WO2020011146A1 - Composés 1,2,4-oxadiazole, leur procédé de préparation et utilisation médicale associée - Google Patents

Composés 1,2,4-oxadiazole, leur procédé de préparation et utilisation médicale associée Download PDF

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Publication number
WO2020011146A1
WO2020011146A1 PCT/CN2019/095201 CN2019095201W WO2020011146A1 WO 2020011146 A1 WO2020011146 A1 WO 2020011146A1 CN 2019095201 W CN2019095201 W CN 2019095201W WO 2020011146 A1 WO2020011146 A1 WO 2020011146A1
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racemate
alkyl
halogen
cycloalkyl
general formula
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PCT/CN2019/095201
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English (en)
Chinese (zh)
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殷惠军
闫旭
宗利斌
刘春艳
史建新
王斌
米桢
司春枫
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中国医药研究开发中心有限公司
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Priority to CN201980018242.4A priority Critical patent/CN111868056B/zh
Publication of WO2020011146A1 publication Critical patent/WO2020011146A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a 1,2,4-oxadiazole compound, a preparation method thereof, a pharmaceutical composition containing the same, and a method for regulating the farnesoid derivative X receptor (Farnesoid X receptor, FXR) activity for use in the treatment and / or prevention of diseases associated with FXR activity.
  • FXR farnesoid derivative X receptor
  • Farnesol derivative X receptor as a bile acid-activated nuclear receptor, can regulate the expression of a variety of metabolic-related genes directly or through the orphan nuclear receptor small heterodimer partner (SHP).
  • FXR was discovered in 1995 after its name was derived from the fact that the receptor can be activated by far physiological levels of farnesol.
  • BAs bile acids
  • FXR Abnormal levels of bile acids are associated with liver inflammation and fibrosis, and the accumulation of bile acids is a more important pathogenic factor for non-alcoholic fatty liver than triglycerides.
  • the activation of FXR can reduce the synthesis and uptake of bile acids in the liver, and increase the bile acid efflux to reduce the net effect of bile acid accumulation in the liver;
  • FXR can up-regulate SHP
  • SHP can inhibit the expression of the important bile acid synthesis enzyme CYP7A1, and then Inhibition of bile acid synthesis (Pharmacol. Ther.
  • FXR can induce FGF15 / 19 to activate FGFR4, and then activate the JNK pathway to inhibit the expression of CYP7A1; FXR up-regulates BSEP and MRP2 and inhibits NTCP to reduce liver cells Internal bile acid levels stimulate bile acid secretion in the tubular membrane of hepatocytes and inhibit bile acid reuptake from the portal vein; FXR can regulate bile acid transport through OST ⁇ / ⁇ , promote bile acid excretion to the circulatory system, and eliminate it through the kidneys.
  • FXR can improve insulin resistance.
  • FXR knockout mice show impaired glucose metabolism clearance, indicating that mice have peripheral insulin resistance.
  • the improvement of FXR activation on insulin resistance may be related to the following mechanism: FXR can reduce the accumulation of lipids in peripheral tissues (such as muscle cells), thereby reducing lipid-related toxicity, especially for diet-induced obese patients (Acta.Pharmacol.Sin .2015,36,44-50); Small intestinal FXR activation can promote FGF19 release into the portal vein.
  • FGF19 has a certain insulin sensitization effect. It has also been reported that FGF19 has a weight loss effect.
  • FGF19 transgenic mice have shown strong resistance to diet induction.
  • FXR can reduce gluconeogenesis and liver glucose output
  • bile acid-fed mice can inhibit the expression of gluconeogenesis-related enzymes, such as PEPCK, G6P and other genes, but has no effect on SHP knockout mice
  • FXR agonists can Decreased mouse PEPCK and G6P, while reducing liver glucose output.
  • FXR can reduce the production of triglycerides and fatty acids and promote their metabolism through various pathways.
  • FXR can inhibit the expression of SREBP1c, inhibit the synthesis and secretion of triglycerides and fatty acids, promote the expression of VLDLR, improve the clearance of VLDL and chylomicrons, inhibit the expression of APOC and MTP, inhibit the assembly of VLDL, induce PPAR ⁇ , and promote the fatty acid.
  • Beta oxidation induces lipoprotein lipase, which in turn enhances the metabolism of lipoproteins and free fatty acids.
  • FXR promotes the uptake of HDL and the reverse transport of cholesterol by positively regulating SRBI, CEH, SCP2, etc. It can also reduce the expression and activity of PCSK9, enhance the elimination of LDLR and LDL, and reduce cholesterol (Curr.Opin.Lipidol.2016 , 27, 295-301).
  • FXR can suppress inflammation by down-regulating the expression of various inflammation-related genes.
  • FXR is closely related to the inflammatory response.
  • FXR gene knockout mice have higher levels of pro-inflammatory and pro-fibroblast factors, including TNF ⁇ , ICAM-1, ⁇ -SMA , TIMP-1, TGF ⁇ and so on.
  • FXR's inhibition of inflammation and fibrosis may be related to the following mechanisms:
  • the main inflammatory inhibition mechanism of FXR activation is to antagonize the NF ⁇ B signaling pathway;
  • FXR activation can improve biliary obstruction, intestinal flora overgrowth, mucosal damage, intestinal bacterial translocation
  • FXR can induce inhibitors of SOCS3, thereby inhibiting the STAT3 signaling pathway;
  • activation of FXR can increase MicroRNA mir29a, and MicroRNA mir29a can regulate the expression of multiple extracellular matrix proteins.
  • FXR can promote liver tissue regeneration and inhibit the development of stem cell tumors.
  • FXR agonists can be used for lipids, especially triglyceride accumulation, and diseases and conditions caused by chronic fat and fibrosis caused by triglyceride accumulation, such as non-alcoholic fatty liver (NAFLD) or non-alcoholic steatohepatitis ( NASH) prevention and treatment (Adv. Ther. 2016, 33, 291-319; Drug Discov. Today, 2012, 17, 988-97).
  • NAFLD non-alcoholic fatty liver
  • NASH non-alcoholic steatohepatitis
  • FXR agonists have become one of the hot topics in the development of innovative drugs worldwide.
  • steroidal FXR agonist obeticholic acid has been successfully approved for primary biliary cirrhosis (PBC), and has shown good efficacy in clinical studies of NASH (FlINT study), and further FXR agonists Rationale for PBC and NASH treatment.
  • the drug has poor selectivity as a steroid drug, and it also has a certain effect on TGR5, which may easily cause side effects such as severe itching and hyperlipidemia.
  • obeticholic acid has severe hepato-enteric circulation, resulting in a high accumulation of the drug in the body, which has caused safety risks. Therefore, non-steroidal FXR agonists with higher selectivity and better pharmacokinetic properties have attracted more attention (Lancet, 2015, 385, 956-65; N. Engl. J. Med. 2016, 375, 631-643).
  • FXR is agonistic and can be developed as a drug for treating diseases related to FXR activity.
  • an object of the present invention is to provide a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or A prodrug or a pharmaceutically acceptable salt thereof,
  • Z is selected from:
  • X is CH, CF, N or NO
  • R 2 is selected from hydrogen, halogen, alkyl, cycloalkyl, wherein said alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, hydroxy, alkyl, alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl, and alkoxy, said alkyl or alkoxy being optionally further substituted with one or more halogens;
  • Cy is aryl or heteroaryl
  • R 1 is selected from-(CH 2 ) m -R 5 or -O (CH 2 ) m -R 5 ; wherein the-(CH 2 ) m -or -O (CH 2 ) m -group is optionally further One or more groups selected from halogen, cyano, hydroxy, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, CO 2 H, SO 3 H;
  • R 5 is selected from hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 6 , NR 6 R 7 , -CO 2 R 6 , -C (O ) R 6 , -C (O) NR 6 R 7 , -N (R 6 ) C (O) R 7 , -C (O) NR 6 SO 2 R 7 , -S (O) p R 6 , -S (O) p NR 6 R 7 , -N (R 6 ) S (O) p R 7 , or -S (O) p NR 6 COR 7 ; the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or heteroaryl is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, haloalky
  • R 6 and R 7 are each independently selected from hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl 1, one or more of the heteroaryl groups are substituted;
  • R 6 and R 7 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol , Carboxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted with one or more groups;
  • Each R 8 may be the same or different, and each is independently selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl , Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1, or 2;
  • n is an integer from 0 to 6;
  • p 0, 1, or 2;
  • q is an integer from 0 to 4.
  • the compound represented by the general formula (I) or a racemate, racemate, enantiomer, diastereomer, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (II) or the general formula (III) or a racemate, a racemate, an enantiomer, Diastereomers, or mixtures thereof, prodrugs or pharmaceutically acceptable salts thereof,
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • R 2 is selected from hydrogen, halogen, alkyl, cycloalkyl, preferably C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, more preferably cyclopropyl; said alkyl or cycloalkyl is optionally further Substituted with one or more groups selected from halogen, hydroxy, alkyl, alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, preferably hydrogen, halogen, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.
  • n 1.
  • Cy is a C 5 -C 6 aryl group or a 5- to 6-membered heteroaryl group, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, imidazolyl, pyrazolyl.
  • R 1 is selected from-(CH 2 ) m -R 5 or -O (CH 2 ) m -R 5 ;
  • R 5 is selected from hydrogen, halogen, alkyl, OR 6 , NR 6 R 7 , -CO 2 R 6 , -C (O) R 6 , -C (O) NR 6 R 7 , -N (R 6 ) C (O) R 7 , -C (O) NR 6 SO 2 R 7 , -S (O) p R 6 , -S (O) p NR 6 R 7 , -N (R 6 ) S (O) p R 7 , or -S (O) p NR 6 COR 7 , preferably -C (O) R 6 , -C (O) NR 6 R 7 , -S (O) p R 6 , -S (O) p NR 6 R 7 , more preferably -C (O) R 6 or -S (O) p NR 6 R 7 , and even more preferably -COOH;
  • R 6 and R 7 are each independently selected from hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl 1, one or more of the heteroaryl groups are substituted;
  • R 6 and R 7 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol ,carboxyl;
  • n is an integer from 0 to 6, preferably 0, 1 or 2; more preferably 0.
  • Each R 8 may be the same or different, and each is independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy;
  • q is an integer from 0 to 4; preferably q is 0 or 1.
  • the compound represented by the general formula (I) according to the present invention includes, but is not limited to, the following compounds:
  • the present invention further provides the preparation of a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to the present invention.
  • the compound IF is subjected to a cyclization reaction to obtain a compound of the general formula (I), wherein the alkaline reagent is preferably sodium acetate;
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • the present invention further provides the preparation of a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to the present invention.
  • compound 1H is reacted with CO and methanol to obtain compound 1J.
  • the basic conditions are preferably sodium acetate, and the catalyst is preferably Pd (dppf) Cl 2.
  • the compound is 1J hydrolysis reaction to obtain a compound of general formula (I), wherein the alkaline reagent is preferably potassium hydroxide;
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition containing the compound represented by the general formula (I) according to the present invention or a racemate, a racemate, an enantiomer, a diastereomer Isomers, or mixtures thereof, prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present invention further provides a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to the present invention, or Use of a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of an FXR agonist.
  • the present invention further provides a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to the present invention, or Use of a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the manufacture of a medicament for the prevention and / or treatment of a disease associated with FXR activity.
  • the present invention provides a compound represented by the general formula (I) according to the present invention or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a precursor thereof.
  • the present invention further provides a compound represented by the general formula (I) or a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof according to the present invention, or A prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use as a medicament for the prevention and / or treatment of diseases related to FXR activity.
  • the present invention further provides a method for preventing and / or treating a disease associated with FXR activity, which comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of the formula (I) according to the present invention
  • a prophylactically or therapeutically effective amount of the formula (I) according to the present invention
  • the disease related to FXR activity may be: chronic intrahepatic cholestasis or extrahepatic cholestasis, or chronic cholestasis or acute intrahepatic cholestasis Liver fibrosis due to the disorder; and / or obstructive or chronic inflammation of the liver; and / or cirrhosis; and / or sebaceous adenopathy and related syndromes; alcohol-induced cirrhosis or bile associated with viral hepatitis Stasis or fibrotic effects; and / or liver failure or liver ischemia after liver resection; and / or steatohepatitis-related chemotherapy; and / or acute liver failure; and / or acute liver failure; and / or inflammatory bowel disease; and / or lipids And lipoprotein disorders; and / or diabetes and clinical complications of diabetes, including diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other clinical manifestations;
  • Preferred diseases associated with FXR activity are non-alcoholic fatty liver, non-alcoholic steatohepatitis, chronic intrahepatic cholestasis or extrahepatic cholestasis, or chronic cholestasis or acute intrahepatic cholestasis of liver fibrosis .
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the field to which the present invention belongs.
  • the acids include inorganic and organic acids, and particularly preferred are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, and lactic acid. , Trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the base includes an inorganic base and an organic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, tromethamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the present invention also includes a prodrug of a compound represented by the general formula (I) of the present invention.
  • the prodrug according to the present invention is a derivative of a compound represented by the general formula (I). They may have weak or even inactive activity, but after administration, under physiological conditions (for example, by metabolism, solvolysis) Or otherwise) into the corresponding biologically active form.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period.
  • water-soluble taste-masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil
  • Soft gelatin capsules are provided as an oral preparation.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which can be natural Produced phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadeceneoxywhale Heptadecaethyleneoxy cetanol, or the condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with fatty acids and hexitol Condensation products of anhydride-derived partial esters, such as polyethylene oxide
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents, and one or more sweeteners.
  • preservatives such as ethyl paraben or n-propyl paraben
  • colorants such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • Oil suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.
  • the sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.
  • dispersible powders and granules suitable for use in the preparation of aqueous suspensions can provide active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are described above. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of the partial ester and ethylene oxide Products such as polyethylene oxide sorbitol monooleate.
  • Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol to form a microemulsion.
  • Injections or microemulsions can be injected into the patient's bloodstream by local, large injections.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol.
  • a sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • any blended fixing oil including synthetic mono- or diesters can be used.
  • fatty acids such as oleic acid can also be prepared for injection.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient's health, the patient's behavior, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment scheme.
  • the present invention may contain a compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not cause other adverse effects, such as allergic reactions and the like.
  • the compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other drugs for treating diseases related to FXR activity. Combination therapy is achieved by administering the individual therapeutic components simultaneously, separately, or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon Atomic alkyl.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhex
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Methyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like.
  • An alkynyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group that shares one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings have complete conjugation. ⁇ electronic system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. Spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl according to the number of common spiro atoms between the rings, preferably monospirocycloalkyl and bisspirocycloalkyl.
  • spirocycloalkyl More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, or 5 yuan / 6 yuan monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to a 5- to 20-membered, full-cyclic polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system.
  • One or more of the rings may contain one or Multiple double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, and more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl.
  • fused cycloalkyl include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a complete Conjugate ⁇ electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan. It can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthalene Radical, benzocycloheptyl and the like.
  • a cycloalkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • groups which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthi
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 to Two or one to three are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like, and preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group that shares one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O ) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a completely conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • Spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl according to the number of common spiro atoms between the rings, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferred are 4-membered / 4-membered, 4-membered-5-membered, 4-membered-6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.
  • Non-limiting examples of spiroheterocyclyl include:
  • fused heterocyclyl refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, but none of the rings have a completely conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining rings Atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • fused heterocyclyl include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, but none of the rings have a total A y-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, and more preferably 7 to 10 yuan.
  • bridged heterocyclyls include:
  • the heterocyclic ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • Aryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferred Pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • mercapto refers to -SH.
  • ester group refers to -C (O) O (alkyl) or -C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to a compound containing a -C (O) R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • sulfonic acid group refers to -S (O) 2 OH.
  • sulfonate group refers to -S (O) 2 O (alkyl), or -S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • sulfonyl refers to a compound 2 R group -S (O), wherein R is an alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aminoacyl refers to -C (O) -NRR ', wherein R and R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aminosulfonyl or “sulfonamido” refers to -S (O) 2 -NRR ', where R and R' are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl base.
  • heterocyclic group optionally substituted with alkyl group means that the alkyl group may but need not exist, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiological / pharmaceutically acceptable salt or prodrug thereof with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the present invention adopts the following technical solutions.
  • compound IA is reacted with Z-CH 2 -Br under basic conditions to obtain compound IB.
  • the basic reagent is preferably potassium tert-butoxide.
  • compound IB is deprotected under acidic conditions to obtain compound IC.
  • the reagent is preferably trifluoroacetic acid; then, under a basic condition, the compound IC is reacted with cyanogen bromide to obtain a compound ID, wherein the basic reagent is preferably potassium carbonate; then, under a basic condition, the compound ID is reacted with hydroxylamine hydrochloride
  • the compound IE is obtained, in which the basic condition is preferably sodium acetate; then, under the effect of the basic condition and the condensing agent, the compound IE is subjected to a condensation reaction to obtain the compound IF, wherein the basic condition is preferably DIEA, and the condensing agent is preferred HATU; Finally, the compound IF is subjected to a cyclization reaction under basic conditions to obtain a compound of the general formula (I), wherein the basic reagent is preferably sodium acetate.
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • the basic condition is preferably DIEA and the condensing agent is preferably HATU;
  • the cyclization reaction is performed under basic conditions to obtain compound IH.
  • the basic reagent is preferably sodium acetate.
  • the compound IH is reacted with CO and methanol to obtain compound 1J.
  • the basic conditions are preferred.
  • the catalyst is preferably Pd (dppf) Cl 2 ; finally, under basic conditions, the compound 1J is hydrolyzed to obtain a compound of the general formula (I), among which the alkaline reagent is preferably potassium hydroxide.
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR was measured using a Brukerdps300 nuclear magnetic analyzer, and the solvents used were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetramethyl. Silane (TMS).
  • MS was measured using a 1100 Series LC / MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).
  • the lc3000 high performance liquid chromatograph and lc6000 high performance liquid chromatograph were used to prepare the liquid phase (manufacturer: Innovative Tongheng).
  • the column was Daisogel C18 10 ⁇ m 60A (20mm ⁇ 250mm).
  • a Shimadzu LC-20AD high-pressure liquid chromatograph (Agilent TC-C18 250 ⁇ 4.6 mm 5 ⁇ m column) and a Shimadzu LC-2010AHT high-pressure liquid chromatograph (Phenomenex C18 250 ⁇ 4.6 mm 5 ⁇ m column) were used.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the thin-layer chromatography (TLC) silica gel plate uses a size of 0.15mm to 0.2mm.
  • the thin-layer chromatography purification product uses a size of 0.4mm to 0.5 mm.
  • the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from the online mall, Beijing Coupling, Sigma, Braunwell, Yi Shiming, Shanghai Shuya, Inokay, Nanjing Medicine stone, Anaiji chemical and other companies.
  • reaction can be performed under an argon atmosphere or a nitrogen atmosphere.
  • An argon or nitrogen atmosphere means that a reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature, which is 20 ° C to 30 ° C.
  • the monitoring of the reaction progress in the examples uses thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developing systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether With ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the eluent system for column chromatography and the developer system for thin-layer chromatography for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate, and dichloromethane system, C: petroleum For ether and ethyl acetate systems, the volume ratio of the solvent is adjusted according to the polarity of the compound. It can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • Example 1 4- (3- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] Synthesis of Octane-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid (1)
  • Step 1 ((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] octane- Synthesis of 8-carboxylic acid tert-butyl ester (Intermediate 1B)
  • Step 2 4-(((8-Azabicyclo [3.2.1] oct-3-yl) oxy) methyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) iso Synthesis of oxazole (Intermediate 1C)
  • Step 5 and Step 6 (3- (3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-azadi Synthesis of methyl cyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) benzoate (intermediate 1G)
  • reaction solution was cooled to room temperature, and the reaction solution was poured into 300 mL of ice water.
  • the filter cake was filtered by suction and dried.
  • Step 7 4- (3-((1R, 3s, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy ) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid (1a) and 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1 Synthesis of octane-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid (1b) (compound 1)
  • Compound 1 was separated and purified through a preparative liquid phase (eluent: 0% -100% acetonitrile: aqueous solution) to obtain 100 mg of compound 1a as a white solid and 30 mg of compound 1b as a white solid.
  • a preparative liquid phase eluent: 0% -100% acetonitrile: aqueous solution
  • Example 2 2-chloro-4- (3-((1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4- (Methyl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid
  • Step 1 (1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-aza Synthesis of Bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (Intermediate 2A)
  • Step 2 4-((((((1R, 3r, 5S) -8-azabicyclo [3.2.1] oct-3-yl) oxy) methyl) -5-cyclopropyl-3- (2, Synthesis of 6-dichlorophenyl) isoxazole (Intermediate 2B)
  • Step 3 (1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -8-aza Synthesis of Bicyclo [3.2.1] octane-8-carbonitrile (Intermediate 2C)
  • Step 4 (1R, 3r, 5S, E) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy) -N ' Of 2-hydroxy-8-azabicyclo [3.2.1] octane-8-formamidine (Intermediate 2D)
  • Step 5 and Step 6 2-chloro-4- (3-((1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole- Synthesis of 4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) -1,2,4-oxadiazol-5-yl) benzoate (Intermediate 2F )
  • Step 7 2-chloro-4- (3-((1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl ) Methoxy) -8-azabicyclo [3.2.1] oct-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid (Compound 2)
  • Example 3 6- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) picolinic acid
  • Example 5 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2-fluorobenzoic acid
  • Example 6 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2-methoxybenzoic acid
  • Step 1 and Step 2 5- (4-bromo-3-methoxyphenyl) -3-((1R, 3r, 5S) -3-((5-cyclopropyl-3- (2,6- Synthesis of dichlorophenyl) isoxazol-4-yl) methoxy) -8-azabicyclo [3.2.1] oct-8-yl) -1,2,4-oxadiazole (Intermediate 6B )
  • Step 3 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy Synthesis of methyl) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2-methoxybenzoate (intermediate 6C)
  • Step 4 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy Synthesis of 8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2-methoxybenzoic acid (Compound 6)
  • Example 7 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -3-methylbenzoic acid
  • the preparation method was the same as that in Example 6, except that 4-bromo-2-methylbenzoic acid was used instead of 4-bromo-3-methoxybenzoic acid to obtain the title compound 7.
  • Example 8 3- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) benzoic acid
  • Example 9 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -3-fluorobenzoic acid
  • the preparation method was the same as that in Example 6, except that 4-bromo-2-fluorobenzoic acid was used instead of 4-bromo-3-methoxybenzoic acid to obtain the title compound 9.
  • Example 10 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2-methylbenzoic acid
  • the preparation method was the same as that in Example 6, except that 4-bromo-3-methylbenzoic acid was used instead of 4-bromo-3-methoxybenzoic acid to obtain the title compound 10.
  • Example 11 4- (3-((1R, 3r, 5S)-(3-((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl Preparation of oxy) -8-azabicyclo [3.2.1] octane-8-yl) -1,2,4-oxadiazol-5-yl) -2- (trifluoromethyl) benzoic acid
  • the preparation method was the same as that in Example 6, except that 4-bromo-3-trifluoromethylbenzoic acid was used instead of 4-bromo-3-methoxybenzoic acid to obtain the title compound 11.
  • Test Example 1 Evaluation of FXR agonistic activity of the compound of the present invention
  • the luciferase reporter assay was used to evaluate the FXR agonistic activity of the compounds of the present invention.
  • the experimental process includes: transmission of luc2P-GAL4-HEK293 stable cell line (transfected with pGL4.35 plasmid from HEK293 cells and establishment by screening with Hygromycin B.
  • the cell contains 9 ⁇ GAL4UAS and firefly luciferase reporter gene.
  • LBD activated by ligand -The GAL4DBD fusion protein can enter the nucleus and bind to 9 ⁇ GAL4UAS and activate the transcription of the downstream luciferase reporter gene) into a 96-well plate with 1 ⁇ 10 4 cells per well.
  • X-tremeGENE HP transfection reagent was used to transfect pBIND-FXR (inserted from FXR-LBD into pFN26A-BIND hRluc-neo Vector construction. Plasmid size is 7.5kb, Amp resistance, contains FXR-LBD, can express FXR-LBD and GAL4DBD fusion protein), the ratio of plasmid to transfection reagent is 1 ⁇ g: 2 ⁇ l, the specific amount is 100ng plasmid per well, 0.2 ⁇ l X-tremeGENE HP Transfection reagent; add test compounds (the highest concentration of each compound is 30 ⁇ M, 3 times dilution, a total of 10 concentrations) to induce luciferase expression.
  • Luciferase Reagent 80 ⁇ l / well
  • Luciferase Reagent 80 ⁇ l / well
  • mix well incubate at room temperature for 20min to allow the cells to lyse fully, and then transfer all the liquid in the well plate to a 96-well microtiter plate using a multi-plate reader (manufacturer: Bio Tek (USA ); Model: Synergy4)
  • Measure the value of firefly luciferin add to each well an amount equal to the initial medium volume Stop & Reagent (80 ⁇ l / well), mix well, incubate at room temperature for 10 min, and then measure Renilla luciferin value.
  • Renilla fluorescence should be measured in the same order as firefly fluorescence.
  • GraphPad Prism 5 software was used to perform curve fitting and EC 50 calculation using non-linear regression method.
  • EC 50 is the semi-effective concentration
  • Top is the maximum effect
  • Bottom is the blank effect
  • HillSlope is the slope.
  • the activity of the compound is shown in Expression 1.
  • Test Example 2 Effects of the compounds of the present invention on blood lipids of LDLR -/- high - fat mice
  • Animals LDLR -/- mice, 24, males, 6-8 weeks of age, weighing 17-25g, purchased from Changzhou Caverns Experimental Animal Co., Ltd., SPF grade, animal production license number: SCXK (Su) 2016- 0010, issuing unit: Changzhou Science and Technology Commission.
  • Feed High-fat feed, purchased from Beijing Boao Parker Biotechnology Co., Ltd., Product #: D12079B, Lot #: 17062202, 12.5kg / carton.
  • the animals were adapted for 3 days. Two weeks after the high-fat diet was fed, they were anesthetized with isoflurane for 3 minutes, and blood was collected by orbital venous plexus blood collection (0.5mL / 3500rpm / heart separation for 10 minutes, and serum was separated.
  • Total cholesterol (TC) and Triglyceride (TG) divided into three groups according to the TC and TG results: model group, Example 2 group, Example 8 group, 8 / group.
  • oral administration was started the next day, twice a day. (bid), each dose was 1mg / kg (2mg / kg / d), the dose volume was 10mL / kg, and the model control group was orally administered with 0.5% CMC-Na.
  • Animal serum was measured with AU480 automatic biochemical analysis system (BECKMAN COULTER) for TC, TG, and low-density lipoprotein (LDL-C) levels, and the mean and standard deviation of each index in each group were calculated.
  • BECKMAN COULTER automatic biochemical analysis system
  • LDL-C low-density lipoprotein
  • the blood concentration and liver concentration of the compound of Example 2 after oral administration are shown in Table 3 below.
  • the blood and liver drug concentrations of the compound of Example 8 after oral administration are shown in Table 4 below.
  • Example 2 and Example 8 of the present invention significantly reduced the levels of TC, TG, and LDL-C in the serum of LDLR -/- high - fat mice.
  • the blood drug concentration is low and the liver drug concentration is high, which indicates that the compound of the present invention can significantly reduce the blood lipid of LDLR -/- high - fat mice, and has good liver targeting.
  • Test Example 3 Efficacy of the compound of the present invention on 1-naphthalene isothiocyanate (ANIT) -induced rat bile acid accumulation model
  • Animals SD rats, males, 7-8 weeks old, weighing 220-240g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., SPF grade, animal production license number: SCXK (Beijing) 2016-0011, Issuer: Beijing Science and Technology Commission.
  • Example 8 After 3 days of animal adaptation, the animals were divided into 3 groups according to body weight: normal group, model group, and Example 8 group, with 10 animals in each group.
  • the dose of Example 8 was 10 mg / kg / d, and the volume was 10 mL / kg. It was administered orally, once a day for a total of 4 days.
  • each animal except the normal group was orally administered with ANIT (98% purity, batch number: C10116101, Shanghai McLean Biochemical Technology Co., Ltd.) once at a dose of 50 mg / kg and an administration volume of 5 mL / kg.
  • ALT Glutamate aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • GTT glutamyl transpeptidase
  • ALT means ALT ⁇ 60U / L
  • E means ALT> 480U / L
  • A means AST ⁇ 200U / L
  • D 500- 700U / L
  • E AST> 700U / L
  • TBIL A means TBIL ⁇ 5 ⁇ M
  • E means TBIL> 100 ⁇ M
  • GGT A means GGT ⁇ 2.0U / L
  • Example 8 of the present invention significantly reduced the levels of ALT, AST, TBIL and GGT in the serum of ANIT rats, indicating that the compound of the present invention can significantly improve the cholestasis of ANIT rats.
  • Test Example 4 Efficacy of the Compound of the Invention on MCD (Methionine Choline Deficiency Feed) Induced NASH (Non Alcoholic Steatohepatitis) Model in Mice
  • mice C57BL / 6 mice, week age: 8-10 weeks, male, weight: 25-28 grams, provided by Beijing Speif Biotechnology Co., Ltd.
  • Feed clean grade normal feed, purchased from Beijing Keao Xieli Feed Co., Ltd. MCD feed, purchased from Research Diets (batch: 18062202 A2, A02082002BR).
  • mice C57BL / 6 male mice were adaptively fed with normal feed for 1 week and randomly divided into 3 groups of 8 mice each.
  • the normal group was given normal feed
  • the model group was given MCD feed
  • the Example 2 group was given the compound of Example 2 of the present invention on the basis of MCD feed at a dose of 30 mg / kg, orally, once a day for a total of four weeks.
  • blood was collected by cardiac puncture and collected in EP tubes. After standing at room temperature for 1 hour, the blood samples were centrifuged at 6000C for 15 minutes at 6000g, the serum was collected and transferred to a new EP tube, and the blood biochemical indicators were detected using the TOSHIBA TBA-40FR automatic blood biochemical detector.
  • Liver was dissected to collect liver tissues from the same parts of each animal and weighed. After grinding the tissue, quantitative volumes of anhydrous methanol (analytical grade) and chloroform (analytical grade) were added and left at 4 ° C for 24 hours. A quantitative volume of 0.7% sodium chloride solution was added, the inorganic phase and the organic phase were separated, and left at 4 ° C for 24 hours. Aspirate quantitative organic phase by blowing liquid nitrogen to make the solvent completely volatilize; add quantitative anhydrous isopropanol (analytical grade) to resuspend the precipitate, and centrifuge at 3000g for 10 minutes at 4 ° C. Liver tissue from the same part of each animal was fixed in 10% formalin for liver pathological examination. Specific detection indicators and scoring standards are shown in Table 6 below.
  • Example 7 The effect of the compound of Example 2 of the present invention on the plasma ALT and AST of MCD-induced NASH mouse model is shown in Table 7 below.
  • ALT A means ALT ⁇ 100U / L
  • D means ALT> 500U / L
  • A means AST ⁇ 100U / L
  • C 300-500U / L
  • D means AST> 500U / L.
  • Table 7 Effect of the compound of Example 2 of the present invention on plasma ALT and AST in MCD-induced NASH mouse model
  • Example 2 of the present invention The effect of the compound of Example 2 of the present invention on liver pathological scores of MCD-induced NASH mouse model is shown in Table 8 below.
  • A means the score ⁇ 1.0
  • D means the score> 2.0.
  • Example 2 of the present invention significantly improves the ALT and AST indexes and liver pathological scores of the MCD-induced NASH mouse model, indicating that the compound of the present invention has a good effect on the MCD-induced NASH mouse model.

Abstract

La présente invention concerne des composés 1,2,4-oxadiazole, leur procédé de préparation et leur utilisation, et en particulier, un composé représenté par une formule générale (I), un procédé de préparation associé, une composition pharmaceutique comprenant le composé, et une utilisation du composé en tant qu'agoniste du récepteur farnésoïde X (FXR). Le composé et la composition pharmaceutique comprenant le composé peuvent être utilisés pour traiter et/ou prévenir des maladies liées à l'activité de FXR, telles que la cholestase, le diabète et ses complications, la stéatose hépatique non alcoolique (NAFLD), la stéatohépatite non alcoolique (NASH), l'obésité ou le syndrome métabolique (dyslipidémie, diabète et complications ayant un indice de masse corporelle anormalement élevé), et une maladie cardiovasculaire. La définition de chaque substituant dans la formule générale (I) est identique à celle donnée dans la description.
PCT/CN2019/095201 2018-07-11 2019-07-09 Composés 1,2,4-oxadiazole, leur procédé de préparation et utilisation médicale associée WO2020011146A1 (fr)

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WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
CN114195777A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
WO2022068815A1 (fr) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Agoniste de petites molécules de fxr, son procédé de préparation et son utilisation
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
EP3919489A4 (fr) * 2019-01-31 2022-10-12 The National Institutes of Pharmaceutical R&D Co., Ltd Composés cycliques aromatiques ou cycliques hétéroaromatiques, procédé de préparation correspondant et utilisation médicale associée
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné

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EP3919489A4 (fr) * 2019-01-31 2022-10-12 The National Institutes of Pharmaceutical R&D Co., Ltd Composés cycliques aromatiques ou cycliques hétéroaromatiques, procédé de préparation correspondant et utilisation médicale associée
WO2021144330A1 (fr) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'agonistes de fxr pour traiter une infection par le virus de l'hépatite d
CN114195777A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
CN114195777B (zh) * 2020-09-18 2023-06-20 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
WO2022068815A1 (fr) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Agoniste de petites molécules de fxr, son procédé de préparation et son utilisation
WO2022152770A1 (fr) 2021-01-14 2022-07-21 Enyo Pharma Effet synergique d'un agoniste de fxr et d'ifn pour le traitement d'une infection par le virus de l'hépatite b
WO2022229302A1 (fr) 2021-04-28 2022-11-03 Enyo Pharma Potentialisation forte d'effets d'agonistes de tlr3 à l'aide d'agonistes de fxr en tant que traitement combiné

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