CN104513213A - Fxr agonist - Google Patents

Fxr agonist Download PDF

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CN104513213A
CN104513213A CN201410493612.9A CN201410493612A CN104513213A CN 104513213 A CN104513213 A CN 104513213A CN 201410493612 A CN201410493612 A CN 201410493612A CN 104513213 A CN104513213 A CN 104513213A
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alkyl
methyl
hydrogen
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amino
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张艳
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
KBP Biosciences Co Ltd
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SHANDONG HENRY MEDICAL SCIENCE AND TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a farnesoid X receptor (FXR) agonist represented by the general formula (I), and a pharmaceutically acceptable salt, an enantiomer, a diastereomer, a tautomer or a solvate thereof, preparing methods of the compounds, pharmaceutical compositions and pharmaceutical preparations containing the compounds, and an application of the compounds in preparation of drugs for treatment and/or prevention of FXR mediated diseases, wherein in the formula (I), R<1>, R<2>, R<3>, R<4>, m, n, p, q, T, L1-L2, an A ring or a B ring are defined in the specification.

Description

FXR agonist
1, technical field
The invention belongs to medical art, relate to FXR agonist, its pharmacy acceptable salt, its enantiomer, diastereomer, tautomer or solvate, the preparation method of these compounds, pharmaceutical composition containing these compounds and pharmaceutical preparation, and these compounds treat and/or prevent the application in the medicine of the disease of FXR mediation in preparation.
2, background technology
Farnesoid X receptor (farnesoid X receptor, FXR) was found as a kind of orphan nuclear receptor in nineteen ninety-five, and its name comes from this receptor and can be activated by the farnesol of physiological levels.FXR belongs to member in nuclear receptor family, and existing Uniform Name is NR1H4 (nuclear receptor subfamily 1, group H, member 4).FXR is mainly distributed in the histoorgans such as liver, small intestine, kidney and suprarenal gland.
1999,3 research groups found that bile acide (bile acids) can activate FXR under physiological concentration simultaneously independently, thus proved that FXR is the acceptor of bile acide.Bile acide has different physiological roles, plays an important role in the process such as running balance of fat and the absorption of liposoluble vitamin, transhipment, distribution and cholesterol.FXR is as the acceptor of bile acide, and the genetic expression being participated in bile acide by regulation and control maintains bile acide balance in vivo.Also find, FXR also plays critical function in the running balance and insulin resistant etc. of glucose.Therefore, FXR is expected to for the treatment of the diseases such as hypercholesterolemia, gall stone, hypertriglyceridemia, cholestasis hepatopathy and diabetes provides new direction.
In recent years find that the multiple primary and secondary bile acide of physiological concentration can activate FXR, wherein gallodesoxycholic acid (chenodexycholic acid, CDCA) the most aptamers that is FXR.2002, (6 α-Ethyl-chenodeoxycholic the acid (6ECDCA) such as Pellicciari, a potent and selective FXR agonist endowed withanticholestatic activity.J Med Chem, 2002,45:3569-3572.) report first high reactivity steroid FXR part 6-ethyl gallodesoxycholic acid (6ECDCA) synthesized.(the Identification of a chemical toolfor the orphan nuclear receptor FXR.J Med Chem such as Maloney in 2000,2000,43:2971-2974) report first highly active non-steroidal FXR agonist GW4064, GW4064 has high reactivity to FXR and highly selective, just becomes the instrument compound exploring FXR function after it is found.Although GW4064 on average has very high FXR agonist activity in extracellular and cellular water, its structure contains toluylene group, has genotoxic potential.In recent years, in order to optimize GW4064, multiple derivative is in the news in succession.
3, summary of the invention
For meeting clinical demand, the invention provides the medicine that a class treats the disease mediated by FXR, concrete technical scheme is as follows:
Logical compound shown in formula I or its pharmacy acceptable salt:
Wherein, R 1for hydrogen, halogen, cyano group, amino, C 1-6alkyl ,-(CH 2) g-C 3-8cycloalkyl or C 1-6alkoxyl group, wherein C 1-6alkyl is optionally by 1-3 independent selected from halo, hydroxyl or C 1-6the group of alkoxyl group replaced,
R 2for hydrogen, halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group,
T is-O-,-S-,-C (R 5) (R 6)-or-N (R 5)-, R 5and R 6independently be hydrogen, C 1-6alkyl or C 3-8cycloalkyl, wherein said C 1-6alkyl or C 3-8cycloalkyl can be replaced by 1-5 fluorine atom,
A ring and B ring independently be 6-14 unit aryl, 5-14 unit heteroaryl, C 3-14the heterocyclic radical of the saturated and/or fractional saturation of cycloalkyl or 3-14 unit,
L 1-L 2for-C (R 8)=C (R 8)-,-R 7-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-O-R 7-,-R 7-O-,-C (O)-R 7-,-S-R 7-,-R 7-S-,-S (O) f-R 7-,-R 7-S (O) f-,-S (O) fn (R 8-S)-, (O) f-R 7-N (R 8)-,-N (R 8) S (O) f-, wherein R 7and R 8independently be selected from hydrogen or C 1-6alkyl, f is the integer of 0-2,
R 3for hydrogen, halogen, amino, C 1-6alkyl amine group, two (C 1-6alkyl) amido, C 1-6alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-6alkyl, cyano group, nitro, azido-, carboxyl, C 2-6alkenyl, C 2-6alkynyl, C 3-6cycloalkyl, C 1-6alkyl, halo C 1-6alkyl, amino-sulfonyl, amino-sulfonyl C 1-6alkyl, formamyl, formamyl C 1-6alkyl, C 1-6alkyl-carbonyl or C 1-6alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-6alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-6alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkylidene group-R 12, SO 2-C 1-6alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p, g and q independently be 0 ~ 5 integer.
Technical solution of the present invention is preferably:
Wherein, R 1for hydrogen, halogen, cyano group, amino, C 1-6alkyl ,-(CH 2) g-C 3-8cycloalkyl or C 1-6alkoxyl group, wherein C 1-6alkyl is optionally by 1-3 independent selected from halo, hydroxyl or C 1-6the group of alkoxyl group replaced,
R 2for hydrogen, halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group,
T is-O-,
A ring and B ring independently be 6-14 unit aryl, 5-14 unit heteroaryl, C 3-14the heterocyclic radical of the saturated and/or fractional saturation of cycloalkyl or 3-14 unit,
L 1-L 2for-C (R 8)=C (R 8)-,-R 7-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-O-R 7-,-R 7-O-,-C (O)-R 7-,-S-R 7-,-R 7-S-,-S (O) f-R 7-,-R 7-S (O) f-,-S (O) fn (R 8-S)-, (O) f-R 7-N (R 8)-,-N (R 8) S (O) f-, wherein R 7and R 8independently be selected from hydrogen or C 1-6alkyl, f is the integer of 0-2,
R 3for hydrogen, halogen, amino, C 1-6alkyl amine group, two (C 1-6alkyl) amido, C 1-6alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-6alkyl, cyano group, nitro, azido-, carboxyl, C 2-6alkenyl, C 2-6alkynyl, C 3-6cycloalkyl, C 1-6alkyl, halo C 1-6alkyl, amino-sulfonyl, amino-sulfonyl C 1-6alkyl, formamyl, formamyl C 1-6alkyl, C 1-6alkyl-carbonyl or C 1-6alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-6alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-6alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkylidene group-R 12, SO 2-C 1-6alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p, g and q independently be 0 ~ 5 integer.
Technical solution of the present invention is more preferably:
Wherein, R 1for hydrogen, C 1-6alkyl or C 3-8cycloalkyl,
R 2for hydrogen, halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group,
A ring and B ring independently be 6-14 unit aryl, 6-14 unit heteroaryl, C 3-8the heterocyclic radical of the saturated and/or fractional saturation of cycloalkyl or 3-8 unit,
L 1-L 2for-C (R 8)=C (R 8)-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-C (O)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-6alkyl,
R 3for hydrogen, halogen, amino, C 1-6alkyl amine group, two (C 1-6alkyl) amido, C 1-6alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-6alkyl, cyano group, nitro, azido-, carboxyl, C 2-6alkenyl, C 2-6alkynyl, C 3-6cycloalkyl, C 1-6alkyl, halo C 1-6alkyl, amino-sulfonyl, amino-sulfonyl C 1-6alkyl, formamyl, formamyl C 1-6alkyl, C 1-6alkyl-carbonyl or C 1-6alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-6alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-6alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkylidene group-R 12, SO 2-C 1-6alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p and q independently be 0 ~ 5 integer.
Technical solution of the present invention is more more preferably:
Wherein, R 1for hydrogen, C 1-4alkyl or C 3-6cycloalkyl,
R 2for hydrogen, halogen, C 1-4alkyl, halo C 1-4alkyl, C 1-4alkoxyl group or halo C 1-4alkoxyl group,
A ring and B ring independently be pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, 3-cyclohexadiene, Pyrrolidine, 2, 3-pyrrolin, 2, 5-pyrrolin, pyrroles, azetidine, imidazoles, 4, 5-glyoxalidine, pyrazoles, 4, 5-pyrazoline, 1, 2, 3-triazole, 1, 2, 4-triazole, tetramethylene sulfide, thiophene, 2, 3-dihydro-thiophene, thiazole, 4, 5-thiazoline, isothiazole, 1, 2, 4-thiadiazoles, tetrahydrofuran (THF), 2, 3-dihydrofuran, furans, 4, 5-dihydro-oxazole, oxazole, 4, 5-dihydro-isoxazole, isoxazole, 1, 2, 4-oxadiazole, phenyl ring, 1, 4, 5, 6-tetrahydropyrimidine, 1, 6-dihydro-pyrimidin, 4, 5-dihydro-pyrimidin, 2-pyridone, 4-pyridone, pyrimidine, 3, 6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1, 2, 3, 4-tetrahydropyridine, 1, 2, 3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1, 2, 3, 4-tetrahydrochysene pyrazine, 2, 3-dihydro pyrazine or pyrazine,
L 1-L 2for-C (R 8)=C (R 8)-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-C (O)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-4alkyl,
R 3for hydrogen, halogen, amino, C 1-4alkyl amine group, two (C 1-4alkyl) amido, C 1-4alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-4alkyl, cyano group, nitro, azido-, carboxyl, C 1-4alkyl, C 2-4alkenyl, C 2-4alkynyl, C 3-6cycloalkyl, halo C 1-4alkyl, amino-sulfonyl, amino-sulfonyl C 1-4alkyl, formamyl, formamyl C 1-4alkyl, C 1-4alkyl-carbonyl or C 1-4alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-4alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-4alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-4alkyl, halo C 1-4alkyl, C 1-4alkylidene group-R 12, SO 2-C 1-4alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p and q independently be 0 ~ 3 integer.
Technical solution of the present invention is further preferably:
Wherein, R 1for hydrogen, C 1-4alkyl or C 3-6cycloalkyl,
R 2for hydrogen, halogen, C 1-4alkyl or halo C 1-4alkyl,
A ring and B ring independently be phenyl ring, pyridine, hexanaphthene, thiophene, 1,2,4-oxadiazole, pentamethylene, piperidines, Pyrrolidine, azetidine, furans, pyrroles, imidazoles, pyrazoles, thiazole, isothiazole, 1,2,4-thiadiazoles, tetrahydrofuran (THF), isoxazole, 2-pyridone, 4-pyridone, 1,2,4-triazole or piperazine
L 1-L 2for-C (R 8)=C (R 8)-or-N (R 8)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-4alkyl,
R 3for hydrogen, halogen, C 1-4alkyl or halo C 1-4alkyl,
R 4for hydrogen, halogen, C 1-4alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-4alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl or C 1-4alkyl,
M, n, p and q independently be 0 ~ 2 integer.
Technical solution of the present invention is particularly preferably:
Wherein, R 1for propyl group, sec.-propyl or cyclopropane base,
R 2for hydrogen, fluorine atom, chlorine atom or methyl,
A ring is phenyl ring or pyridine,
B ring is phenyl ring or hexanaphthene,
L 1-L 2for-CH=CH-,-NHCH 2-,-N (CH 3) CH 2-or-N (CH 2cH 3) CH 2-,
R 3for hydrogen, chlorine atom or trifluoromethyl,
R 4for hydrogen, fluorine atom, chlorine atom, methyl ,-COOH ,-CONHOH or tetrazyl,
M is 0,
N is 2,
P is 0 or 1,
Q is 0,1 or 2.
Detailed Description Of The Invention
" halogen " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, atomic iodine etc.Preferred fluorine atom and chlorine atom.
" C of the present invention 1-6alkyl " represent straight or branched containing the alkyl of 1-6 carbon atom; as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1; 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc.Preferred C 1-4alkyl." C of the present invention 1-4alkyl " refer to containing 1-4 carbon atom above-described embodiment.
" C of the present invention 2-6alkenyl " refer to containing double bond carbonatoms and be the thiazolinyl of the straight or branched of 2-6, as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene base, 1,3-pentadiene base, Isosorbide-5-Nitrae-pentadienyl, 2,4-pentadienyl, Isosorbide-5-Nitrae-hexadienyl, 2,4-hexadienyl etc.Double bond is optionally cis and trans.
" C of the present invention 2-6alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 2-6, as ethynyl, 1-proyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 4-methyl-valerylene base, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention 1-6alkoxyl group " refer to " C 1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, 1-methyl ethoxy, butoxy, 1-methyl propoxy-, 2-methyl propoxy-, 1, 1-dimethylethyloxy, pentyloxy, 1-methylbutoxy group, 2-methylbutoxy group, 3-methylbutoxy group, 1, 1-dimethyl propoxy-, 1, 2-dimethyl propoxy-, 2, 2-dimethyl propoxy-, 1-ethylpropoxy, hexyloxy, 1-methyl pentyloxy, 2-methyl pentyloxy, 3-methyl pentyloxy, 4-methyl pentyloxy, 1, 1-dimethyl butoxy, 1, 2-dimethyl butoxy, 1, 3-dimethyl butoxy, 2, 2-dimethyl butoxy, 2, 3-dimethyl butoxy, 3, 3-dimethyl butoxy, 1-ethyl-butoxy, 2-ethyl-butoxy, 1, 1, 2-trimethylammonium propoxy-, 1, 2, 2-trimethylammonium propoxy-, 1-ethyl-1-methyl propoxy-and 1-Ethyl-2-Methyl propoxy-.Term " C 1-4alkoxyl group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" halo " of the present invention refer to atom that in described group, any one can be substituted replace by halogen, can perhalogeno, i.e. all positions that can be substituted in halogen atom substituent group.
" C of the present invention 1-6haloalkyl " refer to term " C 1-6alkyl " hydrogen atom replaced by one or more halogen atom, halogen is as mentioned before.
" C of the present invention 1-6halogenated alkoxy " refer to term " C 1-6alkoxyl group " hydrogen atom replaced by one or more halogen atom, halogen is as mentioned before.
" C of the present invention 3-14cycloalkyl " refer to that the paraffin section containing 3-14 carbon atom removes the derivative cyclic alkyl of a hydrogen atom, comprise 3-8 unit monocyclic cycloalkyl, 6-14 unit also ring cycloalkyl, 5-12 unit's bridged ring base and 5-12 unit volution base.Preferred C 3-8cycloalkyl, C 3-6cycloalkyl and C 5-6cycloalkyl.Term " C 3-8cycloalkyl ", " C 3-6cycloalkyl ", " C 5-6cycloalkyl " be respectively in following example containing 3-8,3-6, the specific examples of a 5-6 carbon atom.
3-8 unit monocyclic cycloalkyl, comprises the 3-8 saturated monocyclic cycloalkyl of unit and 3-8 unit fractional saturation monocyclic cycloalkyl.The saturated monocyclic cycloalkyl of 3-8 unit, refer to that this monocycle is all saturated carbocyclic ring, the example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc.3-8 unit fractional saturation monocyclic cycloalkyl, refer to that this monocycle is the carbocyclic ring of fractional saturation, the example includes but are not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc.;
6-14 unit ring cycloalkyl, refer to and share by two or more ring texturees the 6-14 cyclic group that two adjacent carbon atoms are formed each other, comprises the saturated and ring cycloalkyl of 6-14 unit and 6-14 unit's fractional saturation and ring cycloalkyl.Preferred 6-12 unit also ring cycloalkyl, 6-10 unit also ring cycloalkyl.Saturated and the ring cycloalkyl of 6-14 unit, refer to that this and cyclic group are all saturated carbocyclic ring, the example includes but not limited to: two rings [3.1.0] hexyl, two rings [4.1.0] heptane base, two rings [2.2.0] hexyl, two rings [3.2.0] heptane base, two rings [4.2.0] octyl, octahydro pentalene base, octahydro-1H-indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation ring cycloalkyl, refers to this and in ring, at least one ring is the carbocyclic ring of fractional saturation, and the example includes but not limited to: oneself-2-thiazolinyl, dicyclo [4.1.0]-3-in heptan thiazolinyl, dicyclo [3.2.0]-3-in heptan thiazolinyl, pungent-3-thiazolinyl of dicyclo [4.2.0], 1,2 of dicyclo [3.1.0], 3,3a-tetrahydrochysene pentalene base, 2,3,3a, 4,7,7a-six hydrogen-1H-indenyl, 1,2,3,4,4a, 5,6, the octahydro naphthyl of 8a-, 1,2,4a, 5,6,8a-hexahydro-naphthyl, 1,2,3,4,5,6,7,8,9,10-decahydro phenanthryl etc.;
5-12 unit bridged ring base, refers to that any two rings share the structure containing 5-12 carbon atom of the atom formation be neither directly connected, and " 5-12 unit bridged ring " comprises the saturated bridged ring base of 5-12 unit, 5-12 unit fractional saturation bridged ring base.The saturated bridged ring base of 5-12 unit, the saturated bridged ring base of preferred 6-10 unit, includes but are not limited to dicyclo [2.1.1] hexyl, dicyclo [2.2.1] heptane base, dicyclo [3.2.1] heptane base, dicyclo [2.2.2] octyl, dicyclo [3.2.1] octyl, dicyclo [3.3.1] octyl, dicyclo [3.3.1] nonyl, dicyclo [4.3.1] nonyl, 4-azabicyclo [5.3.1] decyl etc.5-12 unit fractional saturation bridged ring base, referring in this bridged ring to have has at least a ring to be undersaturated cyclic group, be preferably 6-10 unit fractional saturation bridged ring base, specific examples includes but not limited to dicyclo [2.2.1]-5-in heptan thiazolinyl, dicyclo [3.2.1] oct-6-ene base, dicyclo [4.3.1]-5-in ninth of the ten Heavenly Stems thiazolinyl, bicyclic pentadiene etc.; Preferred 7-10 unit bridged ring base, comprises " the saturated bridged ring base of 7-10 unit " and " 7-10 unit fractional saturation bridged ring base ".
5-12 unit volution base, refers to that a class has at least two rings to share the 5-12 unit condensed cyclic structure of an atom formation, comprises the saturated volution base of 5-12 unit, 5-12 unit fractional saturation volution base.。The saturated volution base of 5-12 unit, refer to that all rings in this volution base are saturated cyclic group, specific examples includes but are not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.5-12 unit fractional saturation volution base, refer in this volution base and have at least a ring to be undersaturated cyclic group, specific examples includes but are not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.Preferred 7-10 unit volution base, comprises " the saturated volution base of 7-10 unit " and " 7-10 unit fractional saturation volution base ".
" 6-14 unit aryl " of the present invention refers to that annular atoms is the cyclic aromatic groups of 6-14 unit carbon atom, comprises 6-8 unit's monocyclic aryl and 8-14 unit fused ring aryl.6-8 unit monocyclic aryl refers to whole undersaturated aryl, such as phenyl, cyclooctatetraenyl etc.8-14 unit fused ring aryl refers to and to be shared by two or more ring texturees that two adjacent carbon atoms are formed each other, a ring is had at least to be the cyclic group of whole undersaturated aromatic nucleus, comprise the whole unsaturated fused ring aryl of 8-14 unit, naphthyl, anthryl and phenanthryl etc., also comprise 8-14 unit fractional saturation fused ring aryl, the such as saturated monocyclic cycloalkyl of benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.Preferred 6-10 unit aryl, term " 6-10 unit aryl " refers to that in above-mentioned " aryl ", annular atoms number is the specific examples of 6-10.The saturated monocyclic cycloalkyl of preferred benzene or benzo 3-8 unit, benzo 3-8 unit fractional saturation monocyclic cycloalkyl further.
Described " 5-14 unit heteroaryl ", its annular atoms, except carbon atom, also comprises one or more heteroatoms, and described " heteroatoms " includes but not limited to Sauerstoffatom, nitrogen-atoms and sulphur atom.Heteroaryl is by carbon or heterocyclic atom bonding.Comprise 5-8 unit's bicyclic heteroaryl and 8-14 unit fused heterocycle aryl.5-8 unit bicyclic heteroaryl includes but not limited to pyrryl, imidazolyl, pyrazolyl, 1, 2, 3-triazol radical, 1, 2, 4-triazol radical, pyridyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 3-thiadiazolyl group, 1, 2, 4-thiadiazolyl group, 1, 3, 4-thiadiazolyl group, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, tetrazyl, oxatriazole base, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 2H-1, 3-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 2H-1, 4-oxazinyl, 4H-1, 4-oxazinyl, Yi oxazinyl, pyridazinyl, pyrimidyl and pyrazinyl etc., 8-14 unit fused heterocycle aryl includes but not limited to benzofuryl, isobenzofuran-base, benzothienyl, indyl, pseudoindoyl, quinolyl, isoquinolyl, indolizine base, indazolyl, phthalazinyl, quinoxalinyl, quinazolyl, benzodiazine base, benzoisoxazole base, benzoxazinyl, benzimidazolyl-, pyridopyridine base, pyrazolo [3,4-b] pyridyl, purine radicals, acridyl and xanthenyl etc.
" heterocyclic radical of the saturated and/or fractional saturation of 3-14 unit " of the present invention refers to that described " heteroatoms " refers to N, S, O, SO and/or SO containing one or more heteroatomic 3-14 cyclic group 2deng, what comprise saturated, fractional saturation has 1-4 and is selected from N, S, O, SO and/or SO 2the two heterocyclic radical of the heteroatomic 3-8 single heterocyclic radical of unit and 5-14 unit.The two heterocyclic radical of 5-14 unit comprises having 1-4 and being selected from N, S, O, SO and/or SO of saturated, fractional saturation 2heteroatomic and ring, volution, bridged ring.The single heterocyclic radical of preferred 3-8 unit, the further single heterocyclic radical of 3-8 unit of preferred saturated, fractional saturation.More preferably the single heterocyclic radical of 5-8 unit, the single heterocyclic radical of 5-7 unit, the single heterocyclic radical of 5-6 unit, the further single heterocyclic radical of 5-8 unit, the single heterocyclic radical of 5-7 unit, the single heterocyclic radical of 5-6 unit of preferred saturated, fractional saturation.
The single heterocyclic radical of 3-8 unit, refers to the monocyclic heterocycles base containing 3-8 annular atoms (wherein at least containing a heteroatoms), comprises 3-8 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 3-8 unit.Preferred 5-7 unit fractional saturation list heterocyclic radical, the saturated single heterocyclic radical of 5-7 unit.3-8 unit fractional saturation list heterocyclic radical, refer to containing double bond, heteroatomic cyclic group, specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline bases, 3,4-dihydro-2H-pyranyls, 5,6-dihydro-4H-1,3-oxazinyl etc.The saturated single heterocyclic radical of 3-8 unit, refer to be all saturated bond containing heteroatomic cyclic group, specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
Described " have 1-4 and be selected from N, S, O and/or SO 2heteroatomic and ring, volution, bridged ring ", specifically refer to and a non-common carbon atom in ring, volution, bridged ring by N, S, O and/or SO 2heteroatoms substitute formed 6-14 unit and heterocyclic radical, 5-12 unit spiro heterocyclic radical, 5-12 unit bridge heterocyclic radical.
6-14 unit heterocyclic radical refer to containing 6-14 annular atoms (wherein at least containing a heteroatoms) by two or more ring texturees share each other two adjacent atoms couple together is formed and ring structure, comprise the first fractional saturation of 6-14 and the first saturated and heterocyclic radical of heterocyclic radical, 6-10.6-14 unit fractional saturation heterocyclic radical, refer to the condensed cyclic structure at least containing a fractional saturation ring, as the structure that benzo 3-8 unit fractional saturation list heterocyclic radical is formed, the structure etc. that 3-8 unit's fractional saturation list heterocyclic radical 3-8 unit fractional saturation list heterocyclic radical are formed, specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1,2,3,4-Pyrrolidine also [3,4-c] pyrroles, etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.Saturated and the heterocyclic radical of 6-10 unit, refer to that whole rings is saturated condensed cyclic structure, as the 3-8 saturated single heterocyclic radical of unit and the saturated single heterocyclic radical of 3-8 unit the structure that formed, specific examples includes but are not limited to: tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl, etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-12 unit bridge heterocyclic radical refers to the caged scaffold formed by 5-12 annular atoms (wherein at least containing a heteroatoms)." 5-12 unit bridge heterocyclic radical " comprises the saturated bridge heterocyclic radical of 5-12 unit, 5-12 unit fractional saturation bridge heterocyclic radical.
The saturated bridge heterocyclic radical of 5-12 unit, refers to that all rings in this bridge heterocycle are saturated cyclic group, and be preferably the saturated bridge heterocyclic radical of 7-8 unit, specific examples includes but not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-12 unit fractional saturation bridge heterocyclic radical, refers in this bridge heterocycle to have to have at least a ring to be undersaturated cyclic group, and be preferably 7-8 unit fractional saturation bridge heterocyclic radical, specific examples includes but not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-12 unit spiro heterocyclic radical refers to the spirane structure formed by 5-12 annular atoms (wherein at least containing a heteroatoms)." 5-12 unit spiro heterocyclic radical " comprises the saturated spiro heterocyclic radical of 5-12 unit, 5-12 unit fractional saturation spiro heterocyclic radical.
The saturated spiro heterocyclic radical of 5-12 unit, refer to that all rings in this spiroheterocyclic are saturated cyclic group, specific examples includes but are not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
5-12 unit fractional saturation spiro heterocyclic radical, refer in this spiroheterocyclic and have at least a ring to be undersaturated cyclic group, specific examples includes but are not limited to: etc. the group etc. that any commutable hydrogen atom of ring texture replacement is formed.
Term " heterocyclic radical of the saturated and/or fractional saturation of 3-8 unit " refers to that in above-mentioned " heterocyclic radical of the saturated and/or fractional saturation of 3-14 unit ", annular atoms number is the specific examples of 3-8 unit.
Particularly preferred compound comprises:
Above-claimed cpd of the present invention can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
Reaction equation:
Reactions steps:
Step 1: raw material 1 is dissolved in ether solvent (as tetrahydrofuran (THF), ether), add Lithium Aluminium Hydride under cooling, room temperature reaction disappears to raw material, cancellation is reacted, and is separated to obtain intermediate 1 through silicagel column.Also can use alcoholic solvent (as methyl alcohol, ethanol), reductive agent is sodium borohydride, and room temperature is to reacting by heating.
Step 2: intermediate 1 is dissolved in inert solvent (as methylene dichloride), add large excessive thionyl chloride (or other chlorinating agents are as phosphorus trichloride), stirred at ambient temperature disappears to raw material, and concentrate system obtains intermediate 2.
Step 3: intermediate 2, raw material 2 are dissolved in polar solvent (as DMF, DMA, acetone etc.), add alkali (as salt of wormwood) and catalytic amount to potassiumiodide (or sodium iodide) stirred at ambient temperature of equivalent to disappear to raw material, add water cancellation, extraction, is separated to obtain intermediate 3 through silicagel column.Also directly intermediate 3 can be obtained by reacting with intermediate 1 and raw material 2 at Mitsunobu reaction conditions (diazonium dicarboxylic acid esters, triphenylphosphine).
Step 4: condition 1: intermediate 3, raw material 3 are obtained formula I in Horner-Wittig reaction conditions (sodium hydride, ether solvent) docking.
Condition 2: intermediate 3, raw material 3 are obtained formula I in Reductive-Amination reaction conditions (acetic acid, sodium borohydride or sodium triacetoxyborohydride) docking.
Raw material 1 in above reaction equation, raw material 2 obtain through simple functional group conversions by the raw material that is easy to get.R in above reaction equation 1, R 2, R 3, R 4, m, n, p, q, T, L 1-L 2, A ring or B ring as defined hereinabove.
Compound of the present invention comprises the compound of any form such as free form, salt form, solvate forms and salt and solvate forms.
Root Ju on the other hand, the invention provides the compounds of this invention of salt and/or solvate forms.
Described salt preferably includes pharmacy acceptable salt, although such as in order to prepare, be separated, the object of purifying also comprises pharmaceutically unacceptable salt.
The salt of the compounds of this invention comprises alkali salt or acid salt.Pharmaceutically acceptable alkali salt comprises the salt of ammonium salt such as leptodactyline, an alkali metal salt such as sodium and potassium, the salt of alkaline earth salt such as calcium and magnesium and the salt of organic bases, comprise primary, secondary, tertiary amine such as Isopropylamine, diethylamine, thanomin, three Yue amine, dicyclohexyl amine and N-methyl-D-glucarnine salt, particular certain cancers.
Acid salt can be pharmacologically acceptable salt or non-pharmacologically acceptable salt.When being non-pharmacologically acceptable salt, it can be used for abstraction and purification the compounds of this invention or its intermediate, and then changes into pharmacologically acceptable salt or free alkali.Pharmaceutically acceptable acid additive salt comprises " Journal of Pharmaceutical Sciences " (J.Pharm.Sci), the salt described in 1977,66,1-19.Described acid is such as hydrogen fumaric acid (hydrogen fumaric acid), fumaric acid, tartrate, ethane-1,2-disulfonic acid, toxilic acid, naphthalene 1,5-sulfonic acid, acetic acid, toxilic acid, succsinic acid, Whitfield's ointment, nonane diacid, 2-[(2,6-dichlorophenyl) is amino] toluylic acid, hydrochloric acid, deuterium chloric acid (deuterochloric aid); Preferred hydrochloric acid.
" pharmacy acceptable salt " of the compounds of this invention refers to the base addition salt that the compounds of this invention and pharmaceutically acceptable, non-toxic alkali or acid are formed or acid salt, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.Organic acid salt comprises formate, acetate, propionic salt, benzene sulfonate, benzoate, tosilate, 2, 3-dyhydrobutanedioic acid salt, camsilate, Citrate trianion, mesylate, esilate, propanesulfonic acid salt, fumarate, gluconate, glutaminate, isethionate, lactic acid salt, maleate, malate, mandelate, mucate, embonate, pantothenate, succinate, tartrate etc., particularly preferably benzoate, benzene sulfonate, tosilate, mesylate, Citrate trianion, maleate, fumarate, tartrate.Inorganic acid salt comprises hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate etc., particularly preferably hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt.Organic alkali salt comprises amine salt, comprise and primary, the second month in a season and tertiary amine, the salt that cyclammonium and basic ion-exchange resins are formed, the salt formed with following organic bases can be selected from: such as arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine and Trometamol etc.Inorganic base salts comprises the salt formed with ammonia, basic metal, alkaline-earth metal, such as ammonium salt and lithium salts, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, barium salt, aluminium salt, molysite, mantoquita, ferrous salt, manganese salt, manganous salt, particularly preferably ammonium salt and sodium salt, sylvite, calcium salt, magnesium salts.
The compounds of this invention of free form can be changed into the respective compound of salt form, vice versa.The compounds of this invention of free form or salt form and/or solvate forms can be changed into the free form of non-solvate form or the respective compound of salt form; Vice versa.
The compounds of this invention can exist with the form of isomer and composition thereof such as optical isomer, diastereomer, cis/trans conformer.Compound of the present invention such as can contain unsymmetrical carbon, and therefore can exist with the form of enantiomorph (enatiomer) or diastereomer and composition thereof such as racemic modification or non-enantiomer mixture.Any asymmetric carbon atom can with (R)-, (S)-or (R, S)-configuration, preferably to exist with (R)-or (S)-configuration.
The compounds of this invention contains one or more asymmetric center, thus can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention has asymmetric center, and this kind of asymmetric center respectively will produce two optical isomers independently, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all stereoisomeric forms in any ratio of these compounds.
If compound of the present invention, containing olefinic double bonds, unless stated otherwise, the present invention includes cis-isomeride and trans-isomer(ide).
Compound of the present invention can exist with tautomeric forms, and it has the tie point of different hydrogen by one or more double-bond shift.Each tautomer and composition thereof is all included in compound of the present invention.
Isomer mixture can such as be separated according to being such as similar to conventional method, to obtain pure isomer as required.The present invention includes the compounds of this invention of any isomeric forms and any isomer mixture thereof.The present invention also comprises the tautomer of the compounds of this invention, as long as tautomer can exist.
Compound of the present invention can such as with the form of the tablet of dressing or non-dressing, glue Nang, Injectable solution or suspension, such as with the form of ampoule, phial, with the form of emulsion, gel, paste, inhalation of dust, foaming agent, tincture, lipstick agent, drops, sprays, or with the form of suppository, such as to be similar to the form of macrolide such as erythromycin series as clarithromycin and Azythromycin, by the administration of any routine, such as enterally administering, such as, comprise nose, cheek, rectum, oral administration; Parenteral admin, such as, comprise intravenously, intramuscular, subcutaneous administration; Or topical, such as comprise through epidermis administration, intranasal administration, intrarterial.
Compound of the present invention can with following form administration: with the form of pharmaceutically-acceptable salts, such as acid salt or base addition salt are as the form administration of metal-salt; Or administration in a free form; Optionally with the form administration of solvate.The compounds of this invention of salt form shows the activity with the same degree of the compounds of this invention of free form, optional solvate forms.
According to the present invention, compound of the present invention can separately or combined for pharmacological agent with one or more other medicines promoting agents.Described other medicines promoting agent comprises such as other FXR agonist.
The invention provides pharmaceutical composition, it comprises the compounds of this invention of free form or pharmacy acceptable salt form and/or solvate forms; And at least one pharmaceutical excipient, such as carrier or thinner, such as comprise weighting agent, tackiness agent, disintegrating agent, flowing regulator, lubricant, sugar and sweeting agent, perfume compound, sanitas, stablizer, wetting agent and/or emulsifying agent, solubilizing agent, for regulating salt and/or the Huan Red agent of osmotic pressure.
Described pharmaceutical composition such as can be produced by mixing, granulation, dressing, dissolving or freezing dry process according to being such as similar to conventional method.Unit dosage can containing such as about 0.5mg to about 2000mg, the activeconstituents of such as 10mg to about 500mg.
The compounds of this invention shows pharmacologically active, therefore can be used as medicine.
The present invention also provides the application in the medicine of the disease of preparation treatment FXR mediation of general formula of the present invention (I) compound or its pharmacy acceptable salt.
The compounds of this invention shows good FXR agonism, therefore can prepare the medicine of the disease treating and/or preventing FXR mediation, and the disease such as hyperlipemia treating and/or preventing FXR mediation (includes but not limited to hyperlipidaemia, hypertriglyceridemia, low blood plasma HDL, high blood plasma LDL, high blood plasma VLDL, hypercholesterolemia, coronary sclerosis etc.), inflammatory bowel disease (including but not limited to Crohn's disease or ulcerative colitis), diabetes B, the complication of 1 type and diabetes B (includes but not limited to diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, Peripheral Arterial Occlusive disease), extrahepatic cholestasis, chronic cholestatic, the hepatic fibrosis that acute intraheptic cholestatic illness causes (includes but not limited to primary biliary cirrhosis, primary sclerosing cholangitis, Progressive symmetric erythrokeratodermia familiar cholestasis, alcohol induced liver cirrhosis and relevant cholestasis), the chronic fatty of the organ caused for the activation of the lipid that strengthens and the particularly Cumulate Sum short fibrosis passage subsequently of tri-glyceride and fibrosis lesion and the illness that produces and disease (include but not limited to the non-alcoholic fatty liver disease in liver and chronic cholestatic conditions, neurodegenerative disease in brain), obesity and Metabolic Syndrome etc.
Again on the one hand, the present invention also provides the method for the disease treating and/or preventing FXR mediation, comprise Mammals general formula of the present invention (I) compound or its pharmacy acceptable salt or their steric isomer being needed this treatment or prevention, such as people.
Set forth the compounds of this invention beneficial effect further below by way of antibacterial activity test, but this should be interpreted as the compounds of this invention only has following beneficial effect.
The external pharmacologically active of experimental example 1 the compounds of this invention
Trial-product: part of compounds of the present invention, prepares according to embodiment method; Contrast medicine GW4064, self-control.
Experimental technique: cytologic experiment (cellular assay), Shanghai Ruizhi Chemical Study Co., Ltd. is entrusted in this experiment.
Adopt the method Cell-based transient co-transfection reporter assay that cell transient transfection examining report is expressed
Adopt HEK293 cell strain, after cultivating 24 h, cell concn is adjusted to 500,000/mL, add lipofectamine (the pBIND 50ng/well prepared, pG5Luc50ng/well, FuGENE HD 0.3ul/well, No FBSmedia3.7 μ L/well) be dispensed into 100 μ L/ holes in 96 orifice plates, 37 DEG C, 5%CO 224 h are cultivated under concentration.Use DMSO dissolved compound, and be diluted to 21 times of final concentrations, after 3 times of dilutions, be transferred to 5 μ L/ holes in 96 orifice plates containing transfectional cell respectively, 37 DEG C, 5%CO 2, hatch 18 h.After removing cell culture medium, every hole adds 20 μ L lysates, vortex 15 min; Add Luciferase Assay Reagent II 30 μ L/ hole, detect luciferase signal; Add termination reaction liquid 30 μ L/ hole, detect renilla luciferase signal.By the exciting rate of following formulae discovery, calculate EC with Prism 5.0 50value.
Signal value=luciferase signal/sea pansy element enzyme signal
Activity ratio %=(compound signal value-background signal value)/(maximum signal level-background signal value) × 100%
Background signal value refers to the signal value of DMSO
Experimental result and conclusion:
Table 1 the compounds of this invention is to the EC of FXR 50value and Activation at Max Conc (activity ratio) %
Conclusion: from table 1, the compounds of this invention has agonist activity to FXR acceptor, shows better activity than GW4064.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
embodiment 1 (E)-3-(the chloro-4-of 2-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) styryl) phenylformic acid (is changed compound 1) preparation
The preparation of 1.2-(amino (2,6-dichlorophenyl) methylene radical)-4-methyl-3-oxopentanoic
3.14 g (10 mmol) 3-(2,6-dichlorophenyl)-5-isopropyl oxazole-4-methyl-formiate is dissolved in 30 mL methyl alcohol, adds 1.0 g Raney's nickels, pass into hydrogen room temperature reaction 2 days.With suction filtered through kieselguhr, concentrated filtrate obtains gray solid 2.8 g, yield 88.6%.
The preparation of 2.3-(2,6-dichlorophenyl)-5-isopropyl 4-thiazolecarboxylic acid methyl esters
By 2.0 g (6.33 mmol) 2-(amino (2,6-dichlorophenyl) methylene radical)-4-methyl-3-oxopentanoic, 1.56 g (6.33mmol) tetrachlorobenzoquinone, 2.82 g (12.7 mmol) thiophosphoric anhydride joins in 40 mL toluene respectively, join in the oil bath being preheating to 120 DEG C and react 30 min, suction filtration, filtrate is spin-dried for, column chromatography (PE:EA=100:1-50:1), obtain red oil 900 mg, yield 43.1%.
3. the preparation of (3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methyl alcohol
900 mg (2.73 mmol) 3-(2,6-dichlorophenyl)-5-isopropyl 4-thiazolecarboxylic acid methyl esters is dissolved in 15 mL tetrahydrofuran (THF)s, adds 114 mg (3.0 mmol) Lithium Aluminium Hydride under ice bath, room temperature reaction 2 h.Carefully add 1 mL methyl alcohol cancellation, then add the saturated metabisulfite solution of 1 mL, stir, suction filtration removing solid, is spin-dried for filtrate column chromatography (PE:EA=100:1-10:1), obtains faint yellow solid 380 mg, yield 46.2%.
The preparation of the chloro-4-of 4.2-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) phenyl aldehyde
By 380 mg (1.26 mmol) (3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methyl alcohol, 197 mg (1.26 mmol) 2-chloro-4-hydroxyl phenyl aldehyde, 330 mg (1.26 mmol) triphenylphosphine joins in 15 mL methylene dichloride respectively, add 255 mg (1.26 mmol) DIAD again, room temperature reaction 15 h.Be spin-dried for solvent, column chromatography (PE:EA=50:1-30:1), give light yellow oil 240 mg, yield 42.9%.
5. the preparation of (E)-3-(the chloro-4-of 2-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) styryl) methyl benzoate
312 mg (1.09 mmol) 3-((diethoxy phosphoryl) methyl) methyl benzoate is dissolved in 15 mL tetrahydrofuran (THF)s; add the NaH of 48 mg (1.2 mmol) 60%; to emerge bubble; add the chloro-4-of 240 mg (0.54 mmol) 2-((3-(2 again; 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) phenyl aldehyde, room temperature reaction 4 h.Be poured into water, add dilute hydrochloric acid and be adjusted to neutrality, extraction into ethyl acetate, be spin-dried for organic phase, column chromatography (PE:EA=100:1-25:1), obtain colorless oil 260 mg, yield 83.3%.
6. (E)-3-(the chloro-4-of 2-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) styryl) benzoic preparation
By 260 mg (0.45 mmol) (E)-3-(the chloro-4-of 2-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group) styryl) methyl benzoate is dissolved in 10 mL tetrahydrofuran (THF)s, add the aqueous solution that 4 mL are dissolved with 160 mg (4.0 mmol) sodium hydroxide, be heated to 50 DEG C of reaction 15 h.Cooling, thin up, dilute hydrochloric acid is adjusted to neutrality, extraction into ethyl acetate, dry, is spin-dried for, obtains white solid 200 mg, yield 80%.
Molecular formula: C 28h 22cl 3nO 3s molecular weight: 557.04 mass spectrums (M+H): 558.0
1H-NMR(DMSO-d6,400 MHz)：δ8.08(1H,s),7.83(1H,d),7.80-7.71(2H,m),7.59-7.53(2H,m),7.51-7.43(2H,m),7.37(1H,d),7.24(1H,d),6.96(1H,d),6.79(1H,dd),4.91(2H,s),3.57(1H,septet),1.38(6H,d).
embodiment 2 4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (first base) amino) methyl) preparation of phenylformic acid (compound 2)
The preparation of 1.4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-isopropyl thiazole
By (3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methyl alcohol (0.5 g, 1.65 mmol) be dissolved in 10 mL methylene dichloride, 5 mL sulfur oxychlorides are added under room temperature, react 6 hours, be spin-dried for solvent, obtain colorless oil, be directly used in next step.
The preparation of 2.3-(2,6-dichlorophenyl)-5-sec.-propyl-4-((5-nitro-6-(trifluoromethyl) pyridine-2-base oxygen base) methyl) isothiazole
Previous step product is dissolved in 10 mL DMA, adds salt of wormwood (0.228 g, 1.65 mmol), stir after 10 minutes and add 5-nitro-6-(trifluoromethyl) pyridine-2-alcohol (0.343 g, 1.65 mmol) and potassiumiodide (0.274 g, 1.65 mmol), react 12 hours under room temperature, add water, extraction into ethyl acetate three times, merges organic phase washing once, concentrated, obtain yellow solid 0.84 g, be directly used in next step.
The preparation of 3.6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3-amine
Crude product 0.84 g that upper step is obtained, zinc powder (1.07 g, 16.4 mmol) and 2 mL acetic acid are mixed in 10 mL methyl alcohol, be warming up to 50 DEG C of reactions 24 hours, filter, concentrated, crude product is dissolved in 100 mL ethyl acetate, three times are washed with saturated sodium bicarbonate aqueous solution, washing is once, dry, concentrated, obtain yellow solid 0.71 g, above three steps add up to yield 93.3%.
The preparation of 4.4-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
By 6-((3-(2; 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3-amine (0.462 g; 1.0mmol) be dissolved in 20 mL methylene dichloride; add p formylbenzoic acid methyl esters (0.82 g; 5.0 mmol) and 5 mL acetic acid; react 72 hours at 40 DEG C, be spin-dried for solvent, be directly used in next step.
The preparation of 5.4-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
20 mL 1 are added in crude product obtained in the previous step, 2-ethylene dichloride, add sodium triacetoxy borohydride (1.06 g, 5.0mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain off-white color solid 0.15 g, two steps add up to yield 24.6%.
The preparation of 6.4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
Take 4-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl amino) methyl) methyl benzoate (0.15 g, 0.246 mmol), add 10 mL formalins, add 1 mL formic acid, be warming up to 100 DEG C of reactions 12 hours, be spin-dried for reaction solution, crude product is dissolved in 50 mL ethyl acetate, washs three times with saturated sodium bicarbonate aqueous solution, and washing once, dry, concentrated, obtain crude product 0.18 g, be directly used in next step.
7.4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
The crude product that upper step obtains is dissolved in 10 mL methyl alcohol, add sodium hydroxide (0.197 g, 4.93 mmol) the aqueous solution 2 mL, be warming up to 40 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=3:1) and obtain white solid 95 mg, yield 63.4%.
Molecular formula: C 28h 24cl 2f 3n 3o 3s molecular weight: 609.09 mass spectrums (M+H): 610.1
1H-NMR(DMSO-d 6,400 MHz)：δ12.89(1H,s),8.02(1H,d),7.89(2H,d),7.47-7.37(4H,m),7.33(1H,dd),6.84(1H,d),5.26(2H,s),4.02(2H,s),3.64(1H,septet),2.47(3H,s),1.36(6H,d).
embodiment 3 4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (second base) amino) methyl) preparation of phenylformic acid (compound 3)
The preparation of 1.4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) is amino) methyl) methyl benzoate
Take 4-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate (0.608 g, 1.0 mmol) be dissolved in 10 mL 1,2-ethylene dichloride, add sodium triacetoxy borohydride (1.06 g, 5.0 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=20:1) and obtain white solid 0.29 g, yield 45.4%.
2.4-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) is amino) methyl) benzoic preparation
By 4-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) amino) methyl) methyl benzoate (0.18 g, 0.282 mmol) be dissolved in 5 mL methyl alcohol, add sodium hydroxide (0.226 g, 5.64 mmol) the aqueous solution 2 mL, be warming up to 40 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain white solid 160 mg, yield 90.8%.
Molecular formula: C 29h 26cl 2f 3n 3o 3s molecular weight: 623.10 mass spectrums (M+H): 624.2
1H-NMR(DMSO-d 6,400 MHz)：δ12.89(1H,s),7.97(1H,d),7.87(2H,d),7.43-7.36(4H,m),7.32(1H,dd),6.82(1H,d),5.27(2H,s),4.01(2H,s),3.64(1H,septet),2.82(2H,q),1.36(6H,d),0.82(3H,t).
embodiment 4 3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (first base) amino) methyl) preparation of phenylformic acid (compound 4)
The preparation of 1.3-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
By 6-((3-(2; 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3-amine (0.91 g; 1.97mmol) be dissolved in 30 mL methylene dichloride; add 3-acyl radical methyl benzoate (1.62 g; 9.87 mmol) and 5 mL acetic acid; react 72 hours at 40 DEG C, be spin-dried for solvent, be directly used in next step.
The preparation of 2.3-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
30 mL methyl alcohol are added in crude product obtained in the previous step, add sodium triacetoxy borohydride (2.09 g, 9.86 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain off-white color solid 0.46 g, two steps add up to yield 38.2%.
The preparation of 3.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
Take 3-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl amino) methyl) methyl benzoate (0.46 g, 0.753 mmol), add 15 mL formalins, add 1 mL formic acid, be warming up to 100 DEG C of reactions 12 hours, be spin-dried for reaction solution, crude product is dissolved in 50 mL ethyl acetate, washs three times with saturated sodium bicarbonate aqueous solution, and washing once, dry, concentrated, obtain light yellow solid 0.31 g, be directly used in next step.
4.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
The crude product that upper step obtains is dissolved in 15 mL methyl alcohol, add sodium hydroxide (0.4 g, 10.0 mmol) the aqueous solution 4 mL, be warming up to 40 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=3:1) and obtain white solid 185 mg, two steps add up to yield 40.2%.
Molecular formula: C 28h 24cl 2f 3n 3o 3s molecular weight: 609.09 mass spectrums (M+H): 610.1
1H-NMR(DMSO-d 6,400 MHz)：δ12.94(1H,s),8.03(1H,d),7.94(1H,s),7.82(1H,d),7.54(1H,d),7.45(1H,t),7.42-7.37(2H,m),7.32(1H,dd),6.85(1H,d),5.26(2H,s),4.01(2H,s),3.64(1H,septet),2.46(3H,s),1.36(6H,d).
embodiment 5 3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (second base) amino) methyl) preparation of phenylformic acid (compound 5)
The preparation of 1.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) is amino) methyl) methyl benzoate
Take 3-((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate (0.608 g, 1.0 mmol) be dissolved in 10 mL 1,2-ethylene dichloride, add sodium triacetoxy borohydride (1.06 g, 5.0 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=20:1) and obtain white solid 0.3 g, yield 47%.
2.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) is amino) methyl) benzoic preparation
By 3-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (ethyl) amino) methyl) methyl benzoate (0.3 g, 0.47 mmol) be dissolved in 10 mL methyl alcohol, add sodium hydroxide (0.376 g, 9.4 mmol) the aqueous solution 4 mL, be warming up to 40 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain white solid 230 mg, yield 78.4%.
Molecular formula: C 29h 26cl 2f 3n 3o 3s molecular weight: 623.10 mass spectrums (M+H): 624.1
1H-NMR(DMSO-d 6,400 MHz)：δ12.93(1H,s),7.98(1H,d),7.92(1H,s),7.80(1H,d),7.53(1H,d),7.43(1H,t),7.41-7.36(2H,m),7.30(1H,dd),6.82(1H,d),5.27(2H,s),4.01(2H,s),3.64(1H,septet),2.81(2H,q),1.36(6H,d),0.81(3H,t).
embodiment 6 (3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (first base) amino) methyl) preparation of phenylformic acid (compound 6)
The preparation of 1.2,6-dichloro benzaldoxime
In dry reaction flask, sodium hydroxide (9.20 g, 230 mmol) is dissolved in 250 mL water, then oxammonium hydrochloride (16.0 g, 230 mmol) is added, by 2,6-dichlorobenzaldehyde (35.0 g, 200 mmol) slowly adds with after 250 mL dissolve with ethanol, reacts 24 hours in 90 DEG C of oil baths, be cooled to room temperature, concentrating under reduced pressure falls ethanol, cooling, filter, drying, obtains white solid 36.0 g, and yield is 94.5%.
The preparation of 2.2,6-bis-chloro-N-hydroxyl imide benzyl chloride
In dry reaction flask, add 2,6-dichloro benzaldoxime (7.60 g, 40.0 mmol) is dissolved in 60 mL DMA, and then adds NCS (5.36 g, 40.1 mmol), under the condition of 45 DEG C, stir 5 h, then system is poured into water, use extracted with diethyl ether aqueous phase, dry organic phase, concentrating under reduced pressure organic phase obtains crude product 9.70 g.
The preparation of 3.5-cyclopropyl-3-(2,6-dichlorophenyl) isoxzzole-4-methyl-formiate
In dry reaction flask, add 3-cyclopropyl-3-propionic acid methyl ester (6.20 g, 43.7 mmol), triethylamine (8.83 g, 87.4 mmol), stirred at ambient temperature reacts 1 h, then the 20 mL ethanol solutions of crude product 9.70 g obtained in the previous step are added, stirring at room temperature 15 h, concentrating under reduced pressure, column chromatography (PE--PE:EA=50:1) obtains product 7.70 g, and yield is 56.5%.
The preparation of 4.3-amino-2-(cyclopropyl carbonyl)-3-(2,6-dichlorophenyl) methyl acrylate
In dry reaction bottle, by 5-cyclopropyl-3-(2,6-dichlorophenyl) isoxzzole-4-methyl-formiate (7.70 g, 24.7 mmol) be dissolved in the methyl alcohol of 35 mL, then three spoonfuls of Raney Ni are added, logical hydrogen room temperature reaction 16 h, suction filtration, concentrating under reduced pressure filtrate obtains 5.10 g crude products.
The preparation of 5.5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-methyl-formiate
In dry reactor, by upper step crude product, (5.10 g), thiophosphoric anhydride (7.21 g, 32.5 mmol), tetrachlorobenzoquinone (3.99 g, 16.2 mmol) be dissolved in 50 mL toluene, be placed in the oil bath being preheated to 120 DEG C to stir 30 minutes, system filtered, filtrate reduced in volume, column chromatography (PE:EA=10:1-1:1), obtains yellow solid 2.51 g.
6. the preparation of (5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methyl alcohol
In dry reaction flask, 5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-methyl-formiate (2.51 g, 7.65 mmol) dissolves with 40 mL THF, add Lithium Aluminium Hydride (305 mg at 0 DEG C in batches, 8.03 mmol), finish under rising to room temperature and react 2h, then add methyl alcohol cancellation under ice bath, add suction filtered through kieselguhr, concentrating under reduced pressure filtrate, silica gel column chromatography (PE:EA=50:1-4:1) obtains product 1.50 g, and yield is 65.4%.
The preparation of 7.4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole
In dry reaction flask, upper step product (1.50 g, 5 mmol) dissolves with 10 mL DCM, drips sulfur oxychloride 5 mL, room temperature reaction 5 h, concentrating under reduced pressure, and toluene band once, is directly used in next step reaction after being spin-dried for.
The preparation of 8.3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
In dry reaction flask, add 4-(chloromethyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole (319 mg, 1.00mmol) with 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) methylamino-) methyl) methyl benzoate (340 mg, 1.00 mmol) dissolve with 8 mLDMA, then salt of wormwood (414 mg are added, 3.00 mmol) and potassiumiodide (166 mg, 1.00 mmol), stirring at room temperature 24 h, add water in system, use EA aqueous phase extracted, drying also concentrates organic phase, column chromatography (PE:EA=20:1-5:1) obtains 360 mg oily matter, yield is 57.8%.
9.3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
By upper step product (360 mg, 0.578 mmol) be dissolved in 5 mL methyl alcohol and 2 mL water, sodium hydroxide (231 mg, 5.78 mmol) is added, stirring at room temperature 4 h under ice bath, 2 h are stirred in the oil bath of 50 DEG C, system pH dilute hydrochloric acid is adjusted to 6, and then concentrating under reduced pressure falls methyl alcohol, and product is separated out, obtain product 300 mg, yield is 85.2%.
Molecular formula: C 28h 22cl 2f 3n 3o 3s molecular weight: 607.1 mass spectrums (M+H): 608.1
1H-NMR(d 6-DMSO,400 MHz)：δ8.00(1H,d),7.88(1H,s),7.78(1H,d),7.40(1H,d),7.38(1H,s),7.37-7.24(3H,m),6.86(1H,d),5.32(2H,s),3.95(2H,s),2.45(3H,s),1.30-1.20(3H,m),0.88-0.80(2H,m).
embodiment 7 3-(((6-((3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methylamino-) methyl) preparation of phenylformic acid (compound 7)
The preparation of 1.2-chloro-6-methyl dichloro benzaldoxime
In dry reaction flask, sodium hydroxide (0.92 g, 23.0 mmol) is dissolved in 25 mL water, adds oxammonium hydrochloride (1.60g, 23.0 mmol), chloro-for 2-6-tolyl aldehyde (3.09 g, 20.0 mmol) is slowly added with after 25 mL dissolve with ethanol, reacts 8 hours in 90 DEG C of oil baths, be cooled to room temperature, concentrating under reduced pressure falls most of ethanol in system, and suction filtration obtains white solid 3.3g, and yield is 97.3%.
The preparation of the chloro-N-hydroxyl of 2.2--6-methylene imine benzyl chloride
In dry reaction flask, add 2-chloro-6-methyl dichloro benzaldoxime (3.3 g, 19.46 mmol), dissolve with 25 mL DMA, then add NCS (2.60 g, 19.46 mmol), at lower stirring 4 h of 45 DEG C, then system is poured into water, uses EA aqueous phase extracted, dry organic phase, concentrating under reduced pressure organic phase obtains yellow oil and is directly used in next step reaction.
The preparation of 3.3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl oxazole-4-methyl-formiate
In dry reaction flask, add 4-methyl-3-oxopentanoic (2.81 g, 19.46 mmol), triethylamine (3.93 g, 38.92 mmol), stirred at ambient temperature reacts 1 hour, then 20 mL ethanol solutions of crude product obtained in the previous step are added, stirring at room temperature 48 h, concentrating under reduced pressure, column chromatography (PE:EA=50:1) obtains 4.70 g oily matter, and yield is 82.2%.
The preparation of 4.2-(amino (the chloro-6-aminomethyl phenyl of 2-) methylene radical)-4-methyl-3-oxopentanoic
In dry reaction bottle, add 3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl oxazole-4-methyl-formiate (4.70 g, 16.0 mmol), with 50 mL dissolve with methanol, then add Raney Ni, with hydrogen exchange, stirring at room temperature 4 days, 35 DEG C of oil baths stir one day, and with suction filtered through kieselguhr, concentrating under reduced pressure filtrate obtains pale yellow oil 4.70 g (crude product).
The preparation of 5.3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl 4-thiazolecarboxylic acid methyl esters
In dry reactor, add 2-(amino (the chloro-6-aminomethyl phenyl of 2-) methylene radical)-4-methyl-3-oxopentanoic (2.37 g, 8.0 mmol) thiophosphoric anhydride (3.56 g, 16.0 mmol), dissolve with 60.0 mL toluene, then tetrachlorobenzoquinone (1.97g is added, 8.0 mmol), stir 20 minutes in the oil bath of 120 DEG C, be cooled to room temperature, concentrating under reduced pressure column chromatography (PE:EA=20:1), obtains oily matter 2.0 g, and yield is 80.7%.
6. the preparation of (3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl thiazole-4-yl) methyl alcohol
In dry reaction flask, add 3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl 4-thiazolecarboxylic acid methyl esters (2.0 g, 6.46mmol), dissolve with 60 mL THF, Lithium Aluminium Hydride (0.736 g is slowly added under ice bath, 19.38 mmol), move to stirred at ambient temperature after adding and react 4 hours, then methyl alcohol and saturated metabisulfite solution (on a small quantity) is added under ice bath, with suction filtered through kieselguhr, concentrating under reduced pressure filtrate, silica gel column chromatography (PE:EA=10:1) obtains pale yellow oil (condensing into solid after placement) 0.53 g, and yield is 29.2%.
The preparation of 7.3-(the chloro-6-aminomethyl phenyl of 2-)-4-(chloromethyl)-5-isopropyl thiazole
In dry reaction flask, add (3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl thiazole-4-yl) methyl alcohol (110 mg, 0.39mmol), dissolve with 10.0 mL DCM, then sulfur oxychloride 0.5 mL is slowly added, stirring at room temperature 1 hour, stopped reaction, concentrating under reduced pressure, gained oily matter is directly used in next step reaction.
8.3-(the preparation of ((6-((3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methylamino-) methyl) methyl benzoate
In dry reaction flask, add 3-(the chloro-6-aminomethyl phenyl of 2-)-4-(chloromethyl)-5-isopropyl thiazole (117 mg, 0.39 mmol) and 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) methylamino-) methyl) methyl benzoate (133 mg, 0.39 mmol) dissolve with 4.0 mLDMA, then salt of wormwood (215 mg are added, 1.56 mmol) and potassiumiodide (65 mg, 0.39 mmol), stirring at room temperature 12 h, 8 h are stirred in the oil bath of 40 DEG C, stopped reaction, add water, use EA aqueous phase extracted, drying also concentrates organic phase, column chromatography (PE:EA=12:1) obtains 140 mg oily matter, yield is 59.4%.
9.3-(((6-((3-(2-chloro-6-aminomethyl phenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methylamino-) methyl) benzoic preparation
In dry reaction flask, add 3-(((6-((3-(the chloro-6-aminomethyl phenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methylamino-) methyl) methyl benzoate (140 mg, 0.232 mmol), with 8.0 mL dissolve with methanol, sodium hydroxide (93 mg are added under ice bath, 2.32 mmol), then 2.0 mL water are added, stirring at room temperature 4 h, 2 h are stirred in the oil bath of 50 DEG C, stopped reaction, then concentrating under reduced pressure falls methyl alcohol, by system pH to 6, concentrating under reduced pressure, column chromatography (PE:EA=5:1) obtains 80 mg white solids, yield is 58.4%.
Molecular formula: C 29h 27clF 3n 3o 3s molecular weight: 589.1 mass spectrums (M+H): 590.2
1H-NMR(CDCl 3,400 MHz)：δ8.07(1H,s),8.02(1H,d),7.71(1H,d),7.64(1H,d),7.47(1H,t),7.22(1H,d),7.16(1H,t),7.07(1H,d),6.72(1H,d),5.30(1H,d),5.14(1H,d),4.01(2H,s),3.61(1H,septet),2.54(3H,s),2.03(3H,s),1.45,1.43(6H,two doublet).
embodiment 8 3-(((6-((3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of phenylformic acid (compound 8)
The preparation of 1.2-chloro-6-fluorobenzaldehyde oxime
In dry reaction flask, add sodium hydroxide (4.18 g, 104.4 mmol), with hydrochloric acid hydroxyl by (7.2 g, 104.4 mmol), by 100 mL water dissolution, more slowly drip chloro-6-fluorobenzaldehyde (15 g of 2-, 94.9 mmol) 100 mL ethanolic solns, be warming up to 90 DEG C reaction 12 hours.System is cooled to room temperature, and concentrating under reduced pressure falls most of ethanol, and suction filtration obtains white solid 16.0 g, and yield is 97.5%.
The preparation of the chloro-6-of 2.2-fluoro-N-hydroxyl imide benzyl chloride
In dry reaction flask, add 2-chloro-6-fluorobenzaldehyde oxime (16.0g, 92.4 mmol), dissolve by 150 mL N,N-dimethylacetamide, then slowly add NCS (12.3 g, 92.4 mmol), be warming up to 45 DEG C and stir 4 hours.Add water by system, by extracted with diethyl ether, organic phase is used saturated common salt water washing, dry, concentrating under reduced pressure obtains colorless oil 21.1 g (crude product).
The preparation of 3.3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl oxazole-4-methyl-formiate
In dry reaction flask, add 4-methyl-3-oxopentanoic (13.3 g, 92.4 mmol), triethylamine (18.7 g, 184.8 mmol), stirred at ambient temperature 1 hour, then adds 50 mL ethanolic solns of the chloro-6-of 2-fluoro-N-hydroxyl imide benzyl chloride 21.1 g crude product, stirred at ambient temperature 15 hours.Concentrating under reduced pressure, silica gel column chromatography (PE:EA=100:1), obtains white solid 11.0g, and two step yields are 39.9%.
The preparation of 4.2-(amino (the chloro-6-fluorophenyl of 2-) methylene radical)-4-methyl-3-oxopentanoic
In dry reaction flask, add 3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl oxazole-4-methyl-formiate (3 g, 10.1 mmol), with 20 mL dissolve with methanol, add 0.9g Raney Ni, room temperature reaction 12 hours after replacing hydrogen.System filtered, concentrating under reduced pressure obtains 3.00g red oil, and yield is 98.7%.
The preparation of 5.3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl 4-thiazolecarboxylic acid methyl esters
In dry reaction flask, add 2-(amino (the chloro-6-fluorophenyl of 2-) methylene radical)-4-methyl-3-oxopentanoic (1 g, 3.30mmol), tetrachlorobenzoquinone (0.738 g, 3.30 mmol) and thiophosphoric anhydride (1.465 g, 6.60 mmol), dissolve with 20 mL toluene, add in the oil bath being preheating to 120 DEG C and react 20 minutes.System filtered, concentrating under reduced pressure, silica gel column chromatography (PE:EA=1:1), obtains yellow solid 0.325 g, and yield is 31.4%.
6. the preparation of (3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl thiazole-4-yl) methyl alcohol
In dry reaction flask, add 3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl 4-thiazolecarboxylic acid methyl esters (900 mg, 2.87mmol), dissolve with 15 mL tetrahydrofuran (THF)s, be cooled to 0 DEG C, slowly add Lithium Aluminium Hydride (120 mg, 3.16 mmol), react 2 hours after being warming up to room temperature.In system, adding saturated ammonium chloride solution to producing without obvious bubble, adding Disodium sulfate decahydrate, filter, concentrating under reduced pressure, silica gel column chromatography (PE:EA=10; 1), obtain dark red solid 640 mg, yield is 78.0%.
The preparation of 7.3-(the chloro-6-fluorophenyl of 2-)-4-(chloromethyl)-5-isopropyl thiazole
In dry reaction flask, add (3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl thiazole-4-yl) methyl alcohol (640 mg, 2.24 mmol), dissolve with 5 mL methylene dichloride, slowly add 5 mL thionyl chlorides, room temperature reaction 5 hours.System concentrating under reduced pressure is obtained oily matter and is directly used in ensuing reaction.
The preparation of 8.5-amino-6-(trifluoromethyl) pyridine-2-alcohol
In dry reaction flask, add 5-nitro-6-(trifluoromethyl) pyridine-2-alcohol (5.88 g, 28.3 mmol), after 200 mL dissolve with methanol, add zinc powder (18.4 g, 283 mmol) in batches, add 2 mL acetic acid again, be warming up to 50 DEG C, reaction is spent the night.By reacting liquid filtering, filter cake methanol wash, is spin-dried for filtrate, obtains yellow solid crude product.
The preparation of 9.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
In dry reaction flask, add crude product and 3-acyl radical methyl benzoate (13.9 g, 84.9 mmol) that step obtains, with 100 mL 1,2-ethylene dichloride dissolvings, then add 1 mL acetic acid, be warming up to 50 DEG C, react 72 hours.Be spin-dried for reaction solution and be directly used in next step reaction.
The preparation of 10.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
In dry reaction flask, the crude product upper step obtained 100 mL anhydrous methanols dissolve, and add sodium cyanoborohydride (5.35 g, 84.9 mmol) under room temperature in batches, are warming up to 50 DEG C of reactions 12 hours.Reaction solution is spin-dried for, silica gel column chromatography (PE:EA=10:1), obtains colorless oil 4.5 g crude product.
The preparation of 11.3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
In dry reaction flask, add 3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate (4.5 g crude product), add 100 mL formalins, then add 2 mL formic acid, be warming up to 100 DEG C of reactions 8 hours.After adding water in system, be extracted with ethyl acetate, dry, concentrated, silica gel column chromatography (PE:EA=5:1), obtains white solid 3.00 g, and four step yields are 31.2%.
The preparation of 12.3-(((6-((3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
In dry reaction flask, add 3-(the chloro-6-fluorophenyl of 2-)-4-(chloromethyl)-5-isopropyl thiazole (300 mg, 0.99mmol), 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate (337 mg, 0.99mmol), with 10 mL N, after N-dimethylacetamide amine solvent, add salt of wormwood (273 mg, 1.98mmol) with potassiumiodide (164mg, 0.99 mmol), lucifuge, room temperature reaction 36 hours.Add water in system, filter, filter cake washes with water, and dry, silica gel column chromatography (PE:EA=20:1), obtains pale yellow oil 550 mg, and yield is 91.4%.
13.3-(((6-((3-(2-chloro-6-fluorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
In dry reaction flask, add 3-(((6-((3-(the chloro-6-fluorophenyl of 2-)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate (300 mg, 0.49 mmol), dissolve with the mixing solutions of methyl alcohol 16 mL and water 4 mL, add sodium hydroxide (196 mg again, 4.9 mmol), be warming up to 45 DEG C, reaction is spent the night.Regulate pH to slightly acidic, system be spin-dried for, silica gel column chromatography (PE:EA=3:1), obtain pale yellow oil 230 mg, yield is 80%.
Molecular formula: C 28h 24clF 4n 3o 3s molecular weight: 593.1 mass spectrums (M+1): 594.1
1H-NMR(CDCl 3,400 MHz):11.68(1H,br s),8.10(1H,s),8.03(1H,d),7.70(1H,d),7.65(1H,d),7.46(2H,t),7.33-7.18(1H,m),7.02(1H,t),6.74(1H,d),5.35(1H,d),5.26(1H,d),4.02(2H,s),3.65(1H,septet),2.54(3H,s),1.45(6H,m).
embodiment 9 3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (first base) amino) methyl) preparation of-N-hydroxybenzamide (compound 9)
The preparation of 1.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
By 5-amino-6-(trifluoromethyl) pyridine-2-alcohol (0.712 g; 4.0 mmol) and 3-acyl radical methyl benzoate (1.97 g; 12.0mmol) be dissolved in 20 mL 1,2-ethylene dichloride, add 1 mL acetic acid; be warming up to 40 DEG C of reactions 72 hours; filter, filtrate concentrates, and crosses silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=5:1) and obtains light yellow solid 0.21 g; be merged together with filter cake, for next step reaction.
The preparation of 2.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
In crude product obtained in the previous step, add 50 mL anhydrous methanols, add sodium cyanoborohydride (1.26 g, 20.0 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, be directly used in next step.
The preparation of 3.3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
To in the reaction flask of previous step crude product, add 50 mL formalins, add 5 mL formic acid, be warming up to 100 DEG C of reactions 4 hours, add water, extraction into ethyl acetate three times, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain yellow oil 0.8 g, three steps add up to yield 58.8%.
The preparation of 4.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
By 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate (0.8 g, 2.35 mmol), 4-(chloromethyl)-3-(2, 6-dichlorophenyl)-5-isopropyl thiazole (0.753 g, 2.35 mmol), potassiumiodide (0.39 g, 2.35 mmol) and salt of wormwood (0.324 g, 2.35 mmol) be mixed in 10 mL DMA, be warming up to 35 DEG C of reactions 8 hours, add 100 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=30:1) and obtain colorless oil 1.3 g, yield 88.5%.
5.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
By 3-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) methyl benzoate (0.35 g, 0.56 mmol) be dissolved in 5 mL methyl alcohol, add sodium hydroxide (0.224 g, 5.6 mmol) the aqueous solution 1 mL, be warming up to 50 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain colorless oil 0.24 g, yield 70.2%.
The preparation of 6.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide
In dry reaction flask, add 3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) phenylformic acid (0.17 g, 0.278 mmol), NH 2oTHP (49 mg, 0.417 mmol), HATU (0.159 g, 0.417 mmol) and triethylamine (84 mg, 0.834 mmol), add 5 mL methylene dichloride, room temperature reaction 12 hours, be spin-dried for reaction solution, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain colorless oil 0.183 g, yield 92.8%.
The preparation of 7.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-hydroxybenzamide
3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide (0.183 g, 0.258 mmol) be dissolved in 10 mL methylene dichloride, hydrogen chloride gas is passed into 1 hour under room temperature, be spin-dried for reaction solution, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=2:1) and obtain white solid 78 mg, yield 48.3%.
Molecular formula: C 28h 25cl 2f 3n 4o 3s molecular weight: 624.1 mass spectrums (M+H): 625.1
1H-NMR(CDCl 3,400 MHz)：δ7.73(1H,s),7.67-7.53(3H,m),7.38(1H,t),7.31-7.24(2H,m),7.19(1H,t),6.72(1H,d),5.27(2H,s),3.95(2H,s),3.64(1H,septet),2.49(3H,s),1.44(6H,d).
embodiment 10 cis-3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of hexahydrobenzoic acid (compound 10)
1. the preparation of cyclohexyl-1,3-dicarboxylic acid methyl ester
By hexanaphthene-1,3-dicarboxylic acid (8.6 g, 50.0 mmol) is dissolved in 60 mL methyl alcohol, adds trimethylchlorosilane (1.63 g under room temperature, 15.0 mmol), react 72 hours, add 100 mL methylene dichloride, saturated sodium bicarbonate aqueous solution washes twice, dry, be spin-dried for solvent, obtain colorless oil, be directly used in next step.
The preparation of 2.3-(methoxycarbonyl) hexahydrobenzoic acid
Previous step product is dissolved in 50 mL methyl alcohol, add 1 N aqueous sodium hydroxide solution 50 mL, ice-water bath moves to room temperature reaction 2 hours after stirring 1 hour, be spin-dried for methyl alcohol, and aqueous phase ethyl acetate is washed once, again aqueous phase concentrated hydrochloric acid is adjusted to pH=2-3, extraction into ethyl acetate three times, merges organic phase, dry, concentrate and obtain white solid 6.3 g, two steps add up to yields 67.7%.
The preparation of 3.3-(methylol) methyl cyclohexanecarboxylaand
In dry reaction flask, add 3-(methoxycarbonyl) hexahydrobenzoic acid (6.3 g, 33.9 mmol), add 100 mL anhydrous tetrahydro furans, tetrahydrofuran solution (2 M of borane dimethylsulf iotade are slowly dripped at-78 DEG C, 18.65 mL, 37.3 mmol), slowly rise to room temperature and continue reaction 24 hours, add saturated aqueous ammonium chloride, extraction into ethyl acetate three times, dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=3:1) and obtain colorless oil 3.2 g, yield 54.9%.
The preparation of 4.3-Formyl-cyclohexyl methyl-formiate
By 3-(methylol) methyl cyclohexanecarboxylaand (3.2 g, 18.6 mmol), pyridine. sulfur trioxide mixture (9.76 g, 61.4 mmol) and triethylamine (12.2 g, 120.9 mmol) be dissolved in 30 mL dimethyl sulfoxide (DMSO), room temperature reaction 2 hours, add water, extraction into ethyl acetate three times, organic phase saturated aqueous common salt washes twice, dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=3:1) and obtain colorless oil 2.11 g, yield 66.6%.
The preparation of 5.5-amino-6-(trifluoromethyl) pyridine-2-alcohol
By 5-nitro-6-(trifluoromethyl) pyridine-2-alcohol (2.67 g, 12.8 mmol) be dissolved in 100 mL anhydrous methanols, add 1 mL acetic acid, add zinc powder (8.34 g, 128 mmol), react 72 hours at 50 DEG C, filter, filter cake methanol wash, filtrate is concentrated obtains yellow solid 2.15 g, yield 94.3%.
6.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl cyclohexanecarboxylaand preparation
By 5-amino-6-(trifluoromethyl) pyridine-2-alcohol (0.801 g; 4.5 mmol) and 3-Formyl-cyclohexyl methyl-formiate (0.766 g; 4.5 mmol) be dissolved in 20 mL methylene dichloride; add several acetic acid; room temperature reaction 2 hours; be spin-dried for solvent, be directly used in next step.
7.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl amino) methyl) methyl cyclohexanecarboxylaand preparation
In crude product obtained in the previous step, add 20 mL methylene dichloride, add sodium triacetoxy borohydride (2.86 g, 13.5mmol), room temperature reaction 12 hours, is spin-dried for solvent, is directly used in next step.
The preparation of 8.3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl cyclohexanecarboxylaand
To in the reaction flask of previous step crude product, add 50 mL formalins, add 5 mL formic acid, be warming up to 100 DEG C of reactions 4 hours, add water, extraction into ethyl acetate three times, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain yellow oil 0.424 g, three steps add up to yield 27.2%.
9. the preparation of cis/trans-3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl cyclohexanecarboxylaand
By 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl cyclohexanecarboxylaand (0.424 g, 1.22mmol), 4-(chloromethyl)-3-(2, 6-dichlorophenyl)-5-isopropyl thiazole (0.391 g, 1.22 mmol), potassiumiodide (0.203 g, 1.22mmol) with salt of wormwood (0.168 g, 1.22 mmol) be mixed in 5 mL DMA, be warming up to 35 DEG C of reactions 8 hours, add 50 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=30:1) and obtain little polarity (trans) product 0.11 g yellow oil, yield 14.3%.Obtain large polarity (cis) product 0.34 g yellow oil, yield 44.2%.
10. the preparation of cis-3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) hexahydrobenzoic acid
By cis-3-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) methyl cyclohexanecarboxylaand (0.34 g, 0.54 mmol) be dissolved in 5 mL methyl alcohol, add sodium hydroxide (0.216g, 5.4 mmol) the aqueous solution 1 mL, be warming up to 50 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain colorless oil, ether/sherwood oil recrystallization obtains white solid 0.18 g, yield 54.1%.
Molecular formula: C 28h 30cl 2f 3n 3o 3s molecular weight: 615.1 mass spectrums (M+H): 616.2
1H-NMR(CDCl 3,400 MHz)：δ10.81(1H,br),7.56(1H,d),7.34-7.29(2H,m),7.22(1H,dd),6.71(1H,d),5.26(2H,s),3.65(1H,septet),2.65(2H,d),2.56(3H,s),2.31(1H,tt),2.13(1H,d),2.00(1H,d),1.86(2H,t),1.55-1.46(1H,m),1.44(6H,d),1.40-1.20(2H,m),1.02(1H,dd),0.90-0.73(1H,m).
trans-the 3-of embodiment 11 (((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of hexahydrobenzoic acid (compound 11)
By trans-3-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) methyl cyclohexanecarboxylaand (0.11 g, 0.174 mmol) be dissolved in 5 mL methyl alcohol, add sodium hydroxide (70mg, 1.74 mmol) the aqueous solution 1 mL, be warming up to 50 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain white solid 47 mg, yield 43.8%.
Molecular formula: C 28h 30cl 2f 3n 3o 3s molecular weight: 616.52 mass spectrums (M+H): 616.2
1H-NMR(CDCl 3,400 MHz)：δ7.57(1H,d),7.34-7.28(2H,m),7.22(1H,dd),6.70(1H,d),5.26(2H,s),3.65(1H,septet),2.72-2.65(1H,m),2.63(2H,d),2.56(3H,s),2.17-2.07(1H,m),2.04-1.66(4H,m),1.65-1.50(2H,m),1.44(6H,d),1.37-1.28(1H,m),1.15-1.03(1H,m).
embodiment 12 N-(3-(2H-tetrazole-5-base) benzyl)-6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxy base) preparation of-N-methyl-2-(trifluoromethyl) pyridine-3-amine (compound 12)
The preparation of 1.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) cyanobenzene
By 5-amino-6-(trifluoromethyl) pyridine-2-alcohol (0.89 g, 5.0 mmol) and 3-cyano-benzoic acid methyl ester (1.97 g, 15.0 mmol) be dissolved in 20 mL 1, in 2-ethylene dichloride, add 1 mL acetic acid, be warming up to 50 DEG C of reactions 12 hours, be spin-dried for reaction solution, crude product is directly used in next step reaction.
The preparation of 2.3-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) cyanobenzene
In crude product obtained in the previous step, add 20 mL anhydrous methanols, add sodium cyanoborohydride (1.58 g, 25.0 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, be directly used in next step.
The preparation of 3.3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) cyanobenzene
To in the reaction flask of previous step crude product, add 20 mL formalins, add 0.5 mL formic acid, be warming up to 100 DEG C of reactions 4 hours, add water, extraction into ethyl acetate three times, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain yellow oil 0.73 g, three steps add up to yield 47.6%.
The preparation of 4.3-(((6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) cyanobenzene
By 3-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) cyanobenzene (0.73 g, 2.38 mmol), 4-(chloromethyl)-3-(2, 6-dichlorophenyl)-5-isopropyl thiazole (0.762 g, 2.38 mmol), potassiumiodide (0.395 g, 2.38 mmol) and salt of wormwood (0.328 g, 2.38 mmol) be mixed in 10 mL DMA, be warming up to 35 DEG C of reactions 8 hours, add 100 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain colorless oil 0.58 g, yield 41.2%.
The preparation of 5.N-(3-(2H-tetrazole-5-base) benzyl)-6-((3-(2,6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-N-methyl-2-(trifluoromethyl) pyridine-3-amine
By 3-(((6-((3-(2, 6-dichlorophenyl)-5-isopropyl thiazole-4-yl) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) cyanobenzene (0.58 g, 0.981 mmol) be dissolved in 5 mL DMA, add sodium azide (0.638 g, 9.81 mmol) and ammonium chloride (0.525 g, 9.81 mmol), be warming up to 110 DEG C of reactions 24 hours, add 50 mL ethyl acetate, saturated aqueous common salt washes twice, organic phase is dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=1:1) and obtain light yellow solid 0.24g, yield 38.6%.
Molecular formula: C 28h 24cl 2f 3n 7o 3s molecular weight: 633.1 mass spectrums (M+H): 634.1
1H-NMR(d 6-DMSO,400 MHz)：δ8.09-8.00(2H,m),7.89(1H,d),7.60-7.50(2H,m),7.46-7.35(2H,m),7.34-7.29(1H,m),6.85(1H,d),5.26(2H,s),4.06(2H,s),3.64(1H,septet),2.49(3H,s),1.36(6H,d).
embodiment 13 4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group-2-(trifluoromethyl) pyridin-3-yl) (first base) amino) methyl) preparation of phenylformic acid (compound 13)
The preparation of 1.4-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
By 5-amino-6-(trifluoromethyl) pyridine-2-alcohol (0.712 g; 4.0 mmol) and p formylbenzoic acid methyl esters (1.97 g; 12.0mmol) be dissolved in 20 mL 1; in 2-ethylene dichloride; add 1 mL acetic acid; be warming up to 40 DEG C of reactions 72 hours, reaction solution concentrates, and obtains yellow crude and is directly used in next step reaction.
The preparation of 2.4-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
In crude product obtained in the previous step, add 50 mL anhydrous methanols, add sodium cyanoborohydride (1.26 g, 20.0 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, be directly used in next step.
The preparation of 3.4-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
50 mL formalins are added in previous step crude product, add 5 mL formic acid, be warming up to 100 DEG C of reactions 8 hours, add water, extraction into ethyl acetate three times, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain yellow oil 0.72 g, three steps add up to yield 52.9%.
4.4-(the preparation of ((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
By 4-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate (0.72 g, 2.11 mmol), 4-(chloromethyl)-3-(2, 6-dichlorophenyl)-5-cyclopropyl isothiazole (0.672 g, 2.11 mmol), potassiumiodide (0.35 g, 2.11 mmol) and salt of wormwood (0.291 g, 2.11 mmol) be mixed in 10 mL DMA, room temperature reaction 12 hours, add 100 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=20:1) and obtain colorless oil 0.95 g, yield 72.3%.
5.4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
By 4-(((6-((5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole-4-base) methoxyl group-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) methyl benzoate (0.622 g, 1.0 mmol) be dissolved in 10 mL methyl alcohol, add sodium hydroxide (0.4 g, 10.0 mmol) the aqueous solution 3 mL, be warming up to 50 DEG C of reactions 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=3:1) and obtain colorless oil 0.423 g, yield 69.5%.
Molecular formula: C 28h 22cl 2f 3n 3o 3s molecular weight: 607.07 mass spectrums (M+H): 608.1
1H-NMR(CDCl 3,400 MHz)：δ8.07(2H,d),7.64(1H,d),7.50(2H,d),7.35-7.30(2H,m),7.22(1H,dd),6.76(1H,d),5.38(2H,s),4.02(2H,s),2.54(3H,s),2.49-2.40(1H,m),1.29-1.21(2H,m),0.94-0.85(2H,m).
embodiment 14 4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of-N-hydroxybenzamide (compound 14)
The preparation of 1.4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide
In dry reaction flask, add 4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) phenylformic acid (0.24 g, 0.394 mmol), NH 2oTHP (69 mg, 0.591 mmol), HATU (0.224 g, 0.591 mmol) and triethylamine (119 mg, 1.18 mmol), add 5 mL methylene dichloride, room temperature reaction 12 hours, be spin-dried for reaction solution, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain colorless oil 0.193 g, yield 69.2%.
The preparation of 2.4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-hydroxybenzamide
4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide (0.193 g, 0.273 mmol) be dissolved in 10 mL methylene dichloride, trifluoroacetic acid 5 mL is added under room temperature, react 3 hours under room temperature, be spin-dried for reaction solution, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=2:1) and obtain white solid 121 mg, yield 71.1%.
Molecular formula: C 28h 23cl 2f 3n 4o 3s molecular weight: 622.08 mass spectrums (M+H): 623.1
1H-NMR(CDCl 3,400 MHz)：δ7.71(2H,d),7.63(1H,d),7.49(2H,d),7.37-7.28(2H,m),7.25-7.20(2H,m),6.76(1H,d),5.37(2H,s),4.00(2H,s),2.54(3H,s),2.49-2.40(1H,m),1.29-1.21(2H,m),0.94-0.85(2H,m).
embodiment 15 3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of-N-hydroxybenzamide (compound 15)
The preparation of 1.3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide
By 3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) phenylformic acid (275 mg, 0.452 mmol), NH 2-OTHP (80 mg, 0.684 mmol), EDCI (122 mg, 0.636mmol), HOBt (110 mg, 0.815 mmol) are dissolved in DCM (20 mL), then add E 3n (83 mg, 0.822 mmol), room temperature reaction 16 h.System added water, with organic solvent extraction, concentrated, column chromatography (PE:EA=10:1-1:1), obtains product 110 mg, yield: 34.4%.
The preparation of 2.3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-N-hydroxybenzamide
By 3-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl)-N-(tetrahydrochysene-2H-pyrans-2-base oxygen base) benzamide (110 mg, 0.155 mmol) be dissolved in 3 mL DCM, drip 1 mL CF 3react 6 h under COOH room temperature, system be spin-dried for, column chromatography (PE:EA=10:1-1:2), obtains product 36mg, yield: 37.3%.
Molecular formula: C 28h 23cl 2f 3n 4o 3s molecular weight: 622.1 mass spectrums (M+H): 623.1
1H-NMR(d 6-DMSO,400 MHz)：δ11.18(1H,s),9.04(1H,s),8.00(1H,d),7.70(1H,s),7.57(1H,d),7.45(1H,d),7.42-7.34(3H,m),7.31(1H,dd),6.85(1H,d),5.31(2H,s),3.98(2H,s),2.46(3H,s),1.48-1.38(1H,m),1.30-1.23(4H,m).
embodiment 16 5-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of-2-fluorobenzoic acid (compound 16)
The preparation of 1.5-amino-6-(trifluoromethyl) pyridine-2-alcohol
5-nitro-6-(trifluoromethyl) pyridine-2-alcohol (800 mg, 3.85 mmol) is joined in 10 mL methyl alcohol, adds zinc powder (2.50 g, 38.5 mmol), then add the acetic acid of 1 mL, 50 DEG C of reaction 16 h.Cooling, suction filtration, concentrated, crude product is dissolved in 100 mL ethyl acetate, washs three times with saturated sodium bicarbonate aqueous solution, and washing is once, dry, concentrated, obtains solid 570mg, yield: 83.1%.
The preparation of the fluoro-5-of 2.2-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) cyanobenzene
By 5-amino-6-(trifluoromethyl) pyridine-2-alcohol (570 mg; 3.2 mmol) be dissolved in 20 mL 1; in 2-ethylene dichloride; add fluoro-5-formylbenzonitrile (1.9 g of 2-; 12.8 mmol) and 2 mL acetic acid, react 36 h at 40 DEG C, be spin-dried for solvent; column chromatography (PE:EA=10:1-1:2) obtains product 430 mg, yield: 43.5%.
The preparation of the fluoro-5-of 3.2-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) cyanobenzene
By fluoro-for 2-5-((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl imino-) methyl) cyanobenzene (430 mg, 1.39 mmol) be dissolved in 10 mL methyl alcohol, add sodium borohydride (950 mg, 25.0 mmol), room temperature reaction 3 h, be spin-dried for solvent, be directly used in next step.
The preparation of the fluoro-5-of 4.2-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) cyanobenzene
Upwards step system adds 10 mL formalins, add 1 mL formic acid, be warming up to 100 DEG C of reaction 16 h, be spin-dried for reaction solution, crude product is dissolved in 100 mL ethyl acetate, wash with saturated sodium bicarbonate aqueous solution, washing is once, dry, concentrated, column chromatography (PE:EA=20:1-1:2) obtains product 230 mg, two step yields: 50.9%.
The preparation of 5.5-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-2-fluorobenzonitrile
In dry there-necked flask, the fluoro-5-of 2-(((6-hydroxyl-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) cyanobenzene (230mg, 0.707 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole (225 mg, 0.707 mmol) dissolve with 10mL DMA, then salt of wormwood (276 mg are added, 2.00 mmol) and potassiumiodide (117 mg, 0.707 mmol), room temperature lucifuge stirs 24 h, add water in system, use EA aqueous phase extracted, drying also concentrates organic phase, column chromatography (PE:EA=20:1-3:1) obtains 215 mg products, yield is 50.1%.
The preparation of 6.5-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-2-fluorobenzamide
In dry reaction flask, add 5-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl)-2-fluorobenzonitrile (200 mg, 0.329 mmol), add 2 mL 1 again, 4-dioxane, 2 mL water, sodium hydroxide (120 mg, 3 mmol) is warming up to 100 DEG C of reaction 48 h.System is spin-dried for, and is directly used in next step.
The preparation of 7.5-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl)-2-fluorobenzoic acid
Upper step crude product is dissolved in 5 mL ethylene glycol, adds water 2 mL, sodium hydroxide (160 mg, 4 mmol), 100 DEG C of reaction 16h.System is neutralized to pH=5, extraction into ethyl acetate, column chromatography (PE:EA=20:1-1:1), obtains crude product 80 mg, prepare silica-gel plate and be further purified (PE:EA=1:1) and obtain pure product 18 mg, 80% pure product 40 mg.
Molecular formula: C 28h 21cl 2f 4n 3o 3s molecular weight: 625.1 mass spectrums (M+H): 625.9
1H-NMR(d 6-DMSO,400 MHz)：13.18(1H,s),8.03(1H,d),7.83(1H,d),7.59-7.45(1H,m),7.44-7.23(4H,m),6.88(1H,d),5.35(2H,s),3.98(2H,s),2.46(3H,s),1.52-1.35(1H,m),1.30-1.25(2H,m),0.88-0.72(2H,m).
embodiment 17 4-(((4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) phenyl) (methyl) amino) methyl) preparation of phenylformic acid (compound 17)
The preparation of 1.4-amino-3-(trifluoromethyl) phenol
Joined in 20 mL methyl alcohol by 4-nitro-3-(trifluoromethyl) phenol (1.2 g, 5.8 mmol), add the Pd/C (250 mg) of 10%, room temperature leads to hydrogen 16 h.Suction filtration, filter cake methanol wash column twice, filtrate concentrates, and obtains solid 890 mg, yield: 86.7%.
The preparation of 2.4-((4-hydroxyl-2-(trifluoromethyl) phenylimino) methyl) methyl benzoate
By 4-amino-3-(trifluoromethyl) phenol (890 mg; 5.03 mmol) be dissolved in 30 mL DCM; add p formylbenzoic acid methyl esters (3.28 g; 20.0 mmol) and 10 mL acetic acid; 36 h are reacted at 40 DEG C; be spin-dried for solvent, be directly used in next step reaction.
The preparation of 3.4-((4-hydroxyl-2-(trifluoromethyl) anilino) methyl) methyl benzoate
The crude product upper step obtained 30 mL dissolve with methanol, add sodium borohydride (1.22 g, 32.1 mmol), room temperature reaction 3h, is spin-dried for solvent, is directly used in next step.
The preparation of 4.4-(((4-hydroxyl-2-(trifluoromethyl) phenyl) (methyl) is amino) methyl) methyl benzoate
Upwards step system adds 30 mL formalins, add 3 mL formic acid, be warming up to 100 DEG C of reaction 16h, be spin-dried for reaction solution, crude product is dissolved in 200 mL ethyl acetate, wash with saturated sodium bicarbonate aqueous solution, washing is once, dry, concentrated, column chromatography (PE:EA=20:1-1:1) obtains product 460 mg, three step yields: 27%.
The preparation of 5.4-(((4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) phenyl) (methyl) is amino) methyl) methyl benzoate
In dry reaction flask, add 4-(chloromethyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole (319 mg, 1.00 mmol) and 4-(((4-hydroxyl-2-(trifluoromethyl) phenyl) (methyl) is amino) methyl) methyl benzoate (339 mg, 1.00 mmol) dissolve with 8 mLDMA, then salt of wormwood (414 mg are added, 3.00 mmol) and potassiumiodide (166 mg, 1.00 mmol), stirring at room temperature 24 h, add water in system, use EA aqueous phase extracted, drying also concentrates organic phase, column chromatography (PE:EA=20:1-2:1) obtains 320 mg products, yield is 51.5%.
6.4-(((4-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) phenyl) (methyl) is amino) methyl) benzoic preparation
By 4-(((4-((5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) phenyl) (methyl) amino) methyl) methyl benzoate (320 mg, 0.515 mmol) be dissolved in 5 mL methyl alcohol and 2 mL water, sodium hydroxide (206 mg are added under ice bath, 5.15 mmol), stirring at room temperature 4 h, 1 h is stirred in the oil bath of 50 DEG C, system pH dilute hydrochloric acid is adjusted to 6, then concentrating under reduced pressure falls methyl alcohol, extraction, obtain crude product 300 mg, column chromatography (PE:EA=20:1-1:1) obtains 260 mg products, yield is 83.1%.
Molecular formula: C 29h 23cl 2f 3n 2o 3s molecular weight: 606.1 mass spectrums (M+H): 607.1
1H-NMR(d 6-DMSO,400 MHz)：12.87(1H,s),7.88(2H,d),7.58-7.50(3H,m),7.48-7.40(3H,m),7.10(1H,dd),6.97(1H,d),4.99(2H,s),3.98(2H,s),2.43(3H,s),1.30-1.20(3H,m),0.87-0.78(2H,m)
embodiment 18 4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of phenylformic acid (compound 18)
The preparation of 1.5-nitro-4-(trifluoromethyl) pyridine-2-alcohol
By 2-hydroxyl-4-5-flumethiazine (3.26 g, 20.0 mmol) be dissolved in the vitriol oil (10 mL), nitrosonitric acid (4 mL) is slowly dripped at 0 DEG C, drip and finish, go at room temperature reaction went to 65 DEG C after one hour and react 4 h, cooling, add trash ice, sodium hydroxide solution with 50% adjusts pH ≈ 6, extraction into ethyl acetate, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography (ethyl acetate: sherwood oil=1:3), obtains white solid 1.42 g, yield 34.1%.
The preparation of 2.5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((5-nitro-4-(trifluoromethyl) pyridine-2-base oxygen base) methyl) isothiazole
By 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole (392 mg, 1.23 mmol) and 5-nitro-4-(trifluoromethyl) pyridine-2-alcohol (256 mg, 1.23 mmol) be dissolved in DMA (10 mL), add salt of wormwood (510 mg, 3.69 mmol) and potassiumiodide (204 mg, 1.23 mmol), room temperature lucifuge stirs 24 h, add water in system, be extracted with ethyl acetate aqueous phase, drying also concentrates organic phase, column chromatography (PE:EA=10:1) obtains 376 mg products, and yield is 62.4%.
The preparation of 3.6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridine-3-amine
By 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((5-nitro-4-(trifluoromethyl) pyridine-2-base oxygen base) methyl) isothiazole (900mg, 1.83 mmol), zinc powder (1.2 g, 18.3 mmol) and acetic acid (440 mg, 7.32 mmol) be mixed in 10 mL methyl alcohol, be warming up to 50 DEG C of reactions 4 hours, filter, concentrated, crude product is dissolved in 100 mL ethyl acetate, washs three times with saturated sodium bicarbonate aqueous solution, and washing once, dry, concentrated, obtain yellow solid 771 mg, yield 91.3%.
The preparation of 4.4-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl imino-) methyl) methyl benzoate
By 6-((5-cyclopropyl-3-(2; 6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridine-3-amine (771 mg; 1.67 mmol) be dissolved in 20 mL 1; in 2-ethylene dichloride; add p formylbenzoic acid methyl esters (550 mg, 3.35 mmol) and 5 mL acetic acid, react 16 hours at 40 DEG C; be spin-dried for solvent, be directly used in next step.
The preparation of 5.4-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl is amino) methyl) methyl benzoate
20 mL methyl alcohol are added in crude product obtained in the previous step (about 1.67 mmol), add sodium triacetoxy borohydride (1.77g, 8.35 mmol), be warming up to 50 DEG C of reactions 12 hours, be spin-dried for solvent, cross silicagel column (sherwood oil: ethyl acetate=10:1) and obtain white solid 271 mg, two steps add up to yield 26.6%.
The preparation of 6.4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) methyl benzoate
By 4-((6-((5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl amino) methyl) methyl benzoate (271 mg, 0.445 mmol), add 10 mL formalins, add 1 mL formic acid, be warming up to 100 DEG C of reactions 12 hours, be spin-dried for reaction solution, crude product is dissolved in 50 mL ethyl acetate, three times are washed with saturated sodium bicarbonate aqueous solution, washing once, dry, concentrated, cross silicagel column (sherwood oil: ethyl acetate=10:1) and obtain white solid 145 mg, yield 52.4%.
7.4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
By 4-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-4-(trifluoromethyl) pyridin-3-yl) (methyl) amino) methyl) methyl benzoate (145 mg, 0.233 mmol) be dissolved in 10 mL methyl alcohol, add hydronium(ion) Lithium Oxide 98min (49 mg, 1.165 mmol) the aqueous solution 2 mL, react 12 hours under room temperature, dilute hydrochloric acid adjusts pH to 5, separate out precipitation, drying obtains white solid 44 mg, yield 31%.
Molecular formula: C 28h 22cl 2f 3n 3o 3s molecular weight: 607.1 mass spectrums (M+H): 608.0
1H-NMR(CDCl 3,400 MHz)：δ8.04(2H,d),7.48-7.35(5H,m),7.02(1H,s),6.85(1H,s),5.05(2H,s),3.84(2H,s),2.40(3H,s),2.12(1H,m),1.15-1.08(2H,m),0.77-0.70(2H,m)。
embodiment 19 4-(((5-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-3-5-flumethiazine-2-base) (first base) amino) methyl) preparation of phenylformic acid (compound 19)
The preparation of the fluoro-2-nitropyridine of the bromo-5-of 1.3-
Take Potassium Persulphate (24.3 g, 90.0 mmol) be mixed in the 30 mL vitriol oils, stirred at ambient temperature 10 minutes, 3-bromo-5-fluorine pyridine-2-amine (5.73 g are slowly added after being cooled to 0 DEG C, 30.0 mmol), slowly room temperature is risen to after adding, continue reaction 4 hours, 100 mL ethyl acetate are added in reaction flask, ammoniacal liquor adjusts pH to 8-9, separate organic phase, organic phase saturated common salt water washing three times, dry, concentrated, silica gel column chromatography (100% sherwood oil-sherwood oil: ethyl acetate=50:1) obtains 3.25 g light yellow oil, yield 49%.
The preparation of the bromo-5-methoxyl group of 2.3--2-nitropyridine
By fluoro-for bromo-for 3-5-2-nitropyridine (3.25 g, 14.7 mmol) be dissolved in 50 mL methyl alcohol, add sodium methylate (1.59 g, 29.4mmol), 60 DEG C are reacted 2 hours, reaction solution concentrates, and silica gel column chromatography (100% sherwood oil-sherwood oil: ethyl acetate=30:1) obtains yellow solid 2.63 g, yield 76.9%.
The preparation of 3.5-methoxyl group-2-nitro-3-5-flumethiazine
By bromo-for 3-5-methoxyl group-2-nitropyridine (2.33 g, 10.0 mmol), 2-chloro-2, 2-methyl difluoroacetate (3.61 g, 25.0mmol), cuprous iodide (3.8 g, 20.0 mmol) and Potassium monofluoride (1.16 g, 20.0 mmol) be mixed in 30 mL N, in dinethylformamide, be warming up to 100 DEG C of lucifuges and react 4 hours, add 15 mL ammoniacal liquor and 20 mL saturated ammonium chloride solution cancellation reaction, stir one hour, separate organic phase, aqueous phase extraction into ethyl acetate three times, merge organic phase to concentrate, silica gel column chromatography (100% sherwood oil-sherwood oil: ethyl acetate=30:1) obtains yellow solid 1.1 g, yield 49.5%.
The preparation of 4.6-nitro-5-5-flumethiazine-3-alcohol
By 5-methoxyl group-2-nitro-3-5-flumethiazine (1.1 g, 4.95 mmol) be dissolved in 15 mL N, in dinethylformamide, add lithium chloride (4.2 g, 99.0 mmol), be warming up to 150 DEG C of reactions 2 hours, reaction solution concentrates, crude product silica gel column chromatography (100% sherwood oil-sherwood oil: ethyl acetate=1:1) obtains light yellow oil 0.52 g, yield 50.5%.
The preparation of 5.6-chlorin-5-trifluoro picoline-3-alcohol
In dry single port reaction flask, 6-nitro-5-5-flumethiazine-3-alcohol (0.52 g, 2.5 mmol) is dissolved in 10 mL methyl alcohol, adds the palladium charcoal of 50 mg 10%, pass into hydrogen, room temperature reaction 12 hours, filter, filter cake washing is once, filtrate merges, concentrated, obtain light yellow oil 0.37 g, yield 83.1%.
The preparation of 6.4-((5-hydroxyl-3-5-flumethiazine-2-base imino-) methyl) methyl benzoate
In dry single port reaction flask; add 6-chlorin-5-trifluoro picoline-3-alcohol (0.37 g; 2.08 mmol) and p formylbenzoic acid methyl esters (1.71 g; 10.4 mmol); add 20 mL methylene dichloride; add several glacial acetic acids, under room temperature, react 24 h, be spin-dried for reaction solution and be directly used in next step.
The preparation of 7.4-((5-hydroxyl-3-5-flumethiazine-2-base is amino) methyl) methyl benzoate
The crude product of previous step gained is dissolved in 10 mL methyl alcohol, slowly adds sodium cyanoborohydride (0.654 g, 10.4 mmol), react 12 h under room temperature, be spin-dried for reaction solution and be directly used in next step.
The preparation of 8.4-(((5-hydroxyl-3-5-flumethiazine-2-base) (methyl) is amino) methyl) methyl benzoate
Previous step gained crude product is added 10 mL formalins, add 1 mL formic acid, be warming up to 100 DEG C of reactions 12 hours, be spin-dried for reaction solution, crude product is dissolved in 50 mL ethyl acetate, three times are washed with saturated sodium bicarbonate aqueous solution, washing is once, dry, concentrated, silica gel column chromatography (100% sherwood oil-sherwood oil: ethyl acetate=10:1) obtains crude oil 0.87 g, is directly used in next step.
The preparation of 9.4-(((5-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-3-5-flumethiazine-2-base) (methyl) is amino) methyl) methyl benzoate
By crude product 0.87 g obtained in the previous step, 4-(chloromethyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole (0.853 g, 3.0mmol), potassiumiodide (0.345 g, 2.08 mmol) and salt of wormwood (0.287 g, 2.08 mmol) be mixed in 10 mL N, in N-N,N-DIMETHYLACETAMIDE, room temperature lucifuge reacts 24 hours, add 100 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain colorless oil 0.25 g, four steps add up to yield 19.3%.
10.4-(((5-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-3-5-flumethiazine-2-base) (methyl) is amino) methyl) benzoic preparation
By 4-(((5-((5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole-4-base) methoxyl group)-3-5-flumethiazine-2-base) (methyl) amino) methyl) methyl benzoate (0.25 g, 0.402 mmol) be dissolved in 5 mL methyl alcohol, add sodium hydroxide (0.161 g, 4.02 mmol) the aqueous solution 2 mL, room temperature reaction 12 hours, dilute hydrochloric acid adjusts pH to acid, extraction into ethyl acetate, dry, concentrated, cross silicagel column (sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain white crude 190 mg, further use high pressure is prepared liquid phase purifying and is obtained white solid 52 mg, yield 21.3%.
Molecular formula: C 28h 22cl 2f 3n 3o 3s molecular weight: 607.1 mass spectrums (M+H): 608.0
1H-NMR(DMSO-d 6,400MHz)δ8.11(1H,d),7.82(2H,d),7.63-7.40(4H,m),7.28(2H,d),5.08(2H,s),4.21(2H,s),2.59(3H,s),2.47-2.41(1H,m),1.28-1.20(2H,m),0.86-0.81(2H,m).
the chloro-4-of embodiment 20 2-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3- base) (methyl) amino) methyl) preparation of phenylformic acid (compound 20)
The preparation of the chloro-5-formylbenzoate of 1.2-
Take 5-bromine 2-chloro-benzoic acid (10.0 g, 42.5 mmol) join in the tetrahydrofuran (THF) of 100 mL dryings,-45 DEG C add isopropylmagnesium chloride Grignard reagent (2 M, 53 mL, 0.106 mol), slowly be warming up to 0 DEG C afterwards, slowly add N, dinethylformamide (9.3 g, 0.127 mol) tetrahydrofuran solution 20 mL, finish and rise to room temperature reaction 12 hours, add dilute hydrochloric acid cancellation reaction, add 500 mL ethyl acetate, separate organic phase, organic phase saturated aqueous common salt washes twice, dry, concentrated, silica gel column chromatography (methylene dichloride-methylene dichloride: methyl alcohol=100:1), obtain yellow solid 4.31 g, yield 54.8%.
The preparation of 2.5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((5-nitro-6-(trifluoromethyl) pyridine-2-base oxygen base) methyl) isothiazole
By 5-nitro-6-(trifluoromethyl) pyridine-2-alcohol (0.431 g, 2.07 mmol), 4-(chloromethyl)-5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole (0.66 g, 2.07 mmol), potassiumiodide (0.345 g, 2.07 mmol) and salt of wormwood (0.287 g, 2.07 mmol) be mixed in 10 mL N, in N-N,N-DIMETHYLACETAMIDE, room temperature lucifuge reacts 48 hours, add 100 mL ethyl acetate, three times are washed with saturated sodium-chloride water solution, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=10:1) and obtain colorless oil 0.83 g, yield 81.6%.
The preparation of 3.6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3-amino
By 5-cyclopropyl-3-(2, 6-dichlorophenyl)-4-((5-nitro-6-(trifluoromethyl) pyridine-2-base oxygen base) methyl) isothiazole (0.83 g, 1.69 mmol), zinc powder (1.1 g, 16.9 mmol) and 0.5 ml acetic acid be mixed in 20 mL methyl alcohol, be warming up to 50 DEG C of reactions 8 hours, filter, concentrated, crude product is dissolved in 200 mL ethyl acetate, three times are washed with saturated sodium bicarbonate aqueous solution, washing once, dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=5:1) and obtain yellow solid 0.52 g, yield 66.9%.
The chloro-5-of 4.2-((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl is amino) methyl) benzoic preparation
By 6-((5-cyclopropyl-3-(2, 6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridine-3-amino (0.52 g, 1.13 mmol), chloro-5-formylbenzoate (1.04 g of 2-, 5.63 mmol) and titanium isopropylate (0.963 g, 3.39 mmol) be dissolved in 20 mL anhydrous methanols, room temperature reaction 72 hours, add sodium cyanoborohydride (0.710 g, 11.3 mmol), reaction is continued 4 hours under room temperature, reaction solution concentrates, cross silicagel column (100% methylene dichloride-methyl chloride: methyl alcohol=50:1) obtain yellow crude 2.05g be directly used in next step reaction.
The chloro-5-of 5.2-(((6-((5-cyclopropyl-3-(2,6-dichlorophenyl) isothiazole-4-base) methoxyl group)-2-(trifluoromethyl) pyridin-3-yl) (methyl) is amino) methyl) benzoic preparation
20 mL formalins are added in previous step crude product, add 1 mL formic acid, be warming up to 100 DEG C of reactions 8 hours, add water, extraction into ethyl acetate three times, organic phase is dry, concentrated, cross silicagel column (100% sherwood oil-sherwood oil: ethyl acetate=1:1) and obtain off-white color 0.121 g, two steps add up to yield 16.6%.
Molecular formula: C 28h 21cl 3f 3n 3o 3s molecular weight: 641.0 mass spectrums (M+H): 642.0
1H-NMR(CDCl 3,400 MHz)：7.94(1H,s),7.63(1H,d),7.60-7.51(1H,m),7.45(1H,d),7.38-7.30(2H,m),7.25-7.17(1H,m),6.76(1H,d),5.38(2H,s),3.95(2H,s),2.52(3H,s),2.49-2.40(1H,m),0.92-0.80(4H,m).

Claims (10)

1. logical compound shown in formula I or its pharmacy acceptable salt:
Wherein, R 1for hydrogen, halogen, cyano group, amino, C 1-6alkyl ,-(CH 2) g-C 3-8cycloalkyl or C 1-6alkoxyl group, wherein C 1-6alkyl is optionally by 1-3 independent selected from halo, hydroxyl or C 1-6the group of alkoxyl group replaced,
R 2for hydrogen, halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group,
T is-O-,-S-,-C (R 5) (R 6)-or-N (R 5)-, R 5and R 6independently be hydrogen, C 1-6alkyl or C 3-8cycloalkyl, wherein said C 1-6alkyl or C 3-8cycloalkyl can be replaced by 1-5 fluorine atom,
A ring and B ring independently be 6-14 unit aryl, 5-14 unit heteroaryl, C 3-14the heterocyclic radical of the saturated and/or fractional saturation of cycloalkyl or 3-14 unit,
L 1-L 2for-C (R 8)=C (R 8)-,-R 7-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-O-R 7-,-R 7-O-,-C (O)-R 7-,-S-R 7-,-R 7-S-,-S (O) f-R 7-,-R 7-S (O) f-,-S (O) fn (R 8-S)-, (O) f-R 7-N (R 8)-,-N (R 8) S (O) f-, wherein R 7and R 8independently be selected from hydrogen or C 1-6alkyl, f is the integer of 0-2,
R 3for hydrogen, halogen, amino, C 1-6alkyl amine group, two (C 1-6alkyl) amido, C 1-6alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-6alkyl, cyano group, nitro, azido-, carboxyl, C 2-6alkenyl, C 2-6alkynyl, C 3-6cycloalkyl, C 1-6alkyl, halo C 1-6alkyl, amino-sulfonyl, amino-sulfonyl C 1-6alkyl, formamyl, formamyl C 1-6alkyl, C 1-6alkyl-carbonyl or C 1-6alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-6alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-6alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkylidene group-R 12, SO 2-C 1-6alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p, g and q independently be 0 ~ 5 integer.
2. compound as claimed in claim 1 or its pharmacy acceptable salt:
Wherein, T is-O-.
3. compound as claimed in claim 2 or its pharmacy acceptable salt:
Wherein, R 1for hydrogen, C 1-6alkyl or C 3-8cycloalkyl,
R 2for hydrogen, halogen, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkoxyl group or halo C 1-6alkoxyl group,
A ring and B ring independently be 6-14 unit aryl, 6-14 unit heteroaryl, C 3-8the heterocyclic radical of the saturated and/or fractional saturation of cycloalkyl or 3-8 unit,
L 1-L 2for-C (R 8)=C (R 8)-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-C (O)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-6alkyl,
R 3for hydrogen, halogen, amino, C 1-6alkyl amine group, two (C 1-6alkyl) amido, C 1-6alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-6alkyl, cyano group, nitro, azido-, carboxyl, C 2-6alkenyl, C 2-6alkynyl, C 3-6cycloalkyl, C 1-6alkyl, halo C 1-6alkyl, amino-sulfonyl, amino-sulfonyl C 1-6alkyl, formamyl, formamyl C 1-6alkyl, C 1-6alkyl-carbonyl or C 1-6alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-6alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-6alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-6alkyl, halo C 1-6alkyl, C 1-6alkylidene group-R 12, SO 2-C 1-6alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p and q independently be 0 ~ 5 integer.
4. compound as claimed in claim 3 or its pharmacy acceptable salt:
Wherein, R 1for hydrogen, C 1-4alkyl or C 3-6cycloalkyl,
R 2for hydrogen, halogen, C 1-4alkyl, halo C 1-4alkyl, C 1-4alkoxyl group or halo C 1-4alkoxyl group,
A ring and B ring independently be pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, 1, 3-cyclohexadiene, Pyrrolidine, 2, 3-pyrrolin, 2, 5-pyrrolin, pyrroles, azetidine, imidazoles, 4, 5-glyoxalidine, pyrazoles, 4, 5-pyrazoline, 1, 2, 3-triazole, 1, 2, 4-triazole, tetramethylene sulfide, thiophene, 2, 3-dihydro-thiophene, thiazole, 4, 5-thiazoline, isothiazole, 1, 2, 4-thiadiazoles, tetrahydrofuran (THF), 2, 3-dihydrofuran, furans, 4, 5-dihydro-oxazole, oxazole, 4, 5-dihydro-isoxazole, isoxazole, 1, 2, 4-oxadiazole, phenyl ring, 1, 4, 5, 6-tetrahydropyrimidine, 1, 6-dihydro-pyrimidin, 4, 5-dihydro-pyrimidin, 2-pyridone, 4-pyridone, pyrimidine, 3, 6-dihydro-2H-pyrans, 2H-pyrans, piperidines, 1, 2, 3, 4-tetrahydropyridine, 1, 2, 3, 6-tetrahydropyridine, 2, 3-dihydropyridine, pyridine, piperazine, 1, 2, 3, 4-tetrahydrochysene pyrazine, 2, 3-dihydro pyrazine or pyrazine,
L 1-L 2for-C (R 8)=C (R 8)-,-N (R 8)-R 7-,-R 7-N (R 8)-,-N (R 8) C (O)-R 7-,-N (R 8) C (O) N (R 8)-,-C (O) N (R 8)-,-C (O)-R 7-N (R 8)-,-C (O)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-4alkyl,
R 3for hydrogen, halogen, amino, C 1-4alkyl amine group, two (C 1-4alkyl) amido, C 1-4alkyl amine group formyl radical, hydroxyl, hydroxyl C 1-4alkyl, cyano group, nitro, azido-, carboxyl, C 1-4alkyl, C 2-4alkenyl, C 2-4alkynyl, C 3-6cycloalkyl, halo C 1-4alkyl, amino-sulfonyl, amino-sulfonyl C 1-4alkyl, formamyl, formamyl C 1-4alkyl, C 1-4alkyl-carbonyl or C 1-4alkyl carbonyl oxy,
R 4for hydrogen, halogen, C 1-4alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-4alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl, C 1-4alkyl, halo C 1-4alkyl, C 1-4alkylidene group-R 12, SO 2-C 1-4alkyl, wherein R 12for COOH, OH or SO 3h,
M, n, p and q independently be 0 ~ 3 integer.
5. compound as claimed in claim 4 or its pharmacy acceptable salt:
Wherein, R 1for hydrogen, C 1-4alkyl or C 3-6cycloalkyl,
R 2for hydrogen, halogen, C 1-4alkyl or halo C 1-4alkyl,
A ring and B ring independently be phenyl ring, pyridine, hexanaphthene, thiophene, 1,2,4-oxadiazole, pentamethylene, piperidines, Pyrrolidine, azetidine, furans, pyrroles, imidazoles, pyrazoles, thiazole, isothiazole, 1,2,4-thiadiazoles, tetrahydrofuran (THF), isoxazole, 2-pyridone, 4-pyridone, 1,2,4-triazole or piperazine
L 1-L 2for-C (R 8)=C (R 8)-or-N (R 8)-R 7-, wherein R 7and R 8independently be selected from hydrogen or C 1-4alkyl,
R 3for hydrogen, halogen, C 1-4alkyl or halo C 1-4alkyl,
R 4for hydrogen, halogen, C 1-4alkyl, COOR 9, CONR 10r 11or tetrazyl, R 9for hydrogen or C 1-4alkyl, R 10and R 11independently be selected from hydrogen, hydroxyl or C 1-4alkyl,
M, n, p and q independently be 0 ~ 2 integer.
6. compound as claimed in claim 5 or its pharmacy acceptable salt:
Wherein, R 1for propyl group, sec.-propyl or cyclopropane base,
R 2for hydrogen, fluorine atom, chlorine atom or methyl,
A ring is phenyl ring or pyridine,
B ring is phenyl ring or hexanaphthene,
L 1-L 2for-CH=CH-,-NHCH 2-,-N (CH 3) CH 2-or-N (CH 2cH 3) CH 2-,
R 3for hydrogen, chlorine atom or trifluoromethyl,
R 4for hydrogen, fluorine atom, chlorine atom, methyl ,-COOH ,-CONHOH or tetrazyl,
M is 0,
N is 2,
P is 0 or 1,
Q is 0,1 or 2.
7. compound as claimed in claim 1 or its pharmacy acceptable salt:
8. the pharmaceutical preparation containing compound described in any one of claim 1-7 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.
9. pharmaceutical composition, containing the compound described in any one of claim 1-7 or its pharmacy acceptable salt, also comprises other medicines activeconstituents.
10. the compound as described in claim 1-7 or its pharmacy acceptable salt are preparing the application treated and/or prevented in the medicine of the disease mediated by FXR.
CN201410493612.9A 2013-09-28 2014-09-24 Fxr agonist Pending CN104513213A (en)

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