CN109053751A - FXR regulator with spirane structure - Google Patents

FXR regulator with spirane structure Download PDF

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CN109053751A
CN109053751A CN201810994739.7A CN201810994739A CN109053751A CN 109053751 A CN109053751 A CN 109053751A CN 201810994739 A CN201810994739 A CN 201810994739A CN 109053751 A CN109053751 A CN 109053751A
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base
alkyl
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黄浩喜
李劲思
刘冠锋
陈垌珲
任俊峰
易守兵
李英富
苏忠海
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Chengdu Haibo Rui Pharmaceutical Co Ltd
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Abstract

The present invention provides a kind of noval chemical compound, which has certain agonist activity to method Buddhist nun's ester derivant X receptor (FXR), for treating the disease and/or illness that mediate including FXR, such as treatment hepatopathy or enterogastric diseases.

Description

FXR regulator with spirane structure
Technical field
The present invention relates to field of medicinal chemistry, more particularly to a kind of compound and application thereof.
Background technique
The full name Fa Ni ester derivant X receptor of FXR, belongs to nuclear receptor superfamily member, is that a kind of bile acid receptor and cholic acid close At biosensor, cholic acid is its native ligand.As a kind of multi-functional transcription factor, sent out by adjusting a variety of target genes Important function is waved, is the important target spot for treating dyslipidemia and the exploitation of anti-fatty liver drug.On mechanism of action, FXR can be adjusted The gene expression of cholesterol 7α-hdroxylase is controlled, CYP7A1 is the biosynthesis rate-limiting enzyme of bile acid.In addition, it can also reinforce into fibre The secretion of cell factor 19 is tieed up, which is the inhibition adjuster of bile acid in gallbladder.FXR can also by regulation liver gluconeogenesis and Decomposition of glycogen controls glycometabolism, controls periphery striated muscle and adipose tissue to the sensibility of insulin, adjusts liver regeneration function It is in progress with cirrhosis is influenced.
Show that FXR takes part in the pathological processes of a variety of diseases in recent study, siltation, gall-bladder such as bile Stone, diabetes and atherosclerosis.FXR agonist can be synthetically formed negative-feedback by interference bile, activate CYP7A1 Transcription, promote more cholesterol to become bile acid.In oncotherapy, FXR also shows huge potentiality, research shows that FXR is related in colon cancer, breast cancer and liver regeneration and liver cancer generation.
At present, it has been reported that the FXR agonist of various structures type, such as: GW4064 can reduce plasma triglyceride Level, but because its oral administration biaavailability is poor, metabolism is fast, high dose when show toxicity and then limit its clinical application；It is difficult to understand Shellfish cholic acid is administered in combination treatment primary biliary cirrhosis (PBC) with ursodesoxycholic acid (UDCA) and has listed, for treatment The clinical test of nonalcoholic steatohepatitis (nonalcoholic steatohepatitis, NASH) is still underway；PX- 104 show safety and good tolerance in the I phase clinic for the treatment of NASH, and II phase clinic is in progress；FXR-450 It can reduce plasma triglyceride and cholesterol levels in dyslipidemia model；Anti-parasite medicine ivermectin is in recent years Also it is found to be FXR ligand, shows the effect of hypoglycemic and norcholesterol.Tropifexor is a kind of novel non-gallbladder of selectivity Juice acid FXR agonist, preclinical zoopery show that the drug can be reduced cholestasis and hepatocellular injury.One into II capable clinical trial phase has evaluated effect and safety of the tropifexor in liver cirrhosis patient.Data are shown, the 28th It observes the GGT for receiving the patient of tropifexor, and ALP, bilirubin, alanine aminotransferase (ALT) and aspartic acid turn ammonia Enzyme (AST) shows dose-dependent reduction.And tropifexor usual safety and tolerance is good under proof load.
Steroid FXR agonist Austria shellfish cholic acid is ratified to list in 27 Nikkei U.S. FDA May in 2016, and Thomson Reuters are pre- The sales volume of the year two thousand twenty is surveyed up to 2,600,000,000 dollars.But the drug has itch, high-density lipoprotein cholesterol reduction and low-density The adverse reactions such as lipoprotein cholesterol raising.Nonsteroidal FXR agonist structure has diversity, and multiple compounds, which have been in, to be faced Bed before or clinical investigation phase.Therefore, when ligand activity it is relatively low/partial agonist/antagonism FXR and ligand only select Property when regulating and controlling related target gene, can avoid some adverse reactions.Steroidal excitomotor is due to containing common steroidal parent nucleus, usually With poor nuclear receptor selectivity, therefore the emphasis of research is turned to the research of nonsteroidal agonist by researcher, though Progress is achieved, but still is improved improved huge space.
Summary of the invention
The present invention relates to general formula (I) compound represented, its pharmaceutically acceptable salt or its stereoisomers:
Wherein R is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, carbonyl, CF3, replace or non-take The C in generation1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C3-8Ring Heterocyclylalkyl, C2-8Alkenyl or C2-8Alkynyl；The substituent group is 1 ~3 cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, carbonyl, C1-6Alkyl, C1-6Alkoxy, C1-6Naphthenic base；It is described Hetero atom is N, O, S；
Ar is selected from C5-10Aryl or 5-10 unit's heteroaryl；Wherein each ring is optionally independently selected from 1,2,3 or 4 below and is taken Replace for base: C1-6Alkoxy, C1-6Alkoxy carbonyl, C1-6Alkoxycarbonyl amino, C1-6Alkyl, (C1-6Alkyl) carbonyl, (C1-6 Alkyl) sulfonyl, acylamino-, amino, carbonyl, carboxyl, cyano, formoxyl, halogen, halogenated C1-3Alkyl, halogenated C1-3Alkoxy, CF3；
A is selected from C5-10Aryl or 5-10 unit's heteroaryl are optionally further selected from halogen, cyano, acyl ammonia by one or more Base, amino, carbonyl, nitro, CF3、C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Virtue Base, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,- C0-8-O-R1、-C0-8-C(O)OR1、-C0-8-C(O)R1、-C0-8-O-C(O)R2、-C0-8-NR3R4、-C0-8-C(O)NR3R4、-N (R3)-C(O)R2、-C(O)N(R3)S(O)2R5Or-N (R2)-C(O)OR1Substituent group replaced；The hetero atom is N, O, S.
Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen Element, cyano, acylamino-, amino, carbonyl, nitro, carboxyl.
In some preferred embodiments, wherein R is selected from substituted or non-substituted C3-6Naphthenic base, the substituent group be 1~ 3 cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, carbonyl, C1-6Alkyl, C1-6Alkoxy, C1-6Naphthenic base.
Further R is selected from cyclopropyl.
In some preferred embodiments, Ar is selected from phenyl；Wherein phenyl ring is optionally independently selected from below 1,2,3 or 4 A substituent group replaces: C1-6Alkoxy, C1-6Alkoxy carbonyl, C1-6Alkoxycarbonyl amino, C1-6Alkyl, (C1-6Alkyl) carbonyl, (C1-6Alkyl) sulfonyl, acylamino-, amino, carboxyl, cyano, formoxyl, halogen, halogenated C1-3Alkyl, halogenated C1-3Alkoxy, CF3。
Further: Ar is selected from phenyl, and the substituent group on phenyl is CF3。
In some preferred embodiments: A be selected from phenyl, pyridyl group,Optionally further Halogen, cyano, acylamino-, amino, carbonyl, nitro, CF are selected from by one or more3、C1-6Alkyl ,-C (O) OR1、-C0-8-C(O) NR3R4、-C(O)-N(R3)S(O)2R5Substituent group replaced, wherein 2 carbon of thiphene ring are connected to piperidines N.
Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen Element, cyano, acylamino-, amino, carbonyl, nitro, carboxyl.
Further: A is selected from flowering structure in its pharmaceutically acceptable salt or its stereoisomer
In some embodiments the present invention have (II) formula possessed by compound, its pharmaceutically acceptable salt or its Stereoisomer:
A be selected from phenyl, pyridyl group,Halogen, cyanogen are further optionally selected from by one or more Base, acylamino-, amino, carbonyl, nitro, CF3、C1-6Alkyl ,-C (O) OR1、-C0-8-C(O)NR3R4、-C(O)-N(R3)S(O)2R5 Substituent group replaced；Wherein 2 carbon of thiazole ring are connected to piperidines N.
Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen Element, cyano, acylamino-, amino, carbonyl, nitro, carboxyl.
As most preferably scheme, compound, pharmaceutically acceptable salt or its solid that the present invention has following structure are different Structure body:
Another aspect of the present invention provides aforementioned formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts and exists Prepare the application in the drug of the disease or situation for preventing or treating FXR mediation；The disease or situation that the FXR is mediated are excellent Selected from cardiovascular disease, atherosclerosis, artery sclerosis, hypercholesterolemia, hyperlipidemia, chronic liver disease, chronic liver disease, Gastrointestinal disease, nephrosis, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or neural sign such as apoplexy.
Hepatitis B is selected from as chronic liver disease described in further preferred scheme, primary hardens (PBC), the dirty property xanthomatosis of brain (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasia, intrahepatic cholestasis of pregnancy, parenteral absorption Associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, Alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease (NASH), liver transfer operation associated graft It is the anti-host disease of object, live donor liver transfer operation regeneration, congenital hepatic fibrosis, choledocholithiasis, granular hepatopathy, pernicious in or beyond liver Tumour, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or 1 primary antibody membrane proteolytic enzyme of α lack Weary disease；The gastrointestinal disease is selected from inflammatory bowel disease (IBD) (including Crohn's disease and routed characteristic of disease enteritis), intestines easily swash synthesis Sign (IBS), bacterial overgrowth, nutrient absorption are bad, reflection postcolon is scorching or microscopic colitis；The nephrosis is selected from glycosuria Sick nephrosis, Focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulus inflammation, chronic transplant glomerulus Disease, arteriosclerotic kidney or polycystic kidney disease；The cardiovascular disease is selected from arteriosclerosis, artery sclerosis, dyslipidemia, height Cholesterolemia or hypertriglyceridemia；The metabolic disease be selected from insulin resistance, type-1 diabetes mellitus, type-2 diabetes mellitus or It is fat.
" C of the present invention1-6Alkyl " refers to " C of the present invention1-6Alkyl " expression linear chain or branched chain contains 1-6 The alkyl of a carbon atom, including such as " C1-4Alkyl ", " C1-3Alkyl " etc., specific example include but is not limited to: methyl, ethyl, N-propyl, isopropyl, normal-butyl, 2- methyl-propyl, 1- methyl-propyl, 1,1- dimethyl ethyl, n-pentyl, 3- methyl butyl, 2- methyl butyl, 1- methyl butyl, 1- ethyl propyl, n-hexyl, 4- methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- first Base amyl, 3,3- dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 1,2- dimethylbutyl, 1,3- dimethyl Butyl, 2,3- dimethylbutyl, 2- ethyl-butyl, 1,2- dimethyl propyl etc..
" C of the present invention2-8Alkenyl " refers to that the carbon atom number containing at least one double bond is the linear chain or branched chain of 2-8 Or cricoid alkenyl, including such as " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Cycloalkenyl " etc., specific example include But it is not limited to: vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyl, 3- cyclobutenyl, 2- methyl-1-propylene base, 1- methyl -2- Acrylic, 1- pentenyl, 2- pentenyl, 3- pentenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl -3- fourth Alkenyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyl, 3- hexenyl, 2- methyl-1-pentene alkenyl, 3- Methyl-1-pentene alkenyl, 1- methyl -2- pentenyl, 3- methyl -2- pentenyl, 2- methyl-3-pentenyl, 1- methyl -4- amylene Base, 3- methyl -4- pentenyl, 1,1- dimethyl -3- cyclobutenyl, 1,2- dimethyl -3- cyclobutenyl, 1,3- dimethyl -2- butylene Base, 2,2- dimethyl -3- cyclobutenyl, 2,3- dimethyl -2- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2- ethyl -1- butylene Base, 2- ethyl -3- cyclobutenyl, 2- heptenyl, 3- heptenyl, 4- heptenyl, 1- octenyl, 3- octenyl, 4- octenyl, 1,3- Butadienyl, 2,4- pentadienyl, 1,4- hexadienyl, 2,4- hexadienyl, 1,5- heptadiene base, 2,5- heptadiene base, 2, 6- octadienyl etc..
" C of the present invention2-8Alkynyl " refers to that the carbon atom number containing three keys is the alkynyl of the linear chain or branched chain of 2-8, In include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., specific example include but is not limited to: acetenyl, 1- propine Base, 2- butynyl, 1- methyl -2-propynyl, valerylene base, 3- pentynyl, 1- methyl -2- butynyl, 2- methyl -3- butine Base, 1,1- dimethyl -2-propynyl, 1- ethyl -2-propynyl, 2- hexin base, 3- hexin base, 1- methyl-valerylene base, 1- first Base -3- pentynyl, 2- methyl -3- pentynyl, 1,1- dimethyl -3- butynyl, 2- ethyl -3- butynyl, 2- heptynyl, 3- heptan Alkynyl, 4- methyl -2- hexin base, 5- methyl -2- hexin base, 2- methyl -3- hexin base, 5- methyl -3- hexin base, 2- methyl - 4- hexin base, 4- methyl -5- hexin base, 2- octynyl, 3- octynyl, 4- octynyl, 4- methyl -2- heptynyl, 5- methyl -3- Heptynyl, 6- methyl -3- heptynyl, 2- methyl -4- heptynyl, 2- methyl -5- heptynyl, 3- methyl -6- heptynyl etc..
" naphthenic base " refers to that the paraffin section of carbon atom removes the monocycle of saturation or fractional saturation derived from a hydrogen atom Cyclic alkyl, including for example " 3~6 yuan of naphthenic base ", " 3~8 yuan of naphthenic base ", " 4~7 yuan of naphthenic base ", " 4~6 yuan of naphthenic base ", " 5~6 yuan of naphthenic base " etc..The example includes but is not limited to: cyclopropyl alkyl, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl Alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methyl ring Pentyl, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl, cyclopentenyl, 1,3- cyclopentadienyl group, ring Hexenyl, 1,4- cyclohexadienyl, cycloheptenyl, 1,4- cycloheptadiene base, cyclo-octene base etc..
" optional " or " optionally " mean ground described later event or environment can with but need not occur, which includes The event or environment generation or not spot occasion.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to that one or more hydrogen atoms in group are replaced by the substituent group of respective number independently of one another.No Speech and explain, substituent group is only in their possible chemistry position, and those skilled in the art can excessively make great efforts not paying In the case of determine (pass through experiment or theoretical) may or impossible substitution.For example, amino or hydroxyl and tool with free hydrogen Having the carbon atom of unsaturated (such as olefinic) key may be unstable when combining.
" heterocycle " refers to containing at least one hetero atom (such as 1,2,3,4 or 5 hetero atom) saturation or fractional saturation Monocyclic heterocyclic compound remove the obtained group of a hydrogen atom.Including such as " 3~8 circle heterocyclic ring base ", " 3~7 circle heterocyclic rings Base ", " 3~6 circle heterocyclic ring base ", " 3~5 circle heterocyclic ring base ", " 4~7 circle heterocyclic ring base ", " 4~6 circle heterocyclic ring base ", " 5~6 circle heterocyclic rings Base ", 6~7 circle heterocyclic ring bases ", " 6~8 circle heterocyclic ring base " etc..3~8 yuan of fractional saturation list heterocycles, refer to containing double bond, hetero atom Cyclic group.The single heterocycle of 3~8 yuan of saturations, refer to all saturated bonds contains heteroatomic cyclic group.Specific example Include but are not limited to: aziridine base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclo acrylic, Azetidinyl, 1,4- dioxane base, 1,3- dioxane base, 1,3- dioxolane base, 1,4- bis- Oxine base, tetrahydrofuran base, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidine Base, 4,5- pyrazoline base, 2,5- dihydrothiophene, tetrahydro-thienyl, 4,5- dihydro-thiazolyl, piperidyl, piperazinyl, morpholine Base, 4,5- dihydro-oxazole base, 4,5- dihydro-isoxazole base, 2,3- dihydro-isoxazole base, 2H-1,2- oxazines base, 6H-1,3- oxazines Base, 4H-1,3- thiazinyl, 6H-1,3- thiazinyl, 2H- pyranose, 2H- pyran-2-one base, 3,4- dihydro -2H- pyranose, 2, 5- dihydrothiophene, 3,4- dihydro -2H- pyranose, 5,6- dihydro -4H-1,3- oxazines base, 1,2,3,6- tetrahydro pyridyl, 1, 2,3,4- tetrahydro pyridyl, 2,3,4,5- tetrahydro pyridyl etc..
" aryl " refers to full carbon monocycle or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, has conjugation Polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of pi-electron system, " C5-10Aryl " refers to the full carbon containing 5-10 carbon Aryl, " 5-10 member aryl " refer to the full carbon aryl containing 5-10 carbon, such as phenyl and naphthalene.The aryl rings can condense in On heteroaryl, heterocycle or cycloalkyl ring, wherein being aryl rings, non-limiting embodiment with the ring that precursor structure links together Include: phenyl, pyridyl group,
Aryl can be substituted or unsubstituted, and when substituted, substituent group is preferably one or more following groups: Halogen, cyano, acylamino-, amino, carbonyl, nitro, CF3、C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 Circle heterocyclic ring base, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 Unit's heteroaryl sulfenyl ,-C0-8-O-R1、-C0-8-C(O)OR1、-C0-8-C(O)R1、-C0-8-O-C(O)R2、-C0-8-NR3R4、-C0-8-C (O)NR3R4、-N(R3)-C(O)R2、-C(O)N(R3)S(O)2R5Or-N (R2)-C(O)OR1Substituent group replaced；The miscellaneous original Son is N, O, S.C1-6Alkoxy carbonyl, C1-6Alkoxycarbonyl amino, (C1-6Alkyl) carbonyl, (C1-6Alkyl) sulfonyl, formyl Base, halogen, halogenated C1-3Alkyl, halogenated C1-3Alkoxy etc..
" halogen " refers to fluorine, chlorine, bromine or iodine.
The compounds of this invention has the advantage that
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt or their stereoisomer have excellent FXR receptor agonist activity, can by safety for treat and/or prevent nonalcoholic fatty liver, primary biliary cirrhosis, The related diseases such as disorders of lipid metabolism, diabetic complication and malignant tumour.
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt or their stereoisomer are shown good Biological stability acts on more longlasting, bioavilability height.
(3) formula (I) compound of the present invention, its pharmaceutically acceptable salt or their stereoisomer are shown lower Toxicity, drug resistance is good, highly-safe
Specific embodiment
In order to further illustrate the present invention, below with reference to embodiment to it is provided by the invention with practice Buddhist nun ester derivant X by The compound and its preparation method and application of body (FXR) agonist is described in detail.
Following abbreviation has meaning as follows:
DMF indicates N,N-dimethylformamide；
NCS indicates N- chlorosuccinimide；
DCM indicates methylene chloride；
DMA table shows n,N-dimethylacetamide；
DIEA indicates N, N- diisopropylethylamine；
THF indicates tetrahydrofuran；
TFA indicates trifluoroacetic acid；
EA indicates ethyl acetate；
PE indicates petroleum ether；
PPh3Indicate triphenylphosphine；
LAH indicates lithium aluminium hydride reduction；
MeOH indicates methanol；
HBTU indicates benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate；
DMAP indicates 4-dimethylaminopyridine；
EDCI represents 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；
TLC indicates thin layer chromatography.
Embodiment 1:4- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base) benzoic acid preparation
Synthesis step is as follows:
Step 1:(E) -2- (trifluoromethyl) benzaldoxime preparation:
At -5 DEG C by NH2Water (15mL) solution of OHHCl (8.0g, 115mmol) be slowly dropped into NaOH (4.8g, In water (15mL) solution 120mmol).2- (trifluoromethyl) benzaldehyde (17.4g, 100mmol) is slowly added dropwise after stirring 15min Ethyl alcohol (15mL) solution and so that the system is maintained at -5 DEG C.Reaction system becomes cloudy, and continuing will after stirring to system becomes clarification System is to slowly warm up to room temperature.After reacting at room temperature 1h, TLC monitoring consumption of raw materials is finished.Reaction system is diluted with water, is extracted with EA It takes three times, merges organic layer, with saturated common salt water washing, anhydrous Na2SO4It is dry, be evaporated target compound (20.2g, yield: It 97%), is yellow oil.
Step 2:(Z)-N- hydroxyl -2- (trifluoromethyl) benzene imido acyl chloride preparation
Under nitrogen protection, into DMF (100mL) solution of (E) -2- (trifluoromethyl) benzaldoxime (9.45g, 50mmol) It is added portionwise into NCS (7.48g, 56mmol), reacts 1h at room temperature.It is poured into water, three times with EA extraction, merges organic Layer, with saturated common salt water washing, anhydrous Na2SO4Dry, target compound is obtained after concentration, and (11.0g, yield: 96%), being light Yellow oil.
The preparation of step 3:5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- carboxylate methyl ester
K is added in the there-necked flask of 250mL2CO3(3.9g, 28.3mmol) and THF (50mL), at nitrogen is replaced 3 times, -10 DEG C THF (26mL) solution of 3- cyclopropyl -3- propionic acid methyl ester (3.9g, 27.5mmol) is slowly added dropwise, is reacted at -10 DEG C After 30min, the THF solution of (Z)-N- hydroxyl -2- (trifluoromethyl) benzene imido acyl chloride (5.8g, 25.9mmol) is added dropwise, at -5 DEG C Lower stirring 30min, which is then moved at 35 DEG C, to react overnight.Water quenching is added into reaction mixture to go out, three times with EA extraction, is associated with Machine layer, with saturated common salt water washing, anhydrous Na2SO4It is dry, the crude product obtained after concentration by column chromatography (PE/EA=20/1~ 5/1) it isolates and purifies to obtain target compound (8.2g, yield 51%), is yellow oil.
Step 4:(5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methanol preparation
By LiAlH4(1.08g, 28.50mmol) is scattered in THF (20mL), and nitrogen is cooled to -10 DEG C after replacing 5 times, Be slowly added dropwise into the system 5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- carboxylate methyl ester (3.09g, THF solution 9.93mmol) controls temperature in 0 DEG C or less reaction 1h.Slowly add water quenching reaction under ice bath, is extracted with EA Three times, merge organic layer, with saturated common salt water washing, anhydrous Na2SO4It is dry, it is evaporated, obtains target compound (2.98g, yield It 96%), is colorless oil.
The preparation of step 5:4- (bromomethyl) -5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole
(5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methanol is added in 250mL there-necked flask (6.0g, 21.19mmol), PPh3(8.3g, 31.79mmol) and methylene chloride (60mL).It is stirred to solution clarification at room temperature It is slowly dropped to CBr4In the dichloromethane solution (30mL) of (10.5g, 31.79mmol), 1.5h is reacted at room temperature.Concentration The crude product obtained afterwards isolates and purifies to obtain target compound (4.2g, yield by column chromatography (PE/EA=10/1~0/1) It 57%), is white solid.
Step 6:3- (5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen The preparation of miscellaneous spiral shell [4.5] decane -8- carboxylic acid tert-butyl ester
Into 100mL there-necked flask be added 3- hydroxyl -1- oxa- -8- azaspiro [4-] decane -8- carboxylic acid tert-butyl ester (2.75g, 10.69mmol) and DMF (40mL), it under nitrogen protection, is added portionwise into NaH (1.03g, 42.76mmol), reacts 0.5h.Then will DMF (10mL) solution of 4- (bromomethyl) -5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole (3.40g, 9.8mmol) Be slowly injected into there-necked flask, after reaction is warming up to 60 DEG C of reaction 1h.TLC shows that consumption of raw materials finishes, and reaction system is careful It is poured into water, three times with EA extraction, merges organic layer, with saturated common salt water washing, anhydrous Na2SO4It is dry, it is obtained after concentration Crude product is isolated and purified by column chromatography (PE/EA=10/1~3/1), obtains target compound (2.70g, yield 53%), is white Color solid.
Step 7:3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- The preparation of azaspiro [4.5] decane
By 3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- azepine Spiral shell [4.5] decane -8- carboxylic acid tert-butyl ester (2.65g, 5.07mmol) is dissolved in methylene chloride (30mL), and trifluoroacetic acid is added (6mL), reacts 1h at room temperature.TLC shows that consumption of raw materials finishes, and reaction solution is concentrated, and crude product is redissolved in ethyl acetate, uses It is saturated Na2CO3Solution tune pH to 9 after being diluted with water three times with EA extraction merges organic layer, anhydrous with saturated common salt water washing Na2SO4Dry, the crude product obtained after concentration is isolated and purified by column chromatography (DCM/MeOH=16/1~8/1), obtains targeted It closes object (1.78g, yield 82%), is white solid.
Step 8:4- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) ethyl benzoate preparation
By 3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- azepine Spiral shell [4.5] decane (211mg, 0.5mmol) and K2CO3(162mg, 1.2mmol) is scattered in DMF (6mL), and nitrogen is replaced 3 times, DMF (4mL) solution for adding parafluorobenzoic acid ethyl ester (118mg, 0.7mmol) reacts overnight at 120 DEG C.TLC shows nothing Reaction solution is poured into water by starting material left, three times with EA extraction, merges organic layer, anhydrous with water and saturated common salt water washing Na2SO4Dry, the crude product obtained after concentration isolates and purifies to obtain target compound by column chromatography (PE/EA=5/1~2/1) (147mg, yield: 52%), being white solid.
Step 9:4- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) benzoic acid preparation
By 4- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen Miscellaneous spiral shell [4.5] decane -8- base) after ethyl benzoate (57mg, 0.1mmol) dissolves with THF (0.8mL) and ethyl alcohol (0.8mL), add Enter water (1.6mL) solution of LiOH (48mg, 2.0mmol), reaction is stayed overnight at room temperature.After being diluted with water with 15% hydrochloric acid solution PH to 5 is adjusted, three times with EA extraction, saturated common salt water washing, anhydrous Na2SO4Dry, the crude product obtained after concentration is thin by preparing Laminate (DCM/MeOH=3/1) isolates and purifies to obtain target compound (35mg, yield: 65%), for white solid.
1H NMR(400MHz,d6-DMSO)δ1.07-1.17(4H,m),1.30-1.49(1H,m),1.49-1.58(3H, m)1.59-1.66(1H,m),1.69-1.77(1H,m),2.27-2.36(1H,m),3.18-3.29(4H,m),3.57(1H,dd, J=7.6Hz, 1.6Hz), 3.71-3.77 (1H, m), 4.00-4.07 (1H, m), 4.20 (2H, s), 6.93 (2H, d, J= 8.8Hz), 7.58 (1H, d, J=7.2Hz), 7.72-7.85 (4H, m), 7.93 (1H, d, J=7.6Hz)
EM (calculated value): 542.2；MS(ESI)m/e(M+H)+: 543.2.
Embodiment 2:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base) benzo [d] thiazole -6- carboxylic acid preparation
Synthesis step is as follows:
The preparation of step 1:2- amino benzo [d] thiazole -6- carboxylate methyl ester
Bromine (3.10g, 19.85mmol) is dissolved in acetic acid (18mL), is slowly added dropwise to 4-aminobenzoic acid methyl esters (3.00g, 19.85mmol), in acetic acid (67mL) solution of KSCN (6.89g, 70.86mmol), reaction is overnight at room temperature.Add water It is quenched, with saturation Na2CO3Solution tune pH to 9.Three times with EA extraction, saturated common salt water washing, anhydrous Na2SO4After dry concentration Crude product obtains target compound (3.30g, yield: 80%), for white solid by column chromatography (PE/EA=3/1).
The preparation of step 2:2- amino benzo [d] thiazole -6- carboxylate methyl ester
Under nitrogen protection, by 2- amino benzo [d] thiazole -6- carboxylate methyl ester (1.04g, 5.0mmol) and H3PO4(9.5mL) It is placed in there-necked flask, is cooled to -5 DEG C, slowly NaNO is added in injection2Water (2.4mL) solution of (1.04g, 15.0mmol), temperature Control is at 0 DEG C hereinafter, continuing to stir 2.5h after adding.Then CuSO is slowly added at -5 DEG C4The water of (2.4g, 15.0mmol) Water (2.4mL) solution of (2.4mL) solution and NaCl (4.38g, 75.0mmol), removes ice salt bath, reacts 1h at room temperature.Then Reaction solution is diluted with water, is extracted with dichloromethane three times, merges organic layer, with saturated common salt water washing, anhydrous Na2SO4It is dry It is dry, the crude product obtained after concentration by column chromatography (PE/EA=5/1) isolate and purify to obtain target compound (700mg, yield: It 62%), is white solid.
Step 3:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decyl- 8- yl) benzo [d]] thiazole -6- carboxylic acid, ethyl ester preparation
By 2- amino benzo [d] thiazole -6- carboxylate methyl ester (68mg, 0.30mmol), 3- ((5- cyclopropyl -3- (2- (trifluoro Methyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- azaspiro [4.5] decane (127mg, 0.30mmol) and DIPEA (78mg, 0.60mmol) is dissolved in DMA (3mL), is reacted overnight at 120 DEG C.TLC shows that consumption of raw materials is complete, and room is down in reaction Temperature is diluted with water, and then three times with EA extraction, merges organic layer, with water and saturated common salt water washing, anhydrous Na2SO4It is dry, it is dense The crude product obtained after contracting by column chromatography (PE/EA=4/1) isolate and purify to obtain target compound (120mg, yield: 35%), For faint yellow solid.
Step 4:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) benzo [d] thiazole -6- carboxylic acid preparation
By 2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen Miscellaneous spiral shell [4.5] decyl- 8- yl) benzo [d]] thiazole -6- carboxylic acid, ethyl ester (120mg, 1.1mmol) is dissolved in THF (2mL) and ethyl alcohol In (2mL) solution, water (3.2mL) solution of LiOH (96mg, 3.4mmol) is added, reaction is stayed overnight at room temperature.It is used after being diluted with water 15% hydrochloric acid solution tune pH to 5, three times with EA extraction, saturated common salt water washing, anhydrous Na2SO4It is dry, it is obtained after concentration Crude product by column chromatography (DCM/MeOH=50/1~15/1) isolates and purifies to obtain target compound, and (yield: 21%) 25mg, is White solid.
1H NMR(400MHz,d6-DMSO)δ1.06-1.18(4H,m),1.48-1.69(5H,m),1.74-1.81(1H, m),2.28-2.37(1H,m),3.34-3.55(2H,m),3.57-3.80(4H,m),3.99-4.08(1H,m),4.21(2H, S), 7.45 (1H, d, J=8.8Hz), 7.59 (1H, d, J=7.6Hz), 7.74-7.87 (3H, m), 7.93 (1H, d, J= 7.6Hz), 8.35 (1H, d, J=2Hz)
EM (calculated value): 599.2；MS(ESI)m/e(M+H)+: 600.2.
Embodiment 3:6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base) niacin preparation
Synthesis step is as follows:
Step 1:6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) ethyl nicotinate preparation
By K2CO3(124mg, 0.9mmol), 3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) first Oxygroup) -1- oxa- -8- azaspiro [4.5] decane (211mg, 0.5mmol) and 6- fluorine nicotinic acid ethyl ester (118mg, 0.7mmol) point It dissipates in DMF (6mL), reacts 3.5h under 100 DEG C of nitrogen protections.After cooling, reaction system is poured into water, EA extraction is added Three times, merge organic layer, with water and saturated common salt water washing, anhydrous Na2SO4Dry, the crude product obtained after concentration passes through thin layer system Slave board (PE/EA=3/1) isolates and purifies to obtain target compound (200mg, yield: 28%), for white oil object.
Step 2:6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) niacin preparation
By 6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen Miscellaneous spiral shell [4.5] decane -8- base) ethyl nicotinate (181mg, 0.32mmol) is dissolved in THF (2mL) and ethyl alcohol (2mL) solution, it is added Water (4mL) solution of LiOH (152mg, 6.34mmol), reaction is stayed overnight at room temperature.After being diluted with water with 15% hydrochloric acid solution tune PH to 5, three times with EA extraction, saturated common salt water washing, anhydrous Na2SO4Dry, the crude product obtained after concentration is through preparing lamellae (DCM/MeOH=15/1) it isolates and purifies to obtain target compound (134mg, yield: 78%), for white solid.
1H NMR(400MHz,d6-DMSO)δ1.05-1.19(4H,m),1.35-1.45(1H,m),1.46-1.58(3H, m)1.60-1.67(1H,m),1.70-1.80(1H,m),2.28-2.36(1H,m),3.41-3.50(2H,m),3.58(1H,dd, J=10.0Hz, 1.6Hz), 3.71-3.88 (3H, m), 4.00-4.07 (1H, m), 4.20 (2H, s), 6.85 (1H, d, J= 8.8Hz), 7.58 (1H, d, J=7.6Hz), 7.72-7.85 (2H, m), 7.87-7.89 (2H, m), 8.62 (1H, d, J= 2.4Hz).
EM (calculated value): 543.2；MS(ESI)m/e(M+H)+: 544.2.
Embodiment 4:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base) thiazole-5-carboxylic acid preparation
Synthesis step is as follows:
Step 1:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decyl- 8- yl) thiazole -5- formic acid preparation
Weigh 3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen Miscellaneous spiral shell [4.5] decane (200mg, 0.64mmol) and 2- diuril azoles -5- methyl formate (75mg, 0.58mmol) are in three mouthfuls of 50mL In bottle, under nitrogen protection, it is added DMA (5mL), adds DIPEA (207mg, 1.6mmol), react 3.5h at 120 DEG C.It is cooling To room temperature, reaction system is poured into water, EA extraction is added three times, merges organic layer, with water and saturated common salt water washing, nothing Water Na2SO4Dry, the crude product obtained after concentration isolates and purifies to obtain target compound by column chromatography (PE/EA=5/1) (238mg, yield: 52%), being white oil object.
Step 2:2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- - 8- azaspiro [4.5] decane -8- base) thiazole-5-carboxylic acid preparation
By 2- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxa- -8- nitrogen Miscellaneous spiral shell [4.5] decane -8- base) thiazole-5-carboxylic acid (238mg, 0.43mmol) is dissolved in THF (2mL) and ethyl alcohol (2mL) solution, It is added in water (4mL) solution of LiOH (25mg, 1.05mmol), reaction is stayed overnight at room temperature.After being diluted with water with 15% hydrochloric acid Solution tune pH to 5, three times with EA extraction, saturated common salt water washing, anhydrous Na2SO4Dry, the crude product obtained after concentration is through column layer Analysis (DCM/MeOH=50/1~15/1) isolates and purifies to obtain target compound (60mg, yield: 26%), for white solid.
1H NMR(400MHz,d6-DMSO)δ1.08-1.19(4H,m),1.22-1.30(1H,m),1.35-1.60(4H, m),1.64-1.75(1H,m),2.28-2.36(1H,m),3.34-3.43(2H,m),3.43-3.60(4H,m),3.71-3.76 (1H, m), 4.20 (2H, s), 7.58 (1H, d, J=7.2Hz), 7.72-7.82 (3H, m), 7.92 (1H, d, J=7.2Hz)
EM (calculated value): 549.2；MS(ESI)m/e(M+H)+: 550.2.
Embodiment 5:6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base)-N- (methyl sulphonyl) niacinamide preparation
Synthesis step is as follows:
Under nitrogen protection, Methanesulfomide (48mg, 0.50mmol) is added to EDCI (121mg, 0.63mmol), DMAP (103mg, 0.84mmol) and 6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- Oxa- -8- azaspiro [4.5] decane -8- base) niacin (114mg, 0.21mmol) methylene chloride (15mL) solution in, at room temperature Reaction is overnight.Then reaction system is poured into water, and with dilute hydrochloric acid tune pH to 6, three times with EA extraction, saturated common salt washing It washs, anhydrous Na2SO4Dry, the crude product obtained after concentration isolates and purifies to obtain target compound through column chromatography (PE/EA=1/1) (30mg, yield: 23%), being white solid.
1H NMR(400MHz,d6-DMSO)δ1.06-1.18(4H,m),1.35-1.57(4H,m),1.60-1.67(1H, M), 1.72-1.80 (1H, m), 2.28-2.36 (1H, m), 3.30 (3H, s), 3.38-3.52 (2H, m), 3.58 (1H, dd, J= 10.0Hz, 2.0Hz), 3.70-3.90 (3H, m), 4.00-4.06 (1H, m), 4.20 (2H, s), 6.68 (1H, d, J=9.2Hz), 7.58 (1H, d, J=7.2Hz), 7.74-7.83 (2H, m), 7.90-8.01 (2H, m), 8.65 (1H, d, J=2.4Hz), 11.79 (1H,s).
EM (calculated value): 620.2；MS(ESI)m/e(M+H)+: 621.2.
Embodiment 6:6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) -1- oxygen Miscellaneous -8- azaspiro [4.5] decane -8- base) niacinamide preparation
Synthesis step is as follows:
Under nitrogen protection, to 6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) - 1- oxa- -8- azaspiro [4.5] decane -8- base) niacin (149mg, 0.27mmol) DMF (6mL) solution in be separately added into HBTU (205mg, 0.54mmol), NH4Cl (145mg, 2.70mmol) and DIPEA (211mg, 1.62mmol), reacts at room temperature 20h.Then reaction solution is poured into water, EA extraction is added three times, merge organic layer, it is anhydrous with water and saturated common salt water washing Na2SO4It is dry, the crude product obtained after concentration by column chromatograph (DCM/MeOH=15/1) obtain target compound (25mg, yield: It 17%), is white solid.
1H NMR(400MHz,d6-DMSO)δ1.05-1.17(4H,m),1.35-1.57(4H,m),1.60-1.67(1H, M), 1.71-1.79 (1H, m), 2.28-2.36 (1H, m), 3.40-3.50 (2H, m), 3.58 (1H, dd, J=10.0Hz, 2.0Hz), 3.68-3.81 (3H, m), 4.00-4.06 (1H, m), 4.20 (2H, s), 6.88 (1H, d, J=8.8Hz), 7.15 (1H, s), 7.58 (1H, d, J=7.2Hz), 7.72-7.85 (3H, m), 7.90-7.99 (2H, m), 8.57 (1H, d, J= 2.0Hz).
EM (calculated value): 542.2；MS(ESI)m/e(M+H)+: 543.2.
Embodiment 7:2- (6- (3-((5- cyclopropyl-3- (2- (trifluoromethyl) phenyl) isoxazole-4- base) methoxyl group)-1- Oxa- -8- azaspiro [4.5] decane -8- base) cigarette) acetic acid preparation
Synthesis step is as follows:
Under nitrogen protection, to 6- (3- ((5- cyclopropyl -3- (2- (trifluoromethyl) phenyl) isoxazole -4- base) methoxyl group) - 1- oxa- -8- azaspiro [4.5] decane -8- base) niacin (149mg, 0.27mmol) DMF (6mL) solution in be separately added into HBTU (205mg, 0.54mmol), glycine (31mg, 0.41mmol) and DIPEA (211mg, 1.62mmol), react at room temperature 20h.Then reaction solution is poured into water, with 15% hydrochloric acid solution tune pH to 5, EA extraction is added three times, merges organic layer, uses Water and saturated common salt water washing, anhydrous Na2SO4Dry, the crude product obtained after concentration is obtained by column chromatography (DCM/MeOH=10/1) To target compound, (10mg, yield: 6%), being white solid.
1H NMR(400MHz,d6-DMSO)δ1.08-1.19(4H,m),1.33-1.60(4H,m),1.58-1.62(1H, M), 1.68-1.75 (1H, m), 2.30-2.37 (1H, m), 3.38-3.50 (2H, m), 3.52 (2H, s), 3.62 (1H, dd, J= 10.0Hz, 2.0Hz), 3.64-3.82 (3H, m), 4.03-4.10 (1H, m), 4.25 (2H, s), 6.90 (1H, d, J=8.8Hz), 7.18 (1H, s), 7.55 (1H, d, J=7.2Hz), 7.70-7.86 (2H, m), 7.88-8.01 (2H, m), 8.63 (1H, d, J= 2.0Hz).
EM (calculated value): 600.2；MS(ESI)m/e(M+H)+: 601.2.
Below by way of biological experiment the present invention is further explained compound advantageous effect, but this should not be interpreted as this hair Bright compound only has following beneficial effect.
Biologic test
Test example 1: the measurement (FXR TR-FRET) of vitro kinase EC50
1: experimental method
1.1: preparing 15mL 1Xbasic and measure buffer, be then used in mixed way.
1.2: for reference compound GW4064, stock concentration 1mM is diluted in 100%DMSO, is then diluted to most 3 times of final concentration.For testing compound, it is diluted to the stock concentration of 1mM in 100%DMSO, is then diluted to ultimate density 3 Times.
1.3: preparing 1x protein solution mixture
A: prepare 2x GST-FXR-LBD/Eu Anti-GST mixture to required volume, GST-FXR-LBD 6nM, Eu Anti-GST is the hole 50nL/.
B: prepare 2x biotin-SRC1/SA-APC mixture to required volume, Bioin-SRC1 1000nM, SA-APC For the hole 50nL/.
C: 2x GST-FXR/Eu Anti-GST and 2x SRC1/SA-APC is mixed by 1:1.
D: 20uL GST-FXR/Eu Anti-GST and SRC1/SA- is added into 384 orifice plates containing test compound APC mixture.
E: by plate with 1000rpm centrifugation 1 minute.
F: plate is incubated at room temperature 180 minutes.
1.1.4:TR-FRET measurement: the printing plate in EnVision plate reader is read.
2: data analysis:
A:. data value standardizes 665/615 (nm).
B: % activation value is calculated.
% activation value is calculated by following equation.
X is each concentration point " 665/615 " value.Min is the average value " 665/615 " of not compound control.Max is The average value " 665/615 " of reference compound control.
3: experimental result
The FXR TR-FRET determination of activity result of 1 embodiment compound of table
As can be seen from the table, which all has certain Farnesoid X receptor (FXR) agonism.Its In, the performance of embodiment 7 is especially prominent: compound EC50 value is higher than positive control GW4064, suitable with Tropifiexor It is even better；Therefore, the compound designed by the present invention can be used as FXR agonist.It has broad application prospects.

Claims (11)

  1. General formula 1. (I) compound represented, its pharmaceutically acceptable salt, its ester or its stereoisomer:
    Wherein R is selected from hydrogen atom, cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, carbonyl, CF3, it is substituted or non-substituted C1-6Alkyl, C1-6Alkoxy, C3-8Naphthenic base, C3-8Ring Heterocyclylalkyl, C2-8Alkenyl or C2-8Alkynyl；The substituent group is 1~3 Cyano, halogen atom, nitro, amino, hydroxyl, carboxyl, carbonyl, C1-6Alkyl, C1-6Alkoxy, C1-6Naphthenic base；The hetero atom For N, O, S；
    Ar is selected from C5-10Aryl or 5-10 unit's heteroaryl；Wherein each ring is optionally independently selected from 1,2,3 or 4 substituent group below Replace: C1-6Alkoxy, C1-6Alkoxy carbonyl, C1-6Alkoxycarbonyl amino, C1-6Alkyl, (C1-6Alkyl) carbonyl, (C1-6Alkane Base) sulfonyl, acylamino-, amino, carbonyl, carboxyl, cyano, formoxyl, halogen, halogenated C1-3Alkyl, halogenated C1-3Alkoxy, CF3；
    A is selected from C5-10Aryl or 5-10 unit's heteroaryl are optionally further selected from halogen, cyano, acylamino-, ammonia by one or more Base, carbonyl, nitro, CF3、C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl group, C3-8Naphthenic base, 3-8 circle heterocyclic ring base, C5-10Aryl, C5-10Aryloxy, C5-10Artyl sulfo, 5-10 unit's heteroaryl, 5-10 unit's heteroaryl oxygroup, 5-10 unit's heteroaryl sulfenyl ,-C0-8- O-R1、-C0-8-C(O)OR1、-C0-8-C(O)R1、-C0-8-O-C(O)R2、-C0-8-NR3R4、-C0-8-C(O)NR3R4、-N(R3)-C (O)R2、-C(O)N(R3)S(O)2R5Or-N (R2)-C(O)OR1Substituent group replaced；The hetero atom is N, O, S.
    Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen, cyanogen Base, acylamino-, amino, carbonyl, nitro, carboxyl.
  2. 2. compound according to claim 1, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature It is:
    Wherein R is selected from substituted or non-substituted C3-6Naphthenic base, the substituent group are 1~3 cyano, halogen atom, nitro, ammonia Base, hydroxyl, carboxyl, carbonyl, C1-6Alkyl, C1-6Alkoxy, C1-6Naphthenic base.
  3. 3. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 Cyclopropyl is selected from R.
  4. 4. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 In:
    Ar is selected from phenyl；Wherein phenyl ring is optionally independently selected from 1,2,3 or 4 substituent group below and is replaced: C1-6Alkoxy, C1-6 Alkoxy carbonyl, C1-6Alkoxycarbonyl amino, C1-6Alkyl, (C1-6Alkyl) carbonyl, (C1-6Alkyl) sulfonyl, acylamino-, ammonia Base, carboxyl, cyano, formoxyl, halogen, halogenated C1-3Alkyl, halogenated C1-3Alkoxy, CF3。
  5. 5. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 In: Ar is selected from phenyl, and the substituent group on phenyl is CF3。
  6. 6. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 In:
    A be selected from phenyl, pyridyl group,Optionally further by one or more selected from halogen, cyano, Acylamino-, amino, carbonyl, nitro, CF3、C1-6Alkyl ,-C (O) OR1、-C0-8-C(O)NR3R4、-C(O)-N(R3)S(O)2R5's Replaced substituent group, wherein 2 carbon of thiphene ring are connected to piperidines N.
    Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen, cyanogen Base, acylamino-, amino, carbonyl, nitro, carboxyl.
  7. 7. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 In:
    A is selected from flowering structure
  8. 8. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, feature exist according to claim 1 In:
    A be selected from phenyl, pyridyl group,Optionally further by one or more selected from halogen, cyano, Acylamino-, amino, carbonyl, nitro, CF3、C1-6Alkyl ,-C (O) OR1、-C0-8-C(O)NR3R4、-C(O)-N(R3)S(O)2R5's Replaced substituent group；Wherein 2 carbon of thiazole ring are connected to piperidines N.
    Wherein R1, R2, R3, R4, R5Independently selected from hydrogen, substituted or non-substituted C1-6Alkyl, wherein the substituent group is halogen, cyanogen Base, acylamino-, amino, carbonyl, nitro, carboxyl.
  9. 9. compound, its pharmaceutically acceptable salt, its ester or its stereoisomer according to claim 1 have following Structure:
  10. 10. claim 1-9 any described formula (I) compound, its stereoisomer or its pharmaceutically-acceptable salts, are preparing For preventing or treating the application in the disease of FXR mediation or the drug of situation；The disease or situation that the FXR is mediated are selected from the heart Vascular diseases, atherosclerosis, artery sclerosis, hypercholesterolemia, hyperlipidemia, chronic liver disease, chronic liver disease, stomach and intestine disease Disease, nephrosis, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or neural sign such as apoplexy.
  11. 11. application according to claim 10, which is characterized in that the chronic liver disease is selected from hepatitis B, primary is hardened (PBC), the dirty property xanthomatosis (CTX) of brain, primary sclerosing cholangitis (PSC), drug induced cholestasia, pregnant liver liner Juice siltation disease, parenteral absorption associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmunity liver Inflammation, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver disease (NASH), the anti-host disease of liver transfer operation related Graft, live donor liver transfer operation regeneration, congenital hepatic fibrosis, choledocholithiasis, meat Malignant tumour, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, blood in or beyond bud hepatopathy, liver Color disease or 1 primary antibody membrane proteolytic enzyme deficiency disease of α；The gastrointestinal disease be selected from inflammatory bowel disease (IBD) (including Crohn's disease and Burst characteristic of disease enteritis), irritable bowel syndrome (IBS), bacterial overgrowth, nutrient absorption are bad, reflection postcolon is scorching or smallness Colitis；The nephrosis is selected from diabetic nephropathy, Focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic renal Bead inflammation, chronic transplant glomerulopathy, arteriosclerotic kidney or polycystic kidney disease；The cardiovascular disease is selected from artery sclerosis Disease, artery sclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia；The metabolic disease be selected from insulin resistance, Type-1 diabetes mellitus, type-2 diabetes mellitus or obesity.
CN201810994739.7A 2018-08-30 2018-08-30 FXR regulator with spirane structure Pending CN109053751A (en)

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US10597391B2 (en) 2016-10-26 2020-03-24 Enanta Pharmaceuticals, Inc. Urea-containing isoxazole derivatives as FXR agonists and methods of use thereof
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US10829486B2 (en) 2018-02-14 2020-11-10 Enanta Pharmacueticals, Inc. Isoxazole derivatives as FXR agonists and methods of use thereof
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WO2022101853A1 (en) 2020-11-16 2022-05-19 Novartis Ag Method of determining liver fibrosis

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