958 A CN 107021958A CN 201710045084 A CN201710045084 A CN 201710045084A CN 107021958 A CN107021958 A CN 107021958A
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alkyl
amino
alkoxy
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halo
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Inventor
吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to the compound shown in formula (I), its pharmaceutically acceptable salt, ester or its stereoisomer, R1、R2、R3、R4, m, n, W, A, Z, E, F, X, Y be defined as in the description；The invention further relates to the preparation method of these compounds, pharmaceutical preparation and for preparing treatment and/or preventing by the application in the medicine of the relevant diseases such as the receptor-mediated NASHs of FXR, PBC, disorders of lipid metabolism, diabetic complication and malignant tumour.

Description

FXR receptor stimulating agents
Technical field
The present invention relates to FXR receptor stimulating agents, its pharmaceutically acceptable salt, its ester and their stereoisomer, Pharmaceutical preparation containing these compounds, and the compound, its pharmaceutically acceptable salt, its ester and theirs is three-dimensional different Structure body, is preparing treatment and/or is preventing by the receptor-mediated NASHs of FXR, PBC, lipid Purposes in the medicine of the relevant diseases such as metabolic disorder, diabetic complication and malignant tumour.
Background technology
FXR acceptors (farnesoid X receptor) belong to ligand-activated transcription factor nuclear receptor family member, with typical core by The highly conserved DNA lands (DBD) of body structure, i.e. amino terminal, carboxyl terminal ligand binding domain (LBD), amino terminal is matched somebody with somebody Body independent transcription activates functional areas (AF1), carboxyl terminal ligand-dependent transcriptional activation functional areas (AF2) and foot chain area. FXR can be with retinoid X receptor (RXR) formation heterodimer, and after part is combined with FXR LBD regions, FXR conformations can be sent out Raw to change, DNA land is attached to the FXR response elements (IR-1) of target gene promoters above, and release Corepressors are (such as NCOR), co-activator has been recruited, so as to play transcriptional control effect.
FXR has expression, including adipose tissue, liver, intestines and stomach, kidney etc., wherein liver in multiple organ-tissues Middle expression quantity enriches the most.FXR signal paths, can directly or indirectly adjust the expression of multiple downstream genes, such as BSEP, SHP, The genes such as CYP7A1, FGFR4, OST α/β, SREBP-1C, and then multiple metabolic pathways are adjusted, such as：Triglycerides, cholesterol, blood Sugar and energy stability are metabolized the metabolism of cholic acid, with diseases such as treating cancer, NASH, metabolic disorder, inflammation Function.By suppress cholic acid synthesis, with reference to and transhipment, adjust its metabolism, be the main attemperator of internal cholic acid balance.
The natural Cholic acids compound in part can excitement FXR acceptors, such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), stone The glycine conjugates of cholic acid (LCA) and taurine and these cholic acid.Natural compound is removed, is researched and developed in the world at present FXR activators can be broadly divided into two major classes, and a class is steroid, and the shellfish cholic acid difficult to understand using Intercept companies is representative (obeticholic acid, OCA), for NASH indication, in the clinical III phases；Another kind of is new point Fructification, the compound such as GW4604 (WO2000/037077) of early stage research and development, although with stronger agonist activity, but its is right Photo-labile and bioavilability is relatively low.In addition, the PX-104 (WO2011020615A1) of Phenex companies research and development is assigned to Gilead companies, are currently in clinical II phases conceptual phase.
The invention that this patent is related to is to provide the compound with new molecular architecture, its can effective excitement FXR acceptors, BSEP and SHP gene expression doses are lifted, while effectively suppressing the expression of CYP7A1 genes.In addition, preferably being controlled to reach The purpose of therapeutic effect, better meets the market demand, it is also desirable to can develop high-efficiency low-toxicity and the preferable FXR acceptors of stability Activator.The present invention will provide a kind of FXR receptor stimulating agents of new structure, and it has good drug effect, is FXR receptor agonisms Agent is used to treating NASH, PBC, disorders of lipid metabolism, diabetic complication and pernicious swollen Knurl provides possibility.
The content of the invention
FXR receptor stimulating agents are targetted it is an object of the invention to provide a class, specific technical scheme is as follows：
Compound, its pharmaceutically acceptable salt, its ester or its stereoisomer shown in scheme 1, formula (I)：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8Alkynyl；
R3Selected from hydrogen atom, the C optionally replaced by one or more substituent P1-6Alkyl, C1-6Alkoxy, C3-8Cycloalkanes Base, C3-8Heterocyclic radical, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl Amino, C1-6Alkylsulfonyloxy；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, Two C1-6Alkyl amino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphur Acyl group, C2-8Alkenyl or C2-8Alkynyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, C1-6Alkoxy, C1-6Alkyl, hydroxyl C1-6Alkyl, halo C1-6Alkyl, carboxyl C1-6Alkyl, carboxyl epoxide C1-6Alkyl, carboxyamino C1-6Alkyl, amino C1-6Alkyl, Amino carbonyl C1-6Alkyl, hydroxyl C1-6Alkoxy, halo C1-6Alkoxy, carboxyl C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6 Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl or two C1-6Alkane Base amino；
W is selected from CH2、NH、O、S、SO、SO2Or CO；A is selected from NH, O or S；
Z is selected from cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, Two C1-6Alkyl amino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl or C2-8Alkynyl；
E is selected from C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
F be selected from be not present, C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
X is selected from C, CH or N；
Y is selected from C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
Connected mode between E, X, Y, F is separately selected from singly-bound or double bond, and the connected mode between E, X, Y, F is extremely Rare one is double bond；
It is not thiazole that E, X, Y, F, which connect the group to be formed,；
M is selected from 0-3 integer；N is selected from 0-4 integer.
Scheme 2, the compound as described in scheme 1, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halo C1-4Alkyl, halo C1-4Alkoxy or C1-4Alkoxy C1-4Alkyl；
R3Selected from C that is unsubstituted or being replaced by one or more substituent P3-6Cycloalkyl or C3-6Heterocyclic radical；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkyl, halo C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl epoxide C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, Amino carbonyl C1-4Alkyl, hydroxyl C1-4Alkoxy, halo C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4 Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl, C1-4Alkyl amino sulfonyl or two C1-4Alkane Base amino；
W is selected from CH2、NH、O、S、SO、SO2Or CO；A is selected from NH, O or S；
Z is selected from 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
E is selected from C, CH, CH2, N, NH, CO, O or S；
F be selected from be not present, C, CH, CH2, N, NH, O, CO or S；
X is selected from C, CH or N；
Y is selected from C, CH, CH2, N, NH, O, CO or S；
Connected mode between E, X, Y, F is separately selected from singly-bound or double bond；Connected mode between E, X, Y, F is extremely Rare one is double bond；
It is not thiazole that E, X, Y, F, which connect the group to be formed,；
M is selected from 0-2 integer；N is selected from 0-3 integer.
Scheme 3, the compound as described in scheme 2, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R3Selected from C that is unsubstituted or being replaced by one or more substituent P3-6Cycloalkyl；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
Benzopyranyl, 4H- chromene -4- ketone groups, benzothienyl, benzoxazolyl, 4H- chromogens alkenyl, benzofuran Base, benzo 1,4- Dioxins base, benzo 4H-1,4- oxazinyls, benzo 4H-1,2- oxazinyls, benzo 4H-1,3- Evil Piperazine base, dihydro cinnolines base, quinazolyl, dihydroquinazoline base, quinolyl, EEDQ base, isoquinolyl, dihydro-isoquinoline Base, quinoline ketone group, isoquinolin ketone group, benzo dihydro pyrazine base, benzopyrazines, ihydro naphthyl, indyl, isoindolyl, benzo Imidazole radicals, benzopyrazoles base or BTA base；
N is selected from 0-2 integer.
Scheme 4, the compound as described in scheme 3, its pharmaceutically acceptable salt, its ester or its stereoisomer：
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, amino, hydroxyl, carboxylic Base, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, methoxyl group, methylamino, dimethylamino, acetyl group, Trifluoromethyl, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, isopropyl, Methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetenyl, methylamino, ethylamino, acetyl Base, acetylamino, mesyl or dimethylamino；
N is selected from 0-2 integer；
Z is selected from saturation 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
Scheme 5, the compound as described in scheme 4, its pharmaceutically acceptable salt, its ester or its stereoisomer：
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, ethyl, propyl group, butyl, methoxy Base, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetyl group or acetylamino；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from unsubstituted or by one or more substituent Q cyclopenta replaced or cyclohexyl；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1 or 2.
Scheme 6, the compound as described in scheme 5, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein, R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methylamino, acetyl group, trifluoro Methyl or trifluoromethoxy；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy, carboxylic Ylmethyl, carboxy ethyl, acetyl group or acetylamino；
W is selected from O；A is selected from O；
Z is selected from cyclohexyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1 or 2.
Scheme 7, the compound as described in scheme 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, have Structure shown in formula (II)：
Wherein,
Z is selected from 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl, halo C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C2-6Alkenyl or C2-6Alkynyl；
F is selected from CH, CH2, N, NH, O or CO；
X is selected from C, CH or N；
Y is selected from CH or N；
Connected mode between X, Y, F is separately selected from singly-bound or double bond, and the connected mode between X, Y, F is at least One is double bond.
Scheme 8, the compound as described in scheme 7, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Z is selected from 5-6 member saturated cyclic alkyls that are unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
F is selected from CH, CH2, N, NH or O；X is selected from C, CH or N；
Y is selected from CH or N；
Connected mode between X, Y, F is separately selected from singly-bound or double bond；Connected mode between X, Y, F is at least One is double bond.
Scheme 9, the compound as described in scheme 8, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein, R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, amino, hydroxyl Base, carboxyl, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, methoxyl group, methylamino, dimethylamino, second Acyl group, trifluoromethyl, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, isopropyl, Methoxyl group, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, carboxymethyl group, carboxy ethyl, acetyl Base, acetylamino, mesyl or dimethylamino；
N is selected from 0-2 integer；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from unsubstituted or by one or more substituent Q cyclopenta replaced or cyclohexyl；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
Connected mode between X, Y, F is separately selected from singly-bound or double bond, and the connected mode between X, Y, F is at least One is double bond.
Scheme 10, the compound as described in scheme 9, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein, R1、R2Separately selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, ethyl, propyl group, butyl, Methoxyl group, methylamino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetyl group or acetylamino；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from cyclohexyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, Two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
F is selected from CH or N；
X is selected from N；
Y is selected from CH；
Connected mode between X, Y is singly-bound, and the connected mode between Y, F is double bond；
N is selected from 1.
Group between such scheme can be mutually combined.
The part of compounds of the present invention
Detailed description of the invention
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atoms and iodine atom etc..
" C of the present invention1-6Alkyl " represents the alkyl containing 1-6 carbon atom of straight or branched, including for example “C1-4Alkyl ", " C1-3Alkyl " etc., instantiation includes but is not limited to：Methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- Methyl-propyl, 1- methyl-propyls, 1,1- dimethyl ethyls, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- methyl butyls, 1- Ethyl propyl, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2, 2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- second Base butyl, 1,2- dimethyl propyls etc..
" C of the present invention2-8Alkenyl " refers to the straight or branched that the carbon number containing at least one double bond is 2-8 Or the alkenyl of ring-type, including such as " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Cycloalkenyl group " etc., instantiation includes But it is not limited to：Vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- methyl-1-propylenes base, 1- methyl -2- Acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl -3- fourths Alkenyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyls, 3- hexenyls, 2- methyl-1-pentenes alkenyl, 3- Methyl-1-pentene alkenyl, 1- methyl -2- pentenyls, 3- methyl -2- pentenyls, 2- methyl-3-pentenyls, 1- methyl -4- amylenes Base, 3- methyl -4- pentenyls, 1,1- dimethyl -3- cyclobutenyls, 1,2- dimethyl -3- cyclobutenyls, 1,3- dimethyl -2- butylene Base, 2,2- dimethyl -3- cyclobutenyls, 2,3- dimethyl -2- cyclobutenyls, 2,3- dimethyl -1- cyclobutenyls, 2- ethyl -1- butylene Base, 2- ethyl -3- cyclobutenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 1- octenyls, 3- octenyls, 4- octenyls, 1,3- Butadienyl, 2,4- pentadienyls, 1,4- hexadienyls, 2,4- hexadienyls, 1,5- heptadiene base, 2,5- heptadiene base, 2, 6- octadienyls etc..
" C of the present invention2-8Alkynyl " refers to the alkynyl for the straight or branched that the carbon number containing three keys is 2-8, its Include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., instantiation includes but is not limited to：Acetenyl, 1- propine Base, 2- butynyls, 1- methyl -2-propynyl, valerylene base, 3- pentynyls, 1- methyl -2- butynyls, 2- methyl -3- butine Base, 1,1- dimethyl -2-propynyl, 1- ethyls -2-propynyl, 2- hexin bases, 3- hexin bases, 1- methyl-valerylene base, 1- first Base -3- pentynyls, 2- methyl -3- pentynyls, 1,1- dimethyl -3- butynyls, 2- ethyl -3- butynyls, 2- heptynyls, 3- heptan Alkynyl, 4- methyl -2- hexin bases, 5- methyl -2- hexin bases, 2- methyl -3- hexin bases, 5- methyl -3- hexin bases, 2- methyl - 4- hexin bases, 4- methyl -5- hexin bases, 2- octynyls, 3- octynyls, 4- octynyls, 4- methyl -2- heptynyls, 5- methyl -3- Heptynyl, 6- methyl -3- heptynyls, 2- methyl -4- heptynyls, 2- methyl -5- heptynyls, 3- methyl -6- heptynyls etc..
" C of the present invention1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl sulfenyl, C1-6Alkyl Carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6 Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy ", refers to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6 Alkyl-S-, C1-6Alkyl-C (O)-, C1-6Alkyl-C (O)-O-, C1-6Alkyl-SO2-、C1-6Alkyl-NH-SO2-、(C1-6Alkyl)2- N-SO2-、C1-6Alkyl-SO2-NH-、C1-6Alkyl-SO2The group that-O- modes are formed, wherein " C1-6Alkyl " text as defined above It is described.
" C of the present invention1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl Carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl amino sulfonyl, two C1-4Alkyl amino sulfonyl ", be Refer to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4Alkyl-C (O)-, C1-4Alkyl-C (O)-O-、C1-4Alkyl-SO2-、C1-4Alkyl-NHSO2-、(C1-4Alkyl)2-N-SO2The group that-mode is formed, wherein " C1-4Alkane Base " text as defined above is described.
" halo C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, carboxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alcoxyl Base C1-6Alkyl, halo C1-6Alkoxy, hydroxyl C1-6Alkoxy, carboxyl C1-6Alkoxy, carboxyl epoxide C1-6Alkyl, carboxyamino C1-6Alkyl, amino carbonyl C1-6Alkyl ", refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, Amino, carboxyl, carboxyl epoxide, carboxyamino, amino carbonyl, C1-6Alkoxy replaces C respectively1-6Alkyl, C1-6Hydrogen in alkoxy The group that atom is formed.
" halo C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, carboxyl C1-4Alkyl, amino C1-4Alkyl, C1-4Alcoxyl Base C1-4Alkyl, halo C1-4Alkoxy, hydroxyl C1-4Alkoxy, carboxyl C1-4Alkoxy, carboxyl epoxide C1-4Alkyl, carboxyamino C1-4Alkyl, amino carbonyl C1-4Alkyl ", refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, Amino, carboxyl, carboxyl epoxide, carboxyamino, amino carbonyl, C1-4Alkoxy replaces C respectively1-4Alkyl, C1-4Hydrogen in alkoxy The group that atom is formed.
" cycloalkyl " refers to that the paraffin section of carbon atom removes the monocyclic of saturation or fractional saturation derived from a hydrogen atom Cyclic alkyl, including for example " 3~6 yuan of cycloalkyl ", " 3~8 yuan of cycloalkyl ", " 4~7 yuan of cycloalkyl ", " 4~6 yuan of cycloalkyl ", " 5~6 yuan of cycloalkyl " etc..The example includes but is not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl Alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methyl ring Pentyl, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl, cyclopentenyl, 1,3- cyclopentadienyl groups, ring Hexenyl, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptadiene base, cyclo-octene base etc..
" heterocyclic radical " refer to containing at least one hetero atom (such as 1,2,3,4 or 5 hetero atoms) saturation or fractional saturation Monocyclic heterocyclic compound remove the obtained group of a hydrogen atom.Including such as " 3~8 circle heterocycles base ", " 3~7 circle heterocycles Base ", " 3~6 circle heterocycles base ", " 3~5 circle heterocycles base ", " 4~7 circle heterocycles base ", " 4~6 circle heterocycles base ", " 5~6 circle heterocycles Base ", 6~7 circle heterocycles bases ", " 6~8 circle heterocycles base " etc..3~8 yuan of fractional saturation list heterocyclic radicals, refer to containing double bond, hetero atom Cyclic group.3~8 yuan of saturation list heterocyclic radicals, refer to all saturated bonds contains heteroatomic cyclic group.Instantiation Include but are not limited to：Aziridine base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclos acrylic, Azetidinyl, 1,4- dioxanes base, 1,3- dioxanes base, 1,3- dioxolane base, 1,4- bis- Oxine base, tetrahydrofuran base, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidine Base, 4,5- pyrazolines base, 2,5- dihydro-thiophenes base, tetrahydro-thienyl, 4,5- dihydro-thiazolyls, piperidyl, piperazinyl, morpholine Base, 4,5- dihydro-oxazoles base, 4,5- dihydro-isoxazoles base, 2,3- dihydro-isoxazoles base, 2H-1,2- oxazinyls, 6H-1,3- oxazines Base, 4H-1,3- thiazinyls, 6H-1,3- thiazinyls, 2H- pyranoses, 2H- pyran-2-ones base, 3,4- dihydro -2H- pyranoses, 2, 5- dihydro-thiophenes base, 3,4- dihydro -2H- pyranoses, 5,6- dihydro -4H-1,3- oxazinyls, 1,2,3,6- tetrahydro pyridyls, 1, 2,3,4- tetrahydro pyridyls, 2,3,4,5- tetrahydro pyridyls etc..
" hetero atom " of the present invention refers to N, O, S, SO and/or SO2Deng preferably N, O, S.
" F is selected from and is not present " of the present invention, refers to that Y is directly connected with phenyl.
In formula (I) (II) of the present inventionRefer to singly-bound or double bond.
" fractional saturation " of the present invention is that ring portion includes at least one double or triple bonds.
Present invention also offers the preparation method of formula (I) compound, (wherein, it include but is not limited to following process routes It is defined as follows representated by each abbreviation：DCM：Dichloromethane；DMF：N,N-dimethylformamide；DMSO：Dimethyl sulfoxide (DMSO)；EA： Ethyl acetate；MeOH：Methanol；PE：Petroleum ether；THF：Tetrahydrofuran；DIBAL-H：Diisobutyl aluminium hydride；TsCl：To toluene Sulfonic acid chloride)
Process route：
R1、R2、R3、R4, m, n, W, A, Z, E, F, X, Y be as it was noted above, A' represents fluorine atom, chlorine atom, bromine atoms and iodine Atom.
Specific illustrative steps are as follows：
1st, the preparation of intermediate 1
Initiation material 1 is dissolved in organic solvent (such as ethanol), initiation material 2 is slowly added in batches, is finished, alkali is added Property solution (such as NaOH solution), be heated to 60 DEG C -90 DEG C react 5-48 hours.Reaction is finished, reaction solution removal of solvent under reduced pressure, Solid is washed with water, and dries, obtains intermediate 1.
2nd, the preparation of intermediate 2
Intermediate 1 is dissolved in organic solvent (such as DMF), parental materials reagent (such as N- chloros are slowly added in batches Succimide), after adding, stir 0.2-5 hours, reaction solution is poured into water.Extracted with organic solvent (such as ethyl acetate) Take, organic phase is washed with water and saturated nacl aqueous solution, dry, remove solvent and obtain intermediate 2.
3rd, the preparation of intermediate 3
Intermediate 2 is dissolved in organic solvent (such as triethylamine), initiation material 3 is added, reacted 5-20 hours.React Finish, removed under reduced pressure solvent, pillar layer separation (such as PE:EA=10:1) intermediate 3 is obtained.
4th, the preparation of intermediate 4
Intermediate 3 is dissolved in organic solvent (such as tetrahydrofuran), ice bath cooling adds diisobutyl aluminium hydride (DIBAL-H) toluene solution, finish be warming up to 20-30 DEG C react 5-20 hour, reaction is finished, ice bath, addition saturation halogen Reaction is quenched in agent (such as ammonium chloride solution), is extracted with organic solvent (such as ethyl acetate), the halogenation of organic phase saturation Agent (such as ammonium chloride solution and sodium chloride solution) is washed, and is dried, and is removed solvent and is obtained intermediate 4.
5th, the preparation of intermediate 5
Intermediate 4 is dissolved in organic solvent (such as dichloromethane), triethylamine is added, then halide is added (for example Phosphorus trichloride, phosphorus tribromide), 20-40 DEG C is reacted 0.5-5 hours.Solvent, pillar layer separation (such as PE are removed after completion of the reaction: EA=10:1) intermediate 5 is obtained.
6th, the preparation of intermediate 6
Prepare or purchase intermediate 6.
7th, the preparation of intermediate 7
Intermediate 6 is dissolved in organic solvent (such as DMF), cooled down, sodium hydride is added, nitrogen is protected Protect, and be warming up to 20-40 DEG C and react 0.2-12 hours, add intermediate 5.Room temperature reaction 0.5-12 hours, reaction is finished, and is added Water (or methanol) is quenched, and is extracted with organic solvent (such as ethyl acetate, dichloromethane), organic phase anhydrous sodium sulfate drying, Concentration, column chromatography is (preferably：PE:EA=2-5:1) intermediate 7 is purified to obtain.
8th, the preparation of formula (I) compound
Intermediate 7 is dissolved in organic solvent (such as methanol, methanol/water, tetrahydrofuran), alkali compounds is added (excellent Elect as：Lithium hydroxide, sodium hydroxide), 25-80 DEG C is reacted 0.5-24 hours.Reaction is finished, and it (is preferably salt to add acid solution Acid) regulation pH value, organic solvent (such as ethyl acetate, dichloromethane) extraction is added, point liquid, organic phase anhydrous sodium sulfate is done It is dry, it is concentrated in vacuo, column chromatography purifying (is preferably：DCM:MeOH=20-50:1) formula (I) compound is obtained.
" pharmaceutically acceptable salt " of compound shown in formula (I) of the present invention refers to acid present in formula (I) compound Functional group and the salt of appropriate inorganic or organic cation (alkali) formation, including with alkali metal or the salt of alkaline-earth metal formation, Ammonium salt, and the salt with nitrogenous organic base formation；And basic functionality (such as-NH present in formula (I) compound2Deng) with The salt of appropriate inorganic or organic anion (acid) formation, including with inorganic acid and organic carboxyl acid.
" ester " of compound shown in formula (I) of the present invention refers to, when formula (I) compound has carboxyl, can occur with alcohol Ester formed by esterification, when formula (I) compound has hydroxyl, can occur with organic acid, inorganic acid, acylate etc. Ester formed by esterification.Under conditions of acid or alkali are present the corresponding acid of hydrolysis generation or alcohol can occur for ester.
" stereoisomer " of the present invention, refers to when the compounds of this invention contains one or more asymmetric centers, because And racemic modification and racemic mixture, single enantiomter, non-enantiomer mixture and single diastereomeric can be used as Isomers.The compounds of this invention has asymmetric center, and this kind of asymmetric center respectively will independently produce two optical isomers, The scope of the present invention includes all possible optical isomer and non-enantiomer mixture and pure or partial-purified chemical combination Thing.If compound of the present invention contains olefinic double bonds, unless stated otherwise, the present invention includes cis-isomer and trans different Structure body.Compound of the present invention can exist with tautomeric forms, and it has by one or more double-bond shifts There is the tie point of different hydrogen.
Further requirement of the present invention protection include compound shown in formula (I), its pharmaceutically acceptable salt, its ester and The pharmaceutical composition of their stereoisomer and one or more pharmaceutical carriers and/or diluent, it can be made pharmaceutically Acceptable any formulation.Being applied to modes such as oral, parenteral, rectum or transpulmonary administrations needs the patient of this treatment. During for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；It may be made as oral Liquid preparation, such as oral solution, oral suspensions, syrup.When oral formulations are made, suitable filling can be added Agent, adhesive, disintegrant, lubricant etc..During for parenteral, injection, including parenteral solution, Injectable sterile can be made into Powder and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, injection is prepared When, additives can be added without, suitable additives can be also added according to the property of medicine.During for rectally, it can be made into Suppository etc..During for transpulmonary administration, inhalant or spray etc. can be made into.
Present invention also offers the compound shown in formula (I) of the present invention, its pharmaceutically acceptable salt, its ester and they Stereoisomer prepare be used for treat and/or prevent FXR mediate disease and relevant disease medicine in application.It is described Disease include：(1) in Chronic Liver or some form of extrahepatic cholestasis illness, or chronic bile smoulders illness or Acute Hepatic Liver fibrosis caused by interior cholestasia illness, hepatic sclerosis, the obstructive or chronic inflammatory disorders of liver, fatty liver and its concurrent Disease, the fatty liver and its complication relevant with alcohol, acute hepatic failure, cholelithiasis, and/or inflammatory bowel disease, primary courage Juice hepatic sclerosis；Due to forcing lipid, particularly triglycerides to accumulate, then promote chronic fat caused by liver fibrosis activation Property and fibroid denaturation caused by illness and disease, such as non-alcoholic fatty liver disease or nonalcoholic steatohepatitis；Lipid or fat Albumen is disorderly, such as atherosclerosis, dyslipidemia, thrombus.(2) clinical complication of I types or type ii diabetes, including glycosuria Characteristic of disease nephrosis, diabetic neuropathy, diabetic retinopathy and its clinical dominant long-term diabetes other observe Result.(3) non-malignant excess proliferative disease or excess proliferative disease, are selected from：Hepatocellular carcinoma, colonic adenoma and polyp Disease, adenocarcinoma of colon, breast cancer, cancer of pancreas, the intestines and stomach and liver neoplasm disease of the cancer of the esophagus and other forms.(4) blood fat generation Thanking to abnormality disease includes atherosclerosis, disorderly bile acid, benign intrahepatic cholestasis, progressive familial hepatic bile Alluvial, PBC, primary sclerotic cholangitis, cholesterol stone, dyslipidemia, the related disease of fibrosis Disease, chronic hepatitis, non-viral hepatitis, IBD, intestinal bacilli illness, liver transplant, fatty liver, hepatic sclerosis, hepatitis, Liver failure, cholestasia, cholelithiasis, non-alcohol fatty liver, alcohol fatty liver, diabetes, miocardial infarction, Apoplexy, thrombus, cancer etc..
The compounds of this invention has advantages below：
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester, its solvate and their solid Isomers has excellent FXR receptor agonist activities, can by safety be used for treat and/or prevent NASH, original The relevant diseases such as hair property biliary cirrhosis, disorders of lipid metabolism, diabetic complication and malignant tumour.
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester, its solvate and their solid Isomers shows good biological stability, acts on more longlasting, bioavilability is high.
(3) formula (I) compound of the present invention, its pharmaceutically acceptable salt, its ester, its solvate and their solid Isomers shows relatively low toxicity, and drug resistance is good, safe.
The compounds of this invention beneficial effect is expanded on further below by way of biological experiment, but this should not be interpreted as this hair Bright compound only has following beneficial effect.
Experimental example 1：The external biochemical analysis of the compounds of this invention
(1) tester：The compounds of this invention, its chemical name and preparation method are shown in the preparation embodiment of each compound.
(2) experimental method：
Detection compound is dissolved in 100%DMSO, after 1000 times of dilution, takes 160nL, then adds 3.84 μ L detections slow Fliud flushing；Target/Antibody mixtures, after 2 times of dilution, add 8 μ L solution；Add the co-activation that 4.0 μ L dilute 4 times Peptide；In incubation at room temperature 60 minutes；In fluorescence microplate reader detection and analyze data after incubation.
(3) experimental result and conclusion：
The biochemical analysis of the compounds of this invention of table 1
From table 1, the compounds of this invention has certain agonism to FXR acceptors, for treatment non-alcoholic fatty The relevant diseases such as liver, PBC, disorders of lipid metabolism, diabetic complication and malignant tumour have important Meaning.
Experimental example 2：Influence of the compounds of this invention to HepG2 cells and people source liver cell BSEP mRNA relative expression quantities
(1) tester：The compounds of this invention, its chemical name and preparation method are shown in the preparation embodiment of each compound.
PBS：Phosphate buffer.
Comparison medicine：PX-102, is the raceme of PX-104 (its structure is as stated in the Background Art).
(2) experimental method：
1. cell, plus compound and collection cell are spread
Digested using pancreatin, collect cell, determine cell concentration；According to count results, cell is resuspended to 7.5e5cell/ ML density；6 porocyte culture plates, 2mL cells are inoculated with per hole；By culture plate as in incubator, in 37 DEG C, 5%CO2Condition is trained Support 24 hours.
Testing compound is diluted to 12150,4050,1350,450,150,50,16.67,5.56 and 1.85 using DMSO μM；The μ L of liquid storage 5 for taking previous step dilution to obtain are added separately in 5mL culture mediums.Obtained working solution concentration is respectively 12150, 4050,1350,450,150,50,16.67,5.56,1.85nM.Control group culture medium is matched somebody with somebody using isometric DMSO instead of liquid storage System；The culture medium of Tissue Culture Plate is removed, working solution and control medium is added；Culture plate is put back into incubator, in 37 DEG C, 5%CO2CMC model 24 hours.
After processing 24 hours, the culture medium of Tissue Culture Plate is removed, with the PBS rinses cell 3 times of precooling (4 DEG C)；Per hole 200 μ L pancreatin (being preheated to 37 DEG C) are added, are gently rocked so that pancreatin uniform fold plate bottom.Culture plate is put back into incubator to incubate Until cell detachment plate bottom.Add 1mL culture mediums and terminate digestion.After gently being blown and beaten several times with pipettor, by all substances in hole In the centrifuge tube for being drawn into 1.5mL Rnase-free, 200 × g is centrifuged 5 minutes；Supernatant is removed, cell sample is collected.
2. extracted and purifying RNA from cell sample
Cell is cracked：Prepare fresh RNA lysates (1mL lysates add 10 μ L 2 mercapto ethanols)；To cell sample plus Enter 600 μ L lysates；Violent vortex 1-2 minutes, makes cell crack completely；Cell pyrolysis liquid is centrifuged 5 points in 12,000 × g Clock；Supernatant is taken to be transferred in RNase-free 1.5mL centrifuge tubes.
RNA extraction purifications：70% ethanol of equivalent is added into cell pyrolysis liquid；Acutely concussion centrifuge tube, fully mixed Close, disperse to add the particulate deposits being likely to form after ethanol as far as possible；Adsorption column is placed on collecting pipe, transfer mixture to absorption In post.700 μ L are at most shifted every time；Room temperature is centrifuged 15 seconds.The solution in collecting pipe is discarded, remaining mixture is all shifted Into adsorption column.Plus 700 μ L eluents I into adsorption column；Room temperature is centrifuged 15 seconds.Plus 500 μ L eluents II into adsorption column；Room Temperature centrifugation 15 seconds.The solution in collecting pipe is discarded, plus 500 μ L eluents II are into adsorption column；Room temperature is centrifuged 1-2 minutes, will be inhaled Attached column is positioned on RNA collecting pipes；50 μ L RNase-free water are added to the center of adsorption column, are incubated at room temperature 1 minute； Room temperature is centrifuged 2 minutes, and RNA is eluted in collecting pipe.
Measure the RNA extracted concentration and quality.RNA is stored in -80 DEG C.
3. RNA reverse transcriptions are cDNA
It is denatured RNA within 5 minutes in 70 DEG C of incubations the RNA extracted in second step.Sample is placed on ice after processing；Make RNA sample is diluted to 200ng/ μ L with RNAse-free water；10 μ L reverse transcription solution is prepared according to following table, and is denatured with 10 μ L RNA is mixed.RNA total amount is 2 μ g in reverse transcription reaction.In experimentation, all reagents are placed on ice.
Reverse transcription is carried out on G-Storm GS1thermal cycler PCR thermal cyclers.Process of reverse-transcription is set such as Under：25 DEG C 10 minutes → 37 DEG C 120 minutes → 85 DEG C 5 minutes → 4 DEG C ∞.Reverse transcription product (cDNA) is stored in -20 DEG C.
4. sample qPCR is tested
According to qPCR amplification efficiencies, suitable cDNA concentration is selected to carry out the qPCR experiments of sample.Third step reverse transcription Obtained cDNA samples, take 10 μ L plus 60 μ L Rnase-free water to dilute 7 times.
Prepare 80 μ L reactant mixture according to following table, 20 μ L are taken with pipettor into 96 hole PCR reaction plates, 3 repetitions (each reacting hole adds 7 μ L 100ng) cDNA samples.
QPCR is carried out on ABI7500 real-time PCRs, and program sets as follows：50 DEG C 2 minutes → 95 DEG C 10 minutes → 95 DEG C 15 seconds → 60 DEG C 60 seconds, wherein 95 DEG C set 40 circulations between 60 seconds in 15 seconds and 60 DEG C.
(3) experimental result and conclusion：
The detection of BSEP mRNA relative expression quantities in the HepG2 cells of the compounds of this invention of table 2. processing
Remarks：MRNA relative expression quantity %=100* [mRNA (tester)/mRNA (PX-102)]
Compound of the embodiment of the present invention has preferable expressional function to BSEP mRNA in HepG2 cells as shown in Table 2, right Have great importance in treatment NASH.
Embodiment
The embodiment of form, further specifically to the above work of the present invention by the following examples It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following examples.It is all to be based on the above of the present invention The technology realized belongs to the scope of the present invention.
Preparation scheme
Preparation example 1：(E) preparation of -2,6- dichloro benzaldoximes
2,6- dichlorobenzaldehydes (25g, 0.14mol) are dissolved in ethanol (200mL), hydroxylamine hydrochloride is slowly added in batches (11g, 0.16mol), is finished, and adds NaOH solution (6.4g, 0.16mol are dissolved in 100mL water), is heated to 90 DEG C of reactions 24 small When.Reaction is finished, reaction solution removal of solvent under reduced pressure, and solid is washed with water (200mL), is dried, is obtained title compound 25.9g, is produced Rate 97%.
Preparation example 2：(Z) preparation of the chloro- N- hydroxyls benzimidoyl chlorine of -2,6- two
By (E) -2,6- dichloro benzaldoximes (25.9g, 0.136mol) are added to DMF (300mL), N- are slowly added in batches Chlorosuccinimide (18.2g, 0.136mol), after adding, 25 DEG C are stirred one hour, and reaction solution is poured into water (500mL). Extracted with ethyl acetate (500mL), organic phase is washed with water (200mL) and saturated nacl aqueous solution (200mL), anhydrous sodium sulfate Dry, remove solvent and obtain title compound 28g, crude product is not purified, carry out next step.
Preparation example 3：5- cyclopropyl -3- (the preparations of 2,6- dichlorophenyl) isoxazole -4- Ethyl formates
By (Z) -2, the chloro- N- hydroxyls benzimidoyl chlorine (28g, 0.125mol) of 6- bis- are dissolved in triethylamine (100mL), are added 3- cyclopropyl -3- oxopropanoates (19.5g, 0.125mol), 25 DEG C are reacted 12 hours.Reaction is finished, removed under reduced pressure solvent, Pillar layer separation (PE:EA=10:1) title compound 24.4g, two step yields 55.1% are obtained.
Preparation example 4：(the preparation of 5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methanol
By 5- cyclopropyl -3-, (2,6- dichlorophenyl) isoxazole -4- Ethyl formates (20g, 61.3mmol) are dissolved in tetrahydrochysene furan Mutter in (300mL), ice bath cooling, add diisobutyl aluminium hydride (DIBAL-H) toluene solution (1.5mol/L, 123mL, 0.184mol), finish be warming up to 25 DEG C react 12 hours, reaction is finished, ice bath, add saturated ammonium chloride solution (200mL) quench Go out reaction, extracted with ethyl acetate (500mL), organic phase saturated ammonium chloride solution (200mL) and saturated nacl aqueous solution (200mL) is washed, anhydrous sodium sulfate drying, is removed solvent and is obtained title compound 16g, yield 92.0%.
Preparation example 5-1：4- (the bromomethyl) -5- cyclopropyl -3- (preparations of 2,6- dichlorophenyl) isoxazoles
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methanol (5.0g, 17.6mmol) is added to dichloro In methane (30mL), triethylamine (1.78g, 17.6mmol) is added, phosphorus tribromide (4.77g, 17.6mmol), 30 DEG C is then added Reaction 2 hours.Solvent, pillar layer separation (PE are removed after completion of the reaction:EA=10:1) title compound 4.3g, yield are obtained 70.4%.
Preparation example 5-2：4- (the chloromethyl) -5- cyclopropyl -3- (preparations of 2,6- dichlorophenyl) isoxazoles
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methanol (5.0g, 17.6mmol) is added to dichloro In methane (30mL), triethylamine (1.78g, 17.6mmol) is added, phosphorus trichloride (2.42g, 17.6mmol), 30 DEG C is then added Reaction 2 hours.Solvent, pillar layer separation (PE are removed after completion of the reaction:EA=10:1) title compound 3.60g, yield are obtained 67.7%.
The 1- of embodiment 1 ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) rings Hexyl) -1H- indole -5-carboxylic acids (compound 1)
(1) preparation of 1,4- dioxo spiros [4.5] decane -8- alcohol
Isosorbide-5-Nitrae-dioxo spiro [4,5] decane -8- ketone (10g, 64mmol) is added in methanol (50mL), ice bath, slowly Sodium borohydride (3.14g, 83mmol) is added portionwise, then heats to 25 DEG C and reacts 2 hours.Reaction is finished, and is concentrated under reduced pressure, and is added Ethyl acetate (100mL), is washed with water (30mL) and saturated nacl aqueous solution (30mL) successively, and organic phase is dry with anhydrous sodium sulfate Dry, concentration obtains title compound 9.6g, yield 94.9%.
(2) preparation of 1,4- dioxo spiros [4.5] decane -8- base 4- toluene sulfonic acide esters
Isosorbide-5-Nitrae-dioxo spiro [4.5] decane -8- alcohol (9.6g, 60mmol) is added in pyridine (20mL), ice bath cooling adds Enter paratoluensulfonyl chloride (13.8g, 72mmol), be then heated to 30 DEG C and react 8 hours.Reaction is finished, and adds ethyl acetate (250mL), successively with 1.0mol/L watery hydrochloric acid (250mL), saturated sodium bicarbonate solution (50mL) washing, organic phase is with anhydrous Sodium sulphate is dried, concentration, column chromatography (petroleum ether:Ethyl acetate=5:1) separate, obtain title compound 13.6g, yield 72.6%.
(3) preparation of 1- (1,4- dioxo spiros [4.5] decane -8- bases) -1H- indole -5-carboxylic acid methyl esters
By 1H- indole -5-carboxylic acids methyl esters (2.8g, 16mmol), Isosorbide-5-Nitrae-dioxo spiro [4.5] decane -8- base 4- methylbenzenes Sulphonic acid ester (10g, 32mmol), cesium carbonate (11.2g, 34mmol) is added in DMA (30mL), is then heated Reacted 2 hours to 120 DEG C.Reaction is finished, and is added ethyl acetate (150mL), is washed in three times with water (200mL), and organic phase is used Anhydrous sodium sulfate drying, concentration, column chromatography (PE:EA=5:1) separate, obtain title compound 1.2g, yield 23.8%.
(4) preparation of 1- (4- oxygen cyclohexyl) -1H- indole -5-carboxylic acid methyl esters
By 1- (1,4- dioxo spiros [4.5] decane -8- bases) -1H- indole -5-carboxylic acids methyl esters (1.2g, 3.8mmol) and right Toluenesulfonic acid (652mg, 3.8mmol) is added in the mixed solution of acetonitrile (30mL) and water (10mL), 90 DEG C of microwave reactions 25 Minute, reaction is finished, and ethyl acetate (200mL) is added, successively with saturated sodium bicarbonate (100mL) and saturated nacl aqueous solution (100mL) is washed, organic phase anhydrous sodium sulfate drying, concentration, pillar layer separation (PE:EA=5:1) product 640mg, is obtained, is produced Rate 62.1%.
(5) preparation of 1- ((trans) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acid methyl esters
1- (4- oxygen cyclohexyl) -1H- indole -5-carboxylic acids methyl esters (640mg, 2.36mmol) is added to methanol (15mL) In, ice bath adds sodium borohydride (136mg, 3.6mmol), then heats to 25 DEG C and reacts 2 hours.Reaction is finished, and is depressurized dense Contracting, adds ethyl acetate (30mL), is washed successively with water (10mL) and saturated nacl aqueous solution (10mL), the anhydrous sulphur of organic phase Sour sodium is dried, concentration, obtains title compound 480mg, yield 74.5%.
(6) 1- ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- indole -5-carboxylic acid methyl esters
1- ((trans) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acids methyl esters (240mg, 0.88mmol) is dissolved in N, N- In dimethylformamide (6mL), ice bath cooling adds NaH (106mg, 4.4mmol), nitrogen protection, and be warming up to 25 DEG C of reactions 1 hour.Add 4- (bromomethyl) -5- cyclopropyl -3- (N of 2,6- dichlorophenyl) isoxazoles (348mg, 1.0mmol), N- diformazans Base formamide (1mL) solution, 25 DEG C are reacted 2 hours, and reaction is finished, and are added water (10mL) and are quenched, are extracted with ethyl acetate (25mL) Take, organic phase anhydrous sodium sulfate drying, concentrate, column chromatography (PE:EA=5:1) product 204mg, yield 43.0%, are obtained.
(7) 1- ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- indole -5-carboxylic acids
By 1- ((trans)-4-((5- cyclopropyl-3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl)- 1H- indole -5-carboxylic acids methyl esters (204mg, 0.38mmol), lithium hydroxide (92mg, 3.8mmol) is added in methanol (6mL), then 60 DEG C are heated to react 2 hours.Reaction is finished, and adds 0.5mol/L watery hydrochloric acid (10mL), is extracted with ethyl acetate (50mL), Organic phase anhydrous sodium sulfate drying, concentration, column chromatography (DCM:MeOH=20:1) product 138mg, yield 69.2%, are obtained.
Molecular formula：C28H26Cl2N2O4Molecular weight：525.4 LC-MS(m/z):525.1(M+H)+
1H-NMR(400MHz,MeOD)δ:8.30(s,1H),7.82(dd,1H,J1=8.8Hz, J2=1.6Hz), 7.45- 7.60 (m, 4H), 7.38 (d, 1H, J=3.2Hz), 6.57 (d, 1H, J=3.2Hz), 4.41 (s, 2H), 4.34-4.38 (m, 2H),2.20-2.23(m,1H),2.01-2.03(m,4H),1.78-1.81(m,2H),1.31-1.39(m,4H),1.19-1.21 (m,4H).
The 1- of embodiment 2 ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) rings Hexyl) -1H- indole -5-carboxylic acids (compound 2)
(1) preparation of 1- ((cis) -4- acetoxyl groups cyclohexyl) -1H- indole -5-carboxylic acid methyl esters
By 1- ((trans) -4- the hydroxy-cyclohexyls) -1H- indole -5-carboxylic acids methyl esters (system in preparation method be the same as Example 1 Standby process, 240mg, 0.88mmol), acetic acid (54mg, 0.90mmol), triphenylphosphine (472mg, 1.8mmol) is dissolved in dry In tetrahydrofuran, nitrogen is protected, and diethyl azodiformate (313mg, 1.8mmol) is added dropwise under ice bath, 25 are warming up to after adding DEG C reaction 2 hours, add ethyl acetate (20mL), washed with saturated nacl aqueous solution (10mL), organic phase anhydrous sodium sulfate Dry, concentration, pillar layer separation (PE:EA=5:1) title compound 220mg, yield 79.4%, are obtained.
(2) preparation of 1- ((cis) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acids
1- ((cis) -4- acetoxyl groups cyclohexyl) -1H- indole -5-carboxylic acids methyl esters (220mg, 0.70mmol) is dissolved in In methanol (5mL), lithium hydroxide (168mg, 7.0mmol) is added, 25 DEG C are reacted 12 hours, add 0.5mol/L watery hydrochloric acid (10mL), is extracted with ethyl acetate (50mL), and organic phase anhydrous sodium sulfate drying is concentrated to give title compound 169mg, yield 92.8%.
(3) preparation of 1- ((cis) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acid methyl esters
1- ((cis) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acids (169mg, 0.65mmol) are dissolved in acetonitrile (5mL) In, addition potassium carbonate (90mg, 0.65mmol), iodomethane (99mg, 0.70mmol), 25 DEG C are reacted 2 hours.Add water (10mL), is extracted, organic phase anhydrous sodium sulfate drying with ethyl acetate (50mL), and concentration obtains title compound 138mg, produces Rate 77.7%.
(4) 1- ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- indole -5-carboxylic acid methyl esters
1- ((cis) -4- hydroxy-cyclohexyls) -1H- indole -5-carboxylic acids methyl esters (120mg, 0.44mmol) is dissolved in N, N- In dimethylformamide (6mL), ice bath cooling adds NaH (53mg, 2.2mmol), nitrogen protection, and be warming up to 25 DEG C of reactions 1 Hour.Add 4- (bromomethyl) -5- cyclopropyl -3- (N of 2,6- dichlorophenyl) isoxazoles (174mg, 0.5mmol), N- diformazans Base formamide (1mL) solution, 25 DEG C are reacted 2 hours, and reaction is finished, and are added water (10mL) and are quenched, are extracted with ethyl acetate (25mL) Take, organic phase anhydrous sodium sulfate drying, concentrate, through column chromatography (PE:EA=5:1) title compound 84mg, yield, are obtained 35.4%.
(5) 1- ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- indole -5-carboxylic acids
By 1- ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - 1H- indole -5-carboxylic acids methyl esters (84mg, 0.16mmol), lithium hydroxide (38mg, 1.6mmol) is added in methanol (6mL), then 60 DEG C are heated to react 2 hours.Reaction is finished, and adds 0.5mol/L watery hydrochloric acid (10mL), is extracted with ethyl acetate (50mL), Organic phase anhydrous sodium sulfate drying, concentration, column chromatography (DCM:MeOH=20:1) product 38mg, yield 45.2%, are obtained.
Molecular formula：C28H26Cl2N2O4Molecular weight：525.4 LC-MS(m/z):525.1(M+H)+
1H-NMR(400MHz,MeOD)δ:8.30(s,1H),7.81(dd,1H,J1=8.8Hz, J2=1.2Hz), 7.45- 7.51 (m, 4H), 7.30 (d, 1H, J=3.2Hz), 6.60 (d, 1H, J=3.2Hz), 4.36 (s, 2H), 4.27-4.30 (m, 1H),3.58-3.59(m,1H),2.27-2.31(m,1H),1.56-2.01(m,8H),1.18-1.19(m,4H).
The 1- of embodiment 3 ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) rings Hexyl) -1H- benzos [d] imidazoles -5- formic acid preparation (compound 3)
(1) preparation of 4- (((trans) -4- hydroxy-cyclohexyls) amino) -3- ethyl nitrobenzoates
The fluoro- 3- ethyl nitrobenzoates (2.13g, 10.0mmol) of 4-, (trans) -4- aminocyclohexanols are weighed successively (1.27g, 11.0mmol) and cesium carbonate (9.77g, 30.0mmol) are added in 1-METHYLPYRROLIDONE (20mL), are warming up to 85 DEG C reaction 6 hours.Reaction solution is cooled to 25 DEG C, adds water (200mL), separates out a large amount of solids, and suction filtration, filter cake washing, vacuum is done It is dry, obtain title compound (2.57g, yield 83.4%).
(2) preparation of 3- amino -4- (((trans) -4- hydroxy-cyclohexyls) amino) ethyl benzoate
4- (((trans) -4- hydroxy-cyclohexyls) amino) -3- ethyl nitrobenzoates (2.57g, 8.3mmol) are dissolved into In methanol (100mL), add under palladium charcoal (180mg), atmosphere of hydrogen and react 2 hours.Suction filtration, filter cake is washed with methanol (50mL), filter Liquid is concentrated, and obtains title compound (2.18g, yield 94.0%).
(3) preparation of 1- ((trans) -4- hydroxy-cyclohexyls) -1H- benzos [d] imidazoles -5- Ethyl formates
3- amino -4- (((trans) -4- hydroxy-cyclohexyls) amino) ethyl benzoate (2.18g, 7.8mmol) is dissolved into In ethylene glycol monomethyl ether (20mL), formamidine acetate (2.41g, 23.4mmol) is added, is placed in 100 DEG C of oil baths and reacts 5 hours.It is cold But, reaction solution is directly concentrated, and crude product is through silica gel column chromatography (dichloromethane:Methanol=20:1) purify, obtain title compound (1.49g, yield 65.9%).
(4) 1- ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- benzos [d] imidazoles -5- Ethyl formates
1- ((trans) -4- hydroxy-cyclohexyls) -1H- benzos [d] imidazoles -5- Ethyl formates (202mg, 0.7mmol) is molten Solve in DMF (5mL), sodium hydride (mass fraction 60%, 52mg, 1.3mmol) is added under ice-water bath, plus It is complete to rise to 25 DEG C and stir 30 minutes, add 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazoles (243mg, 0.7mmol), continue to stir 0.5 hour.Reaction solution adds methanol (1mL) and is quenched, addition water (20mL), dichloromethane (30mL × 2) extract, organic phase merges, saturated nacl aqueous solution (20mL) is washed, anhydrous sodium sulfate drying, concentration, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) title compound (88mg, yield 22.7%), is obtained.
(5) 1- ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- benzos [d] imidazoles -5- formic acid
By 1- ((trans) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - 1H- benzos [d] imidazoles -5- Ethyl formates (88mg, 0.16mmol), are dissolved into tetrahydrofuran (2mL), add 1mol/L hydrogen The lithia aqueous solution (1mL), 25 DEG C are stirred 3 hours.Water (20mL) and ethyl acetate (15mL) are added, point liquid, aqueous phase 1mol/ L salt acid for adjusting pH adds dichloromethane (15mL × 2) extraction to 3, and organic phase merges, and anhydrous sodium sulfate drying, vacuum is dense Contracting, crude product is through silica gel column chromatography (dichloromethane:Methanol=50:1) title compound (25mg, yield 29.9%), is obtained.Molecule Formula:C27H25Cl2N3O4Molecular weight:526.4 LC-MS(m/z)：526.2(M+H)+
1H NMR(400MHz,DMSO-d6)δ:8.39(s,1H),8.19(s,1H),7.88-7.81(m,1H),7.75- 7.66(m,1H),7.66-7.62(m,2H),7.60-7.55(m,1H),4.45-4.32(m,3H),2.40-2.30(m,1H), 2.05-1.78(m,7H),1.20-1.08(m,6H).
The 1- of embodiment 4 ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) rings Hexyl) -1H- benzos [d] imidazoles -5- formic acid preparation (compound 4)
(1) preparation of 4- (((cis) -4- hydroxy-cyclohexyls) amino) -3- ethyl nitrobenzoates
Preparation process is with reference to embodiment 3, reactions steps (1).
(2) preparation of 3- amino -4- (((cis) -4- hydroxy-cyclohexyls) amino) ethyl benzoate
Preparation process is with reference to embodiment 3, reactions steps (2).
(3) preparation of 1- ((cis) -4- hydroxy-cyclohexyls) -1H- benzos [d] imidazoles -5- Ethyl formates
Preparation process is with reference to embodiment 3, reactions steps (3).
(4) 1- ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- benzos [d] imidazoles -5- Ethyl formates
Preparation process is with reference to embodiment 3, reactions steps (4).
(5) 1- ((cis) -4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation of 1H- benzos [d] imidazoles -5- formic acid
Preparation process is with reference to embodiment 3, reactions steps (5).
Molecular formula:C27H25Cl2N3O4Molecular weight:526.4 LC-MS(m/z)：526.2(M+H)+
1H NMR(400MHz,DMSO-d6)δ:12.67(s,1H),8.24-8.22(m,2H),7.83(m,1H),7.64(d, J=8.8Hz, 1H), 7.58-7.56 (m, 2H), 7.48-7.45 (m, 1H), 4.35-4.30 (m, 3H), 3.52 (m, 1H), 2.40- 2.30(m,1H),1.78-1.72(m,5H),1.60-1.48(m,2H),1.18-1.14(m,5H).
The 1- of embodiment 5 (- 4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation (compound 5) of 1H- benzos [d] imidazoles -4- formic acid
(1) preparation of the fluoro- 2- ethyl nitrobenzoates of 3-
The fluoro- 2- nitrobenzoic acids (6.8g, 36.8mmol) of 3- are added in ethanol (80mL), the concentrated sulfuric acid is then added (2mL), reacts 24 hours at 85 DEG C.Reaction solution is concentrated, and adds water (100mL) and ethyl acetate (100mL), and point liquid is organic Mutually it is concentrated in vacuo, obtains title compound (6.2g, yield 79.1%).
(2) preparation of 3- ((4- hydroxy-cyclohexyls) amino) -2- ethyl nitrobenzoates
Preparation process is with reference to embodiment 3, reactions steps (1).
(3) preparation of 2- amino -3- ((4- hydroxy-cyclohexyls) amino) ethyl benzoate
Preparation process is with reference to embodiment 3, reactions steps (2).
(4) preparation of 1- (4- hydroxy-cyclohexyls) -1H- benzos [d] imidazoles -4- Ethyl formates
Preparation process is with reference to embodiment 3, reactions steps (3).
(5) 1- (- 4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) -1H- benzene And the preparation of [d] imidazoles -4- formic acid
Preparation process is with reference to embodiment 3, reactions steps (4), (5).
Molecular formula:C27H25Cl2N3O4Molecular weight:526.4 LC-MS(m/z)：526.2(M+H)+
1H NMR(400MHz,DMSO-d6)δ:8.38 (s, 1H), 7.93 (d, J=8.0Hz, 1H), 7.59-7.47 (m, 4H),7.28-7.24(m,1H),5.14(s,2H),4.45-4.35(m,1H),3.64-3.55(m,1H),2.65-2.60(m, 1H),2.05-1.85(m,6H),1.55-1.45(m,3H),1.22-1.10(m,3H).
The 1- of embodiment 6 (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) - The preparation (compound 6) of 1H- benzos [d] imidazoles -6- formic acid
(1) preparation of the fluoro- 4- ethyl nitrobenzoates of 3-
Weigh the fluoro- 4- nitrobenzoic acids (5.0g, 27.0mmol) of 3- and be dissolved in ethanol (60mL), add the concentrated sulfuric acid (1mL), plus Heat is reacted 6 hours to 85 DEG C, and LC-MS detection reactions are complete, are concentrated under reduced pressure, add saturated sodium bicarbonate aqueous solution (100mL) and Ethyl acetate (150mL), point liquid, organic phase anhydrous sodium sulfate drying, suction filtration, filtrate concentration, obtain title compound (5.6g, Yield 97.2%).
(2) preparation of 3- ((4- hydroxy-cyclohexyls) amino) -4- ethyl nitrobenzoates
Preparation process is with reference to embodiment 3, reactions steps (1).
(3) preparation of 4- amino -3- ((4- hydroxy-cyclohexyls) amino) ethyl benzoate
Preparation process is with reference to embodiment 3, reactions steps (2).
(4) preparation of 1- (4- hydroxy-cyclohexyls) -1H- benzos [d] imidazoles -6- Ethyl formates
Preparation process is with reference to embodiment 3, reactions steps (3).
(5) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) -1H- benzos The preparation of [d] imidazoles -6- Ethyl formates
Preparation process is with reference to embodiment 3, reactions steps (4).
(6) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) cyclohexyl) -1H- benzos The preparation of [d] imidazoles -6- formic acid
Preparation process is with reference to embodiment 3, reactions steps (5).
Molecular formula:C27H25Cl2N3O4Molecular weight:526.4 LC-MS(m/z)：526.2(M+H)+
1H NMR(400MHz,DMSO-d6)δ:8.46(s,1H),8.22(s,1H),7.81-7.79(m,1H),7.69- 7.65(m,3H),7.60-7.57(m,1H),4.56-4.51(m,1H),4.33(s,2H),3.31(s,1H),2.37-2.32(m, 1H),2.00-1.79(m,6H),1.31-1.12(m,7H)。

Claims (11)

1. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer shown in formula (I)：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, C1-6Alkane Epoxide, C1-6Alkyl amino, two C1-6Alkyl amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, halo C1-6Alkyl, halo C1-6Alkane Epoxide, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkane Base amino-sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy, C2-8Alkenyl or C2-8Alkynyl；
R3Selected from hydrogen atom, the C optionally replaced by one or more substituent P1-6Alkyl, C1-6Alkoxy, C3-8Cycloalkyl, C3-8 Heterocyclic radical, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkylsulfonyloxy；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulfonyl Base, C2-8Alkenyl or C2-8Alkynyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl C1-6Alkyl, halo C1-6 Alkyl, carboxyl C1-6Alkyl, carboxyl epoxide C1-6Alkyl, carboxyamino C1-6Alkyl, amino C1-6Alkyl, amino carbonyl C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy, halo C1-6Alkoxy, carboxyl C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl ammonia Base, two C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl-amino, C1-6Alkyl sulphonyl or C1-6Alkyl sulfonyl amino Base；
W is selected from CH2、NH、O、S、SO、SO2Or CO；
A is selected from NH, O or S；
Z is selected from cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two C1-6Alkyl amino, halo C1-6Alkyl, halo C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl or C2-8Alkynyl；
E is selected from C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
F be selected from be not present, C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
X is selected from C, CH or N；
Y is selected from C, CH, CH2、N、NH、O、S、SO、SO2Or CO；
Connected mode between E, X, Y, F is separately selected from singly-bound or double bond, and the connected mode between E, X, Y, F is at least One is double bond；
It is not thiazole that E, X, Y, F, which connect the group to be formed,；
M is selected from 0-3 integer；
N is selected from 0-4 integer.
2. compound as claimed in claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, halogen atom, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, C1-4Alkane Epoxide, C1-4Alkyl amino, two C1-4Alkyl amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, halo C1-4Alkyl, halo C1-4Alkane Epoxide or C1-4Alkoxy C1-4Alkyl；
R3Selected from C that is unsubstituted or being replaced by one or more substituent P3-6Cycloalkyl or C3-6Heterocyclic radical；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, C1-4Alkyl, hydroxyl C1-4Alkyl, halo C1-4 Alkyl, carboxyl C1-4Alkyl, carboxyl epoxide C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl C1-4Alkyl, C1-4Alkoxy, hydroxyl C1-4Alkoxy, halo C1-4Alkoxy, carboxyl C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl ammonia Base, two C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl-amino, C1-4Alkyl sulphonyl or C1-4Alkyl sulfonyl amino Base；
W is selected from CH2、NH、O、S、SO、SO2Or CO；
A is selected from NH, O or S；
Z is selected from 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
E is selected from C, CH, CH2, N, NH, CO, O or S；
F be selected from be not present, C, CH, CH2, N, NH, O, CO or S；
X is selected from C, CH or N；
Y is selected from C, CH, CH2, N, NH, O, CO or S；
Connected mode between E, X, Y, F is separately selected from singly-bound or double bond；Connected mode between E, X, Y, F is at least One is double bond；
It is not thiazole that E, X, Y, F, which connect the group to be formed,；
M is selected from 0-2 integer；
N is selected from 0-3 integer.
3. compound as claimed in claim 2, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R3Selected from C that is unsubstituted or being replaced by one or more substituent P3-6Cycloalkyl；
P is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
Benzopyranyl, 4H- chromene -4- ketone groups, benzothienyl, benzoxazolyl, 4H- chromogens alkenyl, benzofuranyl, benzene And 1,4- Dioxins base, benzo 4H-1,4- oxazinyls, benzo 4H-1,2- oxazinyls, benzo 4H-1,3- oxazinyls, Dihydro cinnolines base, quinazolyl, dihydroquinazoline base, quinolyl, EEDQ base, isoquinolyl, dihydro-isoquinoline base, quinoline Ketone group, isoquinolin ketone group, benzo dihydro pyrazine base, benzopyrazines, ihydro naphthyl, indyl, isoindolyl, benzimidazolyl, Benzopyrazoles base or BTA base；
N is selected from 0-2 integer.
4. compound as claimed in claim 3, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, amino, hydroxyl, carboxyl, first Base, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, methoxyl group, methylamino, dimethylamino, acetyl group, fluoroform Base, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, isopropyl, methoxy Base, ethyoxyl, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetenyl, methylamino, ethylamino, acetyl group, Acetylamino, mesyl or dimethylamino；
N is selected from 0-2 integer；
Z is selected from saturation 5-6 member cycloalkyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
5. compound as claimed in claim 4, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, ethyl, propyl group, butyl, methoxyl group, first Base amino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, ethoxy Base, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetyl group or acetylamino；
W is selected from NH, O or S；
A is selected from NH, O or S；
Z is selected from unsubstituted or by one or more substituent Q cyclopenta replaced or cyclohexyl；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1 or 2.
6. compound as claimed in claim 5, its pharmaceutically acceptable salt, its ester or its stereoisomer：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methylamino, acetyl group, trifluoromethyl or three Fluorine methoxyl group；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy, carboxyl first Base, carboxy ethyl, acetyl group or acetylamino；
W is selected from O；A is selected from O；
Z is selected from cyclohexyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1 or 2.
7. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as claimed in claim 1, with formula (II) structure shown in：
Wherein,
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, bromine atoms, nitro, amino, hydroxyl, carboxyl, first Base, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, methoxyl group, methylamino, dimethylamino, acetyl group, fluoroform Base, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, isopropyl, methoxy Base, ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, carboxymethyl group, carboxy ethyl, acetyl group, Acetylamino, mesyl or dimethylamino；
N is selected from 0-2 integer；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from unsubstituted or by one or more substituent Q cyclopenta replaced or cyclohexyl；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
Connected mode between X, Y, F is separately selected from singly-bound or double bond, the connected mode between X, Y, F at least one For double bond.
8. compound as claimed in claim 7, its pharmaceutically acceptable salt, its ester or its stereoisomer：
R1、R2Separately it is selected from hydrogen atom, cyano group, fluorine atom, chlorine atom, methyl, ethyl, propyl group, butyl, methoxyl group, first Base amino, acetyl group, trifluoromethyl or trifluoromethoxy；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, ethoxy Base, trifluoromethyl, trifluoromethoxy, carboxymethyl group, carboxy ethyl, acetyl group or acetylamino；
W is selected from NH, O or S；
A is selected from NH, O or S；
Z is selected from cyclohexyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl amino, two C1-4Alkyl amino, halo C1-4Alkyl or halo C1-4Alkoxy；
F is selected from CH or N；
X is selected from N；
Y is selected from CH；
Connected mode between X, Y is singly-bound, and the connected mode between Y, F is double bond；
N is selected from 1.
9. compound as claimed in claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein described Compound is selected from：
10. a kind of pharmaceutical composition, it contains compound described in any one of claim 1~9, its is pharmaceutically acceptable Salt, its ester or its stereoisomer, with one or more pharmaceutical carriers and/or diluent.
11. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer as described in any one of claim 1~9 Be used for the purposes for the disease and relevant disease for treating and/or preventing FXR to mediate preparing, described disease include in Chronic Liver or Some form of extrahepatic cholestasis illness, or chronic bile smoulder liver fibre caused by illness or acute intrahepatic cholestasis illness Dimensionization, hepatic sclerosis, the obstructive or chronic inflammatory disorders of liver, fatty liver and its complication, the fatty liver relevant with alcohol and its Complication, acute hepatic failure, cholelithiasis, and/or inflammatory bowel disease, PBC, chronic fatty and fibre The clinical complication of illness and disease, lipid or lipoprotein disorders caused by the denaturation of dimension property, I types or type ii diabetes, it is non-malignant Excess proliferative disease or excess proliferative disease.
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US10485795B2 (en) 2011-07-13 2019-11-26 Gilead Sciences, Inc. FXR (NR1H4) binding and activity modulating compounds
US10329286B2 (en) 2016-06-13 2019-06-25 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10421730B2 (en) 2016-06-13 2019-09-24 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11739065B2 (en) 2016-06-13 2023-08-29 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10774054B2 (en) 2016-06-13 2020-09-15 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
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US10981881B2 (en) 2016-06-13 2021-04-20 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US10562910B2 (en) 2016-08-05 2020-02-18 North & South Brother Pharmacy Investment Company Limited Nitrogen-containing tricyclic compounds and uses thereof in medicine
US11833150B2 (en) 2017-03-28 2023-12-05 Gilead Sciences, Inc. Methods of treating liver disease
US11078198B2 (en) 2017-11-01 2021-08-03 Bristol-Myers Squibb Company Spirocyclic compounds as farnesoid X receptor modulators
US11168079B2 (en) 2017-11-01 2021-11-09 Bristol-Myers Squibb Company Alkene compounds as farnesoid x receptor modulators
US11286252B2 (en) 2017-11-01 2022-03-29 Bristol-Myers Squibb Company Alkene spirocyclic compounds as farnesoid X receptor modulators
US11370785B2 (en) 2017-11-01 2022-06-28 Bristol-Myers Squibb Company Multicyclic compounds as farnesoid X receptor modulators
US10730863B2 (en) 2017-11-01 2020-08-04 Bristol-Myers Squibb Company Bridged bicyclic compounds as farnesoid X receptor modulators
US11208418B2 (en) 2018-02-02 2021-12-28 Sunshine Lake Pharma Co., Ltd. Nitrogenous tricyclic compounds and uses thereof in medicine
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US11225473B2 (en) 2019-01-15 2022-01-18 Gilead Sciences, Inc. FXR (NR1H4) modulating compounds
US11254663B2 (en) 2019-02-15 2022-02-22 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
US11713312B2 (en) 2019-02-15 2023-08-01 Bristol-Myers Squibb Company Substituted bicyclic compounds as farnesoid X receptor modulators
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US11820747B2 (en) 2021-11-02 2023-11-21 Flare Therapeutics Inc. PPARG inverse agonists and uses thereof

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