WO2020038464A1 - 苯氧酸类化合物及其医药用途 - Google Patents

苯氧酸类化合物及其医药用途 Download PDF

Info

Publication number
WO2020038464A1
WO2020038464A1 PCT/CN2019/102273 CN2019102273W WO2020038464A1 WO 2020038464 A1 WO2020038464 A1 WO 2020038464A1 CN 2019102273 W CN2019102273 W CN 2019102273W WO 2020038464 A1 WO2020038464 A1 WO 2020038464A1
Authority
WO
WIPO (PCT)
Prior art keywords
bjmu
compound
bromo
dimethylphenoxy
hydroxyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2019/102273
Other languages
English (en)
French (fr)
Inventor
焦宁
余四旺
宋颂
刘雅萌
杨思敏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Wholesomeyird Sci & Tech Co Ltd
Original Assignee
Beijing Wholesomeyird Sci & Tech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beijing Wholesomeyird Sci & Tech Co Ltd filed Critical Beijing Wholesomeyird Sci & Tech Co Ltd
Priority to AU2019324405A priority Critical patent/AU2019324405B2/en
Priority to US17/182,413 priority patent/US12365643B2/en
Priority to JP2021534420A priority patent/JP7472139B2/ja
Priority to EP19851778.1A priority patent/EP3842410A4/en
Publication of WO2020038464A1 publication Critical patent/WO2020038464A1/zh
Anticipated expiration legal-status Critical
Priority to US19/212,924 priority patent/US20250313522A1/en
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/11—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton
    • C07C255/13—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound oxygen atoms bound to the same saturated acyclic carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
    • C07C59/13—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring

Definitions

  • the invention belongs to the technical field of medicine.
  • the present invention relates to a phenoxy acid compound, a pharmaceutical composition containing the compound, and a medical use of the compound.
  • the compounds of the invention are useful in the prevention and / or treatment of metabolic diseases and complications of such diseases.
  • drugs for diabetes such as insulin drugs, insulin secretion-promoting drugs (including sulfonylureas), insulin sensitizers (thiazolidinediones, biguanides), ⁇ -glucosidase inhibitors (acarbose , Voglibose, miglitol), human glucagon-like peptide (GLP-1) receptor agonist, dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium-glucose cotransporter 2 (SGLT2) inhibitors and other drugs, but these drugs are usually accompanied by problems such as weight gain, limited tolerability, hyperinsulinemia, hypoglycemia, gastrointestinal symptoms and other side effects, as well as gradual decrease in efficacy.
  • insulin drugs insulin secretion-promoting drugs (including sulfonylureas), insulin sensitizers (thiazolidinediones, biguanides), ⁇ -glucosidase inhibitors (acarbose , Voglibose
  • NASH non-alcoholic steatohepatitis
  • the main treatment strategies are (1) metabolic regulation; (2) inhibition of inflammation or oxidative damage; (3) regulation of liver-gut circulation and / or intestinal flora.
  • glucose-lowering drugs such as metformin, thiazolidinediones
  • antioxidants vitamin E, reduced glutathione
  • lipid-lowering drugs statins, fibrates
  • ursodeoxycholic acid and many other drugs
  • the present invention provides compounds represented by formula (I), pharmaceutically acceptable salts or esters thereof, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, and their metabolites Form, or any combination or mixture thereof,
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4;
  • the compound is not 5- (2,4-dichloro-3,6-dimethylphenoxy) -2,2-dimethylvaleric acid; 5- (4-chloro-2,5-di (Methylphenoxy) -2,2-dimethylvaleric acid; 5- (2-chloro-3,6-dimethylphenoxy) -2,2-dimethylvaleric acid; or 5- ( 4-bromo-2,5-dimethylphenoxy) -2,2-dimethylvaleric acid.
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl or C 1 -C 4 alkyl
  • An oxy group is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: halogen (e.g. -F, -Cl, -Br, or -I) , Hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally One or several (eg, one, two, three or four) are independently substituted with a substituent selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy.
  • each of R 3 and R 4 is independently selected from hydrogen, halogen (eg, -F, -Cl, -Br, or -I), nitro, hydroxyl, C 1 -C 4 alkyl; wherein, the hydroxy or C 1 -C 4 alkyl is optionally substituted with one or several (e.g., 1, 2, 3 or 4) independently selected from halogen (e.g., -F, -Cl, -Br, or -I) and a hydroxy substituent.
  • halogen eg., -F, -Cl, -Br, or -I
  • R 3 and R 4 are each independently selected from hydrogen, -F, -Cl, -Br, -I, nitro, hydroxy, methyl, ethyl; wherein, hydroxy, methyl Or ethyl is optionally substituted by one or several (e.g. 1, 2, 3, or 4) independently selected from halogen (e.g. -F, -Cl, -Br or -I) and hydroxyl To replace.
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3, R 4 are independently selected from hydrogen, -F, -Cl, -Br, -I , nitro, hydroxy, methyl.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • the compound has the following characteristics:
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, 1, 2, 3, or 4) substituents independently selected from the group consisting of substituents: -F, -Cl, -Br, -I , hydroxy; preferably, R 1, R 2 are each independently selected from a Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 3 and R 4 are each independently selected from hydrogen, -F, -Cl, -Br, -I, nitro, hydroxyl, methyl, ethyl; wherein the hydroxyl, methyl, or ethyl is optionally One or several (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (eg, -F, -Cl, -Br, or -I) and a hydroxyl group; preferably, R 3 , R 4 are each independently selected from hydrogen, -F, -Cl, -Br, -I, nitro, hydroxyl, and methyl;
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, and cyano;
  • n 1, 2 or 3.
  • the compound has a structure represented by formula (Ia):
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined previously (as defined in formula (I)).
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I), a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, and a solvate , Crystalline forms, their metabolite forms, or any combination or mixture thereof, and one or more pharmaceutically acceptable carriers and / or excipients;
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in the first aspect.
  • the compound has a structure represented by formula (Ia),
  • R 3 is halogen (for example, -F, -Cl, -Br, or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined in formula (I).
  • the compound has a structure represented by the formula (Ia), wherein:
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, 1, 2, 3, or 4) substituents independently selected from the group consisting of substituents: -F, -Cl, -Br, -I , hydroxy; preferably, R 1, R 2 are each independently selected from a Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 4 is selected from hydrogen, -F, -Cl, -Br, -I, nitro, hydroxyl, methyl, ethyl; wherein the hydroxyl, methyl, or ethyl is optionally one or more (e.g., 1, 2, 3, or 4) are independently selected from halogen (for example, -F, -Cl, -Br, or -I) and a hydroxy group; and preferably, R 4 is selected from hydrogen, -F , -Cl, -Br, -I, nitro, hydroxyl, methyl;
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano; n is 1, 2 or 3.
  • the compound is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (Ia), a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, and a solvate , Crystalline forms, their metabolite forms, or any combination or mixture thereof, and one or more pharmaceutically acceptable carriers and / or excipients,
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy;
  • R 3 is selected from -F, -Cl, -Br or -I;
  • R 4 is selected from hydrogen or hydroxyl
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, and cyano;
  • n 1, 2 or 3.
  • the compound is selected from BJMU-1, BJMU-2, BJMU-3, BJMU-415, BJMU-502, BJMU-309, BJMU-11, BJMU-403.
  • the pharmaceutical composition of the second or third aspect optionally comprises an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent is selected from the group consisting of anti-diabetic drugs, anti-obesity drugs, anti-hypertensive drugs, anti-atherosclerotic drugs, lipid-lowering drugs, anti-inflammatory drugs, and anti-oxidative damage drugs.
  • the pharmaceutical composition may be in any form known in the medical field.
  • the pharmaceutical composition can be tablets, pills, suspensions, emulsions, solutions, gels, capsules, powders, granules, elixirs, lozenges, suppositories, injections (including injections, lyophilization Powder), inhalants, sprays, etc.
  • the preferred dosage form depends on the intended mode of administration and therapeutic use.
  • the compounds of the invention their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or any of them
  • the combination or mixture may be present in the pharmaceutical composition in unit dosage form for ease of administration.
  • compositions can be administered by any suitable method known in the art, including, but not limited to, oral, rectal, parenteral, or topical administration.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, elixirs, and the like.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl acetate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (e.g.
  • liquid dosage forms for oral administration may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavoring agents.
  • Solid dosage forms for oral administration include capsules, tablets, pills, lozenges, powders, granules, and the like.
  • solid dosage forms may contain pharmaceutically acceptable inert excipients or carriers, such as fillers (such as lactose, sucrose, glucose, mannitol, starch, microcrystalline cellulose, galactose, crospovidone) And calcium sulfate); binders (such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia gum); wetting agents (such as cetyl alcohol and glyceryl monostearate); disintegrants (Such as agar, calcium carbonate, starch, alginic acid, sodium carboxymethyl cellulose, sodium carboxymethyl starch); lubricants (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, laurel Sodium sulfate); and mixtures thereof.
  • fillers such as lactose, sucrose, glucose, mannitol, starch, microcrystalline cellulose, galactose, crospovidone)
  • the compounds or pharmaceutical compositions of the invention may also be administered by a non-oral route.
  • parenteral for example, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection and infusion.
  • Dosage forms for parenteral administration may be injectable preparations, including injection solutions, sterile powders for injection, or concentrated solutions for injection.
  • injectable dosage forms may contain pharmaceutically acceptable carriers such as sterile water, Ringer's solution and isotonic sodium chloride solution, and suitable additives such as antioxidants, buffers and Bacteriostatic agent.
  • Topical administration such as transdermal administration (such as by transdermal patches or iontophoresis devices), intraocular administration, or intranasal or inhaled administration.
  • Dosage forms for transdermal administration may be topical gels, sprays, ointments and creams.
  • topical dosage forms may contain ingredients that enhance the absorption or penetration of the active compound through the skin or other areas of action.
  • administration will be accomplished using patches of the storage and porous membrane type or solid matrix variety.
  • the dosage form for topical ocular administration may be an eye drop, wherein the compound of the present invention is dissolved or suspended in a suitable carrier.
  • the compound of the present invention is conveniently delivered from a pressure spray container in the form of a solution or suspension, said delivery being by the patient's grasp or pumping, or It is delivered as an aerosol spray formulation from a pressure vessel or sprayer using a suitable propellant.
  • Dosage forms for rectal administration may be suppositories.
  • the pharmaceutical composition of the present invention can be prepared by any well-known pharmaceutical process, such as effective formulations and methods of administration.
  • effective formulations and methods of administration are well known in the art and are described in standard textbooks.
  • Drug formulations are described in, for example, Hoover, John E., Remington's Pharmaceutical Sciences. Mack Publishing Co., Easton, Pennsylvania, 1975; Edited by Liberman et al., Pharmaceutical Department Forms, Marcel Decker, New York, NY, 1980; And edited by Kibbe et al., Handbook of Pharmaceutical Principles (3rd Edition), American Pharmaceutical Association, Washington, 1999.
  • the pharmaceutical composition contains a compound of the invention, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite
  • the amount of the form, or any combination or mixture thereof is 0.01-2000 mg, preferably 0.1-1000 mg, more preferably 1-800 mg, more preferably 10-600 mg, and particularly preferably 50-500 mg.
  • a pharmaceutical composition of the invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of a compound as described herein, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate Substances, crystalline forms, their metabolite forms, or any combination or mixture thereof.
  • a “prophylactically effective amount” refers to an amount sufficient to prevent, prevent, or delay the onset of disease.
  • a “therapeutically effective amount” refers to an amount sufficient to cure or at least partially prevent a disease and its complications in a patient already suffering from the disease.
  • any combination or mixture can vary depending on factors such as the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the manner in which the drug is administered, and simultaneously Other treatments applied, etc.
  • the dosing regimen can be adjusted to obtain an optimal response (eg, a therapeutic or preventive response). For example, a single dose may be given, multiple doses may be given over a period of time, or the dose may be proportionally reduced or increased with the urgency of the therapeutic situation.
  • an optimal response eg, a therapeutic or preventive response.
  • a single dose may be given, multiple doses may be given over a period of time, or the dose may be proportionally reduced or increased with the urgency of the therapeutic situation.
  • the compounds of the present invention are effective for treatment or prevention
  • a typical non-limiting range of the amount is 0.01 to 1000 mg / kg, such as 0.1 to 500 mg / kg.
  • the dosage may vary with the type and severity of the symptoms to be treated.
  • the specific dosing regimen should be adjusted over time according to the needs of the patient and the professional evaluation of the doctor; the dosage range given here is for illustration purposes only and is not limited The use or scope of the pharmaceutical composition of the present invention.
  • the pharmaceutical composition may further comprise an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent is a drug for treating a metabolic disease or related disease, such as an anti-diabetic drug, an anti-obesity drug, an anti-hypertensive drug, an anti-atherosclerotic drug, or a Lipid drugs.
  • the additional pharmaceutically active agent is a drug having anti-inflammatory activity.
  • the additional pharmaceutically active agent is a drug having anti-oxidative injury activity.
  • the additional pharmaceutically active agent is selected from the group consisting of anti-diabetic drugs, anti-obesity drugs, anti-hypertensive drugs, anti-atherosclerotic drugs, lipid-lowering drugs, anti-inflammatory drugs, and anti-oxidative damage drugs.
  • the compounds of the invention in the pharmaceutical composition, the compounds of the invention, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolism
  • the product form, or any combination or mixture thereof is provided with the additional pharmaceutically active agent as an isolated component or a mixed component.
  • the compounds of the invention, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or any combination or mixture thereof with the described Additional pharmaceutically active agents can be administered simultaneously, separately, or sequentially.
  • the compound described in the first aspect of the present invention, the compound defined in the second aspect or the third aspect can be prepared by a variety of methods known for the preparation of this type of compound, for example, as shown in the following reaction scheme. Unless otherwise specified, R 1 to R 7 and n in the reaction scheme and later discussion are as defined above.
  • L is a halogen (for example, -F, -Cl, -Br, or -I); preferably, L is -Cl.
  • Other symbols are as defined in the first aspect or the second aspect.
  • Williamson synthesis is used.
  • a Lewis base e.g. Na 2 CO 3, K 2 CO 3 etc.
  • an aprotic polar solvent e.g. DMF, DMSO, etc.
  • the reaction can be performed in the presence of a phase transfer catalyst such as TBAI (tetrabutylammonium iodide).
  • the hydrolysis can be carried out by means of conventional processes.
  • hydrolysis is performed under alkaline conditions, such as in the presence of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) And 1,4-dioxane; amides, such as N, N-dimethylformamide (DMF) and hexamethylphosphotriamide; and sulfoxides, such as dimethylsulfoxide (DMSO).
  • alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol
  • ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) And 1,4-diox
  • Hydrolysis can also be performed under acidic conditions, such as in the presence of the following reagents: hydrogen halides, such as hydrogen chloride and hydrogen bromide; sulfonic acids, such as p-toluenesulfonic acid and benzenesulfonic acid; pyridinium p-toluenesulfonic acid; And carboxylic acids such as acetic acid and trifluoroacetic acid.
  • hydrogen halides such as hydrogen chloride and hydrogen bromide
  • sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid
  • pyridinium p-toluenesulfonic acid pyridinium p-toluenesulfonic acid
  • carboxylic acids such as acetic acid and trifluoroacetic acid.
  • Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) And 1,4-dioxane; amides, such as N, N-dimethylformamide (DMF) and hexamethyl phosphate triamide; and sulfoxides, such as dimethylsulfoxide (DMSO).
  • alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol
  • ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) And 1,4-dioxane
  • amides such as N, N-dimethylformamide (DMF) and hexamethyl phosphate triamide
  • sulfoxides such as dimethylsulfox
  • the coupling reaction of the compound of formula I-1 prepared as described in step 1B of Scheme 1 and an amine is performed to prepare an amide compound 2-1.
  • the reaction can be performed in the presence or absence of additives, such as 1-hydroxybenzotriazole or 1-hydroxyazabenzotriazole.
  • the reaction is normally and preferably performed in a solvent.
  • a solvent there is no particular limitation on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved, and is capable of dissolving the reagents, at least to a certain extent.
  • suitable solvents include: acetone, nitromethane, DMF, sulfolane, DMSO, NMP, 2-butanone, acetonitrile; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform; and ethers such as tetrahydrofuran and Dioxane.
  • reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention.
  • the preferred reaction temperature will depend on such factors as the nature of the solvent and the starting materials or reagents used.
  • Suitable coupling agents are those typically used in peptide synthesis, including, for example, diimines (such as dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC)), 2-ethoxy- N-ethoxycarbonyl-1,2-dihydroquinoline, 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 2-chloro-1,3-dimethylimidazolium chloride Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diethyl azodicarboxylate-triphenylphosphine, diethyl cyanophosphate, diethyl Phosphoryl azide, 2-chloro-1-methylpyridinium iodide, N, N'-carbonyldiimidazole, benzotriazol-1-yldiethyl phosphate,
  • the amide compound 2-1 can be generated via an acid halide, which can be obtained by reaction with a halogenating agent, such as oxalyl chloride, phosphoryl chloride, and thionyl chloride.
  • a halogenating agent such as oxalyl chloride, phosphoryl chloride, and thionyl chloride.
  • the acyl halide obtained by treatment with an amine under conditions similar to those described in this step can be converted into the corresponding amide compound.
  • the amide group of the amide compound 2-1 is converted into a cyano group in an inert solvent, and a compound of the formula I-2 can be prepared.
  • This step may be a transition metal-catalyzed cyanation reaction.
  • the transition metal catalyst may be a metal palladium catalyst, such as palladium acetate (Pd (OAc) 2 ).
  • Pd (OAc) 2 palladium acetate
  • a cyanation reaction occurs in a Pd (OAc) 2 / Selectfluor catalytic system and acetonitrile to obtain a compound of formula I-2.
  • Acetonitrile serves as both a solvent and a cyano reagent.
  • This step may be a dehydration reaction.
  • a dehydration reaction in an inert solvent in the presence of a dehydrating agent affords a compound of formula I-2.
  • the dehydrating agent may be sulfoxide, phosphorus pentoxide, melamine, trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentachloride, or the like.
  • an esterification reaction of an acid compound of formula I-1 with an alcohol of C 1 -C 4 is performed in an inert solvent in the presence of a catalyst to prepare an ester compound of formula I-3.
  • ester compound of formula I-3 can be formed via an acid halide, which can be obtained by reaction with a halogenating agent.
  • the acid halide obtained by treatment with an alcohol under conditions similar to those described in this step can be converted into the corresponding ester compound.
  • the invention relates to a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or any combination thereof or A mixture, a pharmaceutical composition according to the second aspect or the third aspect, for reducing body weight, reducing body fat, reducing liver fat fraction, preventing or treating obesity, and / or preventing or treating non-alcoholic properties in a subject Use of fatty liver disease (NAFLD), or in the manufacture of a medicament for reducing body weight, reducing body fat, reducing liver fat fraction, preventing or treating obesity, and / or preventing or treating Treating non-alcoholic fatty liver disease (NAFLD) (eg, simple fatty liver or non-alcoholic fatty liver disease (NASH)); wherein the compound is as defined in the second or third aspect.
  • NAFLD fatty liver disease
  • NASH non-alcoholic fatty liver disease
  • the compound has a structure represented by formula (I):
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • the compound has a structure represented by formula (Ia):
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined in formula (I).
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl or C 1 -C 4 alkyl
  • An oxy group is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: halogen (e.g. -F, -Cl, -Br, or -I) , Hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally One or several (eg, one, two, three or four) are independently substituted with a substituent selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy.
  • R 4 is selected from hydrogen, halogen (eg, -F, -Cl, -Br, or -I), a hydroxyl group. In certain embodiments, R 4 is selected from hydrogen or hydroxyl.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • the compound has a structure represented by the formula (Ia), wherein:
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, 1, 2, 3, or 4) substituents independently selected from the group consisting of substituents: -F, -Cl, -Br, -I , hydroxy; preferably, R 1, R 2 are each independently selected from a Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 3 is -F, -Cl, -Br or -I;
  • R 4 is selected from hydrogen, halogen (eg -F, -Cl, -Br or -I), hydroxyl; preferably, R 4 is selected from hydrogen or hydroxyl;
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, and cyano;
  • n 1, 2 or 3.
  • the compound is selected from:
  • the present invention provides a method for reducing body weight, reducing body fat, reducing liver fat fraction, preventing or treating obesity, and / or preventing or treating non-alcoholic fatty liver disease (NAFLD) in a subject.
  • Method comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, Their metabolite form, or any combination or mixture thereof, or the pharmaceutical composition of the third aspect; wherein the compound is as defined in the fourth aspect.
  • the non-alcoholic fatty liver disease includes simple fatty liver or non-alcoholic fatty liver disease (NASH)).
  • the subject has a metabolic disease, and / or the subject has a condition associated with a metabolic disease (e.g., being overweight, excess body fat, and / or elevated Liver fat fraction).
  • a metabolic disease e.g., being overweight, excess body fat, and / or elevated Liver fat fraction.
  • the invention provides a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or any combination thereof Or a mixture, a pharmaceutical composition according to the second or third aspect, for reducing blood glucose levels, increasing insulin sensitivity, preventing or treating insulin resistance, and / or preventing or treating diabetes (e.g. type 2 in a subject) Diabetes), or in the manufacture of a medicament for reducing blood glucose levels, increasing insulin sensitivity, preventing or treating insulin resistance, and / or preventing or treating diabetes (e.g., type 2 diabetes) in a subject ); Wherein the compound is as defined in the second aspect or the third aspect.
  • the compound has a structure represented by formula (I),
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl or C 1 -C 4 alkyl
  • the oxy group is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (e.g. -F, -Cl, -Br, or -I) , Hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally One or several (eg, one, two, three or four) are independently substituted with a substituent selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy.
  • R 3 , R 4 are independently selected from hydrogen, halogen (eg -F, -Cl, -Br or -I), nitro, hydroxyl.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • the compound has the following characteristics:
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, 1, 2, 3, or 4) substituents independently selected from the group consisting of substituents: -F, -Cl, -Br, -I , hydroxy; preferably, R 1, R 2 are each independently selected from a Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 3 and R 4 are independently selected from hydrogen, halogen (for example, -F, -Cl, -Br or -I), nitro, and hydroxyl; and at least one of R 3 and R 4 is halogen;
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, and cyano;
  • n 2, 3, or 4.
  • the compound is selected from:
  • the invention provides a method for reducing blood glucose levels, increasing insulin sensitivity, preventing or treating insulin resistance, and / or preventing or treating diabetes (e.g., type 2 diabetes) in a subject.
  • the method includes administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, and a form of their metabolite.
  • the compound is as defined in the fifth aspect; or the method comprises administering to a subject in need thereof an effective amount of the pharmaceutical composition described in the third aspect.
  • the subject has a metabolic disease, and / or the subject has a condition associated with a metabolic disease (e.g., elevated blood glucose levels, insulin resistance, hyperinsulinemia , And / or reduced glucose tolerance).
  • a metabolic disease e.g., elevated blood glucose levels, insulin resistance, hyperinsulinemia , And / or reduced glucose tolerance.
  • the invention provides a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or any combination thereof Or a mixture, a pharmaceutical composition according to the second or third aspect, for reducing total cholesterol levels, lowering triglyceride levels, lowering low density lipoprotein levels and / or increasing high density lipoprotein levels in a subject Use, or in the manufacture of a medicament for reducing total cholesterol levels, reducing triglyceride levels, reducing low density lipoprotein levels, and / or increasing high density lipoprotein levels in a subject; wherein, The compound is as defined in the second or third aspect.
  • the compound has a structure represented by formula (I):
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • the compound has a structure represented by formula (Ia):
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined before.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally One or several (eg, one, two, three or four) are independently substituted with a substituent selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, 1, 2, 3, or 4) substituents independently selected from the group consisting of substituents: -F, -Cl, -Br, -I , hydroxy; preferably, R 1, R 2 are each independently selected from a Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 4 is hydrogen or hydroxyl
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, and cyano;
  • n 1, 2 or 3.
  • the compound is selected from:
  • the invention provides a method for reducing total cholesterol levels, reducing triglyceride levels, reducing low density lipoprotein levels, and / or increasing high density lipoprotein levels in a subject, the method
  • This includes administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or Any combination or mixture thereof, the compound is as defined in the sixth aspect; or the method comprises administering to a subject in need thereof an effective amount of the pharmaceutical composition described in the third aspect.
  • the subject has a metabolic disease, and / or the subject has a condition associated with a metabolic disease (e.g., elevated total cholesterol levels, elevated triglycerides Levels, elevated low-density lipoprotein levels, and / or reduced high-density lipoprotein levels).
  • a metabolic disease e.g., elevated total cholesterol levels, elevated triglycerides Levels, elevated low-density lipoprotein levels, and / or reduced high-density lipoprotein levels.
  • the present invention provides compounds, pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or any combination thereof Or a mixture, a pharmaceutical composition according to the second or third aspect, for use in the prevention or treatment of a metabolic disease in a subject, or for use in the manufacture of a medicament for use in a subject Preventing or treating a metabolic disease; wherein the compound is as defined in the second or third aspect.
  • the metabolic disease is selected from obesity, non-alcoholic fatty liver disease (NAFLD) (e.g., simple fatty liver or non-alcoholic steatohepatitis (NASH)), metabolic syndrome, type 2 diabetes , Type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance or impaired glucose tolerance, fasting blood glucose abnormalities or hyperglycemia, dyslipidemia or hyperlipidemia (e.g., hypercholesterolemia), and their successors Complications (eg, diabetic complications such as retinopathy, neuropathy, kidney disease, and delayed wound healing, or cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease, hypertension, and stroke).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • metabolic syndrome type 2 diabetes , Type 1 diabetes, insulin resistance, hyperinsulinemia, glucose intolerance or impaired glucose tolerance, fasting blood glucose abnormalities or hyperglycemia, dyslipidemia or hyperlipidemia (e.g., hypercholesterolemia),
  • the compound has a structure represented by formula (I):
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, said C 1 -C 4 alkyl or C 1 -C 4 alkyl
  • An oxy group is optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from the group consisting of: halogen (e.g. -F, -Cl, -Br, or -I) , Hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally One or several (eg, one, two, three or four) are independently substituted with a substituent selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1 and R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl, and methoxy.
  • R 3 , R 4 are independently selected from hydrogen, halogen (eg -F, -Cl, -Br or -I), nitro, hydroxyl.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • the compound has a structure represented by formula (Ia):
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined before.
  • R 1 and R 2 are each independently selected from methyl, ethyl, methoxy, and ethoxy, and the methyl, ethyl, methoxy, and ethoxy are optionally one or more (for example, (1, 2, 3, or 4) substituents independently selected from the following: -F, -Cl, -Br, -I, hydroxyl; preferably, R 1 and R 2 are each independently selected from the group consisting of Group, hydroxy-substituted methyl, ethyl, methoxy;
  • R 3 and R 4 are independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, and hydroxyl;
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano;
  • n 1, 2 or 3.
  • the compound has a structure represented by the formula (Ia), wherein R 3 is a halogen (for example, -F, -Cl, -Br, or -I).
  • R 3 is a halogen (for example, -F, -Cl, -Br, or -I).
  • the compound is selected from:
  • the invention provides a method for preventing or treating a metabolic disease in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable A salt or ester, prodrug, stereoisomer, hydrate, solvate, crystalline form, their metabolite form, or any combination or mixture thereof, said compound being as defined in the seventh aspect; or
  • the method includes administering to a subject in need thereof an effective amount of the pharmaceutical composition of the third aspect.
  • the present invention provides compounds, pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms, or any combination thereof Or a mixture, a pharmaceutical composition according to the second or third aspect, the use as a PPAR ⁇ / ⁇ dual agonist or the use in a subject to prevent and / or treat a disease related to PPAR ⁇ and / or PPAR ⁇ , Or use for the preparation of a PPAR ⁇ / ⁇ dual agonist, or use for the preparation of a medicament for the prevention and / or treatment of a disease related to PPAR ⁇ and / or PPAR ⁇ in a subject; wherein, said The compound is as defined in the second or third aspect.
  • the compound has a structure represented by formula (I):
  • R 1 and R 2 are each independently selected from C 1 -C 4 alkyl or C 1 -C 4 alkoxy, and the C 1 -C 4 alkyl or C 1 -C 4 alkoxy is optionally Or several (e.g. 1, 2, 3 or 4) independently substituted with a substituent selected from halogen (e.g. -F, -Cl, -Br or -I), nitro, amino, hydroxyl Thiol
  • halogen e.g. -F, -Cl, -Br or -I
  • R 3 and R 4 are each independently selected from hydrogen, halogen (for example, -F, -Cl, -Br, or -I), nitro, amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 Alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkylamino; wherein the amino, hydroxyl, mercapto, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1- C 4 alkylthio or C 1 -C 4 alkylamino is optionally substituted with one or more (eg, 1, 2, 3, or 4) substituents independently selected from the group consisting of halogen (E.g. -F, -Cl, -Br or -I), amino, hydroxyl;
  • halogen for example, -F, -Cl, -Br, or -I
  • R 3 and R 4 are halogen
  • R 5 and R 6 are each independently selected from C 1 -C 4 alkyl
  • R 7 is selected from -C (O) X and cyano; wherein X is hydroxyl or C 1 -C 4 alkoxy;
  • n 1, 2, 3, or 4.
  • the compound has a structure represented by formula (Ia):
  • R 3 is halogen (for example -F, -Cl, -Br or -I);
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and n are as defined before.
  • R 1, R 2 are each independently selected from methyl, ethyl, a methyl or ethyl group optionally substituted with one or several (e.g., 1, 2, or 3 4) Substituents independently selected from -F, -Cl, -Br, -I, hydroxyl.
  • R 1, R 2 are each independently selected from methyl, hydroxy-substituted methyl, ethyl.
  • R 3 is -Cl or -Br.
  • R 5 and R 6 are the same as each other. In certain embodiments, R 5 and R 6 are methyl.
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano.
  • n 1, 2 or 3.
  • R 1 , R 2 are each independently selected from methyl, ethyl, which is optionally selected from one or several (eg, 1, 2, 3, or 4) The following substituents are substituted: -F, -Cl, -Br, -I, hydroxy; preferably, R 1 and R 2 are each independently selected from methyl, hydroxy substituted methyl, and ethyl;
  • R 3 is halogen; preferably, R 3 is -Cl or -Br;
  • R 4 is hydrogen or hydroxyl
  • R 5 and R 6 are methyl
  • R 7 is selected from carboxyl, -CO 2 Me, -CO 2 Et, cyano;
  • n 1, 2 or 3.
  • the compound is selected from:
  • the disease associated with PPAR ⁇ and / or PPAR ⁇ is selected from the group consisting of type 2 diabetes, impaired glucose tolerance, insulin resistance syndrome, hypertension, hyperlipidemia (e.g., hypercholesterolemia), metabolic synthesis Disease, visceral obesity, and obesity.
  • type 2 diabetes impaired glucose tolerance
  • insulin resistance syndrome hypertension
  • hyperlipidemia e.g., hypercholesterolemia
  • metabolic synthesis Disease e.g., visceral obesity, and obesity.
  • the invention provides a method for preventing or treating a disease associated with PPAR ⁇ and / or PPAR ⁇ in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound , A pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or any combination or mixture thereof, such a compound as the eighth aspect As defined; or, the method comprises administering to a subject in need thereof an effective amount of the pharmaceutical composition of the third aspect.
  • the method described in any of the above aspects may further include: converting a compound as described herein, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate,
  • the crystalline form, their metabolite form, or any combination or mixture thereof, or a pharmaceutical composition as described herein is used in combination with another pharmaceutically active agent.
  • additional pharmaceutically active agents may be administered in the compounds as described herein, their pharmaceutically acceptable salts or esters, prodrugs, stereoisomers, hydrates, solvates, crystalline forms, their metabolite forms , Or any combination or mixture thereof, or a pharmaceutical composition as described herein is administered before, at the same time or after.
  • the additional pharmaceutically active agent is selected from the group consisting of anti-diabetic drugs, anti-obesity drugs, anti-hypertensive drugs, anti-atherosclerotic drugs, lipid-lowering drugs, anti-inflammatory drugs, and anti-oxidative damage drugs.
  • the method described in any of the above aspects may further include: converting a compound as described herein, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate,
  • the crystalline form, their metabolite form, or any combination or mixture thereof, or a pharmaceutical composition as described herein is administered in combination with an additional therapy.
  • This additional therapy may be any therapy known for metabolic diseases, such as surgery, targeted therapy, immunotherapy, hormone therapy or gene therapy.
  • This additional therapy may be in the administration of a compound as described herein, a pharmaceutically acceptable salt or ester thereof, a prodrug, a stereoisomer, a hydrate, a solvate, a crystalline form, their metabolite form, or Any combination or mixture thereof or a pharmaceutical composition as described herein is administered before, at the same time or after.
  • non-limiting examples of suitable anti-diabetic drugs include thiazolidinediones (such as rosiglitazone or pioglitazone), biguanides (such as metformin or phenformin), and sulfonylureas (such as glitazone Umicarb, Glibenclamide, Glipizide, Chlorpromide or Glipizide), Glucosidase inhibitors (such as acarbose or miglitol), PPAR- ⁇ agonists, PPAR- Gamma agonist, PPAR- ⁇ / gamma dual agonist (e.g., mogastazole), aP2 inhibitor, DPP4 inhibitor (e.g., e.g. sitagliptin or vitagliptin), insulin sensitizer, insulin or meglitin Benzoic acid (such as rieglinide) and so on.
  • thiazolidinediones such as rosigli
  • Non-limiting examples of suitable anti-obesity drugs include ⁇ 3 adrenergic agonists (such as AJ9677 (Takeda / Dainippon), L750355 (Merck) or CP331648 (Pfizer)), lipase inhibitors (such as orlistat) Serotonin (and dopamine) reuptake inhibitors (such as sibutramine or topiramate), thyroid receptor beta compounds (such as those disclosed in WO99 / 00353 and WO 00/039077), CB-1 antagonists (such as Rimonabant) or anorectic drugs (such as dextroamphetamine).
  • ⁇ 3 adrenergic agonists such as AJ9677 (Takeda / Dainippon), L750355 (Merck) or CP331648 (Pfizer)
  • lipase inhibitors such as orlistat
  • Serotonin (and dopamine) reuptake inhibitors such as sibutr
  • Non-limiting examples of suitable lipid-lowering drugs include, selected from MTP inhibitors, cholesterol ester transfer protein inhibitors (such as CP-529414 (Pfizer)), HMG CoA reductase inhibitors (such as pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, or atorvastatin), squalene synthetase inhibitors (such as the ⁇ -U.S. Patent No. 5,712,396) Phosphono-sulfonate), phenylacetic acid derivatives (e.g.
  • fenofibrate gemfibrozil, clobetin, bezazabate, ciprobebate, klibate, etc.
  • LDL receptor activity up-regulators Such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly)
  • lipoxygenase inhibitors such as benzimidazole derivatives disclosed in WO 97/12615, 15-LO disclosed in WO 97/12613 Inhibitors, isothiazolones disclosed in WO 96/38144
  • ACAT inhibitors such as avalimab
  • cholesterol absorption inhibitors ileal Na ⁇ +> / bile acid cotransporter inhibitors.
  • Non-limiting examples of suitable antihypertensive drugs include beta-adrenergic blockers, calcium channel blockers (such as diltiazem, verapamil, nifedipine, amlodipine), diuretics (such as Chlorothiazide, hydrochlorothiazide, flumethazine, hydrofluorothiazide, benzylfluorothiazine, methylchlorothiazide, trichlorothiazide, polithiazide, benzthiazine, teninic acid, chlorothiazide, furfur Sami, bumetanib, amiloride or spironolactone), renin inhibitors, ACE inhibitors (e.g.
  • captopril zofenpril, fosinopril, enalapril, cilapril) , Delapril, pentolapril, quinapril, ramipril or lisinopril), AT-1 receptor antagonists (such as losartan, irbesartan, or valsartan), ET receptor antagonists (e.g. sitaxsentan or atrasentan), dual ET / AII antagonists (e.g. compounds disclosed in WO 00/01389), dual NEP-ACE inhibitors (e.g. omatralax), and Nitrates.
  • AT-1 receptor antagonists such as losartan, irbesartan, or valsartan
  • ET receptor antagonists e.g. sitaxsentan or atrasentan
  • dual ET / AII antagonists e.g. compounds disclosed in WO 00/01389
  • dual NEP-ACE inhibitors e.g. omatral
  • Non-limiting examples of suitable anti-inflammatory drugs include non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac, naproxen, indomethacin, piroxicam, meloxicam, nabumetone, or nimet Shuli), steroidal anti-inflammatory drugs (such as prednisone, dexamethasone, or hydrocortisone), antibodies or antagonists of inflammatory cytokines (e.g., TNF ⁇ , IL-1, IL-6, IL- 8. GM-CSF or PAF antibody or receptor antagonist), anti-inflammatory cytokines (such as IL-10, IL-4, IL-11, IL-13 or TGF ⁇ ) and the like.
  • non-steroidal anti-inflammatory drugs e.g. ibuprofen, diclofenac, naproxen, indomethacin, piroxicam, meloxicam, nabumetone, or nimet Shuli
  • C 1 -C 4 alkyl refers to a group obtained by removing a hydrogen atom from a linear or branched alkane containing 1-4 carbon atoms, and specific examples include, but are not limited to, : Methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, tert-butyl or isobutyl.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • halo refers to the replacement of hydrogen on a group or compound with one or more halogen atoms, including fully halogenated and partially halogenated.
  • alkoxy refers to a group formed in an alkyl-O- manner.
  • alkylamino refers to a group formed in an alkyl-NH- manner.
  • alkylthio refers to a group formed in an alkyl-S- manner.
  • substituted refers to the replacement of one or more hydrogen atoms on a group with one or more substituents, which may be the same or different.
  • C 2 alkyl substituted refers to a group on the C 2 or more hydrogen atoms with one or more substituents.
  • hydroxyl substituted”, “thiol substituted”, or “amino substituted” refers to a hydrogen atom on a hydroxyl group, a hydrogen atom on a thiol group, or a hydrogen atom on an amino group, respectively, by a substituent.
  • the term "pharmaceutically acceptable salt” refers to (i) an acidic functional group (e.g., -COOH) present in a compound provided by the present invention and an appropriate inorganic or organic cation (base) Salt, and includes, but is not limited to, alkali metal salts, such as sodium, potassium, lithium, etc .; alkaline earth metal salts, such as calcium, magnesium, etc .; other metal salts, such as aluminum, iron, zinc, copper Salts, nickel salts, cobalt salts, etc .; inorganic base salts such as ammonium salts; organic base salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt , Ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt,
  • a salt formed by a basic functional group (for example, -NH 2 ) and a suitable inorganic or organic anion (acid) present in the compound provided by the present invention includes, but is not limited to, a hydrohalide such as hydrogen Fluorate, hydrochloride, hydrobromide, hydroiodate, etc .; inorganic acid salts, such as nitrate, perchlorate, sulfate, phosphate, etc .; lower alkane sulfonates, such as mesylate , Triflate, ethanesulfonate, etc .; arylsulfonates, such as benzenesulfonate, p-benzenesulfonate, etc .; organic acid salts, such as acetate, malate, fumarate , Succinate, citrate, tartrate, oxalate, maleate, etc .; amino acid salts such as glycine, trimethylglycine
  • ester refers to an ester of -COOH present in a compound provided by the present invention with an appropriate alcohol, or -OH present in a compound provided by the present invention
  • An ester with a suitable acid for example, a carboxylic acid or an oxygen-containing inorganic acid.
  • suitable ester groups include, but are not limited to, formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, hard fatty acid ester, or palmitate.
  • an ester can undergo a hydrolysis reaction to form the corresponding acid or alcohol.
  • solvate refers to a substance formed by association of a compound of the present invention with a solvent molecule.
  • the solvent may be an organic solvent (for example, methanol, ethanol, propanol, acetonitrile, etc.), for example, the compound of the present invention may form an ethanolate with ethanol.
  • the compounds of the invention may also form hydrates with water.
  • the term "crystalline form" refers to the crystal structure of a substance. During the crystallization of a substance, due to various factors, the intramolecular or intermolecular bonding mode changes, which causes the molecules or atoms to be arranged differently in the lattice space and form different crystal structures.
  • the compound of the present invention may exist in one crystal structure or in multiple crystal structures, that is, it has a "polymorphic form".
  • the compounds of the invention may exist in different crystalline forms.
  • stereoisomers includes conformers and configuration isomers, where the configuration isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the invention may exist as stereoisomers, and therefore encompass all possible stereoisomeric forms, as well as any combination or any mixture thereof. For example a single enantiomer, a single diastereomer or a mixture of the above.
  • the compound of the present invention contains an olefinic double bond, it includes the cis isomer and the trans isomer, and any combination thereof, unless specifically stated.
  • prodrug refers to a compound that can be converted into the present invention in a subject by reactions such as oxidation, reduction, hydrolysis, and the like.
  • the prodrug itself may or may not have the biological activity (eg, modulation of glycolipid metabolism activity, anti-inflammatory activity, antioxidant activity) of the compound of formula (I).
  • a compound of formula (I) including a hydroxy or carboxyl group may be administered in the form of an ester, which is hydrolyzed and converted into a hydroxy or carboxyl compound in vivo.
  • compounds of formula (I) including an amino group are acylated, alkylated, or phosphorylated to form compounds such as Eicosanoylamino, alanylamino, pivaloyloxymethylamino .
  • prodrugs Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).
  • prodrugs according to the present invention include: (i) if the compound of formula (I) contains a carboxylic acid functional group (-COOH), including its esters, for example, (C 1 -C 8 ) alkyl instead of hydrogen; ( ii) if the compound of formula (I) contains an alcohol function (-OH), its ethers are included, such as (C 1 -C 6 ) alkanoyloxymethyl instead of hydrogen; and (iii) if the compound of formula (I) Containing primary or secondary amino functional groups (-NH 2 or -NHR, where R is not H), include its amides, such as replacing one or two hydrogens with (C 1 -C 10 ) alkanoyl.
  • certain compounds of formula (I) may themselves act as prodrugs for other compounds of formula (I).
  • the term "pharmaceutically acceptable carrier or excipient” refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with the subject and the active ingredient, which Is well known in the art (see, for example, Remington's Pharmaceuticals Science. Edited by Gennaro AR, 19th. Pennsylvania. Mack Publishing Company, 1995), and includes but is not limited to: disintegrating agents, adhesives, surfactants, glidants , Lubricants, pH adjusters, ionic strength enhancers, agents to maintain osmotic pressure, agents to delay absorption, diluents, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, etc.
  • non-limiting examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, formazan Cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.
  • Non-limiting examples of binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl fiber Vegetarian.
  • Non-limiting examples of diluents include lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch, and phosphoric acid Calcium hydrogen dihydrate.
  • Non-limiting examples of surfactants include sodium lauryl sulfate and polysorbate 80.
  • Non-limiting examples of glidants include silica and talc.
  • Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate.
  • Non-limiting examples of pH adjusting agents include, but not phosphate buffered saline.
  • Ionic strength enhancers include, but are not limited to, sodium chloride.
  • Agents that maintain osmotic pressure include, but are not limited to, sugar, NaCl, and the like.
  • Agents that delay absorption include, but are not limited to, monostearate and gelatin.
  • Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, trichlorot-butanol, phenol, sorbic acid, and the like.
  • prevention refers to a method performed to prevent or delay the occurrence of a disease or disorder or condition in a subject.
  • treatment refers to a method performed to obtain beneficial or desired clinical results.
  • beneficial or desirable clinical results include, but are not limited to, alleviating symptoms, reducing the scope of the disease, stabilizing (ie, no longer exacerbating) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the disease. Status, and alleviation of symptoms (either in part or in whole), whether detectable or undetectable.
  • treatment can also mean prolonging survival compared to expected survival (if not receiving treatment).
  • the term "subject" refers to a mammal, such as a primate mammal, such as a human.
  • the subject e.g., a human
  • the subject has a metabolic disease, and / or the subject has a condition associated with a metabolic disease (e.g., (i) overweight, excess body fat , And / or elevated liver fat fraction; (ii) elevated total cholesterol levels, elevated triglyceride levels, elevated low-density lipoprotein levels, and / or reduced high-density lipoprotein levels; (iii) ) Elevated blood glucose levels, insulin resistance, and / or decreased glucose tolerance).
  • a metabolic disease e.g., (i) overweight, excess body fat , And / or elevated liver fat fraction; (ii) elevated total cholesterol levels, elevated triglyceride levels, elevated low-density lipoprotein levels, and / or reduced high-density lipoprotein levels; (iii) ) Elevated blood glucose levels, insulin
  • an effective amount refers to an amount sufficient to obtain or at least partially obtain a desired effect.
  • an effective amount for preventing a disease e.g., a metabolic disease or a condition associated with a metabolic disease
  • an amount sufficient to prevent, prevent, or delay the occurrence of a disease e.g., a metabolic disease or a condition associated with a metabolic disease.
  • a therapeutically effective amount is an amount sufficient to cure or at least partially prevent a disease and its complications in a patient already suffering from the disease. It is well within the ability of those skilled in the art to determine such an effective amount.
  • the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the general condition of the patient such as age, weight and sex, the manner in which the drug is administered, and other treatments administered concurrently and many more.
  • a phenoxy acid compound that can achieve at least one of the following technical effects: (1) can significantly inhibit inflammatory signals and inflammatory reactions; (2) can significantly Activate antioxidant response and enhance antioxidant capacity; (3) can significantly improve insulin resistance and lower blood sugar levels; (4) can significantly reduce body fat and blood lipids (such as total cholesterol levels); (5) possess PPAR ⁇ / ⁇ dual agonistic activity (6) It has good safety; therefore, the compounds of the present application can be used to treat metabolic diseases (eg, MS, NAFLD, and / or diabetes) with great clinical value.
  • metabolic diseases eg, MS, NAFLD, and / or diabetes
  • FIG. 1 shows the cytotoxicity of the compound on L02 human normal hepatocytes.
  • the results are expressed as the relative viability of cells in the administration group (10 ⁇ M) and cells in the control group (DMSO group). Among them, compared with the control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figure 2 shows the effect of compounds on LPS-induced NO production in macrophage-like cells of RAW264.7 mice.
  • the results are shown as the phase of NO content in the cell culture supernatant of the administration group (10 ⁇ M) and the control group (DMSO group) Multiples of comparison. Among them, compared with the control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figure 3 shows the effect of the compound on the expression of the NF- ⁇ B reporter gene, and the results are expressed as the multiples of the activity of the luciferase reporter gene in the cells of the administration group (50 ⁇ M) and the cells of the control group (DMSO group). Among them, compared with the control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figure 4 shows the effect of the compound on the activity of the ARE reporter gene, and the results are expressed as the multiples of the luciferase reporter gene activity in the cells of the administration group (50 ⁇ M) and the cells of the control group (DMSO group). Among them, compared with the control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figure 5 shows the effect of compounds on the mRNA levels of PPAR ⁇ (A), PPAR ⁇ (B), PGC1 ⁇ (C), ACOX1 (D), and FABP1 (E).
  • the results are shown as the administration group (1 ⁇ M) cells and the control group.
  • (DMSO group) The relative fold of the relative expression of the corresponding gene mRNA in the cells. Among them, compared with the Gefirozi group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figure 6 shows the effects of compounds on the levels of CPT1 ⁇ (A), phosphorylated GSK3 ⁇ (C), and phosphorylated IRS-1 (D) proteins.
  • the results are shown in the administration group (1 ⁇ M) cells and the control group (DMSO group) cells. Corresponding folds of corresponding protein levels were quantified after immunoblot detection.
  • Figure 7 shows the effect of compounds on blood glucose levels in DB / DB mice.
  • Figures 8A-8B show the effect of compounds on fat content in liver tissue of DB / DB mice.
  • Figure 8A Oil Red O staining
  • Figure 8B H.E. staining.
  • Figure 9 shows the effect of compounds on blood glucose levels in a diabetic + NASH model mouse. Among them, compared with the model control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001; compared with the BJMU group, #P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001.
  • Figure 10 shows the effect of MRI detection compounds on body fat content in a diabetic + NASH model mouse. Among them, compared with the model control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001; compared with the BJMU group, #P ⁇ 0.05, ## P ⁇ 0.01, ### P ⁇ 0.001.
  • Figure 11 shows the effect of compounds on the epididymal white fat weight ratio in a diabetic + NASH model mouse. Among them, compared with the model control group, * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001.
  • Figures 12A-12B show the effect of compounds on fat content in liver tissues of diabetes + NASH model mice.
  • Figure 12A Oil Red O staining
  • Figure 12B H.E. staining.
  • Nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum were recorded with a Bruker AVIII-400 spectrometer.
  • the reaction is monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the developer systems used include but are not limited to: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems.
  • the compound is adjusted, but it can be adjusted by adding a small amount of triethylamine or the like.
  • reaction temperature is room temperature (20-30 ° C).
  • the reagents used in the examples were purchased from companies such as Acroso Rganmes, Aldrich Chemical Company or Terber Chemical.
  • Step 2 Preparation of 5- (4-chloro-2,5-dimethylphenoxy) -2,2-dimethylvaleric acid (BJMU-1)
  • Example 2 the first step was to replace Compound 1-1 in Example 1 with Compound 2-1.
  • Compound BJMU-2 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 66%.
  • Example 3 The first step in Example 3 was replaced by the compound 3-1 in place of the first step compound 1-1 in Example 1.
  • Compound BJMU-3 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 78%.
  • Example 4 the first step was replaced by compound 4-1 instead of the first step compound 1-1 in Example 1.
  • Compound BJMU-109 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 72%.
  • Example 5 the first step was replaced by compound 5-1 instead of the first step compound 1-1 in Example 1.
  • Compound BJMU-209 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 58%.
  • Example 6 the first step was replaced by compound 6-1 in addition to the first step compound 1-1 in Example 1.
  • Compound BJMU-213 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 76%.
  • Example 7 The first step in Example 7 was replaced by the compound 7-1 in place of the first step compound 1-1 in Example 1.
  • Compound BJMU-310 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 56%.
  • the first step in Example 8 was to replace the first step compound 1-1 in Example 1 with compound 8-1.
  • Compound BJMU-315 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 68%.
  • Example 9 the first step was replaced by compound 9-1 in addition to the first step compound 1-1 in Example 1.
  • Compound BJMU-404 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 48%.
  • the first step in Example 10 was to replace the first step compound 1-1 in Example 1 with compound 10-1.
  • Compound BJMU-409 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 65%.
  • the first step in Example 11 was to replace the first step compound 1-1 in Example 1 with compound 11-1.
  • Compound BJMU-413 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 58%.
  • Example 12 the first step was replaced by Compound 12-1 in addition to the first step Compound 1-1 in Example 1.
  • Compound BJMU-412 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 56%.
  • the first step in Example 13 was to replace the first step compound 1-1 in Example 1 with compound 13-1.
  • Compound BJMU-414 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 68%.
  • the first step in Example 14 was to replace the first step compound 1-1 in Example 1 with compound 14-1.
  • Compound BJMU-415 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 66%.
  • the first step in Example 15 was to replace the first step compound 1-1 in Example 1 with compound 15-1.
  • Compound BJMU-416 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 57%.
  • the first step in Example 16 was to replace the first step compound 1-1 in Example 1 with compound 16-1.
  • Compound BJMU-502 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 72%.
  • the first step in Example 17 was to replace the first step compound 1-1 in Example 1 with compound 17-1.
  • 17-3 was synthesized using a similar method described in the first step to the second step of Example 1 with a yield of 80%.
  • Step 4 Preparation of 5- (4-bromo-2,5-dimethylphenoxy) -2,2-dimethylvaleronitrile (BJMU-309)
  • Example 18 In the first step of Example 18, Compound 18-1 was used instead of the first step of Example 1-1, 5-chloro-2-methyl-2-ethylvaleric acid isobutyl. The first step is the addition of 5-chloro-2,2-dimethylvalerate isobutyl. Compound BJMU-401 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 62%.
  • Example 19 In the first step of Example 19, Compound 19-1 was used instead of the first step of Compound 1-1 in Example 1. Compound BJMU-110 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 47%.
  • Example 20-1 In the first step of Example 20, Compound 20-1 was used instead of the first step of Compound 1-1 in Example 1.
  • Compound BJMU-410 was synthesized in a similar manner to that described in the first step to the second step of Example 1 with a yield of 55% in two steps.
  • the first step in Example 21 was to replace the first step compound 1-1 in Example 1 with compound 21-1.
  • Compound BJMU-201 was synthesized in a similar manner as described in the first step to the second step of Example 1. The yield in two steps was 85%.
  • the first step in Example 22 was to replace the first step compound 1-1,5-chloro-2,2-dimethylbutyrate isobutyl ester in Example 1 with compound 22-1.
  • Compound BJMU-111 was synthesized in a similar manner to that described in the first step to the second step of Example 1. The yield in two steps was 75%.
  • Example 23 In the first step of Example 23, the compound 23-1 was used in place of the first step of the compound 1-1,5-chloro-2,2-dimethylhexanoic acid isobutyl in the first step. One step of 5-chloro-2,2-dimethylvaleric acid isobutyl ester.
  • Compound BJMU-403 was synthesized in a similar manner as described in the first step to the second step of Example 1 with a yield of 45% in two steps.
  • RAW264.7 mouse macrophages, human colon cancer cells SW480, human liver cancer cells HepG2 cells, and human liver cells L02 were all derived from the ATCC cell bank.
  • the environment was maintained at 37 ° C., 5% CO 2 and saturated humidity, and cultured to 80% confluence, and then 0.25% trypsin-EDTA digestion treatment was performed.
  • RIPA cell lysate, BCA protein concentration test kit (Biyuntian Biotechnology Research Institute, Jiangsu); Phenylmethanesulfonyl fluoride (PMSF), ⁇ -mercaptoethanol, acrylamide (Sigma, USA); ECL TM Prime Western Blotting detection reagent (Bio -Rad, United States); glycine, sodium dodecylsulfonate (Amresco, United States); RPMI1640 medium, DMEM high glucose medium, trypsin (Gibco, Maryland, United States); fetal bovine serum (GBO, Germany); Nitric Oxide (NO) Detection Kit (Nanjing Jiancheng, China) Luciferase Reporter Gene Detection Kit (Biyuntian Biotechnology Research Institute, Jiangsu); Tranzol Reagent (Tranzol Total RNA Extraction Reagent, Beijing Full-Type Gold Biology) ; 5X All-In-One RT MasterMix Reverse Transcription Kit
  • INC0246 cell culture incubator (Memmert, Germany); Gen5 synergy H1 Take3 (BioTek, USA) multifunctional microplate reader; real-time quantitative PCR instrument, protein electrophoresis system (Bio-Rad, USA); cryogenic refrigerated high-speed centrifuge (Eppendorf, Germany); electrophoresis apparatus and horizontal electrophoresis tank (Beijing Junyi Dongfang Electrophoresis Equipment Co., Ltd., China).
  • This experimental example uses the SRB method to detect the cytotoxicity of compounds.
  • the specific steps are as follows:
  • TCA trichloroacetic acid
  • Relative cell viability refers to the percentage of cells in the sample wells that accounted for the drug to the cell viability in the negative control wells.
  • T0 the average absorbance of the negative control without drug action (negative control) with equal volume of DMSO added to the medium
  • Tx the average absorbance value of the cells after the drug action is fixed and stained
  • C blank The wells were fixed and the average absorbance was measured after staining.
  • test results of normal human hepatocytes in L02 are shown in Figure 1.
  • the results show that the compounds detected are BJMU-1, 2, 3, 110, 111, 113, 114, 115, 201, 203, 204, 205, 209.
  • the normal liver cell viability inhibition rates were all less than 30% (relative cell viability was greater than 70%), and did not show significant cytotoxicity.
  • This experimental example evaluates the regulatory effect of compounds on cellular inflammatory responses by detecting nitric oxide (NO) production and transcriptional activity of the NF- ⁇ B inflammatory signaling pathway.
  • NO nitric oxide
  • NO is an active nitrogen species (RNS) and an important gas signaling molecule. Macrophages can convert arginine to NO and participate in the body's inflammatory response. Therefore, detecting the inhibitory activity of drugs on NO production is one of the classic methods to evaluate its anti-inflammatory ability.
  • Logarithmic growth phase RAW264.7 cells were seeded in a 96-well plate at 1 ⁇ 10 4 cells / 200 ⁇ L of medium. After adherence, the medium was discarded, and modeling and drug treatment were given to establish a normal group (serum-free medium).
  • LPS model group serum-free medium containing 1 ⁇ g / mL LPS
  • model + drug group serum-free medium containing 1 ⁇ g / mL LPS, 10 ⁇ M gemfiprozil or the compound of the present application
  • each group was set up with 3 replicates After the cells were cultured in the incubator for 24 hours, the cell supernatants of each well were collected, and according to the instructions of the NO measurement kit (built in Nanjing), the absorbance value of each well was read at a wavelength of 540 nm to calculate the NO content.
  • the results are shown in Fig. 2.
  • the detected compounds 1, 2, 3, 109, 111, 401, 403, 413, 415, and 502 all can inhibit NO production.
  • Gefiprozil (BJMU) does not have Activity to inhibit NO production.
  • the above results indicate that the compounds of the present application have significant anti-inflammatory activity.
  • NF- ⁇ B is the most important inflammatory signaling pathway.
  • SW480 human colon cancer cells stably transfected with the NF- ⁇ B-driven luciferase reporter gene were used to detect the compound of the present application and the control drug Gefiprozil against NF- ⁇ B. Effects of transcriptional activity, steps include:
  • the measurement gap time of the chemiluminometer is set to 2s, and the measurement time is set to 10s.
  • This experimental example evaluates the luciferase activity in HepG2 human liver cancer cells stably transfected with a luciferase reporter gene driven by an antioxidant response element (ARE) to evaluate the compounds of the present application and the resistance to gefitin Rozé regulates the transcriptional activity of the transcription factor Nrf2 and the oxidative stress signal of the cell.
  • ARE antioxidant response element
  • the results are shown in Figure 4.
  • the tested compounds 1, 2, 3, 401, 403, 404, 409, 412, 415, 416, and 502 all significantly activated the ARE reporter gene activity. There is no significant activation of ARE.
  • the above results indicate that the compounds of the present application can exert anti-oxidant effects by activating antioxidant response elements to induce cellular anti-oxidation and metabolic detoxification gene expression, and have significant anti-oxidant activity.
  • Peroxisome proliferator-activated receptor is an important nuclear receptor that regulates glucose and lipid metabolism, including three subtypes of ⁇ , ⁇ / ⁇ and ⁇ .
  • Peroxisome proliferator-activated receptor ⁇ coactivator 1 ⁇ (PGC-1 ⁇ ) is its co-transcriptional activator.
  • Acyl-CoA oxidase 1 (ACOX1) is the first rate-limiting enzyme for fatty acid beta oxidation.
  • Fatty acid binding protein 1 (FABP1) is highly expressed in the liver and can bind molecules such as fatty acids and heme to reduce their toxicity and damage. Up-regulating the expression levels of these genes can help improve body metabolism, and their agonists are an important class of anti-metabolic drugs.
  • ATCTCCGCCAACAGCTTCTCCT SEQ ID NO: 4
  • TTACACTCTGCACTCCAAAG SEQ ID: NO: 8
  • TTCTCCGGCAAGTACCAACT SEQ ID: NO: 10.
  • the primer synthesis company was Suzhou Hongxun Biotechnology Co., Ltd., using Tranzol reagent (Tranzol total RNA extraction reagent, Beijing Quanshijin Biological) to extract total RNA from the tissue, 5X All-In-One RT MasterMix reverse transcription kit (Abcam , USA), real-time quantitative PCR Master Mix (Beijing Sydney Biotechnology Co., Ltd.), Bio-rad fluorescence real-time quantitative PCR instrument was used for qPCR, and 2- ⁇ CT method was used for data analysis.
  • the expression level of mRNA in the normal control group was set to 1 and the relative expression level of mRNA in the administration group was calculated. To confirm whether the active compounds affect the PPAR pathway and thus further regulate lipid metabolism.
  • the test results are shown in Figure 5.
  • the results of PPAR ⁇ mRNA expression detection are shown in FIG. 5A.
  • the compounds 1, 2, 3, 404, 409, and 416 detected significantly induced PPAR ⁇ mRNA expression more than 1.5 times with significant differences, and were better than gefiprozil.
  • gemfiprozil requires a higher dose (50-100 ⁇ M) to be able to significantly activate PPAR ⁇ , while the dose of the above compound detected is only 1 ⁇ M.
  • the results of PPAR ⁇ mRNA expression detection are shown in FIG. 5B.
  • the detected compounds 2, 3, 309, 415, and 502 significantly induced PPAR ⁇ mRNA expression.
  • ACOX1 mRNA expression test results are shown in Figure 5D.
  • Compounds 1, 2, 3, 109, 404, 409, and 502 detected significantly induced PGC1 ⁇ mRNA expression.
  • gefilozil failed to activate ACOX1 expression.
  • FABP1 mRNA expression test results are shown in Figure 5E.
  • the compounds 1, 2, 3, 112, 404, and 409 detected significantly induced FABP1 expression.
  • gefilozil failed to activate FABP1 expression.
  • the compounds of the present invention can up-regulate the expression of PPAR ⁇ / ⁇ , PGC1 ⁇ , ACOX1, and FABP1, and possess PPAR ⁇ / ⁇ dual agonistic activity and glycolipid metabolism regulating activity not available in gefilozil, and thus are particularly suitable for regulating glycolipids.
  • Metabolic and may have a lipid-lowering activity that is superior to that of gemfibrozil.
  • the inventors also tested the effects of compounds on the expression levels of multiple glucose and lipid metabolism-related genes such as MTTP, UCP1 / 2, Elovl3, and CD36. The results show that the above compounds can significantly regulate the expression of these genes, further confirming the present invention The compound has superior regulation of lipid metabolism activity.
  • CPT1 ⁇ Carnitine palmitoyl transferase
  • AKT protein kinase B / glycogen synthase kinase 3 ⁇
  • IRS-1 insulin receptor substrate 1
  • the inventors have also tested the effects of compounds on the phosphorylation levels of multiple glycolipid metabolism-related proteins such as Akt, HSL, ACC, and PKA substrates.
  • the results show that the above compounds can significantly regulate the phosphorylation levels of these proteins, further confirming The compounds of the present invention are excellent in regulating lipid metabolism activity.
  • mice C57BL / KsJ-leprdb / leprdb Diabetic mice are widely used animal models of type 2 diabetes. Spontaneous mutations in the leptin receptor (Lepr) cause extreme obesity, overeating, Thirst, polyuria. In this experimental example, DB / DB mice (purchased from the Animal Department of the Peking University Medical Department) were selected.
  • mice Twenty-eight db / db mice were selected for the test. Animals with blood glucose of about 7-13 mmol / L were selected and randomly divided into control group, BJMU group (Gefirozi), BJMU-2 group and positive control group (Pioglitazone). There are 7 animals in each group. The administration volume was 10ml / kg, and the control group was given 1% Tween 80-saline; the BJMU group was given a dose of 50mg / kg, and the BJMU-2 was given a dose of 50mg / kg. The positive control group Pioglitazone was administered at a dose of 6 mg / kg. It was administered once a day for 28 consecutive days.
  • mice in each experimental group were separated from blood by serum, necropsied, and weighed by the liver; liver tissues were fixed and examined for pathology, HE staining and oil red O staining (Wuhan Zishan Biotechnology Co., Ltd.), light microscope Observe mouse liver lesions; blood routine indicators (Department of Laboratory Medicine, Peking University School of Medicine): white blood count WBC, red blood cell count RBC, lymphocyte count LY, platelet PLT and other blood routine indicators; blood biochemical indicators (North Department of Laboratory Medicine, Third Hospital): Triglyceride (TG), total cholesterol (T-CHO), high density lipoprotein cholesterol HDL-C, low density lipoprotein cholesterol LDL-C and other blood biochemical indicators.
  • TG Triglyceride
  • T-CHO total cholesterol
  • the blood glucose test results are shown in Figure 7.
  • the tested compound BJMU-2 can significantly reduce blood glucose levels in DB / DB mice, and is even significantly better than the known hypoglycemic drug pioglitazone. Significant hypoglycemic activity. This result indicates that the compound of the present invention exhibits significant hypoglycemic activity.
  • the results of blood lipid indicators are shown in the following table.
  • the tested compound BJMU-2 has better triglyceride-lowering activity than Gefiprozil; in particular, BJMU-2 can reduce the total cholesterol content in the blood of DB / DB mice. In contrast, gefilozil did not show activity to lower total cholesterol in the blood. The above results show that BJMU-2 has a more prominent effect on reducing blood lipids.
  • mice liver and kidney function test data showed (Table 2) that the compounds tested did not produce hepatorenal toxicity after continuous oral administration at a dose of 50 mg / kg for one month. This result indicates that the compounds of the present invention have good safety in vivo.
  • NASH non-alcoholic steatohepatitis
  • mice 35 above-mentioned model mice were selected, and animals with a blood glucose of about 7-13 mmol / L were selected. They were randomly divided into blank control group, model group, BJMU group (Gefirozi), BJMU-1 group, and BJMU-2 group. , BJMU-3 group, 7 in each group (the model group and each administration group were modeled as described in the animal model method). It was administered by gavage with a volume of 10ml / kg. The blank control group and model group were given 1% Tween 80-saline; the BJMU group was given a dose of 50mg / kg and the BJMU-1 was given a dose of 50mg / kg.
  • BJMU-2 was administered at a dose of 50 mg / kg
  • MRI magnetic resonance imaging
  • mice in each experimental group were separated from blood by serum, necropsied, and weighed by the liver; liver tissues were fixed and examined for pathology, HE staining and oil red O staining (Wuhan Zishan Biotechnology Co., Ltd.), light microscope Observe mouse liver lesions; blood routine indicators (Department of Laboratory Medicine, Peking University School of Medicine): white blood count WBC, red blood cell count RBC, lymphocyte count LY, platelet PLT and other blood routine indicators; blood biochemical indicators (North Department of Laboratory Medicine, Third Hospital): Triglyceride (TG), total cholesterol (T-CHO), high density lipoprotein cholesterol HDL-C, low density lipoprotein cholesterol LDL-C and other blood biochemical indicators.
  • TG Triglyceride
  • T-CHO total cholesterol
  • the blood glucose test results are shown in Figure 9.
  • the tested compounds BJMU-1, BJMU-2, and BJMU-3 can significantly reduce the blood glucose levels of the diabetes + NASH model mice, and the blood glucose levels return to almost normal levels after 14 days of administration In contrast, gefilozil did not show significant hypoglycemic activity. This result indicates that the compound of the present invention exhibits significant hypoglycemic activity.
  • the body fat test results are shown in Figure 10.
  • the tested compounds BJMU-1, BJMU-2, and BJMU-3 significantly reduced the body fat content of mice; in contrast, gefilozil did not show a reduction in body fat. Of activity.
  • the above results indicate that the compounds of the present invention have a significant reduction in body fat activity.
  • the test results of white fat-to-weight ratio are shown in FIG. 11.
  • the compounds BJMU-2 and BJMU-3 can significantly reduce the epididymal fat-to-weight ratio in mice, and are better than those of gefitirozine.
  • the above results further show that the compounds of the present invention have a significant reduction in body fat activity.
  • the results of the blood lipid indicators are shown in the following table.
  • the tested compounds BJMU-1, BJMU-2, and BJMU-3 have better triglyceride-lowering activity than Gefiprozil; in particular, BJMU-2 can reduce DB / DB
  • the total cholesterol content in the blood of mice did not show the activity of reducing total cholesterol in the blood.
  • the above results indicate that the compound of the present invention has a more prominent effect of lowering blood lipids.
  • Figs. 12A-12B The results of pathological examination of liver tissue are shown in Figs. 12A-12B.
  • the results show that the compounds BJMU-1, BJMU-2, and BJMU-3 can significantly reduce the fat content in the liver of model mice. Gefitelozil did not exhibit the above activity.
  • the above results indicate that the compounds of the present invention have significant blood fat-reducing activity, and also have significant body fat-reducing activity.
  • mice liver and kidney function test data showed (Table 4) that the compounds tested did not produce hepatorenal toxicity by continuous intragastric administration at a dose of 50 mg / kg for one month. This result indicates that the compounds of the present invention have good safety in vivo.
  • BJMU-1, BJMU-2, and BJMU-3 can reduce blood sugar and blood lipid levels, and can reduce body fat and fat content in the liver.
  • BJMU-2 produces metabolites BJMU-415 and 502 after being metabolized by the liver. Since these two compounds exhibit no less than or even better activity than BJMU-2 in cell-level experiments, BJMU- can be reasonably expected 415, 502 will have at least the above-mentioned excellent in vivo activity of BJMU-2.
  • Nrf2 activators attenuate the nonprogression of nonalcoholic stefatohepatitis-related fibrosis pharmacy. 62-70.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Toxicology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

一种苯氧酸类化合物、其药学上可接受的盐或酯、立体异构体、前药、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；含有所述化合物、其药学上可接受的盐或酯、立体异构体、前药、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的药物组合物；以及所述化合物、其药学上可接受的盐或酯、立体异构体、前药、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的医药用途，其可用于预防和/或治疗代谢性疾病，例如代谢综合征、非酒精性脂肪性肝病和/或糖尿病。

Description

苯氧酸类化合物及其医药用途 技术领域
本发明属于医药技术领域。特别地，本发明涉及一种苯氧酸类化合物，含有所述化合物的药物组合物，以及所述化合物的医药用途。例如，本发明的化合物可用于预防和/或治疗代谢性疾病以及此类疾病的并发症。
背景技术
随着社会和经济的发展，糖尿病、肥胖、脂肪性肝病、代谢综合征等代谢性疾病发病率不断攀升。这些疾病不仅互相关联，还会导致多种严重的并发症以及其他重大疾病如癌症、心脑血管疾病等的风险显著升高，已经成为了人类健康最大的威胁之一。
尽管人们投入了大量的人力物力对代谢性疾病的发病机制和治疗手段进行了长期研究，目前的治疗选择仍然非常有限。例如，全球糖尿病发病率迅速升高，患病人数已达数亿，尤以II型糖尿病患者占绝大多数。针对糖尿病有多种药物，如胰岛素类药物、促胰岛素分泌药物(包括磺酰脲类)、胰岛素增敏剂(噻唑烷二酮类、双胍类)、α-糖苷酶抑制剂(阿卡波糖、伏格列波糖、米格列醇)、人胰高血糖素样肽(GLP-1)受体激动剂、二肽基肽酶4(DPP-4)抑制剂、钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂等药物，但是这些药物通常都伴有体重增加、耐受性有限、高胰岛素血症、低血糖、消化道症状等副作用以及药效逐渐降低等问题。糖尿病还会导致肾病/心脑血管疾病/眼病/神经病变/溃疡等多种并发症，而这些并发症一旦发生就极难逆转，其防治药物一直是研究的热点，但至今尚无针对性的药物，利用其它对症药物治疗或联合治疗效果也一直差强人意。再例如，非酒精性脂肪性肝炎(NASH)是最常见的慢性肝病之一，并可能发展成肝纤维化、肝硬化甚至肝癌，也是肝移植最常见的原因之一。其治疗策略主要有(1)代谢调控；(2)抑制炎症或氧化损伤；(3)调节肝肠循环和/或肠道菌群等。包括降糖药(如二甲双胍、噻唑烷二酮类)、抗氧化剂(维生素E、还原性谷胱甘肽)、降脂药(他汀类、贝特类)、熊去氧胆酸等多种药物都曾经被尝试用于治疗NASH，但目前还没有被FDA正式批准用于治疗NASH的药物，主要治疗方案仍然是生活方式干预。
总之，目前可获得的用于代谢性疾病的药物都受限于一些重要缺陷，一些重要的 代谢性疾病如脂肪性肝炎甚至没有批准的治疗药物，而这些代谢性疾病一旦发生并发症则严重威胁健康和生命安全，寻找新的代谢性疾病治疗药物及代谢性疾病并发症的预防药物迫在眉睫。
发明内容
本申请的本发明人通过深入的研究和创造性的发现，得到了一类苯氧酸类化合物，其具有显著的调节糖脂代谢活性、抗炎活性和/或抗氧化活性，由此提供了下述发明。
化合物
在第一方面，本发明提供了式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，
Figure PCTCN2019102273-appb-000001
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4；
条件是所述化合物不是5-(2,4-二氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸；5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸；5-(2-氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸；或5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸。
在某些实施方案中，R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
在某些实施方案中，R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基、C 1-C 4烷基；其中，所述羟基或C 1-C 4烷基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代。
在某些实施方案中，R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基、乙基；其中，所述羟基、甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代。
在某些实施方案中，R 3、R 4独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
在某些实施方案中，所述化合物具有以下特征：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、 乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基、乙基；其中，所述羟基、甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代；优选地，R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
n为1、2或3。
在某些实施方案中，所述化合物具有式(Ia)所示的结构：
Figure PCTCN2019102273-appb-000002
其中：
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如前定义(如式(I)中定义)。
在某些实施方案中，所述化合物选自：
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)；
5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)；
5-(4-溴-2,5-二乙基苯氧基)-2,2-二甲基戊酸(BJMU-310)；
5-(4-溴-2,3,5-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-315)；
5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)；
5-(4-溴-2,3,6-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-409)；
5-(4-溴-2-碘-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-413)；
5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
5-(4-溴-3,6-二甲基-2-硝基苯氧基)-2,2-二甲基戊酸(BJMU-414)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-3-羟基-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-416)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)；
5-(4-溴-2,5-二甲基苯氧基)-2-乙基-2-甲基戊酸(BJMU-401)；
5-(2,5-二甲基-4-硝基苯氧基)-2,2-二甲基戊酸(BJMU-110)；
5-(4-溴-2-乙基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-410)；
5-(4-溴-2,5-二甲氧基苯氧基)-2,2-二甲基戊酸(BJMU-201)；
4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基丁酸(BJMU-111)；
6-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基己酸(BJMU-403)。
药物组合物
在第二方面，本发明提供了一种药物组合物，其包含式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，以及一种或多种药学上可接受的载体和/或赋形剂；
Figure PCTCN2019102273-appb-000003
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟 基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和n如第一方面所定义。
在某些实施方案中，所述化合物具有式(Ia)所示的结构，
Figure PCTCN2019102273-appb-000004
其中，R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如式(I)中所定义。
在某些实施方案中，所述化合物具有所述式(Ia)所示的结构，其中：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 4选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基、乙基；其中，所述羟基、甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代；优选地，R 4选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基； n为1、2或3。
在某些实施方案中，所述化合物选自：
Figure PCTCN2019102273-appb-000005
Figure PCTCN2019102273-appb-000006
在第三方面，本发明提供了一种药物组合物，其包含式(Ia)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，以及一种或多种药学上可接受的载体和/或赋形剂，
Figure PCTCN2019102273-appb-000007
其中，
R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3选自-F、-Cl、-Br或-I；
R 4选自氢或羟基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
n为1、2或3。
在某些实施方案中，所述化合物选自BJMU-1、BJMU-2、BJMU-3、BJMU-415、BJMU-502、BJMU-309、BJMU-11、BJMU-403。
在某些实施方案中，第二方面或第三方面所述的药物组合物任选地包含另外的药学活性剂。
在某些实施方案中，所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物、降脂药物、抗炎药物、抗氧化损伤药物。
在本发明中，所述药物组合物可以为医学领域已知的任何形式。例如，所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)、吸入剂、喷雾剂等形式。优选剂型取决于预期的给药方式和治疗用途。
在某些实施方案中，本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，可以以单位剂量形式存在于药物组合物中，以便于施用。
本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、或者本发明的药物组 合物，可以通过本领域已知的任何合适的方法来施用，包括但不限于，口服、直肠、肠胃外或局部给药。
一种示例性施用途径是口服给药。用于口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂、酏剂等。除活性化合物以外，液体剂型可含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、醋酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油类(例如棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯及其混合物。除惰性稀释剂以外，口服给药的液体剂型也可包括助剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂等。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、锭剂、粉剂、颗粒剂等。除活性化合物以外，固体剂型可含有药学上可接受的惰性赋形剂或载体，例如填充剂(如乳糖、蔗糖、葡萄糖、甘露醇、淀粉、微晶纤维素、半乳糖、交联聚维酮和硫酸钙)；粘合剂(如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶)；湿润剂(如鲸蜡醇和单硬脂酸甘油酯)；崩解剂(如琼胶、碳酸钙、淀粉、褐藻酸、羧甲基纤维素钠、羧甲基淀粉钠)；润滑剂(如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)；及其混合物。
本发明的化合物或药物组合物也可通过非口服途径给药。
因此，另一种示例性的施用途径是肠胃外给药，例如，皮下注射、静脉注射、腹膜内注射、肌肉注射、胸骨内注射和注入。用于肠道外给药的剂型可以为注射制剂，包括注射液、注射用无菌粉末或注射用浓溶液。除活性化合物以外，注射剂型可含有药学上可接受的载体例如无菌水、林格氏液和等渗氯化钠溶液，也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。
另一种示例性的施用途径是局部给药，例如经皮给药(如通过经皮贴剂或离子电渗装置给药)、眼内给药或者鼻内或吸入给药。用于经皮给药的剂型可以为局部凝胶剂、喷雾剂、软膏剂和霜剂。除活性化合物以外，局部剂型可含有能够提高该活性化合物通过皮肤或其它作用区域的吸收或渗透的成分。当本发明的化合物通过经皮装置给药时，给药将使用存储和多孔膜类型或者固体基质品种的贴剂完成。用于眼部局部给药的剂型可以为滴眼剂，其中本发明的化合物被溶于或者悬浮于适宜的载体中。对于鼻内给药或吸入给药来说，本发明的化合物以溶液剂或悬浮剂的形式从压力喷雾容 器中被方便地递送，所述传递是通过患者压握或者泵送而进行的，或者是作为气溶胶喷雾剂制剂从压力容器或喷雾器中使用适宜的抛射剂而传递的。
另一种示例性的施用途径是直肠给药。用于直肠给药的剂型可以为栓剂。
此外，还可以使用药学领域已知的其它载体材料和给药方式。本发明的药物组合物可以通过任何公知的制药工艺制备，例如有效的制剂和给药方法。关于有效制剂和给药方法的上述考虑因素是本领域中公知的，并且描述于标准教科书中。药物的制剂描述在，例如，Hoover，John E.，Remington′s Pharmaceutical Sciences.Mack Publishing Co.，Easton，Pennsylvania，1975；Liberman等人编辑，Pharmaceutical Dosage Forms，Marcel Decker，New York，N.Y.，1980；以及Kibbe等人编辑，Handbook of Pharmaceutical Excipients(第3版)，American Pharmaceutical Association，Washington，1999。
在某些实施方案中，所述药物组合物含有本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的量为0.01-2000mg，优选为0.1-1000mg，更优选为1-800mg，更优选为10-600mg，特别优选为50-500mg。
本发明的药物组合物可以包括“治疗有效量”或“预防有效量”的如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物。“预防有效量”是指，足以预防，阻止，或延迟疾病的发生的量。“治疗有效量”是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。本领域技术人员理解，如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的治疗有效量可根据如下因素发生变化：待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
在本发明中，可调整给药方案以获得最佳目的反应(例如治疗或预防反应)。例如，可以单次给药，可以在一段时间内多次给药，或者可以随治疗情况的紧急程度按比例减少或增加剂量。
本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物的治疗或预防有效量的典型 非极限范围是0.01～1000mg/kg，例如0.1～500mg/kg。应注意的是，剂量可随需要治疗的症状的类型和严重性不同而发生变化。此外，本领域技术人员理解，对于任一特定患者，特定的给药方案应根据患者需要和医生的专业评价而随时间调整；此处给出的剂量范围只用于举例说明目的，而不限定本发明药物组合物的使用或范围。
在某些实施方案中，所述药物组合物还可以包含另外的药学活性剂。在某些实施方案中，所述另外的药学活性剂是用于治疗代谢性疾病或相关疾病的药物，例如抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物或降脂药物。在某些实施方案中，所述另外的药学活性剂是具有抗炎活性的药物。在某些实施方案中，所述另外的药学活性剂是具有抗氧化损伤活性的药物。在某些实施方案中，所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物、降脂药物、抗炎药物、抗氧化损伤药物。
在某些实施方案中，在所述药物组合物中，本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物与所述另外的药学活性剂作为分离的组分或混合的组分提供。因此，本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物与所述另外的药学活性剂可以同时、分开或相继施用。
通用合成
本发明第一方面所述的化合物、第二方面或第三方面中所定义的化合物可以借助制备这种类型化合物所熟知的多种方法加以制备，例如如下反应流程所示。除非另有指定，反应流程和后面讨论中的R 1至R 7和n是如上所定义的。
下列反应流程阐述式(I)化合物的制备。
流程1：
该流程阐述式(I-1)化合物的制备，其中R 7代表-COOH。
Figure PCTCN2019102273-appb-000008
上式中，L为卤素(例如-F、-Cl、-Br或-I)；优选地，L为-Cl。其他符号如第一 方面或第二方面中定义。
步骤1A
该步骤中，将化合物1-1与化合物1-2进行醚化反应获得化合物1-3。
在某些实施方案中，使用Williamson合成法。在某些实施方案中，在路易斯碱(例如Na 2CO 3、K 2CO 3等)存在下，在非质子极性溶剂(例如DMF，DMSO等)中进行所述醚化反应。如果需要的话，反应可以在相转移催化剂(例如TBAI(四丁基碘化铵))存在下进行。
步骤1B
该步骤中，在溶剂中进行化合物1-3的水解作用，可以制备式(I-1)酸化合物。
水解作用可以借助常规工艺进行。在典型的工艺中，水解作用是在碱性条件下进行的，例如在氢氧化钠、氢氧化钾或氢氧化锂的存在下。适合的溶剂例如包括醇，例如甲醇、乙醇、丙醇、丁醇、2-甲氧基乙醇和乙二醇；醚，例如四氢呋喃(THF)、1，2-二甲氧基乙烷(DME)和1，4-二噁烷；酰胺，例如N，N-二甲基甲酰胺(DMF)和六甲基磷酸三酰胺(phospholictriamide)；和亚砜，例如二甲基亚砜(DMSO)。
水解作用也可以在酸性条件下进行，例如在下列试剂的存在下：卤化氢，例如氯化氢和溴化氢；磺酸，例如对-甲苯磺酸和苯磺酸；对-甲苯磺酸吡啶鎓；和羧酸，例如乙酸和三氟乙酸。适合的溶剂例如包括醇，例如甲醇、乙醇、丙醇、丁醇、2-甲氧基乙醇和乙二醇；醚，例如四氢呋喃(THF)、1，2-二甲氧基乙烷(DME)和1，4-二噁烷；酰胺，例如N，N-二甲基甲酰胺(DMF)和六甲基磷酸三酰胺；和亚砜，例如二甲基亚砜(DMSO)。
流程2：
该流程阐述式(I-2)化合物的制备，其中R 7代表-CN。
Figure PCTCN2019102273-appb-000009
步骤2A(酰胺化反应)
该步骤中，在有或没有偶联剂的存在下，在惰性溶剂中，进行如流程1步骤1B所述制备的式I-1化合物与胺的偶联反应，可以制备酰胺化合物2-1。如果需要的话，该反应可以在有或没有添加剂的存在下进行，例如1-羟基苯并三唑或1-羟基氮杂苯并三唑。
反应正常地和优选地是在溶剂中进行的。对所采用的溶剂的属性没有特别的限制，只要它对反应或所牵涉的试剂没有不良影响，并且至少在一定程度上能够溶解试剂。适合的溶剂的实例包括：丙酮、硝基甲烷、DMF、环丁砜、DMSO、NMP、2-丁酮、乙腈；卤代烃，例如二氯甲烷、二氯乙烷、氯仿；和醚，例如四氢呋喃和二噁烷。
反应可以发生在广泛的温度下，精确的反应温度不是本发明的关键。优选的反应温度将依赖于溶剂属性和所用原料或试剂等因素。
适合的偶联剂是典型用在肽合成中的那些，例如包括二亚胺(例如二环己基碳二亚胺(DCC)、水溶性碳二亚胺(WSC))、2-乙氧基-N-乙氧基羰基-1，2-二氢喹啉、2-溴-1-乙基吡啶鎓四氟硼酸盐(BEP)、2-氯-1，3-二甲基咪唑鎓氯化物、苯并三唑-1-基氧基-三(二甲氨基)鏻六氟磷酸盐(BOP)、偶氮二羧酸二乙酯-三苯膦、氰基磷酸二乙酯、二乙基磷酰基叠氮化物、2-氯-1-甲基吡啶鎓碘化物、N，N’-羰基二咪唑、苯并三唑-1-基二乙基磷酸酯、氯甲酸乙酯或氯甲酸异丁酯。如果需要的话，反应可以在碱的存在下进行，例如N，N-二异丙基乙胺、N-甲基吗啉和三乙胺。
此外，酰胺化合物2-1可以经由酰卤生成，后者可以借助与卤化剂的反应得到，例如草酰氯、磷酰氯和亚硫酰氯。利用与该步骤所述相似的条件用胺处理所得酰卤可以转化为对应的酰胺化合物。
步骤2B
该步骤中，在惰性溶剂中将酰胺化合物2-1的酰胺基转化为氰基，可以制备式I-2化合物。
该步骤可以是过渡金属催化的氰基化反应。所述过渡金属催化剂可以是金属钯催化剂，例如醋酸钯(Pd(OAc) 2)。例如，在惰性气体(例如氩气)保护下，在Pd(OAc) 2/Selectfluor催化体系和乙腈在中发生氰基化反应获得式I-2化合物。乙腈同时作为溶剂和氰基试剂。
此外，该步骤也可以是脱水反应。例如，在脱水剂存在下，于惰性溶剂在中发生脱水反应获得式I-2化合物。所述脱水剂可以是氯化亚砜、五氧化磷、三聚氯氰、三氟乙酸酐、三氯氧磷、五氯化磷等。
流程3：
该流程阐述式(I-3)化合物的制备，其中R 7代表-C(O)X，X为C 1-C 4烷氧基。
Figure PCTCN2019102273-appb-000010
该步骤中，在催化剂存在下于惰性溶剂中进行式I-1酸化合物与C 1-C 4醇的酯化反应，可以制备式I-3酯化合物。
此外，式I-3酯化合物可以经由酰卤生成，后者可以借助与卤化剂的反应得到。利用与该步骤所述相似的条件用醇处理所得酰卤可以转化为对应的酯化合物。
用途及方法
在第四方面，本发明涉及化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、第二方面或第三方面所述的药物组合物，用于在受试者中降低体重、降低体脂肪、降低肝脂肪分数、预防或治疗肥胖症、和/或预防或治疗非酒精性脂肪性肝病(NAFLD)的用途，或者在制备药物中的用途，所述药物用于在受试者中降低体重、降低体脂肪、降低肝脂肪分数、预防或治疗肥胖症、和/或预防或治疗非酒精性脂肪性肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))；其中，所述化合物如第二方面或第三方面中定义。
在某些实施方案中，所述化合物具有式(I)所示的结构：
Figure PCTCN2019102273-appb-000011
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，所述化合物具有式(Ia)所示的结构：
Figure PCTCN2019102273-appb-000012
其中：
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如式(I)中所定义。
在某些实施方案中，R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
在某些实施方案中，R 4选自氢、卤素(例如-F、-Cl、-Br或-I)、羟基。在某些 实施方案中，R 4选自氢或羟基。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
在某些实施方案中，所述化合物具有所述式(Ia)所示的结构，其中：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3为-F、-Cl、-Br或-I；
R 4选自氢、卤素(例如-F、-Cl、-Br或-I)、羟基；优选地，R 4选自氢或羟基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
n为1、2或3。
在某些实施方案中，所述化合物选自：
5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)。
在另一方面，本发明提供了一种用于在受试者中降低体重、降低体脂肪、降低肝脂肪分数、预防或治疗肥胖症、和/或预防或治疗非酒精性脂肪性肝病(NAFLD)的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、 前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或者第三方面所述的药物组合物；其中，所述化合物如第四方面中所定义。
在某些实施方案中，所述非酒精性脂肪性肝病(NAFLD)包括单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))。
在某些实施方案中，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如超重、过量的体脂肪、和/或升高的肝脂肪分数)。
在第五方面，本发明提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、第二方面或第三方面所述的药物组合物，用于在受试者中降低血糖水平、增加胰岛素敏感性、预防或治疗胰岛素抵抗、和/或预防或治疗糖尿病(例如2型糖尿病)的用途，或者在制备药物中的用途，所述药物用于在受试者中降低血糖水平、增加胰岛素敏感性、预防或治疗胰岛素抵抗、和/或预防或治疗糖尿病(例如2型糖尿病)；其中，所述化合物如第二方面或第三方面中所定义。
在某些实施方案中，所述化合物具有式(I)所示的结构，
Figure PCTCN2019102273-appb-000013
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
在某些实施方案中，R 3、R 4独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
在某些实施方案中，所述化合物具有以下特征：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3、R 4独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基；并且，R 3和R 4中至少一个为卤素；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
n为2、3或4。
在某些实施方案中，所述化合物选自：
5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)；
5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)；
5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)；
5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)。
在另一方面，本发明提供了一种用于在受试者中降低血糖水平、增加胰岛素敏感性、预防或治疗胰岛素抵抗、和/或预防或治疗糖尿病(例如2型糖尿病)的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，所述化合物如第五方面中所定义；或者，所述方法包括向有此需要的受试者施用有效量的第三方面所述的药物组合物。
在某些实施方案中，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的血糖水平、胰岛素抵抗、高胰岛素血症、和/或降低的葡萄糖耐量)。
在第六方面，本发明提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、第二方面或第三方面所述的药物组合物，用于在受试者中降低总胆固醇水平、降低甘油三酯 水平、降低低密度脂蛋白水平和/或增加高密度脂蛋白水平的用途，或者在制备药物中的用途，所述药物用于在受试者中降低总胆固醇水平、降低甘油三酯水平、降低低密度脂蛋白水平和/或增加高密度脂蛋白水平；其中，所述化合物如第二方面或第三方面中所定义。
在某些实施方案中，所述化合物具有式(I)所示的结构：
Figure PCTCN2019102273-appb-000014
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，所述化合物具有式(Ia)所示的结构：
Figure PCTCN2019102273-appb-000015
Figure PCTCN2019102273-appb-000016
其中：
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如前定义。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
在某些实施方案中，其中：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 4为氢或羟基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
n为1、2或3。
在某些实施方案中，所述化合物选自：
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)；
5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)。
在另一方面，本发明提供了一种用于在受试者中降低总胆固醇水平、降低甘油三酯水平、降低低密度脂蛋白水平和/或增加高密度脂蛋白水平的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，所述化合物如第六方面所定义；或者，所述方法包括向有此需要的受试者施用有效量的第三方面所述的药物组合物。
在某些实施方案中，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的总胆固醇水平、升高的甘油三酯水平、升高的低密度脂蛋白水平和/或降低的高密度脂蛋白水平)。
在第七方面，本发明提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、第二方面或第三方面所述的药物组合物，用于在受试者中预防或治疗代谢性疾病的用途，或者在制备药物中的用途，所述药物用于在受试者中预防或治疗代谢性疾病；其中，所述化合物如第二方面或第三方面中所定义。
在某些实施方案中，所述代谢性疾病选自肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受或葡萄糖耐量降低、空腹血糖异常或高血糖、血脂异常或高脂血症(例如，高胆固醇血症)，及这些疾病的继发性并发症(例如，糖尿病并发症，如视网膜病、神经病、肾病以及延缓的创伤愈合，或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)。
在某些实施方案中，所述化合物具有式(I)所示的结构：
Figure PCTCN2019102273-appb-000017
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
在某些实施方案中，R 3、R 4独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
所述化合物具有式(Ia)所示的结构：
Figure PCTCN2019102273-appb-000018
其中：
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如前定义。
在某些实施方案中，其中：
R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
R 3、R 4独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；并且，
n为1、2或3。
在某些实施方案中，所述化合物具有所述式(Ia)所示的结构，其中，R 3为卤素(例如-F、-Cl、-Br或-I)。
在某些实施方案中，所述化合物选自：
5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)；
5-(2-氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-209)；
5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)；
5-(4-溴-2,5-二乙基苯氧基)-2,2-二甲基戊酸(BJMU-310)；
5-(4-溴-2,3,5-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-315)；
5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)；
5-(4-溴-2,3,6-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-409)；
5-(4-溴-2-碘-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-413)；
5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
5-(4-溴-3,6-二甲基-2-硝基苯氧基)-2,2-二甲基戊酸(BJMU-414)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-3-羟基-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-416)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)；
5-(4-溴-2,5-二甲基苯氧基)-2-乙基-2-甲基戊酸(BJMU-401)；
5-(2,5-二甲基-4-硝基苯氧基)-2,2-二甲基戊酸(BJMU-110)；
5-(4-溴-2-乙基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-410)；
5-(4-溴-2,5-二甲氧基苯氧基)-2,2-二甲基戊酸(BJMU-201)；
4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基丁酸(BJMU-111)；
6-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基己酸(BJMU-403)。
在另一方面，本发明提供了一种用于在受试者中预防或治疗代谢性疾病的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组 合或混合物，所述化合物如第七方面所定义；或者，所述方法包括向有此需要的受试者施用有效量的第三方面所述的药物组合物。
在第八方面，本发明提供了化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物、第二方面或第三方面所述的药物组合物，用作PPARα/γ双重激动剂或者用于在受试者中预防和/或治疗与PPARα和/或PPARγ相关的疾病的用途，或者用于制备PPARα/γ双重激动剂的用途，或者用于制备药物的用途，所述药物用于在受试者中预防和/或治疗与PPARα和/或PPARγ相关的疾病；其中，所述化合物如第二方面或第三方面中定义。
在某些实施方案中，所述化合物具有式(I)所示的结构：
Figure PCTCN2019102273-appb-000019
其中：
R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
其中，R 3和R 4中的至少一个为卤素；
R 5和R 6各自独立地选自C 1-C 4烷基；
R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
n为1、2、3或4。
在某些实施方案中，所述化合物具有式(Ia)所示的结构：
Figure PCTCN2019102273-appb-000020
其中：
R 3为卤素(例如-F、-Cl、-Br或-I)；
R 1、R 2、R 4、R 5、R 6、R 7和n如前定义。
在某些实施方案中，R 1、R 2各自独立地选自甲基、乙基，所述甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基。
在某些实施方案中，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基。
在某些实施方案中，R 3为-Cl或-Br。
在某些实施方案中，R 5和R 6彼此相同。在某些实施方案中，R 5和R 6为甲基。
在某些实施方案中，R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
在某些实施方案中，n为1、2或3。
在某些实施方案中，其中：
R 1、R 2各自独立地选自甲基、乙基，所述甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基；
R 3为卤素；优选地，R 3为-Cl或-Br；
R 4为氢或羟基；
R 5和R 6为甲基；
R 7选自羧基、-CO 2Me、-CO 2Et、氰基；并且，
n为1、2或3。
在某些实施方案中，所述化合物选自：
5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)。
在某些实施方案中，所述与PPARα和/或PPARγ相关的疾病选自2型糖尿病、糖耐量受损、胰岛素抵抗综合症、高血压、高脂血症(例如高胆固醇症)、代谢综合症、内脏肥胖和肥胖症。
在另一方面，本发明提供了一种用于在受试者中预防或治疗与PPARα和/或PPARγ相关的疾病的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，所述化合物如第八方面所定义；或者，所述方法包括向有此需要的受试者施用有效量的第三方面所述的药物组合物。
在本发明中，以上任一方面所述的方法还可以包括：将如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或如本文所述的药物组合物与另外的药学活性剂联合使用。这种另外的药学活性剂可以在施用如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或如本文所述的药物组合物之前、同时或之后施用。
在某些实施方案中，所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物、降脂药物、抗炎药物、抗氧化损伤药物。
在本发明中，以上任一方面所述的方法还可以包括：将如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或如本文所述的药物组合物与额外的疗法组合施用。这种额外的疗法可以是已知用于代谢性疾病的任何疗法，例如手术、靶向治疗、免疫治疗、激素治疗或基因治疗。这种额外的疗法可以在施用如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物或如本文所述的药物组合物之前、同时或之后施用。
在本发明中，合适的抗糖尿病药物的非限制性实例包括，噻唑烷二酮类(如罗格列酮或吡格列酮)、双胍类(如二甲双胍或苯乙双胍)、磺脲类(如格列美脲、格列本脲、格列齐特、氯磺丙脲或格列吡嗪)、葡萄糖苷酶抑制剂(如阿卡波糖或米格列醇)、PPAR-α激动剂、PPAR-γ激动剂、PPAR-α/γ双重激动剂(如莫格他唑)、aP2抑制剂、DPP4抑制剂(如如西他列汀或维格列汀)、胰岛素敏化剂、胰岛素或氯茴苯酸类(如瑞格列奈)等。
合适的抗肥胖症药物的非限制性实例包括，β3肾上腺素能激动剂(如AJ9677(Takeda/Dainippon)、L750355(Merck)或CP331648(Pfizer))、脂酶抑制剂(如奥利司他)、5-羟色胺(和多巴胺)再摄取抑制剂(如西布曲明或托吡酯)、甲状腺受体β化合物(如WO99/00353和WO 00/039077中公开的化合物)、CB-1拮抗剂(如利莫那班)或厌食药物(如右旋苯丙胺)。
合适的降脂药物(包括抗动脉粥样硬化药物)的非限制性实例包括，选自MTP抑制剂、胆固醇酯转移蛋白抑制剂(如CP-529414(Pfizer))、HMG CoA还原酶抑制剂(如普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀、西立伐他汀或阿伐他汀)、角鲨烯合成酶抑制剂(如美国专利US 5,712,396中公开的α-膦酰基-磺酸酯)、苯乙酸衍生物(如非诺贝特、吉非贝齐、氯贝丁酯、苯扎贝特、环丙贝特、克利贝特等)、LDL受体活性上调剂(如MD-700(Taisho Pharmaceutical Co.Ltd)和LY295427(Eli Lilly))、 脂氧化酶抑制剂(如WO 97/12615中公开的苯并咪唑衍生物、WO 97/12613中公开的15-LO抑制剂、WO 96/38144中公开的异噻唑酮类)、ACAT抑制剂(如阿伐麦布)、胆固醇吸收抑制剂、回肠Na<+>/胆汁酸协同转运蛋白抑制剂。
合适的抗高血压药物的非限制性实例包括，β肾上腺素能阻断剂、钙通道阻断剂(如地尔硫、维拉帕米、硝苯地平、氨氯地平)、利尿剂(如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、泊利噻嗪、苄噻嗪、替尼酸、氯噻酮、呋塞米、布美他尼、阿米洛利或螺内酯)、肾素抑制剂、ACE抑制剂(如卡托普利、佐芬普利、福辛普利、依那普利、西拉普利、地拉普利、喷托普利、喹那普利、雷米普利或赖诺普利)、AT-1受体拮抗剂(如氯沙坦、厄贝沙坦或缬沙坦)、ET受体拮抗剂(如西他生坦或阿曲生坦)、双重ET/AII拮抗剂(如在WO 00/01389中公开的化合物)、双重NEP-ACE抑制剂(如奥马曲拉)以及硝酸脂类。
合适的抗炎药物的非限制性实例包括，非甾体抗炎药(如布洛芬、双氯芬酸、萘普生、吲哚美辛、吡罗昔康、美洛昔康、萘丁美酮或尼美舒利)、甾体抗炎药(如强的松、地塞米松或氢化考的松)、致炎性细胞因子的抗体或拮抗剂(例如，TNFα、IL-1、IL-6、IL-8、GM-CSF或PAF的抗体或受体拮抗剂)、抗炎细胞因子(如IL-10、IL-4、IL-11、IL-13或TGFβ)等。
术语定义
在本发明中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且，本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时，为了更好地理解本发明，下面提供相关术语的定义和解释。
如本文中所使用的，术语“C 1-C 4烷基”是指含有1-4个碳原子的直链或支链烷烃去掉一个氢原子后得到的基团，其具体实例包括但不限于：甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、叔丁基或异丁基。
如本文中所使用的，术语“卤素”包括氟、氯、溴和碘。
如本文中所使用的，术语“卤代”是指基团或化合物上的氢被一个或多个卤素原子取代，包括全卤代和部分卤代。
如本文中所使用的，术语“烷氧基”是指，以烷基-O-方式形成的基团。
如本文中所使用的，术语“烷氨基”是指，以烷基-NH-方式形成的基团。
如本文中所使用的，术语“烷硫基”是指，以烷基-S-方式形成的基团。
如本文中所使用的，术语“被取代”是指基团上的一个或多个氢原子被一个或多个取代基所取代，所述“多个取代基”之间可以相同或不同。例如，“C 2烷基被取代”是指C 2烷基上的一个或多个氢原子被一个或多个取代基所取代。例如，“羟基被取代”、“巯基被取代”或“氨基被取代”分别指羟基上的氢原子、巯基上的氢原子或氨基上的氢原子被取代基所取代。
如本文中所使用的，术语“药学上可接受的盐”是指，(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐，并且包括但不限于，碱金属盐，如钠盐、钾盐、锂盐等；碱土金属盐，如钙盐、镁盐等；其他金属盐，如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等；无机碱盐，如铵盐；有机碱盐，如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及，(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH 2)与适当的无机或者有机阴离子(酸)形成的盐，并且包括但不限于，氢卤酸盐，如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等；无机酸盐，如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等；低级烷磺酸盐，如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等；芳基磺酸盐，如苯磺酸盐、对苯磺酸盐等；有机酸盐，如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等；氨基酸盐，如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
如本文中所使用的，术语“药学上可接受的酯”是指，本发明所提供的化合物中存在的-COOH与适当的醇形成的酯，或者本发明所提供的化合物中存在的-OH与适当的酸(例如，羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于，甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下，可以发生水解反应生成相应的酸或醇。
如本文中所使用的，术语“溶剂合物”是指本发明化合物与溶剂分子缔合形成的物质。所述溶剂可以是有机溶剂(例如甲醇、乙醇、丙醇、乙腈等)，例如本发明化合物可以与乙醇形成乙醇化物。本发明化合物还可以与水形成水合物。
如本文中所使用的，术语“晶型”是指物质的晶体结构。物质在结晶时由于受各 种因素影响，使分子内或分子间键合方式发生改变，致使分子或原子在晶格空间排列不同，形成不同的晶体结构。本发明化合物可以一种晶体结构存在，也可以多种晶体结构存在，即具有“多晶型”。本发明化合物可以不同的晶型存在。
如本文中所使用的，术语“立体异构体”包括构象异构体和构型异构体，其中所述构型异构体主要包括顺反异构体和旋光异构体。本发明化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，及其任何组合或任何混合物。例如单一对映异构体，单一非对映异构体或以上的混合物。当本发明化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。
如本文中所使用的，术语“前药”是指可在受试者体内通过例如氧化、还原、水解等反应转化成本发明的化合物。前药自身可或不可具有式(I)化合物的生物活性(例如，调节糖脂代谢活性，抗炎活性，抗氧化活性)。例如，包括羟基或羧基的式(I)化合物可以酯的形式给药，其在体内水解转化成羟基化合物或羧基化合物。类似地，包括氨基的式(I)化合物发生酰化、烷基化或磷酸化，以形成例如二十烷酰基氨基(Eicosanoylamino)、丙氨酰氨基、新戊酰氧甲基氨基的化合物给药。关于前体药物使用的进一步信息可以参见Pro-drugs as Novel Delivery Systems，Vol.14，ACS Symposium Series(T Higuchi and W Stella)和Bioreversible Carriers in Drug Design，Pergamon Press，1987(ed.E B Roche，American Pharmaceutical Association)。根据本发明的一些前体药物实例包括：(i)若式(I)化合物含有羧酸官能团(-COOH)，则包括它的酯，例如用(C 1-C 8)烷基代替氢；(ii)若式(I)化合物含有醇官能团(-OH)，则包括它的醚，例如用(C 1-C 6)烷酰氧基甲基代替氢；和(iii)若式(I)化合物含有伯或仲氨基官能团(-NH 2或-NHR，其中R不为H)，则包括它的酰胺，例如用(C 1-C 10)烷酰基代替一个或两个氢。此外，某些式(I)化合物本身可以充当其他式(I)化合物的前体药物。
如本文中所使用的，术语“药学上可接受的载体或赋形剂”是指，在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂，其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19th ed.Pennsylvania:Mack Publishing Company,1995)，并且包括但不限于：崩解剂、粘合剂、表面活性剂、助流剂、润滑剂、pH调节剂、离子强度增强剂、维持渗透压的试剂、延迟吸收的试剂、稀释剂、抗氧化剂、着色剂、矫味剂、防腐剂、味道掩蔽剂等。 例如，崩解剂的非限制性实例包括淀粉羟乙酸钠、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、交联聚维酮、聚乙烯吡咯烷酮、甲基纤维素、微晶纤维素、低级烷基-取代的羟丙基纤维素、淀粉、预胶凝化淀粉和藻酸钠。粘合剂的非限制性实例包括微晶纤维素、明胶、糖、聚乙二醇、天然与合成树胶、聚乙烯吡咯烷酮、预胶凝化淀粉、羟丙基纤维素和羟丙基甲基纤维素。稀释剂的非限制性实例包括乳糖(一水合物、喷雾干燥的一水合物、无水等)、甘露糖醇、木糖醇、葡萄糖、蔗糖、山梨糖醇、微晶纤维素、淀粉和磷酸氢钙二水合物。表面活性剂的非限制性实例包括月桂基硫酸钠和聚山梨醇酯80。助流剂的非限制性实例包括二氧化硅和滑石。润滑剂的非限制性实例包括硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂基富马酸钠以及硬脂酸镁与月桂基硫酸钠的混合物。pH调节剂的非限制性实例包括但不磷酸盐缓冲液。离子强度增强剂包括但不限于氯化钠。维持渗透压的试剂包括但不限于糖、NaCl及其类似物。延迟吸收的试剂包括但不限于单硬脂酸盐和明胶。防腐剂包括但不限于各种抗细菌试剂和抗真菌试剂，例如硫柳汞，2-苯氧乙醇，对羟苯甲酸酯，三氯叔丁醇，苯酚，山梨酸等。
如本文中所使用的，术语“预防”是指，为了阻止或延迟疾病或病症或症状在受试者体内的发生而实施的方法。如本文中所使用的，术语“治疗”是指，为了获得有益或所需临床结果而实施的方法。为了本发明的目的，有益或所需的临床结果包括但不限于，减轻症状、缩小疾病的范围、稳定(即，不再恶化)疾病的状态，延迟或减缓疾病的发展、改善或减轻疾病的状态、和缓解症状(无论部分或全部)，无论是可检测或是不可检测的。此外，“治疗”还可以指，与期望的存活期相比(如果未接受治疗)，延长存活期。
如本文中使用的，术语“受试者”是指哺乳动物，例如灵长类哺乳动物，例如人。在某些实施方式中，所述受试者(例如人)患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如(i)超重、过量的体脂肪、和/或升高的肝脂肪分数；(ii)升高的总胆固醇水平、升高的甘油三酯水平、升高的低密度脂蛋白水平和/或降低的高密度脂蛋白水平；(iii)升高的血糖水平、胰岛素抵抗、和/或降低的葡萄糖耐量)。
如本文中所使用的，术语“有效量”是指足以获得或至少部分获得期望的效果的量。例如，预防疾病(例如，代谢性疾病或与代谢性疾病相关的病状)有效量是指，足以预防，阻止，或延迟疾病(例如，代谢性疾病或与代谢性疾病相关的病状)的发生的量；治疗疾病有效量是指，足以治愈或至少部分阻止已患有疾病的患者的疾病和 其并发症的量。测定这样的有效量完全在本领域技术人员的能力范围之内。例如，对于治疗用途有效的量将取决于待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄，体重和性别，药物的施用方式，以及同时施用的其他治疗等等。
发明的有益效果
本申请通过大量研究和反复筛选，得到了一种苯氧酸类化合物，所述化合物能够实现下述的至少一种技术效果：(1)能够显著抑制炎症信号和炎症反应；(2)能够明显激活抗氧化响应和增强抗氧化能力；(3)能够明显改善胰岛素抵抗、降低血糖水平；(4)能够明显降低体脂和血脂(例如总胆固醇水平)；(5)具备PPARα/γ双重激动活性；(6)具备良好的安全性；因此，本申请的化合物能够用于治疗代谢性疾病(例如，MS、NAFLD和/或糖尿病)具有重大的临床价值。
附图说明
图1显示了化合物对L02人正常肝细胞的细胞毒性，结果表示为给药组(10μM)细胞与对照组(DMSO组)细胞的相对活力。其中，与对照组相比，*P<0.05,**P<0.01,***P<0.001。
图2显示了化合物对RAW264.7小鼠巨噬细胞样细胞中LPS诱导的NO生成的影响，结果表示为给药组(10μM)细胞与对照组(DMSO组)细胞培养上清中NO含量相比较的倍数。其中，与对照组相比，*P<0.05,**P<0.01,***P<0.001。
图3显示了化合物对NF-κB报告基因表达的影响，结果表示为给药组(50μM)细胞与对照组(DMSO组)细胞中萤光素酶报告基因活性相比较的倍数。其中，与对照组相比，*P<0.05,**P<0.01,***P<0.001。
图4显示了化合物对ARE报告基因活性的影响，结果表示为给药组(50μM)细胞与对照组(DMSO组)细胞中萤光素酶报告基因活性相比较的倍数。其中，与对照组相比，*P<0.05,**P<0.01,***P<0.001。
图5分别显示了化合物对PPARα(A)、PPARγ(B)、PGC1α(C)、ACOX1(D)、FABP1(E)的mRNA水平的影响，结果表示为给药组(1μM)细胞与对照组(DMSO组)细胞中相应基因mRNA相对表达量相比较的倍数。其中，与吉非罗齐组相比，*P<0.05, **P<0.01,***P<0.001。
图6显示了化合物对CPT1α(A)、磷酸化GSK3β(C)、磷酸化IRS-1(D)蛋白水平的影响，结果表示为给药组(1μM)细胞与对照组(DMSO组)细胞中相应蛋白水平经免疫印迹检测定量后相比较的倍数。
图7显示了化合物对DB/DB小鼠的血糖水平的影响。
图8A-8B显示了化合物对DB/DB小鼠肝组织中脂肪含量的影响。图8A：油红O染色；图8B：H.E.染色。
图9显示了化合物对糖尿病+NASH模型小鼠的血糖水平的影响。其中，与模型对照组比较，*P＜0.05，**P＜0.01，***P＜0.001；与BJMU组比较，#P＜0.05，##P＜0.01，###P＜0.001。
图10显示了MRI检测化合物对糖尿病+NASH模型小鼠体脂含量的影响。其中，与模型对照组比较，*P＜0.05，**P＜0.01，***P＜0.001；与BJMU组比较，#P＜0.05，##P＜0.01，###P＜0.001。
图11显示了化合物对糖尿病+NASH模型小鼠附睾白色脂肪重比的影响。其中，与模型对照组比较，*P＜0.05，**P＜0.01，***P＜0.001。
图12A-12B显示了化合物对糖尿病+NASH模型小鼠肝组织中脂肪含量的影响。图12A：油红O染色；图12B：H.E.染色。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。
除非特别指明，否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本领域技术人员知晓，实施例以举例方式描述本发明，且不意欲限制本发明所要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通过引用合并入本文。
化合物的合成和结构表征
仪器与试剂
MS的测定使用Agilent(ESI)质谱仪，生产商：Agilent,型号：Agilent 6120B
制备高分辨质谱质谱采用PE SCLEX QSTAR光谱仪记录。
核磁氢谱和核磁碳谱采用用Bruker AVIII-400光谱仪记录。
薄层色谱法纯化采用的事研讨产的GF254(0.4-0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC),使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，溶剂的体积比根据化合物调节，但可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应温度为室温(20-30℃)。
实例中所使用的试剂购自Acros oRganmes，Aldrich Chemical Company或者特伯化学等公司。
如本文中使用的缩写具有以下含义：
AcCl：乙酰氯；Ac2O：乙酸酐；DCM：二氯甲烷；aq：水溶液；TBAI：四丁基碘化铵；DMF：N,N二甲基甲酰胺；EtOH：乙醇。
合成实施例
实施例1：5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)的制备
Figure PCTCN2019102273-appb-000021
第一步：5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸异丁酯(Int 1)的制备
将化合物1-1(4-氯-2,5-二甲基苯酚)(780mg，5.0mmol)、5-氯-2,2-二甲基戊酸异丁酯(1144mg，5.2mmol)、TBAI(36.9mg，0.1mmol)、碳酸钾(1380mg，10.0mmol)溶于DMF(30mL)中，在90摄氏度搅拌过夜，TLC监测无续转化趋势，将反应液倒入水中，分层，将水相用乙酸乙酯萃取后，合并有机相，加无水硫酸钠干燥，过滤并浓缩滤液，将粗产品经硅胶柱层析分离得化合物1-2(1.5g)，收率88％。
第二步：5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)的制备
将化合物1-2(5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸异丁酯)(1360mg，4.0mmol)，KOH(1120mg，20.0mmol)，TBAI(36.9mg，0.1mmol)溶于EtOH(7mL) 和H 2O(2mL)的混合溶液，120℃加热回流，反应24h，TLC监测反应完全，加水洗后，用稀盐酸酸化至体系为酸性，用乙酸乙酯萃取三次，合并有机相，加无水硫酸钠干燥，过滤并浓缩滤液，萃取液旋干后柱层析分离纯化，得目标产物BJMU-1(1.1g)，收率96％。
1H NMR(400MHz,Chloroform-d)δ7.07(s,1H),6.62(s,1H),3.90(t,J＝5.9Hz,2H),2.31(s,3H),2.15(s,3H),1.88–1.65(m,4H),1.25(s,6H). 13C NMR(101MHz,CDCl 3)δ185.83,155.68,133.80,130.71,126.06,124.99,113.64,68.46,42.06,36.96,25.21,25.14,20.19,15.68.
实施例2：5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)的制备
Figure PCTCN2019102273-appb-000022
在实施例2中第一步用化合物2-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-2，两步收率66％。
1H NMR(400MHz,Chloroform-d)δ7.25(s,1H),6.64(s,1H),3.90(t,J＝5.9Hz,2H),2.33(s,3H),2.15(s,3H),1.91–1.58(m,4H),1.25(s,6H). 13C NMR(101MHz,CDCl3)δ184.38,156.20,135.57,133.65,126.29,114.58,113.47,68.23,41.94,36.78,25.04,24.98,22.87,15.44
实施例3：5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)的制备
Figure PCTCN2019102273-appb-000023
在实施例3中第一步用化合物3-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-3，两步收率78％。
1H NMR(400MHz,CDCl3)δ6.78(d,J＝9.8Hz,1H),δ6.56(d,J＝7.0Hz,1H),δ3.89(t,J＝6.0Hz,2H),δ2.22(s,3H),δ2.17(s,3H),δ1.85–1.69(m,4H),δ1.25(s,6H). 13C NMR(101MHz,CDCl3)δ184.76,155.12(d,J ＝236.3Hz),152.72(d,J＝2.15),125.60(d,J＝7.57),121.61(J＝18.4),116.82(d,J＝23.74),113.78(d,J＝5.43),68.69,41.94,36.81,25.12,24.94,22.83,15.41. 19F NMR(376MHz,CDCl3),δ-129.00(s,1F)
实施例4：5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)的制备
Figure PCTCN2019102273-appb-000024
在实施例4中第一步用化合物4-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-109，两步收率72％。
1H NMR(400MHz,Chloroform-d)δ7.33(s,1H),3.83(t,J＝5.6Hz,2H),2.53(s,3H),2.26(s,3H),1.89–1.75(m,4H),1.27(s,6H). 13C NMR(101MHz,CDCl3)δ184.31,153.96,136.07,133.23,131.42,121.11,119.16,72.66,41.93,36.69,25.76,24.96,23.90,16.29
实施例5：5-(2-氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-209)的制备
Figure PCTCN2019102273-appb-000025
在实施例5中第一步用化合物5-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-209，两步收率58％。
1H NMR(400MHz,Chloroform-d)δ6.98(d,J＝7.7Hz,1H),6.90(d,J＝7.7Hz,1H),3.90(t,J＝5.7Hz,2H),2.36(s,3H),2.29(s,3H),1.90–1.82(m,4H),1.30(s,6H). 13C NMR(101MHz,Chloroform-d)δ184.6,153.5,135.1,130.1,128.4,128.2,125.6,72.6,41.9,36.7,25.9,24.9,20.1,16.3.
实施例6：5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)的制备
Figure PCTCN2019102273-appb-000026
在实施例6中第一步用化合物6-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-213，两步收率76％。
1H NMR(400MHz,Chloroform-d)δ6.90–6.85(m,1H),6.59(s,1H),4.01(t,J＝5.6,2H),2.48(s,3H),2.41(s,3H),1.80–1.67(m,4H),1.21(s,6H). 13C NMR(101MHz,Chloroform-d)δ182.28,162.75,157.90,138.40,115.43,113.02,111.63,69.37,42.41,37.22,25.19,25.13,24.43,16.80.
实施例7：5-(4-溴-2,5-二乙基苯氧基)-2,2-二甲基戊酸(BJMU-310)的制备
Figure PCTCN2019102273-appb-000027
在实施例7中第一步用化合物7-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-310，两步收率56％。
1H NMR(400MHz,Chloroform-d)δ7.28(s,1H),6.68(s,1H),3.95(t,J＝5.8Hz,2H),2.65(dq,J＝47.2,7.5Hz,4H),1.89–1.70(m,4H),1.28(s,6H),1.21(dt,J＝14.9,7.5Hz,6H). 13C NMR(101MHz,CDCl3)δ184.78,156.11,141.24,132.49,132.34,114.15,112.23,68.12,41.99,36.86,29.73,25.08,22.71,14.50.
实施例8：5-(4-溴-2,3,5-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-315)的制备
Figure PCTCN2019102273-appb-000028
在实施例8中第一步用化合物8-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-315，两步收率68％。
1H NMR(400MHz,Chloroform-d)δ6.59(s,1H),3.89(t,J＝5.9Hz,2H),2.38(s,3H),2.37(s,3H),2.18(s,3H),1.87–1.69(m,4H),1.25(s,6H). 13C NMR (101MHz,Chloroform-d)δ184.6,155.5,137.2,135.5,124.2,119.0,111.5,68.5,41.9,36.8,25.1,25.0,24.4,20.4,12.8.
实施例9：5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)的制备
Figure PCTCN2019102273-appb-000029
在实施例9中第一步用化合物9-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-404，两步收率48％。
1H NMR(400MHz,Chloroform-d)δ6.98(d,J＝7.7Hz,1H),6.88(d,J＝7.7Hz,1H),3.86(t,J＝5.7Hz,2H),2.36(s,3H),2.27(s,3H),1.91–1.57(m,4H),1.27(s,6H). 13C NMR(101MHz,CDCl3)δ184.84,154.44,137.09,129.96,129.37,125.79,120.24,72.59,42.01,36.78,25.85,24.99,23.08,16.49.
实施例10：5-(4-溴-2,3,6-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-409)的制备
Figure PCTCN2019102273-appb-000030
在实施例10中第一步用化合物10-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-409，两步收率65％。
1H NMR(400MHz,Chloroform-d)δ7.23(s,1H),3.67(t,J＝4.8Hz,2H),2.33(s,3H),2.22(m,6H),1.79–1.78(m,4H),1.27(s,6H). 13C NMR(101MHz,CDCl3)δ183.86,154.97,134.85,131.58,131.44,129.91,119.61,72.63,41.91,36.84,25.87,24.98,19.75,15.97,13.82.
实施例11：5-(4-溴-2-碘-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-413)的制备
Figure PCTCN2019102273-appb-000031
在实施例11中第一步用化合物11-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-413，两步收率58％。
1H NMR(400MHz,Chloroform-d)δ7.31(s,1H),4.08(t,J＝7.1Hz,2H),2.39(s,3H),2.31(s,3H),1.82-1.71(m,4H),1.21(s,6H). 13C NMR(400MHz,Chloroform-d)δ180.57,153.80,134.22,133.83,128.46,119.83,91.62,70.78,43.22,37.23,25.18,24.30,22.50,16.04.
实施例12：5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)的制备
Figure PCTCN2019102273-appb-000032
在实施例12中第一步用化合物12-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-412，两步收率56％。
1H NMR(400MHz,Chloroform-d)δ12.30(s,1H),7.22(s,1H),6.38(s,1H),3.88–3.94(t,J＝5.8Hz,2H),3.83(s,3H),2.11(s,3H),1.82-1.73(m,4H),1.25(s,6H). 13C NMR(101MHz,CDCl3)δ185.01,157.10,154.53,133.92,120.38,101.08,97.35,68.42,56.41,41.97,36.74,25.03,24.99,15.14.
实施例13：5-(4-溴-3,6-二甲基-2-硝基苯氧基)-2,2-二甲基戊酸(BJMU-414)的制备
Figure PCTCN2019102273-appb-000033
在实施例13中第一步用化合物13-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-414，两步收率68％。
1H NMR(400MHz,Chloroform-d)δ7.44(s,1H),3.87(t,J＝5.8Hz,2H),2.25(s,6H),1.76–1.63(m,4H),1.22(s,6H). 13C NMR(101MHz,CDCl3)δ184.8,147.8,147.4,135.8,132.2,127.9,119.3,75.3,41.9,36.3,25.6,24.9,17.7,15.7.
实施例14：5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)的制备
Figure PCTCN2019102273-appb-000034
在实施例14中第一步用化合物14-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-415，两步收率66％。
1H NMR(400MHz,CDCl3)δ11.04(brs,1H),6.91(s,1H),5.95(brs,1H),3.83(t,J＝5.9Hz,2H),2.28(s,3H),2.22(s,3H),1.83–1.73(m,4H),1.27(s,6H). 13C NMR(101MHz,CDCl3)δ183.4,147.7,143.4,128.9,124.9,122.4,119.9,73.6,41.9,36.6,26.1,25.1,15.7,15.5.
实施例15：5-(4-溴-3-羟基-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-416)的制备
Figure PCTCN2019102273-appb-000035
在实施例15中第一步用化合物15-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-416，两步收率57％。
1H NMR(400Hz,CDCl3),δ:6.34(s,1H),3.90(t,J＝5.6Hz,2H),2.34(s,3H),2.14(s,3H),1.72-1.81(m,4H),1.25(s,6H). 13C NMR(101Hz,CDCl3),δ:184.7,156.7,150.6,134.8,111.2,106.1,104.7,68.5,41.9,36.8,25.0,24.9,23.2,9.1.
实施例16：5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)的制备
Figure PCTCN2019102273-appb-000036
在实施例16中第一步用化合物16-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-502，两步收率72％。
1H NMR(400MHz,CDCl 3)δ7.41(s,1H),6.71(s,1H),4.62(s,2H),3.94–3.97(m,2H),2.36(s,3H),1.71–1.81(m,4H),1.25(s,6H)； 13C NMR(100MHz,CDCl 3)δ155.8,138.0,132.1,128.6,115.1,113.6,68.1,61.0,41.9,36.7,29.7,25.1,23.1.
实施例17：5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)的制备
Figure PCTCN2019102273-appb-000037
在实施例17中第一步用化合物17-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成17-3，收率80％。
第三步：5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酰胺(17-4)的制备
将化合物17-3(1.64g，5.0mmol)溶于THF(10mL)。在冰浴中搅拌20min。向反应液中缓慢滴加二氯亚砜(1.08mL，14.8mmol)，滴加完毕，加入DMF溶液(5d)。升温至50℃反应2h。反应完毕，反应液冷却至0℃，剧烈搅拌，缓慢加入浓氨水(4mL)，大量白色固体析出。抽滤，THF洗涤，干燥得化合物17-4(1.38g)，收率84％。
第四步：5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)的制备
向100mL schlenk反应瓶中加入化合物17-4(1.30g，4.0mmol)，Pd(OAc) 2(89.6mg， 0.4mmol),selectfluor(283.2mg，0.8mmol),氩气置换三次，加入乙腈(20mL),于60℃搅拌3h，TLC监测无续转化趋势。过滤反应液，减压蒸除溶剂，柱层析分离，得目标产物BJMU-309(0.93g)，收率83％。
1H NMR(400MHz,CDCl3)δ7.27(s,1H),6.68(s,1H),4.39–3.74(m,2H),2.36(s,3H),2.17(s,3H),2.08–1.94(m,2H),1.87–1.68(m,2H),1.41(s,6H). 13C NMR(101MHz,CDCl3)δ＝173.21,135.65,133.67,126.20,124.86,114.75,113.47,67.51,37.76,32.22,26.67,25.50,22.89,15.51.
实施例18：5-(4-溴-2,5-二甲基苯氧基)-2-乙基-2-甲基戊酸(BJMU-401)的制备
Figure PCTCN2019102273-appb-000038
在实施例18中第一步用化合物18-1代替实施例1中的第一步化合物1-1，5-氯-2-甲基-2-乙基戊酸异丁酯代替实施例1中的第一步的5-氯-2,2-二甲基戊酸异丁酯外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-401，两步收率62％。
1H NMR(400MHz,Chloroform-d):δ7.25(s,1H),6.64(s,1H),3.90(td,J＝5.8,2.2Hz,2H),2.33(s,3H),2.14(s,3H),1.87–1.77(m,2H),1.76–1.68(m,2H),1.66–1.48(m,2H),1.18(s,3H),0.98–0.80(t,J＝7.5Hz,3H). 13C NMR(101MHz,Chloroform-d):δ156.18,135.55,133.61,126.23,114.52,113.40,68.23,45.82,34.74,31.61,24.67,22.86,20.74,15.43,8.81.
实施例19：5-(2,5-二甲基-4-硝基苯氧基)-2,2-二甲基戊酸(BJMU-110)的制备
Figure PCTCN2019102273-appb-000039
在实施例19中第一步用化合物19-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-110，两步收率47％。
1H NMR(400MHz,Chloroform-d)δ11.99(s,1H),7.92(s,1H),6.62(s,1H),4.02(t,J＝6.0Hz,2H),2.61(s,3H),2.22(s,3H),1.89–1.73(m,4H),1.26 (s,6H). 13C NMR(101MHz,Chloroform-d)δ184.4,160.6,141.1,134.6,127.5,125.5,113.6,68.5,41.9,36.5,25.0,24.8,21.7,15.6.
实施例20：5-(4-溴-2-乙基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-410)的制备
Figure PCTCN2019102273-appb-000040
在实施例20中第一步用化合物20-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-410，两步收率55％。
1H NMR(400MHz,CDCl3)δ12.14(bs,1H),7.29(s,1H),6.70(s,1H),3.94(t,J＝5.9Hz,2H),2.61(q,J＝7.5Hz,2H),2.38(s,3H),1.75-1.89(m,4H),1.29(s,6H),1.21(t,J＝7.5Hz,3H). 13C NMR(101MHz,CDCl3)δ184.9,155.9,135.6,132.3,132.2,114.9,113.6,68.2,42.0,36.8,25.1,25.0,22.9,22.7,14.1.
实施例21：5-(4-溴-2,5-二甲氧基苯氧基)-2,2-二甲基戊酸(BJMU-201)的制备
Figure PCTCN2019102273-appb-000041
在实施例21中第一步用化合物21-1代替实施例1中的第一步化合物1-1外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-201，两步收率85％。
1H NMR(400MHz,CDCl3)δ7.06(s,1H),6.57(s,1H),4.02(t,J＝6.6Hz,2H),3.86(s,3H),3.83(s,3H),1.94–1.81(m,2H),1.74(dd,J＝11.2,5.0Hz,2H),1.26(s,6H). 13C NMR(101MHz,CDCl3)δ184.19,150.32,148.51,144.33,117.20,101.49,100.75,69.81,57.14,56.86,41.94,36.48,24.98,24.95.
实施例22：4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基丁酸(BJMU-111)的制备
Figure PCTCN2019102273-appb-000042
在实施例22中第一步用化合物22-1代替实施例1中的第一步化合物1-1，5-氯-2,2-二甲基丁酸异丁酯代替实施例1中的第一步的5-氯-2,2-二甲基戊酸异丁酯外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-111，两步收率75％。
1H NMR(400MHz,Chloroform-d)δ11.99(s,0.5H),7.21(s,1H),6.65(s,1H),3.99(t,J＝6.4Hz,2H),2.33(s,3H),2.13-2.10(m,5H),1.30(s,6H). 13C NMR(101MHz,Chloroform-d)δ184.5,156.0,135.5,133.6,126.1,114.6,113.0,64.6,40.7,39.0,25.3,22.9,15.4.
实施例23：4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基己酸(BJMU-403)的制备
Figure PCTCN2019102273-appb-000043
在实施例23中第一步用化合物23-1代替实施例1中的第一步化合物1-1，5-氯-2,2-二甲基己酸异丁酯代替实施例1中的第一步的5-氯-2,2-二甲基戊酸异丁酯外。采用实施例1第一步至第二步所描述的类似方法合成化合物BJMU-403，两步收率45％。
1H NMR(400MHz,CDCl 3):δ(ppm):7.27(s,1H),6.68(s,1H),3.94(t,J＝6.4HZ,2H),2.36(s,3H),2.16(s,3H),1.76-1.84(m,2H),1.46-1.67(m,4H),1.24(s,6H). 13C NMR(100MHz,CDCl 3):δ(ppm):184.6,156.3,135.6,133.6,126.3,114.5,113.5,67.8,42.1,40.0,29.7,24.9,22.8,21.5,15.4.
生物活性实验
以下实验例中体外实验所涉及的细胞、试剂、仪器如下所述：
药物：
实施例制备获得的化合物；对照药物：吉非罗齐(Gemfibrozil，购自北京偶合科技有限公司)。
细胞：
RAW264.7小鼠巨噬细胞、人结肠癌细胞SW480、人肝癌细胞HepG2细胞、人肝脏细胞L02均来源于ATCC细胞库。
培养液：
含10％胎牛血清(FBS)的RPMI1640培养基和含10％胎牛血清(FBS)DMEM高糖培养基。
细胞培养：
维持37℃、5％CO 2和饱和湿度环境，培养至80％汇合后，0.25％胰蛋白酶-EDTA消化处理。
涉及的主要试剂、仪器：
RIPA细胞裂解液、BCA蛋白浓度测试试剂盒(碧云天生物技术研究所，江苏)；Phenylmethanesulfonyl fluoride(PMSF)、β-巯基乙醇、丙烯酰胺(Sigma，美国)；ECL TM Prime Western Blotting detection reagent(Bio-Rad，美国)；甘氨酸、十二烷基磺酸钠(Amresco，美国)；RPMI1640培养基、DMEM高糖培养基、胰蛋白酶(Gibco，Maryland，美国)；胎牛血清(GBO，德国)；一氧化氮(NO)检测试剂盒(南京建成，中国)萤光素酶报告基因检测试剂盒(碧云天生物技术研究所，江苏)；Tranzol试剂(Tranzol总RNA提取试剂，北京全式金生物)；5X All-In-One RT MasterMix反转录试剂盒(Abcam，美国)；CPT1α兔源多克隆抗体(12252S，CST，美国)、p-GSK3β(Ser9)兔源多克隆抗体(9323，CST，美国)、pIRS-1(Ser636/639)兔源多克隆抗体(2388，CST，美国)、β-Tubulin鼠源单克隆抗体(BE0025，EASYBIO，中国)。
INC0246细胞培养箱(Memmert，德国)；Gen5 synergy H1 Take3(BioTek，美国)多功能酶标仪；荧光实时定量PCR仪、蛋白电泳系统(Bio-Rad，美国)；低温冷冻高速离心机(Eppendorf，德国)；电泳仪及水平电泳槽(北京君意东方电泳设备有限公司，中国)。
实验例1.化合物的细胞毒性评价
本实验例通过SRB法检测化合物的细胞毒性，具体步骤如下:
(1)收集对数期细胞，调整细胞悬液浓度约3x10 3/100μL培养基，加到96孔板中间区域，边缘孔加入无菌PBS，5％CO 2、37℃常规培养过夜。
(2)无血清培养基配制化合物，终浓度10μM，去掉96孔板培养基，PBS洗一遍，加入配好的待测化合物，继续常规培养24h。
(3)细胞固定：化合物作用时间终点时，每孔加入50μL 4℃预冷的三氯乙酸(TCA)溶液(30％，w/v)固定细胞，TCA溶液的终浓度为10％。静置5min移入4℃冰箱中固 定1h，取出用去离子水冲洗5遍，室温晾干。
(4)染色：待96孔板室温下晾干后，每孔加入0.4％(w/v)的SRB染液(1％的乙酸配制)70μL，染色30min后倒掉染液，用1％(v/v)乙酸冲洗4次，去除未结合的染料，室温晾干。
(5)检测：用100μL非缓冲Tris-base碱液(10mM，pH＝10.5)溶解与细胞蛋白结合的染料，水平摇床上振荡20min，采用酶标仪540nm处测定光吸收值。
(6)细胞相对活力指药物作用的样品孔细胞占阴性对照孔细胞活力的百分率，计算公式为：细胞相对活力＝(Tx-C)/(T0-C)*100％。其中，T0：培养基中加有等体积的DMSO，没有药物作用的阴性对照的平均吸光值(阴性对照)；Tx：药物作用终点时细胞经过固定，染色后测得平均吸光值；C:空白孔经固定，染色后测得平均吸光值。
对L02人正常肝细胞的检测结果如图1所示，结果显示，所检测的化合物中BJMU-1、2、3、110、111、113、114、115、201、203、204、205、209、212、213、214、404、409、415、416、502处理后的正常肝细胞活力抑制率均小于30％(相对细胞活力大于70％)，未表现出显著的细胞毒性。
实验例2.化合物对细胞炎症反应的调控作用的评价
本实验例通过检测一氧化氮(NO)生成及NF-κB炎症信号通路转录活性以评价化合物对细胞炎症反应的调控作用。
2.1 NO生成的检测
NO是一种活性氮物种(RNS)，也是重要的气体信号分子。巨噬细胞可以把精氨酸转化成NO，参与机体炎症反应。因此检测药物对NO生成的抑制活性是评价其抗炎能力的经典方法之一。将对数生长期RAW264.7细胞按1×10 4个/200μL培养基接种于96孔板，贴壁后，弃培养基，给予造模和药物处理，设立正常组(无血清培养基)，LPS模型组(含1μg/mL LPS的无血清培养基)，模型+药物组(含1μg/mL LPS，10μM吉非罗齐或本申请的化合物的无血清培养基)，每组设3个复孔，培养箱培养24h后，收集各孔细胞上清液，按NO测定试剂盒(南京建成)说明书操作，在540nm波长条件下，读取各孔吸光度值，计算NO含量。
结果如图2所示，所检测的化合物1、2、3、109、111、401、403、413、415、502均能够抑制NO生成，相比之下，吉非罗齐(BJMU)不具备抑制NO生成的活性。 以上结果表明，本申请的化合物具有明显的抗炎活性。
2.2 NF-κB萤光素酶报告基因转录活性检测
NF-κB是最重要的炎症信号通路，利用稳定转染了NF-κB驱动的萤光素酶报告基因的SW480人结肠癌细胞，检测本申请的化合物及对照药物吉非罗齐对NF-κB转录活性的影响，步骤包括:
(1)培养稳定转染NF-κB Luc的细胞至对数生长期，按照1x10 5/2000μL培养基浓度接种于24孔板培养24小时，弃去培养基，无血清培养基配制50μM待测化合物与吉非罗齐加入到24孔板中继续培养6小时。用200μL PBS洗一次，加入100μL报告基因细胞裂解液，冰上裂解10min，吹打收集细胞裂解液。
(2)4℃8000rpm离心10min，吸取上清用于萤光检测。
(3)将化学发光测定仪的测定间隙时间定为2s，测定时间设为10s。设置自动进样，每孔加入50μL萤光素酶检测试剂。以报告基因细胞裂解液为空白对照。
(4)取离心后上清，用BCA法测定蛋白浓度校正报告基因结果。
结果如图3所示，所检测的化合物1、2、209、309、315、404、415均能显著抑制NF-κB报告基因活性。与此相比，吉非罗齐不能抑制NF-κB报告基因活性。上述结果进一步表明本申请的化合物具有明显的吉非罗齐所不具备的抗炎活性。
本领域已知长期慢性炎症反应是MS、NAFLD和糖尿病进展的关键事件，而NF-kB信号的持续激活是其典型特征，抑制NF-kB信号是控制上述疾病进展和并发症发生的重要手段(参考文献[1]-[4])，因此上述实验结果能够表明本申请的化合物能够用于MS、NAFLD和糖尿病及其并发症的预防和/或治疗。
实验例3.化合物对细胞氧化应激信号的调控作用的评价
本实验例通过检测稳定转染了抗氧化响应元件(antioxidant response element,ARE)驱动的萤光素酶报告基因的HepG2人肝癌细胞中萤光素酶活性，来评价本申请的化合物及对吉非罗齐对转录因子Nrf2的转录活性和细胞氧化应激信号的调控作用，报告基因检测操作过程同实验例2.2。
结果如图4所示，所检测的化合物1、2、3、401、403、404、409、412、415、416、502均能显著激活ARE报告基因活性，相比之下，吉非罗齐没有明显的激活ARE 的活性。以上结果表明，本申请的化合物可以通过激活抗氧化响应元件诱导细胞抗氧化和代谢解毒基因表达来发挥抗氧化作用，具有显著的抗氧化活性。
由于本领域已知氧化应激是MS、NAFLD和糖尿病发生和进展过程中最重要的致病因子之一，而抗氧化和激活Nrf2介导的细胞抗氧化响应一直是其预防和治疗的重要策略(参考文献[5]-[9])，因此上述实验结果能够表明本申请的化合物能够用于MS、NAFLD和糖尿病及其并发症的预防和/或治疗。
实验例4.化合物对细胞糖脂代谢信号通路和基因表达的调控作用的评价
过氧化物酶体增殖因子激活受体(PPAR)是调控糖脂代谢的重要核受体，包括α、β/δ和γ三种亚型。过氧化物酶体增殖物激活受体γ辅激活子1α(PGC-1α)是其辅助转录激活因子。酰基辅酶A氧化酶1(ACOX1)是脂肪酸β氧化的第一个限速酶。脂肪酸结合蛋白1(FABP1)在肝脏中高表达，可以结合脂肪酸、血红素等分子以减轻它们的毒性和损伤。上调这些基因的表达水平有助于改善机体代谢，它们的激动剂是一类重要的抗代谢病药物。将本申请的化合物(1μM)、对照药物吉非罗齐(1μM)与人肝癌细胞HepG2孵育6小时后，采用实时荧光定量PCR方法检测细胞中相关基因的mRNA相对表达量。
引物序列:
PPARα
上游:CATTACGGAGTCCACGCGT(SEQ ID NO:1)
下游:ACCAGCTTGAGTCGAATCGTT(SEQ ID NO:2)
PPARγ
上游:GTACTGTCGGTTTCAGAAATGCC(SEQ ID NO:3)
下游:ATCTCCGCCAACAGCTTCTCCT(SEQ ID NO:4)
PGC1α
上游:GCTACGAGGAATATCAGCACGA(SEQ ID NO:5)
下游:TCACACGGCGCTCTTCAA(SEQ ID NO:6)
ACOX1
上游:CTGTAGGACCATTGTCTCG(SEQ ID NO:7)
下游:TTACACTCTGCACTCCAAAG(SEQ ID NO:8)
FABP1
上游:CACCCCCTTGATATCCTTCC(SEQ ID NO:9)
下游:TTCTCCGGCAAGTACCAACT(SEQ ID NO:10)
引物合成公司为苏州泓迅生物科技有限公司，使用Tranzol试剂(Tranzol总RNA提取试剂，北京全式金生物)从组织中提取总RNA，5X All-In-One RT MasterMix反转录试剂盒(Abcam，美国)，实时定量PCR Master Mix(北京艾德莱生物科技有限公司)，应用Bio-rad荧光实时定量PCR仪进行qPCR，利用2 -△△CT法进行数据分析。将正常对照组mRNA的表达量设为1，计算给药组mRNA的相对表达量。以证实活性化合物是否影响PPAR通路，从而进一步调控脂代谢。
检测结果如图5所示。PPARαmRNA表达检测结果如图5A所示，所检测的化合物1、2、3、404、409、416显著诱导PPARαmRNA表达1.5倍以上且有显著性差异、且优于吉非罗齐。特别地，本领域已知吉非罗齐需要较高剂量(50-100μM)才能够明显激活PPARα，而所检测的上述化合物的剂量仅为1μM。
PPARγmRNA表达检测结果如图5B所示，所检测的化合物2、3、309、415、502显著诱导PPARγmRNA表达。
PGC1αmRNA表达检测结果如图5C所示，所检测的化合物1、2、3、409、412、415、502显著诱导PGC1αmRNA表达，相比之下，吉非罗齐不能激活PGC1α表达。
ACOX1 mRNA表达检测结果如图5D所示，所检测的化合物1、2、3、109、404、409、502显著诱导PGC1αmRNA表达，相比之下，吉非罗齐不能激活ACOX1表达。
FABP1 mRNA表达检测结果如图5E所示，所检测的化合物1、2、3、112、404、409显著诱导FABP1表达，相比之下，吉非罗齐不能激活FABP1表达。
以上结果表明，本发明化合物可以上调PPARα/γ、PGC1α、ACOX1和FABP1的表达，具有吉非罗齐所不具备的PPARα/γ双重激动活性和糖脂代谢调控活性，从而特别适用于调节糖脂代谢，并且可能具有优于吉非罗齐的降脂活性。
此外，本发明人也检测了化合物对MTTP、UCP1/2、Elovl3、CD36等多个糖脂代谢相关基因的表达水平的影响，结果显示上述化合物能够明显调控这些基因的表达，进一步印证了本发明化合物优越的调节脂代谢活性。
实验例5.化合物对糖脂代谢相关蛋白水平脂肪酸氧化限速酶CPT1α蛋白水平的影响
肉毒碱棕榈酰基转移酶(CPT1α)是脂肪酸氧化的限速酶，在机体或者组织能量缺乏时，CPT1α催化脂肪酸进入线粒体进行β氧化，同时CPT1α也参与调节脂肪酸诱导的胰岛素抵抗和炎症反应。蛋白激酶B/糖原合酶激酶3β(AKT/GSK3β)信号通路与胰岛素受体底物1(IRS-1)是响应胰岛素信号调节糖代谢的关键信号通路。因此，通过检测化合物对CPT1α蛋白水平和AKT、GSK3β、IRS-1蛋白磷酸化水平的影响能够评价其对糖脂代谢的调控作用。
将人肝癌细胞HepG2分别与1μM本申请的化合物或对照药物孵育24小时后，利用Western blot检测该细胞中CPT1α蛋白水平和AKT、GSK3β、IRS-1磷酸化蛋白水平，利用Image J15.0.1进行灰度扫描后，以β-tubulin蛋白水平为内参进行归一化，得到定量分析结果如图6所示，所检测的化合物1、2、213、404、409、415、502均明显升高CPT1α蛋白水平(图6A)，化合物2、109、213、404、409、411均明显升高GSK3β磷酸化水平(图6B)，化合物2、3、109、209、213、309、404、409、411、412、415、416、502均明显升高IRS-1磷酸化水平(图6C)。以上结果表明，上述化合物能够调控胰岛素信号和脂肪酸氧化，从而改善肝脏的糖脂代谢。
此外，本发明人也检测了化合物对Akt、HSL、ACC、PKA底物等多个糖脂代谢相关蛋白磷酸化水平的影响，结果显示上述化合物能够明显调控这些蛋白的磷酸化水平，进一步印证了本发明化合物优越的调节脂代谢活性。
实验例6.化合物对糖尿病模型小鼠的疗效评价
6.1糖尿病模型：
动物模型：C57BL/KsJ-leprdb/leprdb diabetic(DB/DB)小鼠为广泛应用的2型糖尿病动物模型，由瘦素受体(leptin receptor，Lepr)的自发性突变引起极度肥胖、多食、消渴、多尿。本实验例选取DB/DB小鼠(购于北京大学医学部动物部)。
试验选用28只db/db小鼠，筛选血糖7-13mmol/L左右的动物，按血糖随机分为对照组、BJMU组(吉非罗齐)、BJMU-2组以及阳性对照组(吡格列酮)，每组7只。采用灌胃给药，给药容积为10ml/kg，对照组给予1％吐温80-生理盐水；BJMU组给药剂量为50mg/kg，BJMU-2给药剂量为50mg/kg，阳性对照组给予吡格列酮给药剂量为6mg/kg。每天给药1次，连续给药28天。自口服给药当天起，每天观察动物的生理变 化。每3天测血糖(罗氏血糖仪)，计算血糖差值(Δ)＝当日检测值-血糖初始检测值(以血糖初始差值为零)。
各实验组小鼠，取血分离血清，剖检，取肝脏称湿重；取肝组织固定，做病理学检查，采用H.E.染色和油红O染色(武汉梓杉生物技术有限公司)，光镜下观察小鼠肝脏病变；血常规指标检测(北京大学医学部动物部检验科)：白细胞数WBC、红细胞数RBC、淋巴细胞数LY、血小板PLT等多项血液常规指标；血液生化指标的检测(北医三院检验科)：甘油三酯(TG)、总胆固醇(T-CHO)高密度脂蛋白胆固醇HDL-C、低密度脂蛋白胆固醇LDL-C等多项血液生化指标。
血糖检测结果如图7所示，所检测的化合物BJMU-2能够显著降低DB/DB小鼠的血糖水平，甚至明显优于已知的降糖药物吡格列酮，相比之下吉非罗齐未展现明显的降糖活性。这一结果表明，本发明的化合物展现出了显著的降血糖活性。
血脂指标的检测结果如下表所示，所检测的化合物BJMU-2具备优于吉非罗齐的降低甘油三脂的活性；特别地，BJMU-2能够降低DB/DB小鼠血液中总胆固醇含量，相比之下，吉非罗齐并未展现出降低血液中总胆固醇的活性。以上结果表明，BJMU-2具有更为突出的降低血脂效果。
表1：血脂指标的检测结果
Figure PCTCN2019102273-appb-000044
注：与模型对照组比较，*P＜0.05**P＜0.01。CHOL：总胆固醇；TGL：甘油三酯；AHDL：高密度脂蛋白，ALDL：低密度脂蛋白。
肝组织的病理学检查结果如图8A-8B所示，结果显示，所检测的化合物BJMU-2能够显著降低模型小鼠肝脏中的脂肪含量，相比之下，吉非罗齐及吡格列酮均未展现上述活性。以上结果表明，BJMU-2在具备显著的降低血脂活性的同时，还具备显著的降低肝脏脂肪活性。
此外，小鼠肝功、肾功指标检测数据表明(表2)，所检测的化合物在50mg/kg剂量下连续灌胃给药一个月不会产生肝肾毒性。这一结果表明，本发明的化合物具备良好的体内安全性。
表2：小鼠肝功、肾功数值
Figure PCTCN2019102273-appb-000045
6.2糖尿病+非酒精性脂肪性肝炎(NASH)模型：
动物模型：每只DB/DB小鼠以0.72mg/100g剂量皮下注射40％CCl 4溶液(北京市通广精细化工公司)，连续4周，以获得糖尿病+NASH模型。
试验选用35只上述模型小鼠，筛选血糖7-13mmol/L左右的动物，按血糖随机分为空白对照组、模型组、BJMU组(吉非罗齐)、BJMU-1组、BJMU-2组、BJMU-3组，每组7只(模型组与各给药组均按动物模型方法所述进行造模)。采用灌胃给药，给药容积为10ml/kg，空白对照组、模型组给予1％吐温80-生理盐水；BJMU组给药剂量为50mg/kg，BJMU-1给药剂量为50mg/kg，BJMU-2给药剂量为50mg/kg，BJMU-3给药剂量为50mg/kg。每天给药1次，连续给药28天。自口服给药当天起，每天观察动物的生理变化。每周测血糖，计算血糖差值(Δ)＝当日检测值-血糖初始检测值(以血糖初始差值为零)。给药完成后处死动物，取出五脏以及附睾脂肪，用于实验。每组小鼠取白色附睾脂肪，称重。根据对应体重，求得白色脂肪重比。处死小鼠前，随机选取每组3只小鼠进行磁共振成像(MRI)(EchoMRI-700体脂测试仪)以检测体内 脂肪含量。
各实验组小鼠，取血分离血清，剖检，取肝脏称湿重；取肝组织固定，做病理学检查，采用H.E.染色和油红O染色(武汉梓杉生物技术有限公司)，光镜下观察小鼠肝脏病变；血常规指标检测(北京大学医学部动物部检验科)：白细胞数WBC、红细胞数RBC、淋巴细胞数LY、血小板PLT等多项血液常规指标；血液生化指标的检测(北医三院检验科)：甘油三酯(TG)、总胆固醇(T-CHO)高密度脂蛋白胆固醇HDL-C、低密度脂蛋白胆固醇LDL-C等多项血液生化指标。
血糖检测结果如图9所示，所检测的化合物BJMU-1、BJMU-2、BJMU-3能够显著降低糖尿病+NASH模型小鼠的血糖水平，并且在给药14天后血糖水平几乎恢复到正常水平，相比之下，吉非罗齐未展现明显的降糖活性。这一结果表明，本发明的化合物展现出了显著的降血糖活性。
体脂测试结果如图10所示，所检测的化合物BJMU-1、BJMU-2、BJMU-3能够显著降低小鼠体脂含量；相比之下，吉非罗齐并未展现出降低体脂的活性。上述结果表明，本发明的化合物具备显著的降低体脂活性。
白色脂肪重比检测结果如图11所示，所检测的化合物BJMU-2、BJMU-3能够显著降低小鼠附睾脂肪重比，且优于吉非罗齐。上述结果进一步表明，本发明的化合物具备显著的降低体脂活性。
血脂指标的检测结果如下表所示，所检测的化合物BJMU-1、BJMU-2、BJMU-3具备优于吉非罗齐的降低甘油三脂的活性；特别地，BJMU-2能够降低DB/DB小鼠血液中总胆固醇含量，相比之下，吉非罗齐并未展现出降低血液中总胆固醇的活性。以上结果表明，本发明的化合物具有更为突出的降低血脂效果。
表3：血脂指标的检测结果
Figure PCTCN2019102273-appb-000046
Figure PCTCN2019102273-appb-000047
注：与模型对照组比较，*P＜0.05**P＜0.01。CHOL：总胆固醇；TGL：甘油三酯；AHDL：高密度脂蛋白，ALDL：低密度脂蛋白。
肝组织的病理学检查结果如图12A-12B所示，结果显示，所检测的化合物BJMU-1、BJMU-2、BJMU-3能够显著降低模型小鼠肝脏中的脂肪含量，相比之下，吉非罗齐未展现上述活性。以上结果表明，本发明的化合物在具备显著的降低血脂活性的同时，还具备显著的降低体脂活性。
此外，小鼠肝功、肾功指标检测数据表明(表4)，所检测的化合物在50mg/kg剂量下连续灌胃给药一个月不会产生肝肾毒性。这一结果表明，本发明的化合物具备良好的体内安全性。
表4：小鼠肝功、肾功数值
Figure PCTCN2019102273-appb-000048
以上结果表明，所检测的化合物BJMU-1、BJMU-2、BJMU-3能够降低血糖及血脂水 平，并且能够降低体脂及肝脏中的脂肪含量。特别地，BJMU-2经肝脏代谢后产生代谢产物BJMU-415和502，由于这两个化合物在细胞水平实验中展现出了不低于甚至优于BJMU-2的活性，因此可以合理预期BJMU-415、502将至少具备BJMU-2的上述优良的体内活性。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解：根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
参考文献：
[1]Reddy P,Lent-Schochet D,Ramakrishnan N,McLaughlin M,Jialal I.Metabolic syndrome is an inflammatory disorder:A conspiracy between adipose tissue and phagocytes.Clin Chim Acta 2019；496:35-44.
[2]Chen Z,Yu R,Xiong Y,Du F,Zhu S.A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease.Lipids Health Dis 2017；16:203.
[3]Catrysse L,van Loo G.Inflammation and the Metabolic Syndrome:The Tissue-Specific Functions of NF-kappaB.Trends Cell Biol 2017；27:417-429.
[4]Esser N,Paquot N,Scheen AJ.Anti-inflammatory agents to treat or prevent type 2 diabetes,metabolic syndrome and cardiovascular disease.Expert Opin Investig Drugs 2015；24:283-307.
[5]Chartoumpekis DV,Kensler TW.New player on an old field；the keap1/Nrf2pathway as a target for treatment of type 2 diabetes and metabolic syndrome.Curr Diabetes Rev 2013；9:137-145.
[6]Chowdhry S,Nazmy MH,Meakin PJ,Dinkova-Kostova AT,Walsh SV,Tsujita T,Dillon JF,et al.Loss of Nrf2 markedly exacerbates nonalcohol ic steatohepatitis.Free Radic Biol Med 2010；48:357-371.
Santos JC,Valentim IB,de Araujo OR,Ataide Tda R,Goulart MO.Development of nonalcoholic hepatopathy:contributions of oxidative stress and advanced glycation end products.Int J Mol Sci 2013；14:19846-19866.
[7]Shimozono R,Asaoka Y,Yoshizawa Y,Aoki T,Noda H,Yamada M,Kaino M,et al.Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat model.Mol Pharmacol 2013；84:62-70.
[8]Spahis S,Delvin E,Borys JM,Levy E.Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis.Antioxid Redox Signal 2017；26:519-541.

Claims (23)

  1. 式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；
    Figure PCTCN2019102273-appb-100001
    其中：
    R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
    R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
    其中，R 3和R 4中的至少一个为卤素；
    R 5和R 6各自独立地选自C 1-C 4烷基；
    R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
    n为1、2、3或4；
    条件是所述化合物不是5-(2,4-二氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸；5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸；5-(2-氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸；或5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸。
  2. 权利要求1所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任 选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、羟基；
    优选地，R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；
    优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基。
  3. 权利要求1或2所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、羟基、C 1-C 4烷基；其中，所述羟基或C 1-C 4烷基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代；
    优选地，R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基、乙基；其中，所述羟基、甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代；
    优选地，R 3、R 4独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基。
  4. 权利要求1-3任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    R 5和R 6彼此相同；
    优选地，R 5和R 6为甲基。
  5. 权利要求1-4任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    R 7选自羧基、-CO 2Me、-CO 2Et、氰基。
  6. 权利要求1-5任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异 构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    n为1、2或3。
  7. 权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中：
    R 1、R 2各自独立地选自甲基、乙基、甲氧基、乙氧基，所述甲基、乙基、甲氧基、乙氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：-F、-Cl、-Br、-I、羟基；优选地，R 1、R 2各自独立地选自甲基、羟基取代的甲基、乙基、甲氧基；
    R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基、乙基；其中，所述羟基、甲基或乙基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自卤素(例如-F、-Cl、-Br或-I)和羟基的取代基取代；优选地，R 3、R 4各自独立地选自氢、-F、-Cl、-Br、-I、硝基、羟基、甲基；
    R 5和R 6为甲基；
    R 7选自羧基、-CO 2Me、-CO 2Et、氰基；
    n为1、2或3。
  8. 权利要求1-7任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中，所述化合物具有式(Ia)所示的结构：
    Figure PCTCN2019102273-appb-100002
    其中，R 3为卤素(例如-F、-Cl、-Br或-I)。
  9. 权利要求1-8任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，其中，所述化合物选自：
    5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
    5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)；
    5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)；
    5-(4-溴-2,5-二乙基苯氧基)-2,2-二甲基戊酸(BJMU-310)；
    5-(4-溴-2,3,5-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-315)；
    5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)；
    5-(4-溴-2,3,6-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-409)；
    5-(4-溴-2-碘-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-413)；
    5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
    5-(4-溴-3,6-二甲基-2-硝基苯氧基)-2,2-二甲基戊酸(BJMU-414)；
    5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
    5-(4-溴-3-羟基-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-416)；
    5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
    5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)；
    5-(4-溴-2,5-二甲基苯氧基)-2-乙基-2-甲基戊酸(BJMU-401)；
    5-(2,5-二甲基-4-硝基苯氧基)-2,2-二甲基戊酸(BJMU-110)；
    5-(4-溴-2-乙基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-410)；
    5-(4-溴-2,5-二甲氧基苯氧基)-2,2-二甲基戊酸(BJMU-201)；
    4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基丁酸(BJMU-111)；
    6-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基己酸(BJMU-403)。
  10. 药物组合物，其包含式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，以及一种或多种药学上可接受的载体和/或赋形剂；
    Figure PCTCN2019102273-appb-100003
    其中：
    R 1、R 2各自独立地选自C 1-C 4烷基或C 1-C 4烷氧基，所述C 1-C 4烷基或C 1-C 4烷氧基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基；
    R 3、R 4各自独立地选自氢、卤素(例如-F、-Cl、-Br或-I)、硝基、氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基；其中，所述氨基、羟基、巯基、C 1-C 4烷基、C 1-C 4烷氧基、C 1-C 4烷硫基或C 1-C 4烷基氨基任选地被一个或几个(例如，1个、2个、3个或4个)独立地选自下列的取代基取代：卤素(例如-F、-Cl、-Br或-I)、氨基、羟基；
    其中，R 3和R 4中的至少一个为卤素；
    R 5和R 6各自独立地选自C 1-C 4烷基；
    R 7选自-C(O)X、氰基；其中，X为羟基或C 1-C 4烷氧基；
    n为1、2、3或4；
    优选地，R 1、R 2如权利要求2中所定义；
    优选地，R 3、R 4如权利要求3中所定义；
    优选地，R 5、R 6如权利要求4中所定义；
    优选地，R 7如权利要求5中所定义；
    优选地，n如权利要求6中所定义；
    优选地，R 1、R 2、R 3、R 4、R 5、R 6、R 7和n如权利要求7中所定义。
  11. 权利要求10所述的药物组合物，其中，所述化合物具有式(Ia)所示的结构，
    Figure PCTCN2019102273-appb-100004
    其中，R 3为卤素(例如-F、-Cl、-Br或-I)。
  12. 权利要求10或11所述的药物组合物，其中，所述化合物选自：
    5-(4-氯-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-1)；
    5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-2)；
    5-(4-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-3)；
    5-(2,4-二溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-109)；
    5-(2-氯-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-209)；
    5-(3-氟-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-213)；
    5-(4-溴-2,5-二乙基苯氧基)-2,2-二甲基戊酸(BJMU-310)；
    5-(4-溴-2,3,5-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-315)；
    5-(2-溴-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-404)；
    5-(4-溴-2,3,6-三甲基苯氧基)-2,2-二甲基戊酸(BJMU-409)；
    5-(4-溴-2-碘-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-413)；
    5-(4-溴-2-甲氧基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-412)；
    5-(4-溴-3,6-二甲基-2-硝基苯氧基)-2,2-二甲基戊酸(BJMU-414)；
    5-(4-溴-2-羟基-3,6-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-415)；
    5-(4-溴-3-羟基-2,5-二甲基苯氧基)-2,2-二甲基戊酸(BJMU-416)；
    5-(4-溴-2-(羟甲基)-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-502)；
    5-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基戊腈(BJMU-309)；
    5-(4-溴-2,5-二甲基苯氧基)-2-乙基-2-甲基戊酸(BJMU-401)；
    5-(2,5-二甲基-4-硝基苯氧基)-2,2-二甲基戊酸(BJMU-110)；
    5-(4-溴-2-乙基-5-甲基苯氧基)-2,2-二甲基戊酸(BJMU-410)；
    5-(4-溴-2,5-二甲氧基苯氧基)-2,2-二甲基戊酸(BJMU-201)；
    4-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基丁酸(BJMU-111)；
    6-(4-溴-2,5-二甲基苯氧基)-2,2-二甲基己酸(BJMU-403)。
  13. 权利要求10-12任一项所述的药物组合物，其任选地包含另外的药学活性剂；
    优选地，所述另外的药学活性剂选自抗糖尿病药物、抗肥胖症药物、抗高血压药物、抗动脉粥样硬化药物、降脂药物、抗炎药物、抗氧化损伤药物。
  14. 化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，在制备药物中的用途，所述药物用于在受试者中预防或治疗代谢性疾病；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述代谢性疾病选自肥胖、非酒精性脂肪肝病(NAFLD)(例如，单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、高血糖、高脂血症(例如，高胆固醇血症)，及这些疾病的继发性并发症(例如，糖尿病并发症，如视网膜病、神经病、肾病以及延缓的创伤愈合，或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)。
  15. 化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，用于制备PPARα/γ双重激动剂的用途，或者用于制备药物的用途，所述药物用于在受试者中预防和/或治疗与PPARα和/或PPARγ相关的疾病；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述与PPARα和/或PPARγ相关的疾病选自2型糖尿病、糖耐量受损、胰岛素抵抗综合症、高血压、高脂血症(例如高胆固醇症)、代谢综合症、内脏肥胖和肥胖症。
  16. 化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，在制备药物中的用途，所述药物用于在受试者中降低体重、降低体脂肪、降低肝脂肪分数、预防或治疗肥胖症、 和/或预防或治疗非酒精性脂肪性肝病(NAFLD)；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述非酒精性脂肪性肝病包括单纯性脂肪肝或非酒精性脂肪性肝炎；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如超重、过量的体脂肪、和/或升高的肝脂肪分数)。
  17. 化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，在制备药物中的用途，所述药物用于在受试者中降低血糖水平、增加胰岛素敏感性、预防或治疗胰岛素抵抗、和/或预防或治疗糖尿病(例如2型糖尿病)；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的血糖水平、胰岛素抵抗、高胰岛素血症、和/或降低的葡萄糖耐量)。
  18. 化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物，在制备药物中的用途，所述药物用于在受试者中降低总胆固醇水平、降低甘油三酯水平、降低低密度脂蛋白水平和/或增加高密度脂蛋白水平；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的总胆固醇水平、升高的甘油三酯水平、升高的低密度脂蛋白水平和/或降低的高密度脂蛋白水平)。
  19. 一种用于在受试者中预防或治疗代谢性疾病的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述代谢性疾病选自肥胖、非酒精性脂肪肝病(例如，单纯性脂肪肝或非酒精性脂肪性肝炎)、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛 素血症、葡萄糖不耐受、高血糖、高脂血症(例如，高胆固醇血症)，及这些疾病的继发性并发症(例如，糖尿病并发症，如视网膜病、神经病、肾病以及延缓的创伤愈合，或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)。
  20. 一种用于在受试者中预防或治疗与PPARα和/或PPARγ相关的疾病的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述与PPARα和/或PPARγ相关的疾病选自2型糖尿病、糖耐量受损、胰岛素抵抗综合症、高血压、高脂血症(例如高胆固醇症)、代谢综合症、内脏肥胖和肥胖症。
  21. 一种用于在受试者中降低体重、降低体脂肪、降低肝脂肪分数、预防或治疗肥胖症、和/或预防或治疗非酒精性脂肪性肝病(NAFLD)的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述非酒精性脂肪性肝病包括单纯性脂肪肝或非酒精性脂肪性肝炎；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如超重、过量的体脂肪、和/或升高的肝脂肪分数)。
  22. 一种用于在受试者中降低血糖水平、增加胰岛素敏感性、预防或治疗胰岛素抵抗、和/或预防或治疗糖尿病(例如2型糖尿病)的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的血糖水平、胰岛素抵抗、高胰岛素血症、和/或降低的葡萄糖耐量)。
  23. 一种用于在受试者中降低总胆固醇水平、降低甘油三酯水平、降低低密度脂蛋白水平和/或增加高密度脂蛋白水平的方法，所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或它们的任意组合或混合物；其中，所述化合物为权利要求10-12任一项中所定义的化合物；
    优选地，所述受试者患有代谢性疾病，和/或所述受试者患有与代谢性疾病相关的病状(例如升高的总胆固醇水平、升高的甘油三酯水平、升高的低密度脂蛋白水平和/或降低的高密度脂蛋白水平)。
PCT/CN2019/102273 2018-08-23 2019-08-23 苯氧酸类化合物及其医药用途 Ceased WO2020038464A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2019324405A AU2019324405B2 (en) 2018-08-23 2019-08-23 Phenoxy carboxylic acid compounds and medical uses thereof
US17/182,413 US12365643B2 (en) 2018-08-23 2019-08-23 Phenoxy carboxylic acid compounds and medical uses thereof
JP2021534420A JP7472139B2 (ja) 2018-08-23 2019-08-23 フェノキシカルボン酸化合物およびその医薬用途
EP19851778.1A EP3842410A4 (en) 2018-08-23 2019-08-23 FIBRIC ACID COMPOUND AND ITS MEDICAL USE
US19/212,924 US20250313522A1 (en) 2018-08-23 2025-05-20 Phenoxy carboxylic acid compounds and medical uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810965558.1 2018-08-23
CN201810965558 2018-08-23

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US17/182,413 A-371-Of-International US12365643B2 (en) 2018-08-23 2019-08-23 Phenoxy carboxylic acid compounds and medical uses thereof
US19/212,924 Division US20250313522A1 (en) 2018-08-23 2025-05-20 Phenoxy carboxylic acid compounds and medical uses thereof

Publications (1)

Publication Number Publication Date
WO2020038464A1 true WO2020038464A1 (zh) 2020-02-27

Family

ID=69591994

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/102273 Ceased WO2020038464A1 (zh) 2018-08-23 2019-08-23 苯氧酸类化合物及其医药用途

Country Status (6)

Country Link
US (2) US12365643B2 (zh)
EP (1) EP3842410A4 (zh)
JP (1) JP7472139B2 (zh)
CN (1) CN110857268B (zh)
AU (1) AU2019324405B2 (zh)
WO (1) WO2020038464A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113072448B (zh) * 2021-03-31 2022-11-11 五邑大学 一种芳基吉非罗齐衍生物高价碘化合物及其制备方法

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674836A (en) * 1968-05-21 1972-07-04 Parke Davis & Co 2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereof
US3707566A (en) * 1970-03-30 1972-12-26 Parke Davis & Co Aryloxypentane compounds
US3759986A (en) * 1970-03-30 1973-09-18 Parke Davis & Co Esters of 2,2-dimethyl-5-(aryloxy)-1-pentanols
US3847994A (en) * 1970-03-30 1974-11-12 Parke Davis & Co 2,2-dimethyl-5-(aryloxy)-valeraldehydes
WO1996038144A1 (en) 1995-05-31 1996-12-05 Warner-Lambert Company Isothiazolones
WO1997012613A1 (en) 1995-10-05 1997-04-10 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
US5712396A (en) 1992-10-28 1998-01-27 Magnin; David R. α-phosphonosulfonate squalene synthetase inhibitors
WO1999000353A1 (en) 1997-06-27 1999-01-07 Karo Bio Ab Novel thyroid receptor ligands and method

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0462067A1 (en) * 1990-06-15 1991-12-18 Warner-Lambert Company Gemfibrozil formulations

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3674836A (en) * 1968-05-21 1972-07-04 Parke Davis & Co 2,2-dimethyl-{11 -aryloxy-alkanoic acids and salts and esters thereof
US3707566A (en) * 1970-03-30 1972-12-26 Parke Davis & Co Aryloxypentane compounds
US3759986A (en) * 1970-03-30 1973-09-18 Parke Davis & Co Esters of 2,2-dimethyl-5-(aryloxy)-1-pentanols
US3847994A (en) * 1970-03-30 1974-11-12 Parke Davis & Co 2,2-dimethyl-5-(aryloxy)-valeraldehydes
US5712396A (en) 1992-10-28 1998-01-27 Magnin; David R. α-phosphonosulfonate squalene synthetase inhibitors
WO1996038144A1 (en) 1995-05-31 1996-12-05 Warner-Lambert Company Isothiazolones
WO1997012613A1 (en) 1995-10-05 1997-04-10 Warner-Lambert Company Method for treating and preventing inflammation and atherosclerosis
WO1997012615A1 (en) 1995-10-05 1997-04-10 Warner-Lambert Company Benzimidazole derivatives as 15-lo inhibitors
WO1999000353A1 (en) 1997-06-27 1999-01-07 Karo Bio Ab Novel thyroid receptor ligands and method

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
CATRYSSE LVAN LOO G: "Inflammation and the Metabolic Syndrome: The Tissue-Specific Functions of NF-kappaB", TRENDS CELL BIOL, vol. 27, 2017, pages 417 - 429, XP085028230, DOI: 10.1016/j.tcb.2017.01.006
CHARTOUMPEKIS DVKENSLER TW: "New player on an old field; the keapl/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome", CURR DIABETES REV, vol. 9, 2013, pages 137 - 145
CHEN ZYU RXIONG YDU FZHU S: "A vicious circle between insulin resistance and inflammation in nonalcoholic fatty liver disease", LIPIDS HEALTH DIS, vol. 16, 2017, pages 203
CHOWDHRY SNAZMY MHMEAKIN PJDINKOVA-KOSTOVA ATWALSH SVTSUJITA TDILLON JF ET AL.: "Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis", FREE RADIC BIOL MED, vol. 48, 2010, pages 357 - 371, XP026820730
CREGER, P.: "Structure/Activity Relationship of Gemfibrozil (CI-719) and Related Compounds", PROC. ROY. SOC. MED., vol. 12, 1976, pages 31, XP055687343 *
DATABASE CAS 14 November 2017 (2017-11-14), retrieved from STN Database accession no. 2142154-52-5 *
DATABASE CAS Database accession no. 1467186-48-6 *
DATABASE CAS Database accession no. 1493932-49-2 *
DATABASE CAS Database accession no. 1971711-36-0 *
DATABASE CAS Database accession no. 2009713-28-2 *
DATABASE CAS Database accession no. 2139740-94-4 *
ESSER NPAQUOT NSCHEEN AJ: "Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease", EXPERT OPIN INVESTIG DRUGS, vol. 24, 2015, pages 283 - 307
HOOVER, JOHN E.: "Remington's Pharmaceutical Sciences", 1995, MACK PUBLISHING COMPANY
KIBBE ET AL.: "Handbook of Pharmaceutical Excipients", 1999, AMERICAN PHARMACEUTICAL ASSOCIATION
LIBERMAN ET AL.: "Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
REDDY PLENT-SCHOCHET DRAMAKRISHNAN NMCLAUGHLIN MJIALAL I: "Metabolic syndrome is an inflammatory disorder: A conspiracy between adipose tissue and phagocytes", CLIN CHIM ACTA, vol. 496, 2019, pages 35 - 44
SANTOS JCVALENTIM IBDE ARAUJO ORATAIDE TDA RGOULART MO: "Development of nonalcoholic hepatopathy: contributions of oxidative stress and advanced glycation end products", INT J MOL SCI, vol. 14, 2013, pages 19846 - 19866
See also references of EP3842410A4
SHIMOZONO RASAOKA YYOSHIZAWA YAOKI TNODA HYAMADA MKAINO M ET AL.: "Nrf2 activators attenuate the progression of nonalcoholic steatohepatitis-related fibrosis in a dietary rat mode", MOL PHARMACOL, vol. 84, 2013, pages 62 - 70, XP055516110, DOI: 10.1124/mol.112.084269
SPAHIS SDELVIN EBORYS JMLEVY E: "Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis", ANTIOXID REDOX SIGNAL, vol. 26, 2017, pages 519 - 541
T HIGUCHIW STELLA: "Pro-drugs as Novel Delivery Systems", ACS SYMPOSIUM SERIES, vol. 14

Also Published As

Publication number Publication date
US12365643B2 (en) 2025-07-22
AU2019324405A1 (en) 2021-04-22
JP2021535210A (ja) 2021-12-16
US20220119333A1 (en) 2022-04-21
US20250313522A1 (en) 2025-10-09
CN110857268B (zh) 2022-10-04
EP3842410A4 (en) 2022-07-06
AU2019324405B2 (en) 2022-09-22
CN110857268A (zh) 2020-03-03
JP7472139B2 (ja) 2024-04-22
EP3842410A1 (en) 2021-06-30

Similar Documents

Publication Publication Date Title
CN110105200B (zh) 用于治疗纤维化的经取代的芳族化合物及相关方法
JP5990160B2 (ja) 抗酸化炎症モジュレーターを使用して肥満を処置する方法
JP6023250B2 (ja) ジグリシドエーテル誘導体治療剤およびその使用方法
JP2017125036A (ja) アンドロゲン受容体調節薬のエステル誘導体およびそれらの使用のための方法
CN107417666A (zh) 溴代苄醚衍生物、及其制法和药物组合物与用途
RU2416606C2 (ru) Соединения и способы для ингибирования взаимодействия bcl белков с компонентами по связыванию
JP2007509842A (ja) 心血管障害の処置のためにＡｐｏＡ１の発現を誘導するための、一酸化窒素部分を含む化合物
JP2007509035A (ja) Ｅｇｒ−１エンハンサー要素に関連する疾患の処置
CA3128416A1 (en) Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof
WO2012159107A1 (en) Inhibition of renal fibrosis
CN103917093B (zh) 视蛋白结合配体、组合物及使用方法
US20250313522A1 (en) Phenoxy carboxylic acid compounds and medical uses thereof
JP7838842B2 (ja) 病的状態の治療における使用のための芳香族分子
CN107522657B (zh) 一种具有ppar多重激动活性的化合物及其制备方法和应用
JP2021522244A (ja) チューブリン重合阻害活性及び免疫調節特性を有する化合物
JP2020536119A (ja) 代謝性疾患治療用化合物及びその製造方法、並びに応用
CN105198786A (zh) 芳基取代的酰胺类化合物及其制备方法、包含其的药物组合物及其应用
JP2015518484A (ja) ゲラニルゲラニルアセトン類似化合物及びその使用
JP7254703B2 (ja) Ｒｏｒガンマモジュレーター及びその使用
CN114349745B (zh) 一种用于治疗心肌缺血的药物及其制备方法
CN104892457B (zh) 一种异羟肟酸类衍生物、其药物组合物、制备方法及用途
JP7378156B2 (ja) Ｋｅａｐ１／ｎｒｆ２タンパク質間相互作用の１，４－置換イソキノリン阻害剤
CN101054372B (zh) 嘧啶取代苯丙酸衍生化合物、其制法和在治疗多囊肾疾病中的用途
CN110251498A (zh) 一类调节法尼醇受体活性的化合物及其用途
WO2006043510A1 (ja) エステル誘導体及びその医薬用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19851778

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021534420

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019851778

Country of ref document: EP

Effective date: 20210323

ENP Entry into the national phase

Ref document number: 2019324405

Country of ref document: AU

Date of ref document: 20190823

Kind code of ref document: A