WO2022057672A1 - 新型fxr小分子激动剂制备及其用途 - Google Patents

新型fxr小分子激动剂制备及其用途 Download PDF

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WO2022057672A1
WO2022057672A1 PCT/CN2021/116794 CN2021116794W WO2022057672A1 WO 2022057672 A1 WO2022057672 A1 WO 2022057672A1 CN 2021116794 W CN2021116794 W CN 2021116794W WO 2022057672 A1 WO2022057672 A1 WO 2022057672A1
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general formula
compound
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French (fr)
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赵一爽
张振伟
吴国辉
汪鹏
杨生生
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凯思凯迪（上海）医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • A61K31/435—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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine, and relates to the preparation and use of a class of non-steroidal compounds as FXR agonists. Specifically, it relates to a class of organic small molecule compounds that can act as FXR agonists and their enantiomers, diastereomers, tautomers, racemates, hydrates, solvates, A preparation method of a prodrug or a pharmaceutically acceptable salt thereof and its application in the preparation of a medicine for treating FXR-related diseases.
  • Farnesoid X receptor is a member of the nuclear receptor superfamily, which is a ligand-dependent nuclear transcription factor, which is mainly expressed in the liver, intestine, kidney, bile duct and other systems; It is activated by the endogenous ligand bile acid and participates in important links such as bile acid metabolism and cholesterol metabolism, so it is also called bile acid receptor.
  • FXR is directly involved in regulating the expression of more than 300 genes including physiological processes such as lipid metabolism, glucose metabolism, inflammation, fibrosis, liver regeneration, cell differentiation and proliferation.
  • FXR activated by endogenous ligand bile acids, plays an important role in triglyceride (TG) metabolism.
  • TG triglyceride
  • FXR can regulate the key enzymes, lipoproteins and corresponding receptors involved in TG metabolism.
  • the content of TG in the liver and circulating blood reaches a steady state balance. Therefore, up to now, there have been many FXR synthetic ligand molecules in the field of metabolic diseases such as the liver.
  • FXR agonist molecules are used in the treatment of liver diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and nonalcoholic fatty liver disease (NASH). ), etc., has shown excellent clinical effects. So far, obeticholic acid (OCA), an FXR agonist molecule that will be the first to be approved for marketing, has been proven to significantly improve a variety of metabolic symptoms, such as reducing liver fat content, reducing inflammation and inhibiting liver fibrosis. Wait.
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • NASH nonalcoholic fatty liver disease
  • FXR is closely related to the occurrence and development of tumors.
  • FXR acts as a tumor suppressor gene.
  • the expression of FXR is low. After activation of FXR, it significantly inhibits the progression of liver or rectal cancer by inhibiting the activity of ⁇ -catenin.
  • FXR agonist OCA can significantly inhibit the proliferation, migration and colony formation of intrahepatic cholangiocarcinoma.
  • FXR agonists can be used as a new antiviral drug candidate, and studies have confirmed that FXR ligands can be used as a new therapeutic strategy for inhibiting the replication of hepatitis B virus (HBV).
  • FXR agonists inhibit HBV surface antigen synthesis, inhibit HBV DNA and RNA replication, and most importantly, inhibit HBV cccDNA production.
  • HCV hepatitis C virus
  • the FXR agonist GW4064 can inhibit the invasion of HCV into hepatocytes by indirect means. Therefore, agonist molecules of FXR also have great prospects as antiviral drugs.
  • the purpose of the present invention is to provide a novel FXR agonist molecule with simple preparation method and good inhibitory effect.
  • the first aspect of the present invention provides a compound represented by general formula I, or its enantiomer, diastereomer, tautomer, racemate, hydrate, solvate drug, prodrug, or a pharmaceutically acceptable salt thereof.
  • Ar is selected from the following group: substituted or unsubstituted C 6 -C 10 aryl, substituted or unsubstituted 5-9 membered heteroaromatic rings (including monocyclic or fused rings, containing 1-3 selected from oxygen, heteroatoms in sulfur and nitrogen);
  • R 1 is selected from: substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 5-9 membered heterocycle (containing 1-3 heteroatoms selected from oxygen, sulfur and nitrogen);
  • R 21 , R 22 , R 23 are each independently selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy;
  • W is selected from the group consisting of hydrogen or deuterium
  • V is selected from the group consisting of hydrogen or deuterium
  • U is selected from the group consisting of O or NH
  • X is selected from the group consisting of O, NH, CH 2 or CHR 2 , wherein R 2 is selected from the group consisting of deuterium, substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • Y is selected from the group consisting of O, NH, CH 2 or CHR 3 , wherein R 3 is selected from the group consisting of deuterium, substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl;
  • substitution refers to that one or more hydrogen atoms on the group are independently replaced by a substituent selected from the following group: deuterium, halogen, halogenated C 1 -C 6 alkyl, halogenated C 1 -C C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkoxy, cyano or nitro.
  • the Ar is selected from the following group: a substituted or unsubstituted C 6 -C 10 aryl group, a substituted or unsubstituted 5-9 membered heteroaromatic ring, wherein the aryl group or heteroaryl substituents are selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
  • R 21 , R 22 and R 23 are each independently selected from the group consisting of hydrogen, halogen, halogenated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • the R 1 is selected from the following group: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl .
  • the R 21 , R 22 and R 23 are each independently hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, trifluoromethyl, or trifluoromethoxy.
  • Ar is selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-7 membered heteroaromatic ring (including monocyclic or condensed ring, containing 1-3 selected from heteroatoms in oxygen, sulfur and nitrogen).
  • the Ar is selected from substituted or unsubstituted groups selected from the following group: benzene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrimidine ring, pyridazine ring, furan ring, thiophene ring, pyrrole ring, thiazole ring, or imidazole ring.
  • the R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 4 alkyl, and substituted or unsubstituted cyclopropyl.
  • the Ar is a substituted or unsubstituted benzene ring.
  • the Ar is selected from the following group: 2,5-dichlorophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-trifluoromethoxyphenyl .
  • the X is selected from: O, NH, CH 2 or CHR 2 , wherein R 2 is selected from the following group: deuterium, substituted or unsubstituted C 1 -C 6 alkyl, C 3 - C 6 cycloalkyl; said Y is selected from: O, NH, CH 2 or CHR 2 , wherein R 2 is selected from the group consisting of: deuterium, substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl.
  • the compound is selected from the following group:
  • the compound of formula (I) has the structure shown in the following formula:
  • the second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention.
  • Compound I
  • X is NH
  • Y is O
  • the definitions of R 1 , R 21 , R 22 , R 23 , Ar, W, V and U are as described in the first aspect of the present invention
  • X is O
  • Y is NH
  • the definitions of R 1 , R 21 , R 22 , R 23 , Ar, W, V and U are as described in the first aspect of the present invention
  • X is NH
  • Y is CH 2
  • the definitions of R 1 , R 21 , R 22 , R 23 , Ar, W, V and U are as described in the first aspect of the present invention.
  • the compound represented by general formula VIII is prepared by the following steps:
  • the compound represented by the general formula XI is prepared by the following steps:
  • the raw material with the corresponding optical configuration is used for preparation.
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the compound represented by the general formula I as described in the first aspect of the present invention, or its enantiomer, diastereomer, mutual Variants, racemates, hydrates, solvates, metabolites, prodrugs, pharmaceutically acceptable salts; and pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides a compound represented by the general formula I as described in the first aspect of the present invention, or its enantiomer, diastereomer, tautomer, exoisomer Use of a racemate, hydrate, solvate, prodrug or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating a disease or condition related to FXR activity or expression level.
  • the FXR-related diseases are selected from the group consisting of diseases related to bile acid metabolism, glucose metabolism, lipid metabolism, inflammation, and/or liver fibrosis process.
  • the FXR-related diseases are non-alcoholic fatty liver disease (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, non-alcoholic fatty liver disease Cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.
  • NASH non-alcoholic fatty liver disease
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • gallstones non-alcoholic fatty liver disease Cirrhosis, liver fibrosis, cholestatic liver disease, hyperlipidemia, hypercholesterolemia, or diabetes.
  • the pharmaceutical composition is used as an FXR agonist.
  • the pharmaceutical composition is used to reduce the levels of ALP, ALT, AST and TBA in serum.
  • the pharmaceutical composition is used to reduce the content of hydroxyproline in liver tissue.
  • the pharmaceutical composition is used to downregulate the expression of ⁇ -SMA and Col1 ⁇ 1 mRNA in liver tissue.
  • the pharmaceutical composition is used to inhibit the synthesis of HBV surface antigen, inhibit the replication of HBV DNA and RNA, and inhibit the production of HBV cccDNA.
  • the pharmaceutical composition is used to reduce the content of collagen in the liver.
  • the pharmaceutical composition is prepared by the following method: mixing the compound of formula I with pharmaceutically acceptable excipients (such as excipients, diluents, etc.) to prepare tablets for oral administration , capsules, granules or syrups, etc.
  • pharmaceutically acceptable excipients such as excipients, diluents, etc.
  • the inventors of the present application have developed a class of non-steroidal compounds that can be used as FXR agonists, which have agonistic ability to FXR at the molecular and cellular levels.
  • the levels of ALP, ALT, AST and TBA can reduce the content of hydroxyproline in liver tissue, down-regulate the expression of á-SMA and Col1á1 mRNA in liver tissue, reduce the content of collagen in liver, inhibit the synthesis of HBV surface antigen, and inhibit the expression of HBV DNA and RNA.
  • Replication inhibits the production of HBV cccDNA.
  • the compound of the present invention has the advantages of high FXR agonistic activity, simple synthesis, easy availability of raw materials, and the like, and can be used for preparing medicines for treating FXR-related diseases. On this basis, the present invention has been completed.
  • the halogen is F, Cl, Br or I.
  • C1-C6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C3-C6 means having 3, 4, 5 or 6 carbon atoms, depending on analogy.
  • alkyl refers to a saturated linear or branched hydrocarbon moiety
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, without limitation include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl and tert-butyl.
  • alkoxy denotes a -O-(C1-C6 alkyl) group.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety
  • C3-C6 cycloalkyl refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring, without limitation Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkoxy means cycloalkyl-O-, cycloalkyl as described above.
  • aryl refers to a hydrocarbyl moiety comprising one or more aromatic rings.
  • aryl groups include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, fluorenyl, anthracenyl, and phenanthryl.
  • heteroaryl refers to a moiety comprising one or more aromatic rings having at least one heteroatom (eg, N, O or S).
  • heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, quinazolinyl, quinolinyl, isoquinolinyl, indolyl, and the like.
  • alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, and heteroaryl groups described herein are substituted and unsubstituted groups.
  • Possible substituents on alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl and heteroaryl include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1 - C6 Alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 20 cycloalkyl, C 3 -C 20 cycloalkenyl, C 1 -C 20 heterocycloalkyl, C 1 - C 20 heterocycloalkenyl, C 1 -C 6 alkoxy, aryl, heteroaryl, heteroaryloxy, C 1 -C 10 alkylamino, C 1 -C 20 dialkylamino, arylamino , diarylamino
  • the substitution is monosubstitution or polysubstitution
  • the polysubstitution is disubstitution, trisubstitution, tetrasubstitution, or pentasubstitution.
  • the disubstituted refers to having two substituents, and so on.
  • the pharmaceutically acceptable salts of the present invention may be salts of anions with positively charged groups on the compounds of formula I.
  • Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate acid, glutamate, glucuronate, lactate, glutamate or maleate.
  • salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium, such as tetramethylammonium.
  • “pharmaceutically acceptable salt” refers to the salts formed by the compound of formula I with an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, Nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid , Glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic
  • any one of Ar, R 1 , R 21 , R 22 , R 23 , W, V, X, Y, and Z is one of the specific compounds described in the Examples, respectively. the corresponding group.
  • the compounds of the present invention possess asymmetric centers, chiral axes and chiral planes, and may exist as racemates, R-isomers or S-isomers. Those skilled in the art can obtain the R-isomer and/or S-isomer from the racemate by conventional technical means.
  • the preparation method comprises the following steps:
  • the compound represented by the general formula VIII can also be prepared with reference to circuit 1, and further comprises the following steps:
  • R 1 , R 21 , R 22 , R 23 , Ar, W, V, U, X and Y are as defined above.
  • compositions and their therapeutic uses are provided.
  • the compounds provided by the present invention can be used alone or mixed with pharmaceutically acceptable excipients (such as excipients, diluents, etc.) to prepare tablets, capsules, granules or syrups for oral administration.
  • the pharmaceutical composition can be prepared according to conventional methods in pharmacy.
  • the pharmaceutical composition of the present invention contains the active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier.
  • the “active ingredient” in the present invention refers to the compound of formula I described in the present invention.
  • compositions of the present invention are used to prepare medicines for treating FXR-related diseases. This invention
  • the "active ingredients" and pharmaceutical compositions described are useful as FXR agonists.
  • the active ingredient can be used to prepare a medicament for preventing and/or treating diseases regulated by FXR agonists.
  • a “safe and effective amount” refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose.
  • the "one dose” is one tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • the mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention may be administered alone or in combination with other therapeutic agents (eg, hypolipidemic agents).
  • other therapeutic agents eg, hypolipidemic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • reagents and anhydrous solvents used were purchased from Chinese commercial companies, and were used directly unless otherwise specified; BrukerAM-400 and Varian Mercury plus-400 nuclear magnetic resonance instruments were used for 1 H and 13 C NMR, and Agilent 6230 mass spectrometers were used for mass spectrometry, and 200-300 mesh column chromatography silica gel (Qingdao Ocean Chemical Plant), HSGF254 TLC plate (Yantai Chemical Research Institute).
  • the compound of the present invention is prepared according to any method selected from the following route 1, route 2 and route 3, using suitable starting materials:
  • Aqueous potassium carbonate solution (3N, 182mmol) was added dropwise to a stirring solution of hydroxylamine hydrochloride (182mmol) in ethanol (100mL) at 0°C, and 2,6-dichlorobenzaldehyde II-1 (20g, 114mmol) was dissolved in 100ml ethanol, and then added to the hydroxylamine solution, the temperature was raised to 90 °C, and the reaction was carried out for two hours. The mixture was allowed to cool to room temperature and then concentrated to a solid. A solution of water/ethanol (1000 mL/100 mL) was added and stirred to break up the solid, filtered, and dried under vacuum at 50° C. overnight to obtain the compound intermediate (18.4 g).
  • Triethylamine (8.2 g) was added to methyl 3-cyclopropyl-3-oxopropanoate (82 mmol) and stirred for 30 minutes. Then it was cooled to 10°C, and a solution of III-1 (18.3 g, 82 mmol) in absolute ethanol (80 mL) was added dropwise (internal temperature did not exceed 30°C), and the reaction was carried out at room temperature overnight. Ethyl acetate (100 mL) was added to dilute the reaction solution, washed with water, and the aqueous phase was extracted with ethyl acetate (100 mL each, 3 times in total). The organic phases were mixed, washed with saturated brine, and the combined organic phases were concentrated.
  • reaction solution was slowly poured into ice water, and 1M aqueous hydrochloric acid was added to adjust the pH to about 2, extracted with ethyl acetate (100 mL each time, three times in total), the combined organic phases were concentrated, and the intermediate alcohol was obtained by column chromatography; and triphenylphosphine (59mmol) were dissolved in dichloromethane (60mL), cooled to 0°C, under nitrogen protection, a solution of carbon tetrabromide (62mmol) in dichloromethane (60mL) was added dropwise, and the reaction was performed at room temperature for 4h .
  • reaction solution was cooled to room temperature, diluted with water (5 mL), adjusted to about pH 2 with 1M aqueous hydrochloric acid solution, then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, the combined organic phases were concentrated, and the obtained crude product was passed through a column Chromatography gave the final product 2 as a white solid (0.18 g, 82% yield).
  • Example 3 From methyl 4-amino-3-fluorobenzenecarboxylate XII-2, intermediate XVII-2 was prepared with reference to the synthesis of intermediate XVII-1 of Example 2, and then prepared through route 3, and synthesized The route is as follows:
  • the synthetic route of embodiment 10 is as follows:
  • the synthetic route of embodiment 12 is as follows:
  • the synthetic route of embodiment 13 is as follows:
  • the synthetic route of embodiment 14 is as follows:
  • the synthetic route of embodiment 15 is as follows:
  • the synthetic route of embodiment 16 is as follows:
  • VIII-11 is prepared according to the synthesis of intermediate VIII-1, and 16 is prepared by route 1, wherein:
  • the pGAL4-FXR-LBD and pG5-Luc plasmids used in the reporter gene detection system were constructed according to conventional molecular cloning methods. The main steps are: using PCR technology to insert the FXR (NM_001206979.2) cDNA sequence corresponding to the amino acid sequence of FXR-LBD (212-476AA) into the pGAL4 vector BamHI and NotI restriction sites to obtain pGAL4-FXR-LBD; pG5-Luc and phRL-TK plasmids were donated by Shanghai Institute of Materia Medica, Chinese Academy of Sciences; the plasmids were transformed into DH5 ⁇ Escherichia coli by the CaCl 2 method, and the corresponding plasmid DNAs were obtained after further culture and amplification and purification with a plasmid extraction kit (TIANGEN, #D107).
  • FXR NM_001206979.2
  • HEK293T cells were seeded in 96-well plates at a density of 1 ⁇ 10 4 /well one day before plasmid transfection. According to transfection reagent Transfection of cells was performed according to the instructions of HD (Promega, #E2311).
  • the main steps are: take one well as an example, add the plasmids pGAL4-FXR-LBD, pG5-Luc and phRL-TK to 10uL of Opti-MEM TM I medium (Gibco, #11058021) at the ratio of 20ng, 50ng and 5ng Mix well; add 0.25uL of HD, after mixing, let stand for 5 min at room temperature; then add 10 uL of the mixture to the cell well containing 100 uL of culture medium.
  • the compound was diluted with a 3-fold gradient at the highest concentration of 1 uM, and 10 concentrations were added to the cell culture medium for treatment for 24 hours. Two duplicate wells were divided, and LJN452 compound was used as a positive control.
  • the ratio of Firefly-Luc/Renilla-Luc was used as the activating activity of the compound on FXR, and was normalized with the ratio of the solvent DMSO group.
  • the dose-response curve was fitted with four parameters using GraphPad Prism6.0 software, and the EC 50 was calculated. value.
  • the experimental data show that the compounds have certain FXR agonistic activity, wherein the EC 50 values of Examples 1, 2, 4, 7, 8, and 16 are all less than 10 nM, especially the EC 50 value of Example 8 is less than 5 nM, which has a very strong EC 50 value.
  • FXR agonistic activity The FXR agonistic activity data of each example is shown in Table 1.
  • the D-type HBV was collected and concentrated in the culture medium, and its viral titer was determined by quantitative PCR.
  • the human primary hepatocytes purchased from Reed Liver Disease Research Co., Ltd.
  • cryopreserved in liquid nitrogen were thawed, the cell density was adjusted to 6 ⁇ 10 5 cells/ml, and plated into a 48-well plate, and 220uL was added to each well. (about 1.3 ⁇ 10 5 cells), placed in 5% CO 2 and cultured at 37°C overnight.
  • the D-type HBV was added to the PHH cells at a ratio of 800 genome equivalents/cell; on the third day, the compound treatment was started.
  • HBV DNA hepatitis B virus surface antigen
  • HBeAg hepatitis B virus e antigen
  • the cell culture supernatant was collected on the 8th day after compound treatment, and HBV DNA, HBeAg and HBsAg were detected respectively.
  • HBV DNA, HBeAg and HBsAg were detected respectively.
  • QIAamp 96 DNA Blood Kit QIAGEN, #51161
  • 100ul of cell culture supernatant was taken to extract DNA;
  • HBV plasmid DNA was used as the standard, and the content of HBV DNA was quantitatively detected by qPCR.
  • HBsAg and HBsAg were detected according to the instructions of the ELISA kit.
  • the method is briefly described as follows: firstly, dilute the sample 8-fold (15ul cell supernatant + 105ul PBS); then take 50ul of standard, sample and control, and add them to the detection plate, then add 50ul enzyme conjugate to each well, 37°C Incubate for 60 minutes; wash the plate with washing solution and blot dry, then add 50ul of premixed luminescent substrate, incubate at room temperature for 10 minutes in the dark, and finally measure the luminescence value with a microplate reader.
  • the cell viability was determined according to the instructions of the CCK-8 kit. The method is briefly described as follows: After the 8th day of compound treatment, after the cell culture supernatant was collected, add 180ul fresh medium and 20ul CCK-8 to each well, and incubate at 37°C after mixing. After 2.5 hours, the absorbance value (450nm/650nm) was measured by a microplate reader.
  • HBV DNA inhibition rate (1- HBV DNA copy number of compound/HBV DNA copy number of DMSO control) ⁇ 100%
  • HBsAg inhibition rate (1-HBsAg(IU/ml) of sample/HBsAg(IU/ml) of DMSO control) ⁇ 100%;
  • HBeAg inhibition rate (1-HBeAg(PEIU/ml) of sample/HBeAg(PEIU/ml) of DMSO control) ⁇ 100%;
  • Cell viability (signal value of sample ⁇ signal value of medium control)/(signal value of DMSO control ⁇ signal value of medium control) ⁇ 100%.
  • HBV DNA inhibition rate HBsAg inhibition rate
  • HBeAg inhibition rate cell viability of the compounds in the in vitro model of primary hepatocyte (PHH) infection with HBV are shown in the following table.

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Abstract

本发明公开了一种FXR(法尼醇X受体)小分子激动剂及其制备方法，结构如式I所示。式中，各取代基的定义如说明书中所述。本发明的化合物具有FXR激动活性高、合成简单、原料易得等优点，能够用于治疗FXR相关疾病的药物。

Description

新型FXR小分子激动剂制备及其用途 技术领域
本发明属于医药领域，涉及一类作为FXR激动剂的非甾体化合物的制备和用途。具体而言，涉及一类可作为FXR激动剂的有机小分子化合物及其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、前药、或其药学上可接受的盐的制备方法以及其在制备治疗FXR相关疾病药物中的应用。
背景技术
类法尼醇X受体(Farnesoid X receptor)是核受体超家族的一员，属于配体依赖的核转录因子，其主要表达于肝脏、肠道、肾脏、胆管等系统；FXR因其可被内源性配体胆汁酸激活,参与胆汁酸代谢与胆固醇代谢等重要环节，故又称胆汁酸受体。FXR可直接参与调节包括脂代谢、糖代谢、炎症、纤维化、肝再生、细胞分化和增殖等生理过程在内的300多个基因的表达。在自然环境中其配体包括初级胆汁酸鹅脱氧胆酸、次级胆酸石胆酸、脱氧胆酸等。如，被内源性配体胆汁酸激活后的FXR在甘油三酯(triglyceride,TG)代谢过程中起着重要作用,FXR可通过调控与TG代谢的关键酶、脂蛋白和相应受体,从而使肝脏及循环血液中TG含量达到稳态平衡。所以，截至目前，已有多个FXR合成型配体分子在肝脏等代谢性疾病应用领域。
FXR激动剂分子在治疗肝脏疾病，如原发性胆汁性肝硬化(primary biliary cirrhosis,PBC),原发性硬化性胆管炎(primary sclerosing cholangitis,PSC)和非酒精性脂肪肝(nonalcoholic steatohepatitis,NASH)等方面，已呈现出优异临床效果。至目前，即将最先被批准上市的FXR激动剂分子奥贝胆酸(obeticholic acid,OCA)已被证实可显著改善多种代谢性症状，如降低肝脂肪含量，减少炎症反应和抑制肝纤维化等。但，OCA也日益凸显出诸多临床短板，如引起瘙痒，高密度脂蛋白(high-density lipoprotein cholesterol,HDLc)降低，低密度脂蛋白(low-density lipoprotein cholesterol,LDLc)升高等。因此，临床需求方面，急需出现新的临床效果好，毒副作用低的FXR激动剂分子。
此外，有研究证实，FXR与肿瘤的发生发展密切相关。在多种肿瘤中，FXR扮演着抑癌基因的角色。例如，在肝细胞癌和直肠癌中，FXR呈低表达状态，FXR活化后，通过抑制β-catenin的活性，显著抑制肝癌或直肠癌的进展。新近研究表明，在胆管癌中，FXR的激动剂OCA能够显著抑制肝内胆管细胞的增殖、迁移及克隆形成等。
再者，FXR激动剂作可为一种新的抗病毒候选药物，有研究证实，FXR配体能够作为一种新的乙型肝炎病毒(hepatitis B virus,HBV)复制的抑制治疗策略。FXR激动剂可抑制HBV表面抗原合成，抑制HBV DNA和RNA的复制，最重要的是，可抑制HBV cccDNA的产生。在丙型肝炎病毒(hepatitis C virus,HCV)方面，FXR激动剂GW4064可通过间接方式抑制HCV入侵肝组织细胞。所以，FXR的激动剂分子亦具有作为开发抗病毒药物的巨大前景。
综上所述，本领域尚缺乏制备方法简单，抑制效果好的新型FXR激动剂分子。
发明内容
本发明的目的是提供一种制备方法简单，抑制效果好的新型FXR激动剂分子。
本发明的第一方面，提供了一种通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、前药，或其药学上可接受的盐。
Figure PCTCN2021116794-appb-000001
其中，
Ar选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的5-9元的杂芳环(包括单环或稠合环，含有1-3个选自氧、硫和氮中的杂原子)；
R 1选自：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基、取代或未取代的5-9元的杂环(含有1-3个选自氧、硫和氮中的杂原子)；
R 21、R 22、R 23各自独立地选自下组：氢、氘、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基；
W选自下组：氢或氘；
V选自下组：氢或氘；
U选自下组：O或NH；
X选自下组：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；
Y选自下组：O、NH、CH 2或CHR 3，其中R 3选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；
其中，所述的取代指基团上的一个或多个氢原子各自独立地被选自下组的取代基所替代：氘、卤素、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、氰基或硝基。
在另一优选例中，所述的Ar选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的5-9元的杂芳环，其中，所述的芳基或杂芳基的取代基选自下组：氢、氘、氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、或三氟甲氧基。
在另一优选例中，R 21、R 22、R 23各自独立地选自下组：氢、卤素、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6烷氧基。
在另一优选例中，所述的R 1选自下组：甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环丁基或环戊基。
在另一优选例中，所述的R 21、R 22、R 23各自独立地为氢、氘、氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、或三氟甲氧基。
在另一优选例中，Ar选自下组：取代或未取代的苯基、取代或未取代的5-7元的杂芳环(包括单环或稠合环，含有1-3个选自氧、硫和氮中的杂原子)。
在另一优选例中，所述的Ar选自取代或未取代的选自下组的基团：苯环、吡啶环、嘧啶环、哒嗪环、嘧啶环、哒嗪环、呋喃环、噻吩环、吡咯环、噻唑环，或咪唑环。
在另一优选例中，所述的R 1选自下组：取代或未取代的C 1-C 4烷基、取代或未取代的环丙基。
在另一优选例中，所述的Ar为取代或未取代的苯环。
在另一优选例中，所述的Ar选自下组：2,5-二氯苯基、2-甲基苯基、2-三氟甲基苯基、2-三氟甲氧基苯基。
在另一优选例中，所述的X选自：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；所述的Y选自：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2021116794-appb-000002
在另一优选例中，所述的式(I)化合物具有如下式所示的结构：
Figure PCTCN2021116794-appb-000003
本发明的第二方面，提供了一种如本发明第一方面所述的化合物的制备方法，所述的方法包括：通过选自下组路线一，路线二或路线三所述的方法制备式I化合物：
路线一：
Figure PCTCN2021116794-appb-000004
(a’)通式VIII所示的化合物与XI所示的化合物在碱性条件下反应成通式XV所示的化合物；
(b’)通式XV所示的化合物与盐酸羟胺反应生成通式XVI所示的化合物；
(c’)通式XVI所示的化合物在光气、三光气、或者羰基二咪唑的作用下反应生成通式I所示的化合物，
其中，X为NH，Y为O，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如本发明第一方面所述；
路线二：
Figure PCTCN2021116794-appb-000005
(a”)通式VIII所示的化合物与XIV所示的化合物在碱性条件下反应成通式XVII所示的化合物；
(b”)通式XVII所示的化合物在碱的作用下与水合肼反应生成通式XVIII所示的化合物；
(c”)通式XVIII所示的化合物在光气、三光气或者羰基二咪唑的作用下反应生成通式I所示的化合物；
其中，X为O，Y为NH，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如本发明第一方面所述；
路线三：
Figure PCTCN2021116794-appb-000006
(a”')通式XVII所示的化合物与二氯亚砜在微量N,N-二甲基甲酰胺作用下反应成通式XIX所示的化合物；
(b”')通式XIX所示的化合物在碱的作用下与甘氨酰胺反应生成通式XX所示的化合物；
(c”')通式XX所示的化合物在三氯氧磷的作用下反应生成通式I所示的化合物，
其中，X为NH，Y为CH 2，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如本发明第一方面所述。
在另一优选例中，通式VIII所示的化合物通过以下步骤制备：
Figure PCTCN2021116794-appb-000007
(a)以取代苯甲醛通式II所示的化合物为起始原料在碱的作用下与盐酸羟胺反应得到中间体后用N-氯代丁二酰亚胺(NCS)氯代后成通式III所示的化合物；
(b)然后将通式III所示的化合物与相应的3-氧代丙酸酯反应得到通式IV所示的化合物；
(c)将通式IV所示的化合物中的酯在还原剂的作用下还原成相应的醇，再进行溴代后生成V所示的化合物，
(d)通式V所示的化合物与VI所示的化合物在碱性条件下反应成通式VII所示的化合物；
(e)通式VII所示的化合物在三氟乙酸的作用下反应得到通式VIII所示的化合物；
各式中，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如本发明第一方面所述。
在另一优选例中，通式XI所示的化合物通过以下步骤制备：
Figure PCTCN2021116794-appb-000008
(f)通式IX所示的化合物与硫氰化钠在液溴的作用下或者与四丁基硫氰酸铵在苄基三甲基溴化铵的作用下反应得到通式X所示的化合物；
(g)将通式X所示的化合物与溴化亚铜、溴化铜、氯化亚铜或氯化铜在亚硝酸特丁酯作用下反应，得到通式XI所示的化合物。
各式中，R 21、R 22、R 23的定义如本发明第一方面所述。
通式XIV所示的化合物通过以下步骤制备：
Figure PCTCN2021116794-appb-000009
(h)通式XII所示的化合物与硫氰化钠在液溴的作用下或者与四丁基硫氰酸铵在苄基三甲基溴化铵的作用下反应得到通式XIII所示的化合物；
(i)将通式XIII所示的化合物与溴化亚铜、溴化铜、氯化亚铜或氯化铜在亚硝酸特丁酯作用下反应，得到通式XIV所示的化合物。
各式中，R 21、R 22、R 23的定义如本发明第一方面所述。
在另一优选例中，当产物存在光学异构体时，采用对应的光学构型的原料进行制备。
本发明的第三方面，提供了一种药物组合物，其包含如本发明第一方面所述的通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、代谢产物、前药、药学上可接受的盐；和药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、前药或其药学上可接受的盐的用途，其用于制备治疗与FXR活性或表达量相关的疾病或病症的药物组合物。
在另一优选例中，所述的FXR相关疾病选自下组：胆汁酸代谢、糖代谢、脂代谢、炎症、和/或肝脏纤维化过程相关疾病。
在另一优选例中，所述FXR相关疾病为非酒精性脂肪肝(NASH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、胆结石、非酒精性肝硬化、肝纤维化、胆汁淤积性肝病、高血脂症、高胆固醇血症或糖尿病。
在另一优选例中，所述的药物组合物用作FXR激动剂。
在另一优选例中，所述的药物组合物用于降低血清中ALP、ALT、AST、TBA的水平。
在另一优选例中，所述的药物组合物用于降低肝脏组织中羟脯氨酸的含量。
在另一优选例中，所述的药物组合物用于下调肝脏组织中α-SMA及Col1α1mRNA表达。
在另一优选例中，所述的药物组合物用于抑制HBV表面抗原合成，抑制HBV  DNA和RNA的复制，抑制HBV cccDNA的产生。
在另一优选例中，所述的药物组合物用于减少肝脏中胶原含量。
在另一优选例中，所述的药物组合物是通过以下方法制备的：用式I化合物与可药用的辅料(例如赋形剂、稀释剂等)混合，配制成口服给药的片剂、胶囊剂、颗粒剂或糖浆剂等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本申请的发明人经过广泛而深入地研究，研发出一类可作为FXR激动剂的非甾体化合物，在分子水平和细胞水平对FXR均有激动能力，研究表明本申请的化合物能够降低血清中ALP、ALT、AST、TBA的水平，降低肝脏组织中羟脯氨酸的含量，下调肝脏组织中á-SMA及Col1á1mRNA表达，减少肝脏中胶原含量，抑制HBV表面抗原合成，抑制HBV DNA和RNA的复制，抑制HBV cccDNA的产生。本发明的化合物具有FXR激动活性高、合成简单、原料易得等优点，能够用于制备用于治疗FXR相关疾病的药物。在此基础上，完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，所述卤素为F、Cl、Br或I。
在本发明中，术语“C1-C6”是指具有1、2、3、4、5或6个碳原子，“C3-C6”是指具有3、4、5或6个碳原子，依此类推。
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C6烷基”是指具有1至6个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中，术语“烷氧基”表示-O-(C1-C6烷基)基团。例如术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中，术语“环烷基”表示饱和的环状烃基部分，例如术语“C3-C6环烷基”是指在环上具有3至6个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基和环己基等。
在本发明中，术语“环烷氧基”表示环烷基-O-，环烷基如上所述。
在本发明中，术语“芳基”表示包含一个或多个芳环的烃基部分。芳基的例子包括但不限于苯基(Ph)、萘基、芘基、芴基、蒽基和菲基。
在本发明中，术语“杂芳基”表示包含一个或多个具有至少一个杂原子(例如N,O或S)的芳环的部分。杂芳基的例子包括呋喃基、吡咯基、噻吩基、噁唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、异喹啉基和吲哚基等。
除非另外说明，本文所述的烷基、烷氧基、环烷基、环烷氧基、芳基和杂芳基为取代的和未取代的基团。烷基、烷氧基、环烷基、环烷氧基、芳基和杂芳基上可能的 取代基包括，但不限于：羟基、氨基、硝基、腈基、卤素、C 1-C 6烷基、C 2-C 10烯基、C 2-C 10炔基、C 3-C 20环烷基、C 3-C 20环烯基、C 1-C 20杂环烷基、C 1-C 20杂环烯基、C 1-C 6烷氧基、芳基、杂芳基、杂芳氧基、C 1-C 10烷基氨基、C 1-C 20二烷基氨基、芳基氨基、二芳基氨基、C 1-C 10烷基氨磺酰基、芳基氨磺酰基、C 1-C 10烷基亚氨基、C 1-C 10烷基磺基亚氨基、芳基磺基亚氨基、巯基、C 1-C 10烷硫基、C 1-C 10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。另一方面，环烷基、杂环烷基、杂环烯基、芳基和杂芳基也可互相稠合。
本发明中，所述取代为单取代或多取代，所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基，依此类推。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地，可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子，例如四甲基铵离子。
在另一优选例中，“药学上可接受的盐”是指式I化合物同选自下组的酸形成的盐类：氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等；或者式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐；或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
在另一优选例中，所述的化合物中，Ar、R 1、R 21、R 22、R 23、W、V、X、Y、和Z中任一个分别为实施例中所述具体化合物中所对应的基团。
本发明的化合物具有不对称中心、手性轴和手性平面，并且可以以外消旋体、R-异构体或S-异构体的形式存在。本领域技术人员能够采用常规技术手段由外消旋体拆分获得R-异构体和/或S-异构体。
制备方法
本发明的通式I所示的化合物的制备方法，合成路线如下：
路线一：
Figure PCTCN2021116794-appb-000010
所述制备方法包括以下步骤：
(a)以芳基甲醛通式II所示的化合物为起始原料在碱的作用下与盐酸羟胺反应得到中间体后用N-氯代丁二酰亚胺(NCS)氯代后成通式III所示的化合物；
(b)然后将通式III所示的化合物在碱的作用下与相应的3-氧代丙酸酯反应得到通式IV所示的化合物；
(c)将通式IV所示的化合物中的酯在还原剂的作用下还原成相应的醇，再进行溴代后生成V所示的化合物；
(d)通式V所示的化合物与VI所示的化合物在碱的作用下反应成通式VII所示的化合物；
(e)通式VII所示的化合物在三氟乙酸的作用下反应得到通式VIII所示的化合物；
(a')通式VIII所示的化合物与XI所示的化合物在碱的作用下反应成通式XV所示的化合物；
(b')通式XV所示的化合物在碱的作用与盐酸羟胺反应生成通式XVI所示的化合物；
(c')通式XVI所示的化合物在光气、三光气或者羰基二咪唑的作用下反应生成通式I所示的化合物。
其中，通式XI所示的化合物通过以下步骤制备：
Figure PCTCN2021116794-appb-000011
(f)通式IX所示的化合物与硫氰化钠在液溴的作用下或者与四丁基硫氰酸铵在苄基三甲基溴化铵的作用下反应得到通式X所示的化合物；
(g)然后将通式X所示的化合物与溴化亚铜、溴化铜、氯化亚铜或氯化铜在亚硝酸特丁酯作用下反应得到通式XI所示的化合物；
线路2
Figure PCTCN2021116794-appb-000012
通式VIII所示的化合物也可参照线路1制得，此外还包括以下步骤：
(h)通式XII所示的化合物与硫氰化钠在液溴的作用下或者与四丁基硫氰酸铵在苄基三甲基溴化铵的作用下反应得到通式XIII所示的化合物；
(i)然后将通式XIII所示的化合物与溴化亚铜、溴化铜、氯化亚铜或氯化铜在亚硝酸特丁酯作用下反应得到通式XIV所示的化合物；
(a”)通式VIII所示的化合物与XIV所示的化合物在碱的作用下反应成通式XVII所示的化合物；
(b”)通式XVII所示的化合物在碱的作用下与水合肼反应生成通式XVIII所示的化合物；
(c”)通式XVIII所示的化合物在光气、三光气或者羰基二咪唑的作用下反应生成通式I所示的化合物
线路3
Figure PCTCN2021116794-appb-000013
通式XVII所示的化合物也可参照线路2制得，此外还包括以下步骤：
(a”')通式XVII所示的化合物与二氯亚砜在微量N,N-二甲基甲酰胺作用下反应成 通式XIX所示的化合物；
(b”')通式XIX所示的化合物在碱的作用下与甘氨酰胺反应生成通式XX所示的化合物；
(c”')通式XX所示的化合物在三氯氧磷的作用下反应生成通式I所示的化合物。
其中，R 1、R 21、R 22、R 23、Ar、W、V、U、X和Y的定义如前所述。
药物组合物及其治疗用途
本发明提供的化合物，可以单独使用，或者将其与可药用的辅料(例如赋形剂、稀释剂等)混合，配制成口服给药的片剂、胶囊剂、颗粒剂或糖浆剂等。该药物组合物可以按照制药学上常规方法制得。本发明的药物组合物包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的式I化合物。
本发明所述的“活性成分”和药物组合物用于制备治疗FXR相关疾病的药物。本发明
所述的“活性成分”和药物组合物可用作FXR激动剂。在另一优选例中，所述的活性成分可以用于制备预防和/治疗受FXR激动剂调节的疾病的药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2021116794-appb-000014
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括5(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他治疗药物(如降血脂药)联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物 (如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
所用仪器及主要实验材料如下：
所用试剂和无水溶剂从中国商业公司购买，除特别说明，均直接使用； 1H和 13C NMR用BrukerAM-400型和Varian Mercury plus-400型核磁共振仪，质谱采用Agilent6230型质谱仪，及200-300目柱层析硅胶(青岛海洋化工厂)，HSGF254 TLC板(烟台市化工研究院)。
本发明的化合物按照选自以下线路1、线路2和线路3的任一方法，选用合适的起始原料进行制备：
线路1
Figure PCTCN2021116794-appb-000015
线路2
Figure PCTCN2021116794-appb-000016
线路3
Figure PCTCN2021116794-appb-000017
实施例中间体VIII-1合成：
Figure PCTCN2021116794-appb-000018
0℃下将碳酸钾水溶液(3N，182mmol)逐滴加入搅拌中的盐酸羟胺(182mmol)的乙醇(100mL)溶液中，2,6-二氯苯甲醛II-1(20g，114mmol)溶于100ml乙醇中，然后加入 到羟胺溶液中，将温度升高到90℃，反应两小时。等待混合物冷却到室温然后浓缩至固体。加入水/乙醇(1000mL/100mL)溶液搅拌打碎固体，过滤，50℃下真空干燥过夜，得到化合物中间体(18.4g)。将此中间体溶于N,N-二甲基甲酰胺(50mL)，在0℃下逐滴加入N-氯代丁二酰亚胺(97mmol)的N,N-二甲基甲酰胺(100mL)溶液中，搅拌过夜。将反应液倒入0℃的冰水中，然后用甲基叔丁基醚(每次200mL，共3次)萃取，用饱和食盐水洗涤有机相，合并有机相浓缩得到粗品。往装有粗品的烧瓶中加入正己烷(600mL)，利用磁子搅拌，过滤，将固体在真空下(30℃)干燥得到中间体III-1(18.3g，收率73％)。 1H NMR(400MHz,CDCl 3)δ7.43–7.39(m,2H),7.39–7.33(m,1H)。
将三乙胺(8.2g)加入到3-环丙基-3-氧代丙酸甲酯(82mmol)中，搅拌30分钟。然后冷却到10℃，再将III-1(18.3g，82mmol)的无水乙醇(80mL)溶液逐滴加入其中(内温不超过30℃)，反应在室温下过夜。加入乙酸乙酯(100mL)稀释反应液，用水洗涤，并用乙酸乙酯(每次100mL，共3次)萃取水相。混合有机相，用饱和食盐水洗涤，合并有机相浓缩。向浓缩物中加入100mL乙醚搅拌，真空下除去溶剂可得到固体产物IV-1(21.6g，收率84％)。 1H NMR(400MHz,CDCl 3)δ7.43–7.39(m,2H),7.39–7.33(m,1H),3.72(s,3H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：312[M+H] +。
将IV-1(21.6g，69mmol)溶于四氢呋喃(140mL)中，冷却到0℃，向溶液中缓慢滴加二异丁基氢化铝的甲苯溶液(1.5M,102mL)，反应液在室温下搅拌6h。将反应液缓慢倒入冰水中，并加入1M盐酸水溶液调节pH约等于2，乙酸乙酯(每次100mL，共三次)萃取，合并有机相浓缩，柱层析得到中间体醇；将此中间体和三苯基膦(59mmol)溶于二氯甲烷(60mL)中，冷却至0℃，在氮气保护下，逐滴加入四溴化碳(62mmol)的二氯甲烷(60mL)溶液，室温反应4h。将反应液除去溶剂得到油状物，经柱层析得到中间体V-1(15.3g收率96％)。 1H NMR(400MHz,CDCl 3)δ7.49–7.44(m,2H),7.43–7.37(m,1H),4.25(d,J＝1.3Hz,2H),2.21–2.09(m,1H),1.35–1.28(m,2H),1.25–1.18(m,2H)；MS(ESI,m/z)：346[M+H] +。
在0℃下，向内向-N-BOC-3-羟基-8-氮杂双环[3.2.1]辛烷VI-1(1.48g，6.5mmol)的无水四氢呋喃(20mL)溶液中加入叔丁醇钾(6.5mmol)，搅拌30分钟，然后逐滴加入V-1(4.3mmol)的无水四氢呋喃(5mL)溶液，反应8h。向反应液中加入水(20mL)，用乙酸乙酯(每次15mL，共3次)萃取，有机相用饱和食盐水洗涤，合并有机相浓缩，柱层析得到中间体VII-1(1.44g)。将中间体VII-1(1.44g，2.9mmol)溶于二氯甲烷(8mL)中，冷却至0℃，逐滴加入三氟乙酸(8mL)，室温搅拌3h。在真空下除去溶剂，加入乙酸乙酯(20mL)溶解，用2N氢氧化钠溶液，饱和食盐水洗涤，除去溶剂得到中间体VIII-1(638mg，收率56％)。 1H NMR(400MHz,CDCl 3)δ7.42–7.39(m,2H),7.36–7.31(m,1H),4.27–4.18(m,2H),4.10–3.96(m,2H),3.53(t,J＝4.8Hz,1H),2.16–2.07(m,1H),1.91–1.69(m,6H),1.64(d,J＝14.4Hz,2H),1.26–1.22(m,2H),1.14–1.08(m,2H)；MS(ESI,m/z)：393[M+H] +。
实施例1合成：
Figure PCTCN2021116794-appb-000019
将中间体IX-1(16.8g，142.3mmol)，四丁基硫氰酸铵(142.3mmol)，苄基三甲基溴化铵(142.3mmol)加入到圆底烧瓶，在氮气保护下加入二氯甲烷(140mL)，室温反应三天。将反应液加水淬灭，加入饱和碳酸氢钠溶液调节反应体系至中性，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体X-1(2.5g，收率10％)。MS(ESI,m/z)：176[M+H] +。
将X-1(2.5g，14.3mmol)，溴化亚铜(22mmol)，乙腈(50mL)加入到三颈圆底烧瓶中搅拌，在氮气保护下缓慢滴加亚硝酸特丁酯(2.9mmol)，加热至30℃反应48小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XI-1(2.12g，收率62％)。MS(ESI,m/z)：239[M+H] +。
将中间体VIII-1(0.43g，1.09mmol)，中间体XI-1(1.09mmol)，碳酸铯(1.6mmol)，加入到圆底烧瓶，在氮气保护下加入N,N-二甲基乙酰胺(5mL)，加热至60℃反应12小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XV-1(0.55g，收率91％)。MS(ESI,m/z)：551[M+H] +。
将中间体XV-1(0.55g，1mmol)，盐酸羟胺(2.6mmol)，无水乙醇(10mL)加入到三颈圆底烧瓶中搅拌，在氮气保护下缓慢滴加三乙胺(2.6mmol)，加热至90℃反应12小时。将反应液冷却至室温，加水淬灭，蒸除乙醇之后用乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XVI-1(0.58g，收率99％)。MS(ESI,m/z)：584[M+H] +。
将中间体XVI-1(0.58g，0.99mmol)，N，N'-羰基二咪唑(1.2mmol)，1,4-二氧六环(5mL)加入圆底烧瓶，然后加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(1.2mmol)，加热至100℃反应4小时。将反应液冷却至室温，加水(5mL)稀释，用1M盐酸水溶液调节pH约等于2，然后用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，合并有机相浓缩所得粗品再经柱层析得到终产物白色固体1(0.28g收率64％)。 1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.28(s,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：610[M+H] +。
实施例2的合成：
Figure PCTCN2021116794-appb-000020
实施例2的制备从化合物XII-1出发通过路线2制备得到，合成路线如下：
Figure PCTCN2021116794-appb-000021
将中间体XII-1(6g，35.6mmol)，四丁基硫氰酸铵(35.6mmol)，苄基三甲基溴化铵(35.6mmol)加入到圆底烧瓶，在氮气保护下加入二氯甲烷(50mL)，室温反应三天。将反应液加水淬灭，加入饱和碳酸氢钠溶液调节反应体系至中性，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XIII-1(2.62g，收率32％)。MS(ESI,m/z)：227[M+H] +。
将XIII-1(2.62g，11.6mmol)，溴化亚铜(17.9mmol)，乙腈(30mL)加入到三颈圆底烧瓶中搅拌，在氮气保护下缓慢滴加亚硝酸特丁酯(2.32mmol)，加热至30℃反应48小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XIV-1(2.35g，收率70％)。MS(ESI,m/z)：290[M+H] +。
将中间体VIII-1(0.34g，0.86mmol)，中间体XIV-1(0.86mmol)，碳酸铯(1.3mmol)，加入到圆底烧瓶，在氮气保护下加入N,N-二甲基乙酰胺(5mL)，加热至60℃反应12小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XVII-1(0.5g，收率96％)。MS(ESI,m/z)：602[M+H] +。
将中间体XVII-1(0.5g，0.83mmol)，水合肼(20.6mmol)，无水乙醇(10mL)加入到三颈圆底烧瓶中搅拌，在氮气保护下加热至90℃反应48小时。将反应液冷却至室温，加水淬灭，蒸除乙醇之后用乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XVIII-1(0.28g，收率56％)。MS(ESI,m/z)：602[M+H] +。
将中间体XVIII-1(0.21g，0.35mmol)，N，N'-羰基二咪唑(0.42mmol)，1,4-二氧六环(2mL)加入圆底烧瓶，然后在氮气保护下加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(0.42mmol)，加热至100℃反应4小时。将反应液冷却至室温，加水(5mL)稀释，用1M盐酸水溶液调节pH约等于2，然后用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，合并有机相浓缩，所得粗品再经柱层析得到终产物白色固体2(0.18g收率82％)。 1H NMR(400MHz,d-DMSO)δ7.77(s,1H),7.64–7.62(m,2H),7.59–7.52(m,1H),7.31–7.28(m,1H),4.25(s,2H),4.15(s,2H),3.49(s,1H),1.97–1.93(m,2H),1.77–1.67(m,6H),1.57(s,2H),1.18–1.02(m,4H)；MS(ESI,m/z)：628[M+H] +。
实施例3的合成：
Figure PCTCN2021116794-appb-000022
实施例3的制备从4-氨基-3-氟苯羧酸甲酯XII-2出发参考实施例2的中间体XVII-1的合成制备得到中间体XVII-2，然后通过路线3制备得到，合成路线如下：
Figure PCTCN2021116794-appb-000023
将中间体XVII-2(0.57g，0.95mmol)，甲苯(5mL)加入圆底烧瓶，然后在氮气保护下加入N,N-二甲基甲酰胺(0.02ml)以及二氯亚砜(1mL)，加热至110℃反应1小时。将反应液浓缩，所得粗品即中间体XIX-2(0.3g)直接用于下步反应。MS(ESI,m/z)：606[M+H] +。
将中间体XVII-2粗品(0.3g)，甘氨酰胺(64mg，0.58mmol)，乙腈(5mL)加入圆底烧瓶，然后在氮气保护下加入三乙胺(0.58mmol)，加热至40℃反应2小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到中间体XX-2(0.25g，收率81％)。MS(ESI,m/z)：644[M+H] +。
将中间体XX-2(0.25g，0.48mmol)，1,4-二氧六环(5mL)加入圆底烧瓶，然后在氮气保护下加入三氯氧磷(1mL)，加热至100℃反应3小时。将反应液冷却至室温，加水淬灭，乙酸乙酯萃取，合并有机相浓缩，经柱层析得到终产物白色固体3(0.04g，收率13％)。 1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),4.16(s,br,2H),3.55–3.50(m,1H),2.39–2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：626[M+H] +。
实施例4的合成：
Figure PCTCN2021116794-appb-000024
实施例4的合成路线如下：
Figure PCTCN2021116794-appb-000025
从原料III-1出发按照合成中间体VIII-1的合成方法用异丁酰基乙酸甲酯代替3-环丙基-3-氧代丙酸甲酯合成化合物VIII-2，然后通过路线1制备得到4，其中：
白色固体4收率21％， 1H NMR(400MHz,DMSO-d 6)δ8.18(s,1H),7.65–7.63(m,3H),7.59–7.52(m,2H),4.20(s,4H),3.47(s,1H),3.38(t,J＝6.8Hz,1H),1.96-1.91(m,2H),1.82(s,4H),1.69(d,J＝14.8Hz,2H),1.32(d,J＝7.2Hz,6H).；MS(ESI,m/z)：612[M+H] +。
实施例5的合成：
Figure PCTCN2021116794-appb-000026
实施例5的合成路线如下：
Figure PCTCN2021116794-appb-000027
从原料III-1出发按照合成中间体VIII-1的合成方法用3-环丁基-3-氧代丙酸甲酯代替3-环丙基-3-氧代丙酸甲酯合成化合物VIII-3，然后通过路线1制备得到5，其中：
白色固体5收率19％， 1H NMR(400MHz,DMSO-d 6)δ8.19(s,1H),7.67-7.65(m,3H),7.60–7.53(m,2H),4.30(s,1H),4.21–4.15(m,2H),3.63–3.61(m,2H),2.26–1.83(m,11H),1.80–1.76(m,3H),1.65(d,J＝14.8Hz,1H).MS(ESI,m/z)：624[M+H] +。
实施例6的合成：
Figure PCTCN2021116794-appb-000028
实施例6的合成路线如下：
Figure PCTCN2021116794-appb-000029
从原料IX-2出发按照合成中间体XI-1的合成方法用4-氨基-2-甲基苄腈代替4-氨基苄腈合成化合物XI-2，然后通过路线1制备得到6，其中：
白色固体5收率20％， 1H NMR(400MHz,DMSO-d 6)δ7.69–7.61(m,2H),7.61–7.53(m,1H),7.51–7.39(m,2H),4.28(s,2H),4.22(br,s,1H),3.50–3.42(m,1H),3.28–3.21(m,2H),2.55(s,3H),2.38–2.31(m,1H),2.02–1.91(m,2H),1.87–1.78(m,4H),1.76–1.67(m,2H),1.19–1.06(m,4H).MS(ESI,m/z)：625[M+H] +。
实施例7的合成：
Figure PCTCN2021116794-appb-000030
实施例7的合成路线如下：
Figure PCTCN2021116794-appb-000031
从原料IX-3出发按照合成中间体XI-1的合成方法用4-氨基-3-氯苄腈代替4-氨基苄腈合成化合物XI-3，然后通过路线1制备得到7，其中：
白色固体7收率21％， 1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.75(s,1H),7.69–7.62(m,2H),7.61–7.55(m,1H),4.28(s,2H),4.19(s,br,2H),3.55-3.49(m,1H),2.38–2.32(m,1H),1.99–1.92(m,2H),1.89–1.72(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：644[M+H] +。
实施例8的合成：
Figure PCTCN2021116794-appb-000032
实施例8的合成路线如下：
Figure PCTCN2021116794-appb-000033
从原料IX-4出发按照合成中间体XI-1的合成方法用4-氨基-3-氟苯腈代替4-氨基苄腈合成化合物XI-4，然后通过路线1制备得到8，其中：
白色固体8收率24％， 1H NMR(400MHz,d-DMSO)δ8.06(s,1H),7.69–7.62(m,2H),7.61–7.49(m,2H),4.28(s,2H),4.24(s,br,2H),3.55–3.50(m,1H),2.39-2.29(m,1H),2.02–1.92(m,2H),1.89–1.70(m,6H),1.19–1.05(m,4H)；MS(ESI,m/z)：628[M+H] +。
实施例9的合成：
Figure PCTCN2021116794-appb-000034
实施例9的合成路线如下：
Figure PCTCN2021116794-appb-000035
从原料III-2出发通过路线1制备得到9，其中：
白色固体9收率29％， 1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.74–7.62(m,2H),7.57–7.46(m,1H),7.33–7.24(m,2H),4.31(s,2H),4.19(s,br,2H),3.56–3.50(m,1H),2.35–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；MS(ESI,m/z)：578[M+H] +。
实施例10的合成：
Figure PCTCN2021116794-appb-000036
实施例10的合成路线如下：
Figure PCTCN2021116794-appb-000037
从原料III-3出发通过路线1制备得到10，其中：
白色固体10收率28％， 1H NMR(400MHz,d-DMSO)δ8.18(s,1H),7.73–7.62(m,1H),7.59–7.48(m,3H),7.44–7.29(m,2H),4.35(s,2H),4.21(s,br,2H),3.58–3.53(m,1H),2.36–2.29(m,1H),2.05–1.91(m,2H),1.89–1.65(m,6H),1.16–1.04(m,4H)；MS(ESI,m/z)：560[M+H] +。
实施例11的合成：
Figure PCTCN2021116794-appb-000038
实施例11的合成路线如下：
Figure PCTCN2021116794-appb-000039
从原料III-4出发通过路线1制备得到11，其中：
白色固体11收率29％， 1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.92–7.89(m,1H),7.85–7.71(m,2H),7.69-7.52(m,3H),4.25(s,2H),4.21(s,br,2H),3.55–3.46(m,1H),2.38–2.24(m,1H),2.02–1.90(m,2H),1.89–1.68(m,6H),1.19-1.04(m,4H).
MS(ESI,m/z)：610[M+H] +。
实施例12的合成：
Figure PCTCN2021116794-appb-000040
实施例12的合成路线如下：
Figure PCTCN2021116794-appb-000041
从原料III-5出发通过路线1制备得到12，其中：
白色固体12收率19％， 1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.80–7.59(m,3H),7.58–7.50(m,3H),4.35(s,2H),4.21(s,br,2H),3.60–3.48(m,1H),2.38–2.24(m,1H),2.05–1.92(m,2H),1.91–1.65(m,6H),1.18–1.02(m,4H).
MS(ESI,m/z)：626[M+H] +。
实施例13的合成：
Figure PCTCN2021116794-appb-000042
实施例13的合成路线如下：
Figure PCTCN2021116794-appb-000043
从原料III-6出发通过路线1制备得到13，其中：
白色固体13收率29％， 1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.63(m,1H),7.58–7.51(m,1H),7.45–7.24(m,4H),4.35–4.10(m,4H),3.58–3.49(m,1H),2.37–2.25(m,1H),2.21(s,3H),2.05–1.94(m,2H),1.92–1.73(m,6H),1.19–1.03(m,4H).
MS(ESI,m/z)：556[M+H] +。
实施例14的合成：
Figure PCTCN2021116794-appb-000044
实施例14的合成路线如下：
Figure PCTCN2021116794-appb-000045
从原料III-7出发通过路线1制备得到14，其中：
白色固体14收率29％， 1H NMR(400MHz,d-DMSO)δ8.74(d,J＝5.2Hz,2H),8.20(s,1H),7.72(d,J＝5.2Hz,2H),7.66(d,J＝8.4Hz,1H),7.55(d,J＝8.4Hz,1H),4.51(s,2H),4.29(s,2H),3.72(s,1H),2.38–2.34(m,1H),2.11–2.06(m,2H),2.01–1.91(m,6H),1.13–1.11(m,2H),1.06–1.05(m,2H).
MS(ESI,m/z)：543[M+H] +。
实施例15的合成：
Figure PCTCN2021116794-appb-000046
实施例15的合成路线如下：
Figure PCTCN2021116794-appb-000047
从原料III-1出发按照合成中间体VIII-1的合成方法用氘代氢化锂铝代替二异丁基氢化铝合成化合物中间体VIII-10，然后通过路线1制备得到15，其中：
白色固体15(收率58％)。 1H NMR(400MHz,d-DMSO)δ8.19(s,1H),7.70–7.61(m,3H),7.60–7.53(m,2H),4.21(s,br,2H),3.55–3.48(m,1H),2.39–2.29(m,1H),2.03–1.91(m,2H),1.88–1.79(m,4H),1.78–1.64(m,2H),1.19–1.03(m,4H)；MS(ESI,m/z)：612[M+H] +。
实施例16的合成：
Figure PCTCN2021116794-appb-000048
实施例16的合成路线如下：
Figure PCTCN2021116794-appb-000049
从V-1出发按照中间体VIII-1的合成制备得到VIII-11，通过路线1制备得到16，其中：
白色固体16(收率21％)， 1H NMR(400MHz,d-DMSO)δ.8.18(s,1H),7.72–7.60(m,3H),7.59–7.51(m,2H),4.20–3.85(m,2H),3.66–3.20(m,2H),2.95–2.48(m,1H),2.29–2.03(m,1H),2.02–1.88(m,2H),1.78–1.69(m,4H),1.66–1.43(m,2H),1.19–1.03(m,4H)
MS(ESI,m/z)：609[M+H] +。
药理实验实施例：
基于报告基因活性检测的方法检测化合物的FXR激动活性的方法：
1.1质粒pGAL4-FXR-LBD和pG5-Luc的构建及制备
报告基因检测系统所用pGAL4-FXR-LBD和pG5-Luc质粒按常规分子克隆方法进行构建。主要步骤为：利用PCR技术将FXR-LBD(212-476AA)氨基酸序列对应的FXR(NM_001206979.2)cDNA序列，插入pGAL4载体BamHI和NotI酶切位点，获得pGAL4-FXR-LBD；pG5-Luc和phRL-TK质粒获赠于中国科学院上海药物研究所；利用CaCl 2法将质粒转化DH5α大肠杆菌，进一步培养扩增后用质粒抽提试剂盒(TIANGEN，#D107)纯化获得相应质粒DNA。
1.2质粒共转染HEK293T细胞及化合物处理
质粒转染前一天将HEK293T细胞以1×10 4/well的密度接种于96孔板。按照转染试剂
Figure PCTCN2021116794-appb-000050
HD(Promega，#E2311)的说明书进行细胞转染。主要步骤为：以一个孔为例，将质粒pGAL4-FXR-LBD、pG5-Luc和phRL-TK按20ng、50ng和5ng的比例加入10uL的Opti-MEM TM I培养基(Gibco，#11058021)中混匀；再加入0.25uL的
Figure PCTCN2021116794-appb-000051
HD，混匀后室温静置5min；再将此10uL混合物加入至含100uL培养液的细胞孔中。细胞共转染后6h，将化合物以1uM为最高浓度，以3倍梯度进行稀释，共分10个浓度加入细胞培养液中进行处理24h，共分2个复孔，以LJN452化合 物为阳性对照。
1.3 Dual-Glo Luciferase检测
细胞经化合物处理24h后，按
Figure PCTCN2021116794-appb-000052
Luciferase Assay System(Promega，#E2940)说明书进行检测。主要步骤为：每孔吸弃50uL培养液，再加入50uL Dual-
Figure PCTCN2021116794-appb-000053
Luciferase试剂，室温振荡10min；取80uL裂解反应液至白色不透光optiPlate-96孔板，用MD i3x多功能酶标仪检测萤火虫萤光素酶(Firefly luciferase)的发光信号值(Firefly-Luc)；再加入40uL
Figure PCTCN2021116794-appb-000054
Stop&
Figure PCTCN2021116794-appb-000055
试剂，室温振荡10min；再用MD i3x多功能酶标仪检测海肾萤光素酶(Renilla luciferase)的发光信号值(Renilla-Luc)。以Firefly-Luc/Renilla-Luc的比值作为化合物对FXR的激活活性，并以溶剂DMSO组的比值进行归一化处理，使用GraphPad Prism6.0软件以四参数拟合剂量-反应曲线，计算EC 50值。
2.结果
实验数据表明化合物均有一定的FXR激动活性，其中实施例1，2，4，7，8，16的EC 50值均小于10nM，特别是实施例8的EC 50值小于5nM，具有非常强的FXR激动活性。各实施例FXR激动活性数据见表1。
表1化合物的FXR激动活性
供试样品 FXR细胞水平活性EC 50(nM)
实施例1 ＊＊＊
实施例2 ＊＊＊
实施例3 ＊＊
实施例4 ＊＊＊
实施例5 ＊
实施例6 ＊＊
实施例7 ＊＊＊
实施例8 ＊＊＊＊
实施例9 ＊＊
实施例10 ＊＊
实施例11 ＊＊
实施例12 ＊＊
实施例13 ＊
实施例14 ＊
实施例15 ＊＊＊
实施例16 ＊＊＊
LJN452 ＊＊＊
＊＊＊＊:EC 50(nM)<5；＊＊＊:5<EC 50(nM)<10；＊＊:10<EC 50(nM)<50；＊:50<EC 50(nM)
药理实验实施例二：
基于人原代肝细胞(PHH)体外感染模型检测化合物的体外抗HBV活性
1.方法
1.1 HBV病毒感染人原代肝细胞建立HBV体外感染模型及化合物处理
用含10％FBS的DMEM培养HepG2.2.15细胞72h后，在培养液中收集并浓缩获 得D型HBV，通过定量PCR测定其病毒滴度。复苏冻存于液氮的人原代肝细胞(购自瑞德肝脏疾病研究有限公司)，将细胞密度调整为6×10 5细胞/ml，并铺种到48孔板中，每孔加220uL(约为1.3×10 5个细胞)，置于5％CO 2、37℃培养过夜。第2天，将D型HBV以800基因组当量/细胞的比例加入到PHH细胞中；第3天，开始化合物处理，化合物以10uM浓度，3个复孔，连续处理8天，每2天更换一次含化合物的培养液，以DMSO作为阴性对照。
1.2收集细胞培养上清检测HBV DNA，乙型肝炎病毒表面抗原(HBsAg)和乙型肝炎病毒e抗原(HBeAg)
化合物处理第8天后收集细胞培养上清，分别检测HBV DNA，HBeAg和HBsAg。按照QIAamp 96 DNA Blood Kit(QIAGEN，#51161)说明书，取100ul细胞培养上清提取DNA；以HBV质粒DNA作为标准品，qPCR定量检测HBV DNA的含量。按照ELISA试剂盒说明书检测HBsAg和HBsAg。方法简述如下：先将样品8倍稀释(15ul细胞上清+105ul PBS)；然后分别取50ul的标准品，样品和对照品加入到检测板中，然后每孔加入50ul酶结合物，37℃孵育60分钟；用洗液洗板后吸干，然后加入50ul预混发光底物，室温避光孵育10分钟，最后酶标仪测定发光值。
1.3 CCK-8检测化合物对细胞活力的影响
按照CCK-8试剂盒说明书测定细胞活力，方法简述如下：化合物处理第8天后，待细胞培养上清收集之后，每孔加入180ul新鲜培养基和20ul的CCK-8，混匀之后37℃孵育2.5小时，酶标仪测定吸光值(450nm/650nm)。
1.4数据处理
分别按下列公式进行计算：
HBV DNA抑制率＝(1-化合物的HBV DNA拷贝数/DMSO对照的HBV DNA拷贝数)×100％；
HBsAg抑制率＝(1-样品的HBsAg(IU/ml)/DMSO对照的HBsAg(IU/ml))×100％；
HBeAg抑制率＝(1-样品的HBeAg(PEIU/ml)/DMSO对照的HBeAg(PEIU/ml))×100％；
细胞活力＝(样品的信号值-培养基对照的信号值)/(DMSO对照的信号值-培养基对照的信号值)×100％。
2.结果
化合物在原代肝细胞(PHH)感染HBV的体外模型中的HBV DNA抑制率、HBsAg抑制率、HBeAg抑制率和细胞活力的具体实验结果见下表。
Figure PCTCN2021116794-appb-000056
Figure PCTCN2021116794-appb-000057
＊:Inhibition％<50；＊＊:Inhibition％>50；a：化合物浓度为0.5uM
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、前药，或其药学上可接受的盐：
    Figure PCTCN2021116794-appb-100001
    其中，
    Ar选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的5-9元的杂芳环(包括单环或稠合环，含有1-3个选自氧、硫和氮中的杂原子)；
    R 1选自：取代或未取代的C 1-C 6烷基、取代或未取代的C 3-C 6环烷基、取代或未取代的5-9元的杂环(含有1-3个选自氧、硫和氮中的杂原子)；
    R 21、R 22、R 23各自独立地选自下组：氢、氘、卤素、取代或未取代的C 1-C 6烷基、取代或未取代的C 1-C 6烷氧基；
    W选自下组：氢或氘；
    V选自下组：氢或氘；
    U选自下组：O或NH；
    X选自下组：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；
    Y选自下组：O、NH、CH 2或CHR 3，其中R 3选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；
    其中，所述的取代指基团上的一个或多个氢原子各自独立地被选自下组的取代基所替代：氘、卤素、卤代C 1-C 6烷基、卤代C 1-C 6烷氧基、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 6环烷基、C 3-C 6环烷氧基、氰基或硝基。
  2. 如权利要求1所述的化合物，其特征在于，所述的Ar选自下组：取代或未取代的C 6-C 10芳基、取代或未取代的5-9元的杂芳环，其中，所述的芳基或杂芳基的取代基选自下组：氢、氘、氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、或三氟甲氧基。
  3. 如权利要求1所述的化合物，其特征在于，所述的R 1选自下组：甲基、乙基、正丙基、异丙基、正丁基、异丁基、环丙基、环丁基或环戊基。
  4. 如权利要求1所述的化合物，其特征在于，所述的R 21、R 22、R 23各自独立地为氢、氘、氟、氯、溴、甲基、乙基、正丙基、异丙基、正丁基、异丁基、三氟甲基、或三氟甲氧基。
  5. 如权利要求1所述的化合物，其特征在于，所述的X选自：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基；所述的Y选自：O、NH、CH 2或CHR 2，其中R 2选自下组：氘、取代或未取代的C 1-C 6烷基、C 3-C 6环烷基。
  6. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2021116794-appb-100002
  7. 如权利要求1所述的化合物的制备方法，其特征在于，所述的方法包括：通过选自下组路线一，路线二或路线三所述的方法制备式I化合物：
    路线一：
    Figure PCTCN2021116794-appb-100003
    (a’)通式VIII所示的化合物与XI所示的化合物在碱性条件下反应成通式XV所示的化合物；
    (b’)通式XV所示的化合物与盐酸羟胺反应生成通式XVI所示的化合物；
    (c’)通式XVI所示的化合物在光气、三光气、或者羰基二咪唑的作用下反应生成通式I所示的化合物，
    其中，X为NH，Y为O，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如权利要求1所述；
    路线二：
    Figure PCTCN2021116794-appb-100004
    (a”)通式VIII所示的化合物与XIV所示的化合物在碱性条件下反应成通式XVII所示的化合物；
    (b”)通式XVII所示的化合物在碱的作用下与水合肼反应生成通式XVIII所示的化合物；
    (c”)通式XVIII所示的化合物在光气、三光气或者羰基二咪唑的作用下反应生成通式I所示的化合物；
    其中，X为O，Y为NH，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如权利要求1所述；
    路线三：
    Figure PCTCN2021116794-appb-100005
    (a”')通式XVII所示的化合物与二氯亚砜在微量N,N-二甲基甲酰胺作用下反应成通式XIX所示的化合物；
    (b”')通式XIX所示的化合物在碱的作用下与甘氨酰胺反应生成通式XX所示的化合物；
    (c”')通式XX所示的化合物在三氯氧磷的作用下反应生成通式I所示的化合物，
    其中，X为NH，Y为CH 2，R 1、R 21、R 22、R 23、Ar、W、V、U的定义如权利要求1所述。
  8. 一种药物组合物，其包含如权利要求1所述的通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、代谢产物、前药、药学上可接受的盐；和药学上可接受的载体。
  9. 如权利要求1所述的通式I所示的化合物，或其对映异构体、非对映异构体、互变异构体、外消旋体、水合物、溶剂合物、前药或其药学上可接受的盐的用途，其特征在于，用于制备治疗与FXR活性或表达量相关的疾病或病症的药物组合物。
  10. 如权利要求9所述的用途，其特征在于，所述的FXR相关疾病选自下组：胆汁酸代谢、糖代谢、脂代谢、炎症、和/或肝脏纤维化过程相关疾病。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023120086A (ja) * 2022-02-17 2023-08-29 カスケード ファーマシューティカルズ、インコーポレーテッド 新型ｆｘｒ小分子作動剤の製造およびその使用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4608079A (en) * 1983-08-02 1986-08-26 American Cyanamid Company Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents
CN1956984A (zh) * 2004-04-01 2007-05-02 安万特药物公司 1,3,4－噁二唑－2－酮作为PPAR－δ调节剂
CN106146483A (zh) * 2015-04-23 2016-11-23 上海迪诺医药科技有限公司 杂环类法尼酯衍生物x受体调节剂
CN108064223A (zh) * 2014-12-17 2018-05-22 吉利德科学公司 含羟基的fxr(nr1h4)调节化合物
CN109906223A (zh) * 2016-10-04 2019-06-18 英安塔制药有限公司 异噁唑类似物作为fxr激动剂及其使用方法
CN110452235A (zh) * 2018-05-08 2019-11-15 中国科学院上海药物研究所 一类含氟异噁唑类化合物及其制备方法、药物组合物和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4608079A (en) * 1983-08-02 1986-08-26 American Cyanamid Company Imidazolidinones, and imidazolidinethiones, process and intermediates for the preparation thereof, and use of said compounds as herbicidal agents
CN1956984A (zh) * 2004-04-01 2007-05-02 安万特药物公司 1,3,4－噁二唑－2－酮作为PPAR－δ调节剂
CN108064223A (zh) * 2014-12-17 2018-05-22 吉利德科学公司 含羟基的fxr(nr1h4)调节化合物
CN106146483A (zh) * 2015-04-23 2016-11-23 上海迪诺医药科技有限公司 杂环类法尼酯衍生物x受体调节剂
CN109906223A (zh) * 2016-10-04 2019-06-18 英安塔制药有限公司 异噁唑类似物作为fxr激动剂及其使用方法
CN110452235A (zh) * 2018-05-08 2019-11-15 中国科学院上海药物研究所 一类含氟异噁唑类化合物及其制备方法、药物组合物和用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023120086A (ja) * 2022-02-17 2023-08-29 カスケード ファーマシューティカルズ、インコーポレーテッド 新型ｆｘｒ小分子作動剤の製造およびその使用
JP7450951B2 (ja) 2022-02-17 2024-03-18 カスケード ファーマシューティカルズ、インコーポレーテッド 新型ｆｘｒ小分子作動剤の製造およびその使用

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