CN107021957A - FXR receptor stimulating agents - Google Patents

FXR receptor stimulating agents Download PDF

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Publication number
CN107021957A
CN107021957A CN201710045048.8A CN201710045048A CN107021957A CN 107021957 A CN107021957 A CN 107021957A CN 201710045048 A CN201710045048 A CN 201710045048A CN 107021957 A CN107021957 A CN 107021957A
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alkyl
amino
group
alkoxy
carboxyl
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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 therefore desirable to be able to develop high-efficiency low-toxicity and the preferable FXR of stability by Body activator.The present invention will provide a kind of FXR receptor stimulating agents of new structure, and it has good drug effect, be that FXR acceptors swash Dynamic agent is used to treating NASH, PBC, disorders of lipid metabolism, diabetic complication and pernicious Tumour 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, C that is unsubstituted or being replaced by one or more substituent P1-6Alkyl, C1-6Alkoxy, C3-8 Cycloalkyl, C3-8Heterocyclic radical, C1-6Alkyl sulphonyl, C1-6Alkyl amino sulfonyl, two C1-6Alkyl amino sulfonyl, C1-6Alkyl Sulfonamido, 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 aryl or heteroaryl unsubstituted or 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 not is thiophene, and work as R that E, X, Y, F, which connect the group to be formed,3During for isopropyl, E, X, Y, F connect the group to be formed It is not phenyl ring or imidazoles；
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 unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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 or O；
F is selected from and is not present, C, CH, CH2, N, NH, CO or O；
X is selected from C, CH or N；
Y is selected from C, CH, CH2, N, NH, CO or O；
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；
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 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 unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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, benzoxazolyl, 4H- chromogens alkenyl, benzofuranyl, benzo 1,4- Dioxin base, benzo 4H-1,4- oxazinyls, benzo 4H-1,2- oxazinyls, benzo 4H-1,3- oxazinyls, dihydro are scolded Quinoline base, quinazolyl, dihydroquinazoline base, quinolyl, EEDQ base, isoquinolyl, dihydro-isoquinoline base, quinoline ketone group, Isoquinolin ketone group, benzo dihydro pyrazine base, benzopyrazines base, ihydro naphthyl, indyl, benzimidazolyl, benzopyrazoles base, benzene And triazolyl or isoindolyl；
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, butyl, methoxyl group, methylamino, 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, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl or two Methylamino；
Z is selected from unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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 5, the compound as described in scheme 4, 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, cyclobutyl, cyclopenta；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group or acetylamino；
W is selected from NH, O or S；A is selected from NH, O or S；
Z is selected from phenyl, pyrrole radicals, pyrazolyl, imidazole radicals, furan unsubstituted or replaced by one or more substituent Q Mutter base, pyridine radicals, pyrimidine radicals, thienyl, thiazolyl, oxazolyls；
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.
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, trifluoromethyl or trifluoro methoxy Base；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy, second Acyl group or acetylamino；
W is selected from O or S；
A is selected from O or S；
Z is selected from phenyl that is unsubstituted or being replaced by one or more substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, propyl group, first Epoxide, ethyoxyl, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1.
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 unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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；
X is selected from C, CH or N；Y is selected from CH or N；
F is selected from CH, CH2, N, NH or O；
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；
Work as R3During for isopropyl, it is not imidazoles that X, Y, F, which connect the group to be formed,.
Scheme 8, the compound as described in scheme 7, 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, isobutyl group, the tert-butyl group, butyl, methoxyl group, methylamino, dimethylamino, second Acyl group, trifluoromethyl, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl or two Methylamino；
W is selected from NH, O or S；A is selected from NH, O or S；
N is selected from 0-2 integer；
Z is selected from unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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；
X is selected from C, CH or N；Y is selected from CH or N；
F is selected from CH, CH2, N or NH；
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：
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；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, trifluoromethyl, trifluoromethoxy, acetyl group or acetylamino；
W is selected from O；A is selected from O；
Z is selected from phenyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q be selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, methyl, ethyl, propyl group, methoxyl group, ethyoxyl, Methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
The cyclic group that X, Y, F are collectively formed forms following structure together with phenyl ring：
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 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- pentenyls Deng.
" 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 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 C1-4Alcoxyl, carboxyl epoxide C1-4Alkyl, carboxyamino C1-4 Alkyl, amino carbonyl C1-4Alkyl ", refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, ammonia Base, carboxyl, carboxyl epoxide, carboxyamino, amino carbonyl, C1-4Alkoxy replaces C respectively1-4Alkyl, C1-4Hydrogen in alkoxy is former The group that son is formed.
" aryl " of the present invention refers to aromatic ring, such as phenyl, naphthyl, anthryl.
" heteroaryl " of the present invention refers to containing the undersaturated cyclic group of at least one hetero atom, including " 5~8 Unit's heteroaryl, 5~7 unit's heteroaryls ", " 5~6 unit's heteroaryl ", described hetero atom has nitrogen, oxygen and sulphur etc., while former including carbon Son, nitrogen-atoms and sulphur atom are by the situation of oxo.It is specifically as follows " 5~8 unit's heteroaryls containing 1~3 O, S and/or N ", " contains 1~2 O, S and/or N 5~8 unit's heteroaryls ", " 5~8 unit's heteroaryls containing 2~3 O, S and/or N ", " containing 1~2 O, S And/or N 5~6 unit's heteroaryls ", " 5~6 unit's heteroaryls containing 2~3 O, S and/or N ".Instantiation includes but not only limited In furyl, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyls, imidazoles Base, pyrazolyl, 1,2,3- triazolyls, 1,2,4- triazolyls, 1,2,3- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,5- Evil bis- Oxazolyl, 1,3,4- oxadiazolyls, pyridine radicals, 2- pyridones, 4- pyridones, pyrimidine radicals, 1,4- Dioxins base, pyridazine Base, pyrazinyl, 1,2,3- triazine radicals, 1,3,5-triazines base, 1,2,4,5- tetrazine bases etc., it is preferably " 5~6 unit's heteroaryl ".
" 5~8 yuan of aryl " refers to that annular atom removes hydrogen atom for the cyclic nonaromatics of 5~8 yuan of carbon atoms Group is obtained, is preferably " 5~6 yuan of aryl ".
" 3-8 members cycloalkyl " of the present invention, refers to that the paraffin section of 3-8 carbon atom removes a hydrogen atom and derived Fractional saturation or saturation monocyclic cyclic alkyl, including such as " 3-6 members cycloalkyl ", " 4-7 members cycloalkyl ", " 4-6 member cycloalkanes Base ", " 5-6 members cycloalkyl " etc..It is specifically as follows " 3-8 members saturated cyclic alkyls ", " 3-8 member fractional saturations cycloalkyl ", " 5-6 members Saturated cyclic alkyls ", " 5-6 member fractional saturations cycloalkyl ".3-8 member saturated cyclic alkyls include 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 cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc.； 3-8 member fractional saturation cycloalkyl includes but is not limited to：Cyclopentenyl, 1,3- cyclopentadienyl groups, cyclohexenyl group, 1,4- cyclohexadiene Base, cycloheptenyl, 1,4- cycloheptadiene base, cyclo-octene base.
" 3-8 circle heterocycles base " of the present invention refers to containing 3-8 annular atom and contains at least one hetero atom (example Such as 1,2,3,4 or 5 hetero atoms) saturation or the monocyclic heterocyclic compound of fractional saturation remove the base that a hydrogen atom is obtained Group.Including such as " 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 base ", " 6-8 circle heterocycles base " etc..It is specifically as follows：It is " former containing 1-2 N, O and/or S Son 3-8 circle heterocycles base ", " the 3-8 members saturated heterocyclyl containing 1-2 N, O and/or S atom ", " 5-6 members saturated heterocyclyl ", " the 5-6 circle heterocycles base containing 1-2 N, O and/or S atom ", " the 5-6 members saturated heterocyclyl containing 1-2 N, O and/or S atom ". 3-8 member fractional saturation list heterocyclic radicals, refer to containing double bond, heteroatomic cyclic group.3-8 member saturation list heterocyclic radicals, refer to complete Contain heteroatomic cyclic group for saturated bond in portion." hetero atom " of the present invention refers to N, O, S, SO and/or SO2Deng, It is preferred that N, O, S, more preferably N, O.
" fractional saturation " of the present invention is that ring portion includes at least one double or triple bonds.
" 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.
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；DMSO：Dimethyl sulfoxide (DMSO)；EA：Ethyl acetate；MeOH：Methanol； NBS：N- bromo-succinimides；NCS：N- chlorosuccinimides；PE：Petroleum ether；THF：Tetrahydrofuran；DIBAL-H：Two is different Butyl aluminum hydride；DMAP：DMAP)
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
Scheme one：By intermediate 6 and intermediate 5, alkaline reagent (such as potassium carbonate, cesium carbonate) is dissolved in organic solvent (example Such as acetonitrile) in, it is heated to 40-100 DEG C and reacts 0.2-24 hours, reaction is finished, add organic solvent (such as ethyl acetate), uses Water washing, organic phase anhydrous sodium sulfate drying removes solvent, through column chromatography (such as PE:EA=1-5:1) intermediate 7 ', is obtained, Intermediate 7 ' is dissolved in organic solvent (such as dichloromethane/trifluoroacetic acid), 20-30 DEG C is reacted 0.2-12 hours.Reaction is finished, Organic solvent (such as ethyl acetate) is added, with alkaline solution (such as saturated sodium bicarbonate solution) and water washing, organic phase is used Anhydrous sodium sulfate drying, removes solvent, through column chromatography (such as PE:EA=1:1-1:5) intermediate 7, is obtained.
Scheme two：Intermediate 6 is dissolved in organic solvent (such as DMF), intermediate 5, alkalescence is added Reagent (such as potassium carbonate, cesium carbonate), is warming up to 100 DEG C and stirs 6-24 hours, reaction is complete, concentration, and crude product is through silica gel column layer Analyse (such as petroleum ether:Ethyl acetate=5:1) purify, obtain intermediate 7.
8th, the preparation of formula (I) compound
Scheme one：By intermediate 7, alkaline reagent (such as lithium hydroxide) is dissolved in organic solvent (such as methanol), heating Reacted 0.2-24 hours to 20-80 DEG C.Reaction is finished, and acid reagent (such as watery hydrochloric acid) is added, with organic solvent (such as acetic acid Ethyl ester) extraction, organic phase anhydrous sodium sulfate drying, removing solvent, through column chromatography (such as DCM:MeOH=20:1) formula, is obtained (I) compound.
Scheme two：Intermediate 7 is dissolved in organic solvent (such as methanol/water), an alkaline reagent (such as hydronium(ion) is added Lithia), 20-40 DEG C is stirred 6-24 hours, acid solution (such as watery hydrochloric acid) regulation pH=2-7, separates out solid, and suction filtration is done It is dry, obtain formula (I) compound.
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.
" 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 formula (I) compound of the present invention refer to when formula (I) compound has asymmetric carbon atom, meeting Enantiomter is produced, when compound has carbon-carbon double bond or cyclic structure, cis-trans-isomer can be produced, when compound is present When ketone or oxime, dynamic isomer, the enantiomter of all formula (I) compounds, diastereoisomer, racemization isomery can be produced Body, cis-trans-isomer, dynamic isomer, geometric isomer, epimer and its mixture, are included in the scope of the invention In.
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.Such as tablet, capsule, pill, granule, oral solution, oral suspensions, syrup, injection Liquid, injection sterile powder, concentrated solution for injection, suppository, inhalant or spray etc..
" carrier " of the present invention includes but is not limited to filler, diluent, adhesive, wetting agent, disintegrant, lubrication It is agent, surfactant, preservative, colouring agent, flavouring, aromatic, effervescent agent, emulsifying agent, flocculant, deflocculant, antibacterial Agent, solubilizer.
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.
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.
Comparison medicine：PX-104, concrete structure is shown in background technology；PX-102, the raceme for being PX-104.
PBS：Phosphate buffer.
(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 12,000 × g of temperature is centrifuged 15 seconds.The solution in collecting pipe is discarded, plus 500 μ L eluents II are into adsorption column；Room temperature centrifuges 1-2 Minute, adsorption column is positioned on RNA collecting pipes；50 μ L RNase-free water are added to the center of adsorption column, room temperature is incubated Educate 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 GS1 thermal 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 ℃。
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 of 15 seconds and 60 DEG C are between 60 seconds 40 circulations are set.
(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
The detection of BSEP mRNA relative expression quantities in the HepG2 cells of the compounds of this invention of table 3. processing
Remarks：MRNA relative expression quantity %=100* [mRNA (tester)/mRNA (PX-102 or PX-104)]
From table 2, table 3, the compounds of this invention has preferable expressional function to BSEP mRNA in HepG2 cells, for Treatment NASH has great importance.
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 is obtained, two steps add up to yield 55.1%.
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) product 4.3g, yield 70.4% are obtained.
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) product 3.60g, yield 67.7% are obtained.
The 3- of embodiment 1 (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation (compound 1) of Indole-6-carboxylic acid
(1) preparation of 1H- indole -6-carboxylic methyl esters
1H- Indole-6-carboxylic acids (1.0g, 6.2mmol), potassium carbonate (856mg, 6.2mmol) are added to DMF (10mL) In, addition iodomethane (1.14g, 8.0mmol), lucifuge, 25 DEG C are reacted 2 hours.Reaction is finished, and adds ethyl acetate (100mL), Washed successively with water (30mL) and saturated nacl aqueous solution (30mL), organic phase anhydrous sodium sulfate drying, remove solvent, obtain Title compound 1.03g, yield 94.9%.
(2) preparation of the bromo- 1H- indole -6-carboxylic methyl esters of 3-
1H- indole -6-carboxylic methyl esters (1.03g, 5.9mmol) are added in DMF (20mL), N- bromos are added at -78 DEG C DMF (10mL) solution of succimide (1.26g, 7.1mmol), is slowly increased to 30 DEG C and reacts 1 hour.Reaction is finished, and is added Ethyl acetate (150mL), successively with saturated nacl aqueous solution (50mL), water (50mL) washing, organic phase is dry with anhydrous sodium sulfate It is dry, remove solvent, column chromatography (PE:EA=5:1) title compound 1.2g, yield 80.0%, are obtained.
(3) preparation of the bromo- 1H- indoles -1,6- dicarboxylic esters of the 1- tert-butyl groups -6- methyl -3-
By the bromo- 1H- indole -6-carboxylic methyl esters (1.2g, 4.72mmol) of 3-, di-tert-butyl dicarbonate (1.31g, 6.0mmol), DMAP (576mg, 4.72mmol) is added in tetrahydrofuran (30mL), and 30 DEG C are reacted 2 hours.Instead It should finish, add ethyl acetate (150mL), washed successively with 1mol/L watery hydrochloric acid (10mL) and water (50mL), organic phase nothing Aqueous sodium persulfate is dried, and is removed solvent and is obtained title compound 1.6g, yield 95.8%.
(4) preparation of 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) phenol
By 4- bromophenols (1.73g, 10mmol), connection boric acid pinacol ester (2.54g, 10mmol), cesium carbonate (3.26g, 10mmol)、Pd(dppf)Cl2(173mg) is added in Isosorbide-5-Nitrae-dioxane (30mL), and 90 DEG C are reacted 6 hours, and reaction is finished, Ethyl acetate (120mL) is added, is washed with saturated nacl aqueous solution (50mL), organic phase anhydrous sodium sulfate drying, is removed molten Agent, pillar layer separation (PE:EA=10:1) title compound 1.50g, yield 68.2%, are obtained.
(5) preparation of 1- tert-butyl groups 6- methyl 3- (4- hydroxy phenyls) -1H- indoles -1,6- dicarboxylic esters
By the bromo- 1H- indoles -1,6- dicarboxylic esters (500mg, 1.41mmol) of 1- tert-butyl group 6- methyl 3-, 4- (4,4,5,5- Tetramethyl -1,3,2- dioxaborolanes -2- bases) phenol (339mg, 1.54mmol), cesium carbonate (652mg, 2.0mmol), Pd(dppf)Cl2(50mg) is added in Isosorbide-5-Nitrae-dioxane (20mL), and 90 DEG C are reacted 4 hours, and reaction is finished, and add acetic acid second Ester (120mL), is washed, organic phase anhydrous sodium sulfate drying with saturated nacl aqueous solution (50mL), removes solvent, column chromatography point From (PE:EA=10:1) title compound 221mg, yield 42.7%, are obtained.
(6) 1- tert-butyl groups 6- methyl 3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) Phenyl) -1H- indoles -1,6- dicarboxylic esters preparation
By the 1- tert-butyl group 6- methyl 3- (4- hydroxy phenyls) -1H- indoles -1,6- dicarboxylic esters (221mg, 0.60mmol), 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazoles (218mg, 0.72mmol), potassium carbonate (124mg, 0.90mmol) add in acetonitrile (5mL), be then heated to 60 DEG C and react 2 hours.Reaction is finished, and adds ethyl acetate (50mL), Washed with water (25mL), organic phase anhydrous sodium sulfate drying, remove solvent, column chromatography (PE:EA=5:1) title compound, is obtained Thing 217mg, yield 57.1%.
(7) 3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- indoles - The preparation of 6- carboxylate methyl esters
By 1- tert-butyl group 6- methyl 3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) benzene Base) -1H- indoles -1,6- dicarboxylic esters (217mg, 0.34mmol) are dissolved in the mixed of dichloromethane (1mL) and trifluoroacetic acid (1mL) Close in solution, 25 DEG C are reacted 1 hour.Reaction is finished, and adds ethyl acetate (50mL), with saturated sodium bicarbonate solution (10mL) and Water (10mL) is washed, organic phase anhydrous sodium sulfate drying, removes solvent, column chromatography (PE:EA=1:1) title compound, is obtained 115mg, yield 63.4%.
(8) 3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- indoles - The preparation of 6- carboxylic acids
By 3- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- indoles -6- Carboxylate methyl ester (115mg, 0.22mmol), lithium hydroxide (53mg, 2.2mmol) is added in methanol (3mL), is then heated to 60 DEG C Reaction 2 hours.Reaction is finished, and adds 0.5mol/L watery hydrochloric acid (10mL), is extracted with ethyl acetate (50mL), organic phase nothing Aqueous sodium persulfate is dried, and removes solvent, column chromatography (DCM:MeOH=20:1) product 25mg, yield 21.9%, are obtained.Molecular formula： C28H20Cl2N2O4Molecular weight：519.4LC-MS(m/z):519.1(M+H)+
1H-NMR(400MHz,MeOD)δ:8.10 (s, 1H), 7.68 (d, 3H, J=8.8Hz), 7.50-7.54 (m, 3H), 7.44 (s, 1H), 7.45-7.47 (m, 1H), 6.88 (d, 2H, J=8.4Hz), 6.75 (s, 1H), 4.94 (s, 2H), 2.33- 2.36(m,1H),1.20-1.22(m,4H).
The 1- of embodiment 2 (4-((5- cyclopropyl-3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl)-1H- The preparation (compound 2) of indole -5-carboxylic acid
(1) preparation of 1- (4- hydroxy phenyls) -1H- indole -5-carboxylic acid's methyl esters
By 1H- indole -5-carboxylic acids methyl esters (700mg, 4.0mmol), 4- iodophenols (1.76g, 8.0mmol), copper acetate (100mg) is added in DMA (10mL), nitrogen protection, is then heated to 160 DEG C and is reacted 2 hours.React Finish, add ethyl acetate (50mL), washed successively with water (15mL) and saturated nacl aqueous solution (10mL), the anhydrous sulphur of organic phase Sour sodium is dried, and removes solvent, column chromatography (PE:EA=5:1) product 230mg, yield 21.5%, are obtained.
(2) 1- (4-((5- cyclopropyl-3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl)-1H- indoles- The preparation of 5- carboxylate methyl esters
Preparation method in the step of reference implementation example 1 (6), adds 1- (4- hydroxy phenyls) -1H- indole -5-carboxylic acid's methyl esters (230mg, 0.86mmol), 4- (bromomethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazoles (298mg, 0.86mmol), Obtain product 215mg, yield 46.8%.
(3) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- indoles - The preparation of 5- formic acid
The preparation method of the step of reference implementation example 1 (8), adds 1- (4-((5- cyclopropyl-3- (2,6- dichlorophenyl) Yi Evil Azoles -4- bases) methoxyl group) phenyl) -1H- indole -5-carboxylic acids methyl esters (215mg, 0.40mmol), obtain product 100mg, yield 47.8%.
Molecular formula：C28H20Cl2N2O4Molecular weight：519.4LC-MS(m/z):519.1(M+H)+
1H-NMR(400MHz,MeOD)δ:8.48(s,1H),7.84(dd,1H,J1=1.2Hz, J2=8.4Hz), 7.52- 7.54 (m, 2H), 7.28-7.49 (m, 5H), 6.98 (d, 2H, J=8.8Hz), 6.74 (d, 1H, J=1.2Hz), 4.97 (s, 2H),2.38-2.40(m,1H),1.18-1.25(m,4H).
The 1- of embodiment 3 (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation (compound 3) of benzo [d] imidazoles -5- formic acid
(1) 4- (the chloromethyl) -5- cyclopropyl -3- (preparations of 2,6- dichlorophenyl) isoxazoles
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methanol (1g, 3.52mmol) is dissolved in thionyl chloride In (25mL), oil bath heating is reacted 16 hours, TLC (petroleum ethers to 80 DEG C:Ethyl acetate=5:1) detection reaction is complete, vacuum Concentration, obtains title compound (1.02g, yield 96%).
(2) preparation of 4- ((4- methoxyphenyls) amino) -3- ethyl nitrobenzoates
The fluoro- 3- ethyl nitrobenzoates (2.13g, 10mmol) of 4- are dissolved in 1-METHYLPYRROLIDONE (25mL), hydrogen is added Change sodium (mass fraction 60%, 0.6g, 15mmol) and anisidine (1.23g, 10mmol), oil bath heating is to 100 DEG C, and reaction 16 is small When, TLC (petroleum ethers:Ethyl acetate=10:1) detection reaction is complete, is down to room temperature, add water (200mL), ethyl acetate (50mL × 2) extract, anhydrous sodium sulfate drying, it is concentrated in vacuo, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=10:1) purify, Obtain title compound (2.69g, yield 85%).
(3) preparation of 3- amino -4- ((4- methoxyphenyls) amino) ethyl benzoate
4- ((4- methoxyphenyls) amino) -3- ethyl nitrobenzoates (2.69g, 8.5mmol) are dissolved in methanol In (100mL), palladium charcoal (269mg) is added, leads to hydrogen and reacts 16 hours, TLC (petroleum ethers:Ethyl acetate=5:1) detection reaction Completely, palladium charcoal is filtered off, title compound (2.36g, yield 97%) is concentrated in vacuo to obtain.
(4) preparation of 1- (4- methoxyphenyls) -1H- benzos [d] imidazoles -5- Ethyl formates
3- amino -4- ((4- methoxyphenyls) amino) ethyl benzoate (2.36g, 8.24mmol) is dissolved in orthoformic acid three In ethyl ester (50mL), oil bath heating to 100 DEG C react 16 hours, TLC (petroleum ethers:Ethyl acetate=10:1) detection has been reacted Entirely, added water (100mL), ethyl acetate extraction (100mL × 2), and anhydrous sodium sulfate drying is concentrated in vacuo, crude product is through silica gel column layer Analyse (petroleum ether:Ethyl acetate=10:1) purify, obtain title compound (1.69g, yield 69%).
(5) preparation of 1- (4- hydroxy phenyls) -1H- benzos [d] imidazoles -5- Ethyl formates
By 1- (4- methoxyphenyls) -1H- benzos [d] imidazoles -5- Ethyl formates (1g, 3.37mmol), dichloromethane is dissolved in In alkane (10mL), Boron tribromide (1mol L dichloromethane solutions, 10.11mL, 10.11mmol) is added under ice bath, reaction 16 is small When, TLC (petroleum ethers:Ethyl acetate=1:1) detection reaction is complete, and add water (20mL), ethyl acetate extraction (50mL × 2), nothing Aqueous sodium persulfate is dried, and is concentrated in vacuo, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=1:1) purify, obtain product (381mg, yield 40%).
(6) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -5- Ethyl formates
1- (4- hydroxy phenyls) -1H- benzos [d] imidazoles -5- Ethyl formates (500mg, 1.77mmol) are dissolved in N, N- bis- In NMF (20mL), addition 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazoles (535.6mg, 1.77mmol), cesium carbonate (1.73g, 5.31mmol), is warming up to 100 DEG C and stirs 16 hours, TLC (petroleum ethers:Ethyl acetate= 5:1) detection reaction is complete, is concentrated in vacuo, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=5:1) purify, obtain product (651mg, yield 67%).
(7) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -5- formic acid
By 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos [d] Imidazoles -5- Ethyl formates (300mg, 0.547mmol) are dissolved in methanol/water (10mL/10mL), add a hydronium(ion) lithia (68.9mg, 1.641mmol), 25 DEG C are stirred 16 hours, watery hydrochloric acid regulation pH=2, separate out white solid, suction filtration, solid vacuum Dry, obtain title compound (169mg, yield 59.3%).
Molecular formula:C27H19Cl2N3O4Molecular weight:520.4LC-MS(m/z)：520.1(M+H)+
1H NMR(400MHz,DMSO-d6)δ:12.92(brs,1H),8.63(s,1H),8.30(s,1H),7.93-7.91 (m, 1H), 7.67-7.60 (m, 2H), 7.57-7.52 (m, 4H), 7.04 (d, J=8.8Hz, 2H), 4.97 (s, 2H), 1.22- 1.15(m,5H).
The 1- of embodiment 4 (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation (compound 4) of benzo [d] imidazoles -4- formic acid
(1) 4- (the bromomethyl) -5- cyclopropyl -3- (preparations of 2,6- dichlorophenyl) isoxazoles
By (5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methanol (1.65g, 5.8mmol) is dissolved in dichloromethane In alkane (20mL), phosphorus tribromide (3.14g, 11.6mmol) is added dropwise under ice bath, completion of dropping returns to 25 DEG C, continues reaction 4 small When.System is concentrated in vacuo, and crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=40:1) purify, obtain product (1.8g, yield 89.4%).
(2) preparation of the chloro- 2- ethyl nitrobenzoates of 3-
The chloro- 2- nitrobenzoic acids (6.8g, 33.7mmol) of 3- are added in ethanol (80mL), the concentrated sulfuric acid is then added (2mL), reacts 24 hours at 85 DEG C.Room temperature is cooled to, is concentrated in vacuo, water (100mL) and ethyl acetate (100mL) is added, Divide liquid, gained organic phase is concentrated in vacuo, and obtains title compound (6.0g, yield 77.5%).
(3) preparation of 3- ((4- methoxyphenyls) amino) -2- ethyl nitrobenzoates
By the chloro- 2- ethyl nitrobenzoates (3.22g, 14.0mmol) of 3-, P-nethoxyaniline (5.2g, 42.3mmol) and Cesium carbonate (13.7g, 42.0mmol) is added in Isosorbide-5-Nitrae-dioxane (100mL), and nitrogen protection is lower to add three (dibenzylidenes third Ketone) double (diphenylphosphine) -9,9- dimethyl xanthenes (1.61g, 2.8mmol) of two palladiums (1.3g, 1.42mmol) and 4,5-, 110 Reacted 24 hours at DEG C.Reaction solution is concentrated in vacuo, and crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=50:1) purify, obtain Title compound (1.0g, yield 22.6%).
(4) preparation of 2- amino -3- ((4- methoxyphenyls) amino) ethyl benzoate
Preparation process, with reference to the step of embodiment 3 (3).
(5) preparation of 1- (4- methoxyphenyls) -1H- benzos [d] imidazoles -4- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (4).
(6) preparation of 1- (4- hydroxy phenyls) -1H- benzos [d] imidazoles -4- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (5).
(7) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -4- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (6).
(8) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -4- formic acid
Preparation process, with reference to the step of embodiment 3 (7).
Molecular formula:C27H19Cl2N3O4Molecular weight:520.4LC-MS(m/z)：520.1(M+H)+
1H NMR(400MHz,DMSO-d6)δ:8.66(s,1H),7.90-7.80(m,1H),7.75-7.70(m,1H), 7.65-7.60(m,2H),7.58-7.50(m,3H),7.45-7.40(m,1H),7.08-7.01(m,2H),4.97(s,2H), 2.04-1.96(m,1H),1.20-1.10(m,4H).
The 1- of embodiment 5 (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation (compound 5) of benzo [d] imidazoles -6- formic acid
(1) preparation of the fluoro- 4- ethyl nitrobenzoates of 3-
Weigh the fluoro- 4- nitrobenzoic acids (5.0g, 27mmol) of 3- and be dissolved in ethanol (100mL), add the concentrated sulfuric acid (1mL), plus Heat is concentrated under reduced pressure to 80 DEG C of back flow reactions 16 hours, adds water (100mL) and ethyl acetate (100mL), point liquid, organic phase use Anhydrous sodium sulfate drying, filtering, filtrate concentration obtains title compound (5.1g, yield 88.5%).
(2) preparation of 3- ((4- methoxyphenyls) amino) -4- ethyl nitrobenzoates
By the fluoro- 4- ethyl nitrobenzoates (2.13g, 10mmol) of 3-, cesium carbonate (6.52g, 20mmol) and to methoxyl group Aniline (1.23g, 10mmol) is added in acetonitrile (60mL), and being warming up to 80 DEG C under nitrogen protection reacts 24 hours, and reaction solution is dense Contracting, adds water (100mL) and ethyl acetate (100mL), point liquid, organic phase anhydrous sodium sulfate drying, filtering, filtrate concentration, Crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=20:1) purify, obtain product (0.81g, yield 25.6%).
(3) preparation of 4- amino -3- ((4- methoxyphenyls) amino) ethyl benzoate
Preparation process, with reference to the step of embodiment 3 (3).
(4) preparation of 1- (4- methoxyphenyls) -1H- benzos [d] imidazoles -6- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (4).
(5) preparation of 1- (4- hydroxy phenyls) -1H- benzos [d] imidazoles -6- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (5).
(6) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -6- Ethyl formates
Preparation process, with reference to the step of embodiment 3 (6).
(7) 1- (4- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- benzos The preparation of [d] imidazoles -6- formic acid
Preparation process, with reference to the step of embodiment 3 (7).
Molecular formula:C27H19Cl2N3O4Molecular weight:520.36LC-MS(m/z)：520.1(M+H)+
1H NMR(400MHz,DMSO-d6)δ:8.60 (s, 1H), 7.99 (s, 1H), 7.87 (d, J=1.2Hz, 1H), 7.82-7.80 (m, 1H), 7.64-7.62 (m, 2H), 7.56-7.51 (m, 3H), 7.05 (d, J=8.8Hz, 2H), 4.98 (s, 2H),1.22-1.14(m,6H).
The 3- of embodiment 6 (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) benzene Base) -1H- Indole-6-carboxylic acids preparation (compound 6)
(1) preparation of the iodo- 1H- indole -6-carboxylic methyl esters of 3-
1H- indole -6-carboxylic methyl esters (5.26g, 30.0mmol) are added in DMF (40mL), added Potassium hydroxide (3.36g, 60.0mmol).Then the N,N-dimethylformamide solution of elemental iodine (8.0g, 31.5mmol) is added dropwise (10mL), completion of dropping is reacted 2 hours at 25 DEG C.System is poured into frozen water, separates out solid, is depressurized suction filtration, is obtained title compound 8.2g, yield 90.8%.
(1) preparation of 3- (2- chloro-4-methoxies phenyl) -1H- indole -6-carboxylic methyl esters
By the iodo- 1H- indole -6-carboxylic methyl esters (3.01g, 10mmol) of 3-, (2- chloro-4-methoxies phenyl) boric acid (2.05g, 11mmol), sodium carbonate (2.12g, 20mmol) and [1,1'- double (diphenylphosphine) ferrocene] palladium chloride (408mg, 0.56mmol) it is added in Isosorbide-5-Nitrae-dioxane (40mL) and water (4mL), lower 100 DEG C of nitrogen protection is reacted 12 hours.React Finish, add ethyl acetate (120mL), washed with saturated nacl aqueous solution (50mL), organic phase anhydrous sodium sulfate drying is dense Contracting, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) purify, obtain title compound 1.75g, yield 55.4%.
(3) preparation of 3- (2- chloro-4-hydroxyls phenyl) -1H- indole -6-carboxylic methyl esters
3- (2- chloro-4-methoxies phenyl) -1H- indole -6-carboxylic methyl esters (1.75g, 5.54mmol) are added to anhydrous In dichloromethane (20mL), the dichloromethane solution (1mol/L, 27.7mL, 27.7mmol) of Boron tribromide, drop are added dropwise under ice bath Add it is complete, be raised to 30 DEG C react 12 hours.System adds methanol (10mL) and is quenched, and is concentrated in vacuo, crude product is through silica gel column chromatography (two Chloromethanes:Methanol=50:1) purify, obtain title compound 1.2g, yield 71.7%.
(4) preparation of 3- (4- ((tert-butyl group dimethyl silyl) epoxide) -2- chlorphenyls) -1H- indole -6-carboxylic methyl esters
3- (2- chloro-4-hydroxyls phenyl) -1H- indole -6-carboxylic methyl esters (350mg, 1.16mmol) are added to dichloromethane In alkane (20mL), triethylamine (293mg, 2.9mmol) and DMAP (14mg, 0.115mmol) are added, is added portionwise Tert-butyl chloro-silicane (263mg, 1.74mmol), reacts 2 hours at 30 DEG C.System adds water (20mL), point liquid, organic Anhydrous sodium sulfate drying is mutually used, title compound is concentrated in vacuo to obtain, it is not purified to be directly used in next step.
(5) 1- tert-butyl groups 6- methyl 3- (4- ((tert-butyl group dimethyl silyl) epoxide) -2- chlorphenyls) -1H- indoles -1,6- two The preparation of carboxylate
3- (4- ((tert-butyl group dimethyl silyl) epoxide) -2- chlorphenyls) -1H- indole -6-carboxylic methyl esters (crude product) are dissolved in In dichloromethane (20mL), triethylamine (293mg, 2.9mmol) and DMAP (14mg, 0.115mmol) are added, point Criticize to add at di-tert-butyl dicarbonate (379mg, 1.74mmol), 30 DEG C and react 2 hours.System adds water (20mL), point liquid, has Machine mutually uses anhydrous sodium sulfate drying, is concentrated in vacuo to obtain title compound, not purified to be directly used in next step.
(6) preparation of 1- tert-butyl groups 6- methyl 3- (2- chloro-4-hydroxyls phenyl) -1H- indoles -1,6- dicarboxylic esters
By 1- tert-butyl group 6- methyl 3- (4- ((tert-butyl group dimethyl silyl) epoxide) -2- chlorphenyls) -1H- indoles -1,6- two Carboxylate is dissolved in tetrahydrofuran (10mL), is added anti-at 4-butyl ammonium fluoride trihydrate (726mg, 2.3mmol), 30 DEG C Answer 2 hours.System is concentrated in vacuo, and crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=3:1) purify, obtain title compound 340mg, three step yields 72.9%.
(7) 1- tert-butyl groups 6- methyl 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) first Epoxide) phenyl) -1H- indoles -1,6- dicarboxylic esters preparation
By the 1- tert-butyl group 6- methyl 3- (2- chloro-4-hydroxyls phenyl) -1H- indoles -1,6- dicarboxylic ester (340mg, 0.85mmol), 4- (chloromethyl) -5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazoles (326mg, 0.94mmol) and cesium carbonate (554mg, 1.70mmol) is added in DMF (10mL), and the preparation method of the step of reference implementation example 1 (6) must be marked Inscribe compound 400mg, yield 70.4%.
(8) 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation of methyl indole-6-carboxylate
Preparation method in the step of reference implementation example 1 (7), adds 1- tert-butyl group 6- methyl 3- (2- chloro- 4- ((5- rings third Base -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- indoles -1,6- dicarboxylic esters (400mg, 0.60mmol), title compound 300mg, yield 88.0% are obtained.
(9) 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- The preparation of Indole-6-carboxylic acid
By 3- (the chloro- 4- of 2- ((5- cyclopropyl -3- (2,6- dichlorophenyl) isoxazole -4-bases) methoxyl group) phenyl) -1H- Yin The aqueous solution (1mL) of diindyl -6- methyl formates (150mg, 0.26mmol) and lithium hydroxide monohydrate (55mg, 1.3mmol) adds Enter in methanol (3mL), be then heated to 30 DEG C and react 12 hours.Preparation method in the step of reference implementation example 1 (8) obtains titled Compound 90mg, yield 62.5%.
Molecular formula:C28H19Cl3N2O4Molecular weight:553.8LC-MS(m/z)：553.1(M+H)+
1H NMR(400MHz,DMSO-d6)δ:12.60 (brs, 1H), 11.70 (d, J=2.0Hz, 1H), 8.07 (s, 1H), 7.69-7.68 (m, 1H), 7.66-7.61 (m, 3H), 7.58-7.54 (m, 1H), 7.45-7.35 (m, 2H), 7.05 (d, J= 2.8Hz,1H),6.87-6.84(m,1H),4.95(s,2H),1.25-1.10(m,5H)。

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, C that is unsubstituted or being 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 or 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, C1-6Alkoxy, carboxyl C1-6Alkyl, carboxyl epoxide C1-6Alkyl, carboxyamino C1-6Alkyl, amino C1-6Alkyl, amino carbonyl Base C1-6Alkyl, hydroxyl C1-6Alkoxy, halo C1-6Alkoxy, carboxyl C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl ammonia Base, C1-6Alkyl-carbonyl, two C1-6Alkyl amino, 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 aryl or heteroaryl unsubstituted or 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 not is thiophene, and work as R that E, X, Y, F, which connect the group to be formed,3During for isopropyl, it is not benzene that E, X, Y, F, which connect the group to be formed, Ring or imidazoles；
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, C1-4Alkoxy, C1-4Alkyl, hydroxyl C1-4Alkane Base, halo C1-4Alkyl, carboxyl C1-4Alkyl, carboxyl epoxide C1-4Alkyl, carboxyamino C1-4Alkyl, amino C1-4Alkyl, amino carbonyl Base C1-4Alkyl, 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 unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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 or O；
F be selected from be not present, C, CH, CH2, N, NH, CO or O；
X is selected from C, CH or N；
Y is selected from C, CH, CH2, N, NH, CO or O；
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；
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 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 unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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, benzoxazolyl, 4H- chromogens alkenyl, benzofuranyl, benzo 1,4- dioxies Heterocycle hexadienyl, benzo 4H-1,4- oxazinyls, benzo 4H-1,2- oxazinyls, benzo 4H-1,3- oxazinyls, dihydro cinnolines It is base, quinazolyl, dihydroquinazoline base, quinolyl, EEDQ base, isoquinolyl, dihydro-isoquinoline base, quinoline ketone group, different Quinoline ketone group, benzo dihydro pyrazine base, benzopyrazines base, ihydro naphthyl, indyl, benzimidazolyl, benzopyrazoles base, benzo Triazolyl or isoindolyl；
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, butyl, methoxyl group, methylamino, 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, methoxyl group, ethoxy Base, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl or diformazan ammonia Base；
Z is selected from unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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.
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, acetyl group or acetylamino；
W is selected from NH, O or S；
A is selected from NH, O or S；
Z be selected from phenyl that is unsubstituted or being replaced by one or more substituent Q, pyrrole radicals, pyrazolyl, imidazole radicals, furyl, Pyridine radicals, pyrimidine radicals, thienyl, thiazolyl, oxazolyls；
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.
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, trifluoromethyl or trifluoromethoxy；
R3Selected from cyclopropyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, trifluoromethyl, trifluoromethoxy, acetyl group Or acetylamino；
W is selected from O or S；
A is selected from O or S；
Z is selected from phenyl that is unsubstituted or being replaced by one or more substituent Q；
Q be selected from cyano group, amino, hydroxyl, carboxyl, nitro, fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, propyl group, methoxyl group, Ethyoxyl, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy；
The cyclic group that E, X, Y, F are collectively formed forms following structure together with phenyl ring：
N is selected from 1.
7. compound as claimed in claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, 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, isobutyl group, the tert-butyl group, butyl, methoxyl group, methylamino, dimethylamino, acetyl group, fluoroform Base, trifluoroethyl or trifluoromethoxy；
R3Selected from cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, hydroxyl, carboxyl, methyl, ethyl, propyl group, methoxyl group, ethoxy Base, trifluoromethyl, trifluoromethoxy, acetenyl, methylamino, ethylamino, acetyl group, acetylamino, mesyl or diformazan ammonia Base；
W is selected from NH, O or S；
A is selected from NH, O or S；
N is selected from 0-2 integer；
Z is selected from unsubstituted or by one or more substituent Q phenyl replaced or 5-6 unit's heteroaryls；
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；
X is selected from C, CH or N；
Y is selected from CH or N；
F is selected from CH, CH2, N or NH；
Connected mode between X, Y, F is separately selected from singly-bound or double bond；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, acetyl group or acetylamino；
W is selected from O；
A is selected from O；
Z is selected from phenyl that is unsubstituted or being replaced by 1-2 substituent Q；
Q is selected from cyano group, amino, hydroxyl, carboxyl, nitro, halogen atom, methyl, ethyl, propyl group, methoxyl group, ethyoxyl, first ammonia Base, dimethylamino, trifluoromethyl or trifluoromethoxy；
The cyclic group that X, Y, F are collectively formed forms following structure together with phenyl ring：
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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