WO2021004487A1 - Thiazolidinedione derivative and pharmaceutical composition comprising same - Google Patents

Thiazolidinedione derivative and pharmaceutical composition comprising same Download PDF

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WO2021004487A1
WO2021004487A1 PCT/CN2020/100888 CN2020100888W WO2021004487A1 WO 2021004487 A1 WO2021004487 A1 WO 2021004487A1 CN 2020100888 W CN2020100888 W CN 2020100888W WO 2021004487 A1 WO2021004487 A1 WO 2021004487A1
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alkyl
deuterated
alkoxy
hydrogen
halogenated
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PCT/CN2020/100888
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Chinese (zh)
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吕彬华
盛泽林
庞旭东
崔大为
刘瑞峰
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苏州泽璟生物制药股份有限公司
上海泽璟医药技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P3/08—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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • the present invention relates to the field of medicine, in particular to a thiazolidinedione derivative and a pharmaceutical composition containing the same.
  • Non-alcoholic fatty liver disease affects approximately 10%-30% of ordinary adults and 60-80% of patients with type II diabetes. In the United States, the incidence of NAFLD accounts for about 10-46% of the total population, and about 10-30% of patients will develop nonalcoholic steatohepatitis (NASH, nonalcoholic steatohepatitis).
  • NASH nonalcoholic steatohepatitis
  • Non-alcoholic steatohepatitis is manifested by the appearance of inflammation and fatty degeneration of liver cell damage, which can lead to major diseases such as advanced liver fibrosis, cirrhosis, liver failure and liver tumors. By 2025, its drug use is expected to exceed US$35-40 billion.
  • PPAR Peroxisome proliferator-activated receptor
  • PPAR ⁇ is the main regulator of liver ⁇ oxidation and microsomal omega oxidation, and the lack of PPAR ⁇ can lead to excessive accumulation of lipids in the liver. Therefore, activation of PPAR ⁇ can enhance the expression of fatty acid oxidation genes, thereby reducing the probability of liver fatty disease, but its therapeutic effect on type II diabetes is relatively weak.
  • PPAR ⁇ can control weight gain, enhance physical endurance, improve insulin sensitivity, and improve atherosclerosis.
  • PPAR ⁇ is mainly expressed in adipose tissue and immune system, and is closely related to adipocyte differentiation, body immunity and insulin resistance. It can improve insulin sensitivity, reduce inflammation, reduce the lipid concentration of free fatty acids and lower blood pressure, but it has an effect on lipid metabolism. The regulation of disorder is weak (Cave MC, Clair HB, etc., Biochimica et Biophysica Acta 2016, 1859(9), 1083-1099).
  • PPAR ⁇ selective agonists such as thiazolidinedione derivatives (such as Pioglitazone, Rosiglitazone and Lobeglitazone) have been approved for the treatment of type II diabetes.
  • these drugs are also off-label for the treatment of non-alcoholic fatty liver disease.
  • the existing thiazolidinedione drugs are likely to cause side effects such as weight gain, edema, and fractures, which limits their therapeutic applications.
  • the purpose of the present invention is to provide a new class of compounds that have multiple agonistic effects on peroxisome proliferator-activated receptors (PPAR), have better pharmacodynamic properties and better safety properties.
  • PPAR peroxisome proliferator-activated receptors
  • the first aspect of the present invention provides a thiazolidinedione compound having a structure of formula (I), or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, hydrates or Solvate, or its prodrug molecule:
  • R 1 is hydrogen, deuterium or -CH 2 R 24 ;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different, and are independently selected from substituted or unsubstituted Substitution of the following groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substituted C1-C6 alkoxy, halogen, amino, nitro, hydroxy, ester, cyano, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 17 , -(CH 2 ) n O(CH 2 ) m R 17 , -(CH 2 ) n SR 17 , -(CH
  • a 1 is selected from C, CH or CD
  • a 2 , A 3 and A 4 are each independently selected from CR 15 or CR 15 R 16 ;
  • R 15 and R 16 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, -(CH 2 ) n C(O)OR 17 , cyano, C3 -C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the following group: hydrogen, deuterium, C1-C18 alkyl , Deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
  • R 17 and R 18 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl ; Wherein the substitution independently refers to the substitution of one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1- C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycl
  • R 19 and R 20 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, Heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halo C1-C18 alkyl , C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, ester, C3-C
  • X 1 and X 2 are each independently oxygen or sulfur
  • X 3 is nitrogen
  • R 25 , R 26 , R 27 , R 28 and R 29 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl , Heterocyclyl, C6-C14 aryl, heteroaryl, or R 25 and R 26 combine with adjacent X 1 , X 2 and P to form a substituted 5-16 membered heterocyclic group; wherein the substitution is independently Refers to being substituted by one or more substituents selected from the following group: deuterium, C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6 -C14 aryl, halogenated C6-C14 aryl, heteroaryl, halogen, amino, nitro, -COR 30 , -COOR 30 ,
  • R 30 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, Amino and heterocyclyl, wherein said substitution independently refers to being substituted by one or more substituents selected from the following group: C1-C18 alkyl, C6-C14 aryl;
  • n is independently an integer of 0, 1 or 2;
  • n is independently an integer of 0, 1, 2, 3, 4 or 5;
  • heterocyclic group is a 4-7 membered monocyclic ring, 7-11 membered bicyclic ring or 8-16 membered tricyclic ring containing 1-4 heteroatoms selected from N, O, and S;
  • heteroaryl group is a 5-14 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, S;
  • the additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
  • R 1 is hydrogen, deuterium or -CH 2 R 24 ;
  • X 1 and X 2 are each independently oxygen or sulfur
  • X 3 is nitrogen
  • R 25 , R 26 , R 27 , R 28 and R 29 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl , Heterocyclyl, C6-C14 aryl, heteroaryl; wherein, the substitution independently refers to substitution by one or more substituents selected from the following group: deuterium, C1-C18 alkyl, halogenated C1-C18 Alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, halogenated C6-C14 aryl, heteroaryl, halogen, amino, nitro, -COR 30 , -COOR 30 , -OCOOR 30 , cyano, hydroxyl;
  • R 30 is selected from the following unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, amino, Heterocyclic group.
  • R 1 is hydrogen or deuterium.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different, and Independently selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substituted C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkyl.
  • a 1 is selected from C, CH or CD.
  • a 2 , A 3 and A 4 are each independently selected from CR 15 or CR 15 R 16 ;
  • R 15 and R 16 are the same or different, and are each independently selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy , Deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, -(CH 2 ) n C(O)OR 17 , cyano, C3-C8 cycloalkyl;
  • R 17 is selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substitute C1-C6 alkoxy, amino, hydroxy, C3-C8 cycloalkyl.
  • a 1 and A 2 are connected by a single bond.
  • a 3 and A 4 are connected by a double bond.
  • the additional condition is that when R 1 is hydrogen, at least two of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
  • R 1 is hydrogen
  • at least three of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
  • R 1 is hydrogen
  • at least six of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
  • R 1 is hydrogen
  • a 1 is CD
  • R 1 is hydrogen
  • a 2 is CD 2 .
  • R 1 is hydrogen
  • a 1 and A 2 form CDCHD.
  • a 1 and A 2 form CDCD 2 .
  • R 12 when R 1 is hydrogen, R 12 is OCD 3 .
  • R 13 is OCD 3 .
  • R 1 is hydrogen
  • R 12 and R 13 are OCD 3
  • a 1 is CD
  • R 1 -R 14 , A 1 -A 4 are as described above;
  • the additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
  • it is a thiazolidinedione compound represented by the general formula (III), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, or hydrate Or solvate, or its prodrug molecule:
  • R 15 , R 16 , R 21 and R 23 are independently selected from hydrogen or deuterium;
  • R 22 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to one selected from the group Or multiple substituent substitutions: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen , Amino, nitro, hydroxy, cyano, ester, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl
  • R 1 -R 14 , R 19 , R 20 , m and n are as described above;
  • the additional condition is that when R 1 is hydrogen, at least one of R 1 -R 16 and R 19 -R 23 is deuterated or deuterated.
  • it is a thiazolidinedione compound represented by the general formula (IV), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, or hydrate Or solvate, or its prodrug molecule:
  • R 12 and R 13 are independently selected from the following group: C1-C6 alkoxy, deuterated C1-C6 alkoxy;
  • R 22 is selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, and deuterated C1-C18 alkyl;
  • R 1 -R 11 , R 14 -R 16 and R 23 are independently selected from hydrogen or deuterium.
  • At least one of R 1 -R 16 and R 22 -R 23 is deuterated or deuterated.
  • At least two of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
  • At least three of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
  • At least six of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
  • R 12 is OCD 3 .
  • R 13 is OCD 3 .
  • R 12 and R 13 are OCD 3 .
  • R 15 is D.
  • R 15 and R 16 are D.
  • a 1 is a CD
  • the CD has an R configuration or an S configuration, preferably an S configuration.
  • the compound is selected from the following group:
  • a pharmaceutical composition which is characterized in that it contains a pharmaceutically acceptable carrier and one or more of the thiazolidine two having the structure of formula (I) described in the first aspect of the present invention.
  • it also contains drugs for preventing and/or treating diseases selected from the group consisting of cardiovascular diseases, metabolic diseases, infections, immune diseases, inflammations, and cancers.
  • the third aspect of the present invention provides the thiazolidinedione compound with the structure of formula (I) according to the first aspect of the present invention, or its enantiomers, diastereomers, resonance forms, crystal forms, and pharmaceutically
  • acceptable salts, hydrates or solvates, or prodrug molecules thereof characterized in that they are used to prepare pharmaceutical compositions for the prevention and/or treatment of diseases selected from the following group: Inflammation, cardiovascular disease, infection, immune disease, metabolic disease, cancer.
  • the inflammation is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, liver fibrosis, gallstones, primary biliary cirrhosis, primary sclerosing Cholangitis, liver cirrhosis, diabetes, atherosclerosis, obesity, alcoholic liver disease.
  • NASH non-alcoholic steatohepatitis
  • non-alcoholic fatty liver disease liver fibrosis
  • gallstones primary biliary cirrhosis
  • primary sclerosing Cholangitis liver cirrhosis
  • diabetes atherosclerosis
  • obesity obesity
  • alcoholic liver disease alcoholic steatohepatitis
  • the fourth aspect of the present invention provides the thiazolidinedione compound with the structure of formula (I) according to the first aspect of the present invention, or its enantiomers, diastereomers, resonance forms, crystal forms, and pharmacological
  • the use of acceptable salts, hydrates or solvates, or prodrug molecules thereof, is characterized in that they are used to prepare a pharmaceutical composition that is a peroxisome proliferator activated receptor (PPAR) agonist.
  • PPAR peroxisome proliferator activated receptor
  • Figures 1 to 4 are the mouse histopathological changes score results obtained in the NASH model of C57BL/6 mice induced by STZ-HFD feed with test compounds 5A and 5B.
  • Figures 5 to 8 are the results of animal histopathological changes in the experimental rabbit NASH model induced by HFD-CHOL of test compound 5B.
  • the inventors unexpectedly prepared a compound with multiple agonistic effects on PPAR receptors, better pharmacodynamic properties and better safety properties. On this basis, the inventor completed the present invention.
  • alkyl refers to a straight or branched chain alkane group containing 1-18 carbon atoms (C1-C18 alkyl), especially 1-6 carbon atoms (C1-C6 alkyl).
  • Typical "alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl Alkyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.
  • C1-C6 alkyl refers to straight or branched chain alkyl, including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, iso Butyl.
  • Substituted alkyl means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkenyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon double bond. Typical groups include vinyl or allyl.
  • (C 2 -C 6 )alkenyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl , (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl , 2,3-Dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (Z)-1-hexenyl, (E)-2 -Pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-Pentenyl
  • alkynyl refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon triple bond substituent. Typical groups include ethynyl.
  • (C 2 -C 6 )alkynyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group, including 1, 2, 3 or 4 rings, each containing 3-8 carbon atoms (such as C3-C8 cycloalkyl) .
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spiro ring, bridged ring or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (not including heteroaromatic ring), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-8 carbon atoms. Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl” means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include spirocyclic or fused ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), fused ring alkyl, fused cycloalkenyl, fused ring hetero Cyclic or fused-ring aromatic ring groups, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aryl groups may be optionally substituted.
  • heterocyclyl refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 4-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), At least one heteroatom is present in a ring with at least one carbon atom.
  • Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms. These heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms.
  • the nitrogen or sulfur atoms can be oxidized, and the nitrogen atoms can also be Is quaternized.
  • the heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholino, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc.
  • Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more atoms above are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy and carboxylate.
  • groups are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy and carboxylate.
  • aryl refers to an aromatic cyclic hydrocarbon compound group having 1, 2, 3, 4 or 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl” means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position.
  • Typical substituents may be optionally substituted.
  • Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
  • heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • the heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc.
  • Heteroaryl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • amino refers to -NH 2 .
  • halo refers to substitution by halogen.
  • alkoxy refers to a straight-chain or branched alkoxy group, such as "C1-C6 alkoxy”, which refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, without limitation Ground includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably it is a C1-C4 alkoxy group.
  • deuterated alkoxy has a similar meaning and refers to a group obtained by replacing one or more or all of the hydrogens in the "alkoxy" with deuterium, such as "C1-C6 deuterated alkoxy".
  • ester group refers to a -COOR group with a structure, wherein R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above.
  • carbonyl refers to -C(O)R, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or For substituted aryl, heterocycle, or substituted heterocycle, the aforementioned groups are as defined above.
  • R and R can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, and each of the foregoing groups is as defined above.
  • R and R" may be the same or different in the dialkylamine segment.
  • sulfonamido refers to a -SO 2 NRR" group with a structure, where R and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above. R and R" may be the same or different in the dialkylamine segment.
  • ureido refers to -NRC(O)NR'R", where R, R'and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
  • amino acid refers to a class of compounds containing both amino and carboxyl groups, which can be divided into ⁇ -, ⁇ -, ⁇ -amino acids and the like according to the different positions of the amino groups on the carbon chain. Including but not limited to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, Asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine, etc.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
  • a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
  • Any one of A 1 , A 2 , A 3 and A 4 is the corresponding group in the specific compound described below.
  • the compound is preferably the compound prepared in the embodiment.
  • salts that the compounds of the present invention may form also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts.
  • the term "salt” as used herein refers to a salt in the acid or basic form formed with an inorganic or organic acid and a base.
  • the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion (“internal salt”) that may be formed is contained in Within the scope of the term "salt”.
  • salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process.
  • the compound of the present invention may form a salt.
  • the compound can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or freeze-dried in an aqueous solution.
  • the basic fragments contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate.
  • Benzene sulfonate hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g.
  • 2-naphthalenesulfonate nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
  • the acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases.
  • Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and bicyclohexyl Amine, Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
  • small molecular alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide
  • dialkyl sulfate E.g., dimethyl sulfate, diethyl,
  • prodrugs and solvates of the compounds of the present invention are also covered.
  • prodrug herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process to produce the compound, salt, or solvate of the present invention when treating related diseases.
  • the compounds of the present invention include solvates such as hydrates.
  • the compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
  • All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention.
  • the independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them.
  • the chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974.
  • racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and recrystallization.
  • the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed.
  • very pure compounds of the invention are also part of the invention.
  • All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
  • Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin the mixture and other mixtures.
  • the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
  • the mixture of isomers can contain various isomer ratios.
  • a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those skilled in the art and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in fact, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different.
  • isotopes of compounds that can be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention .
  • Certain isotope-labeled compounds of the present invention such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates.
  • Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the scheme disclosed in the schematic diagram and/or the example.
  • a specific enantiomer of the compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant.
  • the pure enantiomer if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
  • the compounds of the present invention can be combined with any number of substituents or functional groups to expand their coverage.
  • the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents.
  • each position of the substituents may be the same or different.
  • substitution as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds.
  • the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence.
  • the present invention is not intended to limit the permitted substitution of organic compounds in any way.
  • the present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases.
  • stable refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
  • the compound of general formula (I) can be combined with other drugs known to treat or improve similar conditions.
  • the original drug administration mode and dosage can remain unchanged, while the compound of formula I is administered simultaneously or subsequently.
  • a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used.
  • the combination of drugs also includes taking the compound of formula I and one or more other known drugs in overlapping time periods.
  • the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.
  • Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: bile acid receptor (FXR) agonists (such as Obeticholic acid, tropifexor, GS-9674), peroxidase Proliferator-activated receptor (PPAR) agonists (such as Elafibranor, saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor (THR ⁇ ) agonists (such as MGL-3196), diacylglycerol-O-acyltransferase (DGAT) Inhibitors (such as Pradigastat, PF-06865571), acetyl-coenzyme A carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) ) Inhibitors (such as Vismodegib), galectin inhibitors (such as GR-MD-02),
  • Inflammation cardiovascular disease, infection, immune disease, metabolic disease or cancer involved in this application include (but not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), bile Stasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or liver fibrosis; arteriosclerosis, dyslipidemia, high cholesterol Hyperemia or hypertriglyceridemia; type I diabetes, type II diabetes or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, or colorectal cancer.
  • PBC primary sclerosis
  • PSC primary sclerosing cholecystitis
  • bile Stasis autoimmune hepatitis
  • viral hepatitis such as
  • resonant body refers to the limit structural formula of the same compound molecule.
  • the relative position of the nucleus remains unchanged, but the arrangement of electrons (usually ⁇ electrons and unshared electron pairs) is different.
  • pharmaceutically acceptable salt refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts are the salts of the compounds of this invention with acids.
  • Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
  • a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium or calcium salt
  • ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium or calcium salt
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • prodrug molecule includes itself which may be biologically active or inactive. When taken by a proper method, it undergoes metabolism or chemical reaction in the human body to transform into a compound of formula (I), or A salt or solution composed of a compound of formula (I).
  • the prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and gly
  • the dosage form of the pharmaceutical composition includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, topical liniment, or controlled release or sustained release or nano formulation .
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered.
  • the daily administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
  • the present invention has the following main advantages:
  • the compound of the present invention has multiple agonistic effects on PPAR receptors, has better pharmacodynamic performance and better safety performance.
  • the compound of the present invention has better pharmacokinetic properties, such as higher maximum blood drug concentration and/or drug plasma exposure.
  • the compound of the present invention has the pharmacodynamic effect of significantly reducing non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
  • NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument.
  • the solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc.
  • the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).
  • Liquid mass spectrometry is detected by Waters SQD2 mass spectrometer.
  • HPLC measurement uses Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100x 3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
  • the filter cake was rinsed with water, and then added to the pre-prepared sodium hydroxide (2.7g) aqueous solution (14.5mL), and stirred at room temperature for 1 hour.
  • the obtained mixture was filtered, and an aqueous hydrochloric acid solution (20% wt, 14.5 mL) was added dropwise to the obtained filtrate. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes and filtered.
  • the filter cake was rinsed with water and dried under vacuum at 60°C for 4 hours.
  • the obtained crude product was recrystallized from ethanol and water to obtain the target compound (1.9 g, yield 48.2%).
  • Step 4 Preparation of (E)-2-(4-hydroxyphenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl) methyl acrylate
  • the resulting mixture was concentrated in vacuo to remove the solvent, and then toluene (4 mL) and methanol (12 mL) were added. The resulting mixture was stirred at 60°C for 2 hours, then lowered to room temperature and stirred at room temperature for 16 hours, stirred in an ice bath for 1 hour, and filtered. The filter cake was rinsed with methanol and dried under vacuum to obtain the target compound (2.2 g, yield 81.0%).
  • the seventh step (E)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl)phenoxy)phenyl)-3-(3-methoxy Preparation of methyl-5-(methoxy-d 3 )phenyl) acrylate
  • the filter cake was rinsed with acetic acid, and the filtrate was concentrated in vacuo to remove part of the solvent and then extracted with dichloromethane (50 mL ⁇ 2).
  • the combined organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a crude product.
  • the crude product was recrystallized with absolute ethanol to obtain the target compound (1.06 g, yield 48.0%).
  • Step 2 Preparation of (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-hydroxyphenyl)acrylic acid
  • the filter cake was rinsed with water and added to a pre-prepared aqueous solution (30 mL) of sodium hydroxide (5.5 g). The resulting mixture was stirred for 1 hour and then filtered. An aqueous hydrochloric acid solution (20% wt, 30 mL) was added dropwise to the filtrate. After dripping, the reaction solution was stirred for 30 minutes and filtered. The filter cake was rinsed with water and dried in vacuum at 60°C for 4 hours to obtain a crude product. The crude product was recrystallized from ethanol and water to obtain the target compound (3.64 g).
  • the resulting mixture was concentrated in vacuo to remove the solvent, and then toluene (4 mL) and methanol (12 mL) were added. The resulting mixture was stirred at 60°C for 2 hours, then lowered to room temperature and stirred at room temperature for 16 hours, stirred in an ice bath for 1 hour, and filtered. The filter cake was rinsed with methanol and dried under vacuum to obtain the target compound (1.84 g, yield 78.5%).
  • the filter cake was rinsed with acetic acid, and the filtrate was concentrated in vacuo to remove part of the solvent and then extracted with dichloromethane (80 mL ⁇ 2).
  • the combined organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered.
  • the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a crude product.
  • the crude product was recrystallized with absolute ethanol to obtain the target compound (1.08 g, yield 59.8%).
  • the first step (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5- (Yl)methyl)phenoxy)phenyl)acrylic acid
  • the pH of the aqueous phase is adjusted to 1 with hydrochloric acid and then filtered, the filter cake is washed with water and dried to obtain a crude product.
  • the obtained crude product was purified by silica gel column chromatography to obtain the target compound (0.66 g, yield 77.1%).
  • the first step the preparation of (E)-3-(3,5,-dimethoxyphenyl)-2-(4-hydroxyphenyl)acrylic acid
  • the third step Preparation of methyl (E)-3-(3,5,-dimethoxyphenyl)-2-(4-(4-formylphenoxy)phenyl)acrylic acid
  • the reaction solution was cooled to room temperature, then methanol (750 mL) was added and heated to reflux for 2 hours. The resulting mixture was cooled, stirred in an ice bath for 30 minutes, and filtered. The filter cake was rinsed with methanol (350 mL), and then vacuum dried at 50° C. for 3 hours to obtain the target compound (101.4 g, yield 68.3%).
  • Test Example 1 Test of the agonistic activity of the compound on PPAR ⁇ in HEK293 cells
  • the storage concentration of all plasmids is 0.5mg/ml
  • Test Example 2 Test of the agonistic activity of the compound on PPAR ⁇
  • the histidine-labeled PPAR ⁇ (ligand binding domain, 25nM protein) and 25nM biotin-labeled PGC1 ⁇ co-activator protein and 0.4 ⁇ g fluorescent receptor (anti-histidine antibody-conjugated beads) were combined with 20mM Hepes/NaOH ( pH 7.4), 80 mM NaCl, 0.08% Tween 20, 0.8 mM DTT and 0.08% BSA in an incubation buffer. The mixture was pre-incubated at 22°C for 30 minutes, including incubation buffer (basic control), reference agonist (positive control group), and test compound groups with different concentrations. After that, a fluorescent donor (streptavidin-coupled beads) was added.
  • the compound of the present invention has good PPAR ⁇ agonistic activity.
  • Heparin sodium 1% heparin sodium anticoagulation test tube, add 15ul 1% heparin sodium solution to the clean EP tube to moisten the tube wall, dry it in a blast drying chamber at 60°C, and place it in a frozen storage for later use.
  • the rats should be adapted to rearing for one week and freely take in food.
  • test product DMSO/PEG400 (5/95) is prepared into a solution, and the prepared drug is stored at 4°C or used on the day of preparation.
  • venous blood was taken from the rat’s posterior venous plexus, and 1% heparin was placed Sodium anticoagulation test tube.
  • the compound of the present invention exhibits better metabolic properties in rats, and both the plasma exposure amount AUC and the maximum blood drug concentration C max perform well.
  • the compound of the present invention has better pharmacokinetic properties, such as higher maximum blood drug concentration and drug plasma exposure.
  • Newborn mice were injected subcutaneously with streptozotocin (STZ) 48 hours after birth to establish diabetic mice. After four weeks of feeding, 21 diabetic male mice were selected (fasting blood glucose>10mmol/L). Divided into 3 groups according to body weight and blood sugar, and started feeding on high-fat diet (HFD).
  • HFD high-fat diet
  • HFD normal
  • the drug was administered orally once a day (p.o, q.d) at the beginning of the third week, and the administration volume was 10ml/kg for a total of 4 weeks.
  • Example Compound 5B reduces the inflammatory pathology score.
  • Example Compounds 5A and 5B significantly reduced the balloon-like pathology score.
  • the compounds 5A and 5B of the present invention have a good therapeutic effect on non-alcoholic steatohepatitis induced by STZ and high-fat diet (HFD).
  • the model animals were given high-fat and high-cholesterol feed every day, and each animal was given 100g per day for 8 weeks.
  • the model was given compound treatment at the 5th week and was orally administered once a day (p.o, q.d) for 4 weeks.
  • Example Compound 5B significantly reduces the pathological score of steatosis.
  • Example Compound 5B significantly reduced the balloon-like pathology score.
  • Example Compound 5B significantly reduces the pathological score of non-alcoholic steatosis.
  • Example Compound 5B significantly reduces the pathological score of liver fibrosis.
  • the compound 5B of the present invention has a good therapeutic effect on HFD-CHOL-induced non-alcoholic steatohepatitis.

Abstract

A thiazolidinedione derivative having the structure shown in formula (I) and a pharmaceutical composition comprising same, the definitions of each group and substituent being as described in the description. Also provided is a use of the compound as a peroxisome proliferator-activated receptor (PPAR) agonist, particularly a use in preventing and/or treating non-alcoholic fatty liver disease or a related disease.

Description

噻唑烷二酮衍生物以及包含其的药物组合物Thiazolidinedione derivatives and pharmaceutical compositions containing them 技术领域Technical field
本发明涉及药物领域，具体地涉及一种噻唑烷二酮衍生物以及包含其的药物组合物。The present invention relates to the field of medicine, in particular to a thiazolidinedione derivative and a pharmaceutical composition containing the same.
背景技术Background technique
非酒精性脂肪性肝病(NAFLD)影响到约10％～30％的普通成人以及60-80％的II型糖尿病患者。在美国，NAFLD的发病率约占总人口的10-46％，其中约10-30％的患者会发展成为非酒精性脂肪性肝炎(NASH，nonalcoholic steatohepatitis)。非酒精性脂肪性肝炎(NASH)表现为炎症及肝细胞损伤的脂肪变性现象的出现，会导致晚期肝脏纤维化、肝硬化、肝衰竭及肝脏肿瘤等重大疾病。到2025年，预计其用药将超过350-400亿美元。早期在研的靶点包括PPAR、FXR、GLP、ACC及THR β等等，但到目前为止，NASH临床上还没有被批准的治疗药物(Sumida Y,Yoneda M.,J Gastroenterol 2018,53,362–376)。 Non-alcoholic fatty liver disease (NAFLD) affects approximately 10%-30% of ordinary adults and 60-80% of patients with type II diabetes. In the United States, the incidence of NAFLD accounts for about 10-46% of the total population, and about 10-30% of patients will develop nonalcoholic steatohepatitis (NASH, nonalcoholic steatohepatitis). Non-alcoholic steatohepatitis (NASH) is manifested by the appearance of inflammation and fatty degeneration of liver cell damage, which can lead to major diseases such as advanced liver fibrosis, cirrhosis, liver failure and liver tumors. By 2025, its drug use is expected to exceed US$35-40 billion. Early targets in research include PPAR, FXR, GLP, ACC, and THR β, etc., but so far, there are no clinically approved therapeutic drugs for NASH (Sumida Y, Yoneda M., J Gastroenterol 2018,53,362–376 ).
过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)是调节目标基因表达的核内受体转录因子超家族成员。根据结构的不同，PPAR可分为α、β(或δ)和γ三种类型。Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor transcription factor superfamily that regulates the expression of target genes. According to different structures, PPAR can be divided into three types: α, β (or δ) and γ.
其中，PPARα是肝脏β氧化和微粒体ω氧化的主要调控者，PPARα缺失会导致肝脏中脂质过量积累。因此活化PPARα可以增强脂肪酸氧化基因表达，从而降低肝脏脂肪病变的发生概率，但其对II型糖尿病的治疗作用相对较弱。PPARδ可以控制体重增加，增强身体耐力，提高胰岛素敏感性，以及改善动脉粥样硬化。PPARγ主要表达于脂肪组织及免疫系统，与脂肪细胞分化、机体免疫及胰岛素抵抗关系密切，可以提高胰岛素敏感性、减少炎症的发生、降低游离脂肪酸的脂质浓度及降低血压，但其对脂代谢紊乱的调节作用较弱(Cave MC,Clair HB，etc.，Biochimica et Biophysica Acta 2016,1859(9),1083–1099)。Among them, PPARα is the main regulator of liver β oxidation and microsomal omega oxidation, and the lack of PPARα can lead to excessive accumulation of lipids in the liver. Therefore, activation of PPARα can enhance the expression of fatty acid oxidation genes, thereby reducing the probability of liver fatty disease, but its therapeutic effect on type II diabetes is relatively weak. PPARδ can control weight gain, enhance physical endurance, improve insulin sensitivity, and improve atherosclerosis. PPARγ is mainly expressed in adipose tissue and immune system, and is closely related to adipocyte differentiation, body immunity and insulin resistance. It can improve insulin sensitivity, reduce inflammation, reduce the lipid concentration of free fatty acids and lower blood pressure, but it has an effect on lipid metabolism. The regulation of disorder is weak (Cave MC, Clair HB, etc., Biochimica et Biophysica Acta 2016, 1859(9), 1083-1099).
研究表明，针对非酒精性脂肪性肝疾病单一的PPAR激动剂很难实现理想的治疗效果。因此，目前开发多重激动剂(如双重激动剂或三重激动剂)是重要研究方向之一。Studies have shown that a single PPAR agonist for non-alcoholic fatty liver disease is difficult to achieve an ideal therapeutic effect. Therefore, the current development of multiple agonists (such as dual agonists or triple agonists) is one of the important research directions.
噻唑烷二酮类衍生物(如匹格列酮(Pioglitazone)、罗格列酮(Rosiglitazone)以及洛贝格列酮(Lobeglitazone))等PPARγ选择性激动剂已经被批准用于治疗II型糖尿病。另外，这类药物也被标签外用于非酒精性脂肪性肝疾的治疗。但是，现有噻唑烷二酮类药物因为其容易引起体重增加、水肿以及骨折等副作用从而限制了其治疗应用。PPARγ selective agonists such as thiazolidinedione derivatives (such as Pioglitazone, Rosiglitazone and Lobeglitazone) have been approved for the treatment of type II diabetes. In addition, these drugs are also off-label for the treatment of non-alcoholic fatty liver disease. However, the existing thiazolidinedione drugs are likely to cause side effects such as weight gain, edema, and fractures, which limits their therapeutic applications.
基于尚未满足的临床需求，本领域仍需要开发对PPAR受体有多重激动作用、具有更好药效学性能和更好的安全性能的化合物。Based on the unmet clinical needs, there is still a need in the art to develop compounds that have multiple agonistic effects on PPAR receptors, have better pharmacodynamic properties and better safety properties.
发明内容Summary of the invention
本发明的目的在于提供一类新型的对过氧化物酶体增殖物激活受体(PPAR)有多重激动作用、具有更好药效学性能和更好的安全性能的化合物。The purpose of the present invention is to provide a new class of compounds that have multiple agonistic effects on peroxisome proliferator-activated receptors (PPAR), have better pharmacodynamic properties and better safety properties.
本发明的第一方面，提供了具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：The first aspect of the present invention provides a thiazolidinedione compound having a structure of formula (I), or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, hydrates or Solvate, or its prodrug molecule:
Figure PCTCN2020100888-appb-000001
Figure PCTCN2020100888-appb-000001
式中：Where:
R 1是氢、氘或-CH 2R 24； R 1 is hydrogen, deuterium or -CH 2 R 24 ;
R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13和R 14相同或不同，且独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、酯基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 17、-(CH 2) nO(CH 2) mR 17、-(CH 2) nSR 17、-(CH 2) nCOR 17、-(CH 2) nC(O)OR 17、-(CH 2) nS(O) mR 17、-(CH 2) nNR 17R 18、-(CH 2) nC(O)NR 17R 18、-(CH 2) nC(O)NHR 18、-(CH 2) nNR 18C(O)R 17和-(CH 2) nNR 18S(O) mR 17；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 17、-(CH 2) nSR 17、-(CH 2) nCOR 17、-(CH 2) nC(O)OR 17、-(CH 2) nS(O) mR 17、-(CH 2) nNR 18R 17、-(CH 2) nC(O)NR 18R 17、-(CH 2) nC(O)NHR 18、-(CH 2) nNR 18C(O)R 17、-(CH 2) nNR 18S(O) mR 17； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different, and are independently selected from substituted or unsubstituted Substitution of the following groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substituted C1-C6 alkoxy, halogen, amino, nitro, hydroxy, ester, cyano, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 17 , -(CH 2 ) n O(CH 2 ) m R 17 , -(CH 2 ) n SR 17 , -(CH 2 ) n COR 17 , -(CH 2 ) n C(O)OR 17 ,- (CH 2 ) n S(O) m R 17 , -(CH 2 ) n NR 17 R 18 , -(CH 2 ) n C(O)NR 17 R 18 , -(CH 2 ) n C(O)NHR 18 , -(CH 2 ) n NR 18 C(O)R 17 and -(CH 2 ) n NR 18 S(O) m R 17 ; wherein the substitution independently refers to one or more selected from the group Substituent substitution: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, Nitro, hydroxyl, cyano, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 17 , -(CH 2 ) n SR 17 , -(CH 2 ) n COR 17 , -(CH 2 ) n C(O)OR 17 , -(CH 2 ) n S(O) m R 17 , -(CH 2 ) n NR 18 R 17 , -(CH 2 ) n C(O)NR 18 R 17 , -(CH 2 ) n C(O)NHR 18 , -(CH 2 ) n NR 18 C(O)R 17 , -(CH 2 ) n NR 18 S(O) m R 17 ;
A 1选自C、CH或CD； A 1 is selected from C, CH or CD;
A 2、A 3和A 4分别独立地选自CR 15或CR 15R 16； A 2 , A 3 and A 4 are each independently selected from CR 15 or CR 15 R 16 ;
R 15和R 16相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、酯基、-(CH 2) nC(O)OR 17、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝 基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 19、-(CH 2) nSR 19、-(CH 2) nCOR 19、-(CH 2) nC(O)OR 19、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 15 and R 16 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, -(CH 2 ) n C(O)OR 17 , cyano, C3 -C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the following group: hydrogen, deuterium, C1-C18 alkyl , Deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkane Group, heterocyclic group, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 19 , -(CH 2 ) n COR 19 , -(CH 2 ) n C (O)OR 19 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C(O)R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
R 17和R 18相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 19、-(CH 2) nSR 20、-(CH 2) nCOR 20、-(CH 2) nC(O)OR 20、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 17 and R 18 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl ; Wherein the substitution independently refers to the substitution of one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1- C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 20 , -(CH 2 ) n COR 20 , -(CH 2 ) n C(O)OR 20 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C( O) R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
R 19和R 20相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、羰基、羧基、酰胺基、磺酰胺基、脲基； R 19 and R 20 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, Heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halo C1-C18 alkyl , C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, ester, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, hetero Aryl, carbonyl, carboxyl, amide, sulfonamide, urea group;
R 24是-OH、-O-氨基酸、-OP(O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH)OP(＝O)(OH) 2、-OP(O)(X 1R 25)(X 2R 26)、-OP(O)(X 1R 25)(X 3R 28R 29)、-OCH 2P(O)(X 1R 25)(X 2R 26)、-OCH 2P(O)(X 1R 25)(X 3R 28R 29)、-P(O)(OH) 2、-P(O)(X 1R 25)(X 2R 26)、-OC(O)-R 27或者-OC(O)O-R 27； R 24 is -OH, -O-amino acid, -OP(O)(OH) 2 , -OP(=O)(OH)OP(=O)(OH) 2 , -OP(=O)(OH)OP (=O)(OH)OP(=O)(OH) 2 , -OP(O)(X 1 R 25 )(X 2 R 26 ), -OP(O)(X 1 R 25 )(X 3 R 28 R 29 ), -OCH 2 P(O)(X 1 R 25 )(X 2 R 26 ), -OCH 2 P(O)(X 1 R 25 )(X 3 R 28 R 29 ), -P( O)(OH) 2 , -P(O)(X 1 R 25 )(X 2 R 26 ), -OC(O)-R 27 or -OC(O)OR 27 ;
X 1、X 2分别独立地是氧或者硫； X 1 and X 2 are each independently oxygen or sulfur;
X 3是氮； X 3 is nitrogen;
R 25、R 26、R 27、R 28和R 29独立地选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基，或者R 25和R 26与相邻的X 1、X 2和P结合形成取代5-16元杂环基；其中，所述取代独立地指被选自下组的一个或多个取代基取代：氘、C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、C3-C8环烷基、杂环基、C6-C14芳基、卤代C6-C14芳基、杂芳基、卤素、氨基、硝基、-COR 30、-COOR 30、-OCOOR 30、氰基、羟基、酰胺基、磺酰胺基； R 25 , R 26 , R 27 , R 28 and R 29 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl , Heterocyclyl, C6-C14 aryl, heteroaryl, or R 25 and R 26 combine with adjacent X 1 , X 2 and P to form a substituted 5-16 membered heterocyclic group; wherein the substitution is independently Refers to being substituted by one or more substituents selected from the following group: deuterium, C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6 -C14 aryl, halogenated C6-C14 aryl, heteroaryl, halogen, amino, nitro, -COR 30 , -COOR 30 , -OCOOR 30 , cyano, hydroxyl, amide, sulfonamide;
R 30选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、C3-C8环烯基、C6-C14芳基、氨基、杂环基，其中所述取代独立地指被选自下组的一个或多 个取代基取代：C1-C18烷基、C6-C14芳基； R 30 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, Amino and heterocyclyl, wherein said substitution independently refers to being substituted by one or more substituents selected from the following group: C1-C18 alkyl, C6-C14 aryl;
m独立为0、1或2的整数；且m is independently an integer of 0, 1 or 2; and
n独立为0、1、2、3、4或5的整数；n is independently an integer of 0, 1, 2, 3, 4 or 5;
Figure PCTCN2020100888-appb-000002
独立为单键或双键；
Figure PCTCN2020100888-appb-000003
表示单键；
Figure PCTCN2020100888-appb-000002
Independent as single bond or double bond;
Figure PCTCN2020100888-appb-000003
Represents a single key;
所述“杂环基”为含1-4个选自N、O、S的杂原子的4-7元单杂环、7-11元双杂环或8-16元三杂环；The "heterocyclic group" is a 4-7 membered monocyclic ring, 7-11 membered bicyclic ring or 8-16 membered tricyclic ring containing 1-4 heteroatoms selected from N, O, and S;
所述“杂芳基”为含1-4个选自N、O、S的杂原子的5-14元杂芳环；The "heteroaryl group" is a 5-14 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, S;
附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有一个是氘代的或者氘。 The additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
在另一优选例中，R 1是氢、氘或-CH 2R 24； In another preferred embodiment, R 1 is hydrogen, deuterium or -CH 2 R 24 ;
R 24是-OH、-OP(O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH)OP(＝O)(OH) 2、-OP(O)(X 1R 25)(X 2R 26)、-OP(O)(X 1R 25)(X 3R 28R 29)、-OCH 2P(O)(X 1R 25)(X 2R 26)、-OCH 2P(O)(X 1R 25)(X 3R 28R 29)、-P(O)(OH) 2、-P(O)(X 1R 25)(X 2R 26)、-OC(O)-R 27或者-OC(O)O-R 27； R 24 is -OH, -OP(O)(OH) 2 , -OP(=O)(OH)OP(=O)(OH) 2 , -OP(=O)(OH)OP(=O)( OH)OP(=O)(OH) 2 , -OP(O)(X 1 R 25 )(X 2 R 26 ), -OP(O)(X 1 R 25 )(X 3 R 28 R 29 ), -OCH 2 P(O)(X 1 R 25 )(X 2 R 26 ), -OCH 2 P(O)(X 1 R 25 )(X 3 R 28 R 29 ), -P(O)(OH) 2. -P(O)(X 1 R 25 )(X 2 R 26 ), -OC(O)-R 27 or -OC(O)OR 27 ;
X 1、X 2分别独立地是氧或者硫； X 1 and X 2 are each independently oxygen or sulfur;
X 3是氮； X 3 is nitrogen;
R 25、R 26、R 27、R 28和R 29独立地选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中，所述取代独立地指被选自下组的一个或多个取代基取代：氘、C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、C3-C8环烷基、杂环基、C6-C14芳基、卤代C6-C14芳基、杂芳基、卤素、氨基、硝基、-COR 30、-COOR 30、-OCOOR 30、氰基、羟基； R 25 , R 26 , R 27 , R 28 and R 29 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl , Heterocyclyl, C6-C14 aryl, heteroaryl; wherein, the substitution independently refers to substitution by one or more substituents selected from the following group: deuterium, C1-C18 alkyl, halogenated C1-C18 Alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, halogenated C6-C14 aryl, heteroaryl, halogen, amino, nitro, -COR 30 , -COOR 30 , -OCOOR 30 , cyano, hydroxyl;
R 30选自未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、C3-C8环烯基、C6-C14芳基、氨基、杂环基。 R 30 is selected from the following unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, amino, Heterocyclic group.
在另一优选例中，R 1是氢、氘。 In another preferred example, R 1 is hydrogen or deuterium.
在另一优选例中，R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13和R 14相同或不同，且独立地选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基。 In another preferred embodiment, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different, and Independently selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substituted C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkyl.
在另一优选例中，A 1选自C、CH或CD。 In another preferred example, A 1 is selected from C, CH or CD.
在另一优选例中，A 2、A 3和A 4分别独立地选自CR 15或CR 15R 16； In another preferred embodiment, A 2 , A 3 and A 4 are each independently selected from CR 15 or CR 15 R 16 ;
R 15和R 16相同或不同，且各自独立地选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、-(CH 2) nC(O)OR 17、氰基、C3-C8环烷基； R 15 and R 16 are the same or different, and are each independently selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy , Deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, -(CH 2 ) n C(O)OR 17 , cyano, C3-C8 cycloalkyl;
R 17选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、C3-C8环烷基。 R 17 is selected from the following group: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substitute C1-C6 alkoxy, amino, hydroxy, C3-C8 cycloalkyl.
在另一优选例中，A 1和A 2通过单键连接。 In another preferred example, A 1 and A 2 are connected by a single bond.
在另一优选例中，A 3和A 4通过双键连接。 In another preferred example, A 3 and A 4 are connected by a double bond.
在另一优选例中，附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有两个是氘代的或者氘。 In another preferred example, the additional condition is that when R 1 is hydrogen, at least two of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
在另一优选例中，当R 1是氢时，A 1-A 4、R 1-R 14至少有三个是氘代的或者氘。 In another preferred example, when R 1 is hydrogen, at least three of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
在另一优选例中，当R 1是氢时，A 1-A 4、R 1-R 14至少有六个是氘代的或者氘。 In another preferred example, when R 1 is hydrogen, at least six of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
在另一优选例中，当R 1是氢时，A 1是CD。 In another preferred example, when R 1 is hydrogen, A 1 is CD.
在另一优选例中，当R 1是氢时，A 2是CD 2。 In another preferred example, when R 1 is hydrogen, A 2 is CD 2 .
在另一优选例中，当R 1是氢时，A 1和A 2形成CDCHD。 In another preferred example, when R 1 is hydrogen, A 1 and A 2 form CDCHD.
在另一优选例中，当R 1是氢时，A 1和A 2形成CDCD 2。 In another preferred example, when R 1 is hydrogen, A 1 and A 2 form CDCD 2 .
在另一优选例中，当R 1是氢时，R 12是OCD 3。 In another preferred embodiment, when R 1 is hydrogen, R 12 is OCD 3 .
在另一优选例中，当R 1是氢时，R 13是OCD 3。 In another preferred embodiment, when R 1 is hydrogen, R 13 is OCD 3 .
在另一优选例中，当R 1是氢时，R 12和R 13是OCD 3，A 1是CD。 In another preferred example, when R 1 is hydrogen, R 12 and R 13 are OCD 3 , and A 1 is CD.
在另一优选例中，其为通式(II)所示的化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：In another preferred embodiment, it is a compound represented by general formula (II), or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, Or its prodrug molecule:
Figure PCTCN2020100888-appb-000004
Figure PCTCN2020100888-appb-000004
R 1-R 14、A 1-A 4如上文所述； R 1 -R 14 , A 1 -A 4 are as described above;
附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有一个是氘代的或者氘。 The additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
在另一优选例中，其为通式(III)所示的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：In another preferred embodiment, it is a thiazolidinedione compound represented by the general formula (III), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, or hydrate Or solvate, or its prodrug molecule:
Figure PCTCN2020100888-appb-000005
Figure PCTCN2020100888-appb-000005
式中：Where:
R 15、R 16、R 21和R 23独立地选自氢或氘； R 15 , R 16 , R 21 and R 23 are independently selected from hydrogen or deuterium;
R 22选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代 C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 19、-(CH 2) nSR 19、-(CH 2) nCOR 19、-(CH 2) nC(O)OR 19、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 22 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to one selected from the group Or multiple substituent substitutions: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen , Amino, nitro, hydroxy, cyano, ester, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 19 , -(CH 2 ) n COR 19 , -(CH 2 ) n C(O)OR 19 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C(O)R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
R 1-R 14、R 19、R 20、m和n如上文所述； R 1 -R 14 , R 19 , R 20 , m and n are as described above;
附加条件是：当R 1是氢时，R 1-R 16、R 19-R 23至少有一个是氘代的或者氘。 The additional condition is that when R 1 is hydrogen, at least one of R 1 -R 16 and R 19 -R 23 is deuterated or deuterated.
在另一优选例中，其为通式(IV)所示的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：In another preferred embodiment, it is a thiazolidinedione compound represented by the general formula (IV), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, or hydrate Or solvate, or its prodrug molecule:
Figure PCTCN2020100888-appb-000006
Figure PCTCN2020100888-appb-000006
式中：Where:
R 12和R 13独立地选自下组：C1-C6烷氧基、氘代C1-C6烷氧基； R 12 and R 13 are independently selected from the following group: C1-C6 alkoxy, deuterated C1-C6 alkoxy;
R 22选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基； R 22 is selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, and deuterated C1-C18 alkyl;
R 1-R 11、R 14-R 16和R 23独立地选自氢或氘。 R 1 -R 11 , R 14 -R 16 and R 23 are independently selected from hydrogen or deuterium.
在另一优选例中，R 1-R 16、R 22-R 23至少有一个是氘代的或者氘。 In another preferred embodiment, at least one of R 1 -R 16 and R 22 -R 23 is deuterated or deuterated.
在另一优选例中，R 1-R 16、R 22-R 23至少有两个是氘代的或者氘。 In another preferred example, at least two of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
在另一优选例中，R 1-R 16、R 22-R 23至少有三个是氘代的或者氘。 In another preferred example, at least three of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
在另一优选例中，R 1-R 16、R 22-R 23至少有六个是氘代的或者氘。 In another preferred example, at least six of R 1 -R 16 and R 22 -R 23 are deuterated or deuterated.
在另一优选例中，R 12是OCD 3。 In another preferred embodiment, R 12 is OCD 3 .
在另一优选例中，R 13是OCD 3。 In another preferred embodiment, R 13 is OCD 3 .
在另一优选例中，R 12和R 13是OCD 3。 In another preferred embodiment, R 12 and R 13 are OCD 3 .
在另一优选例中，R 15是D。 In another preferred embodiment, R 15 is D.
在另一优选例中，R 15和R 16是D。 In another preferred embodiment, R 15 and R 16 are D.
在另一优选例中，A 1为CD，且所述CD具有R构型或S构型，优选S构型。 In another preferred example, A 1 is a CD, and the CD has an R configuration or an S configuration, preferably an S configuration.
在另一优选例中，所述化合物选自下组：In another preferred embodiment, the compound is selected from the following group:
Figure PCTCN2020100888-appb-000007
Figure PCTCN2020100888-appb-000007
Figure PCTCN2020100888-appb-000008
Figure PCTCN2020100888-appb-000008
Figure PCTCN2020100888-appb-000009
Figure PCTCN2020100888-appb-000009
Figure PCTCN2020100888-appb-000010
Figure PCTCN2020100888-appb-000010
Figure PCTCN2020100888-appb-000011
Figure PCTCN2020100888-appb-000011
Figure PCTCN2020100888-appb-000012
Figure PCTCN2020100888-appb-000012
本发明的第二方面，提供了一种药物组合物，其特征在于，含有药学上可接受的载 体和一种或多种本发明第一方面所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子。In the second aspect of the present invention, a pharmaceutical composition is provided, which is characterized in that it contains a pharmaceutically acceptable carrier and one or more of the thiazolidine two having the structure of formula (I) described in the first aspect of the present invention. Ketone compounds, or their enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or prodrug molecules thereof.
在另一优选例中，还含有预防和/或治疗选自下组的疾病的药物：心血管疾病、代谢性疾病、感染、免疫性疾病、炎症、癌症。In another preferred embodiment, it also contains drugs for preventing and/or treating diseases selected from the group consisting of cardiovascular diseases, metabolic diseases, infections, immune diseases, inflammations, and cancers.
本发明的第三方面，提供了本发明第一方面所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子的用途，其特征在于，用于制备药物组合物，所述药物组合物用于预防和/或治疗选自下组的疾病：炎症、心血管疾病、感染、免疫性疾病、代谢性疾病、癌症。The third aspect of the present invention provides the thiazolidinedione compound with the structure of formula (I) according to the first aspect of the present invention, or its enantiomers, diastereomers, resonance forms, crystal forms, and pharmaceutically The use of acceptable salts, hydrates or solvates, or prodrug molecules thereof, characterized in that they are used to prepare pharmaceutical compositions for the prevention and/or treatment of diseases selected from the following group: Inflammation, cardiovascular disease, infection, immune disease, metabolic disease, cancer.
在另一优选例中，所述炎症选自下组：非酒精性脂肪肝炎(NASH)、非酒精性脂肪肝病、肝纤维化、胆结石、原发性胆汁性肝硬化、原发性硬化性胆管炎、肝硬化、糖尿病、动脉粥样硬化、肥胖、酒精性肝病。In another preferred embodiment, the inflammation is selected from the group consisting of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease, liver fibrosis, gallstones, primary biliary cirrhosis, primary sclerosing Cholangitis, liver cirrhosis, diabetes, atherosclerosis, obesity, alcoholic liver disease.
本发明的第四方面，提供了本发明第一方面所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子的用途，其特征在于，用于制备为过氧化物酶体增殖剂激活受体(PPAR)激动剂的药物组合物。The fourth aspect of the present invention provides the thiazolidinedione compound with the structure of formula (I) according to the first aspect of the present invention, or its enantiomers, diastereomers, resonance forms, crystal forms, and pharmacological The use of acceptable salts, hydrates or solvates, or prodrug molecules thereof, is characterized in that they are used to prepare a pharmaceutical composition that is a peroxisome proliferator activated receptor (PPAR) agonist.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, I will not repeat them here.
附图说明Description of the drawings
图1至图4是测试化合物5A和5B在C57BL/6小鼠经STZ-HFD饲料诱导的NASH模型中所得的小鼠病理组织学变化评分结果。Figures 1 to 4 are the mouse histopathological changes score results obtained in the NASH model of C57BL/6 mice induced by STZ-HFD feed with test compounds 5A and 5B.
图5至图8是测试化合物5B在HFD-CHOL诱导的实验兔NASH模型中所得动物病理组织学变化结果。Figures 5 to 8 are the results of animal histopathological changes in the experimental rabbit NASH model induced by HFD-CHOL of test compound 5B.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，意外地制备了一种对PPAR受体有多重激动作用、具有更好药效学性能和更好的安全性能的化合物。在此基础上，发明人完成了本发明。After long-term and in-depth research, the inventors unexpectedly prepared a compound with multiple agonistic effects on PPAR receptors, better pharmacodynamic properties and better safety properties. On this basis, the inventor completed the present invention.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.
术语“烷基”是指直链或支链烷烃基，包含1-18个碳原子(C1-C18烷基)，尤其指1-6个碳原子(C1-C6烷基)。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基、辛基、2,2,4-三甲基戊基、壬基、癸基、十一烷基、十二烷基等等。术语“C1-C6烷基”指的是直链或支链烷基，包括1-6个碳原子，如甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基。“取代的烷基”是指烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e、P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。 The term "alkyl" refers to a straight or branched chain alkane group containing 1-18 carbon atoms (C1-C18 alkyl), especially 1-6 carbon atoms (C1-C6 alkyl). Typical "alkyl" includes methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, isopentyl, heptyl, 4,4-dimethylpentyl Alkyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc. The term "C1-C6 alkyl" refers to straight or branched chain alkyl, including 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, iso Butyl. "Substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocycle; R e can independently represent hydrogen, alkyl, cycloalkane Group, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted.
术语“烯基”是指直链或支链烃基含有2-18个碳原子，至少一个碳碳双键的取代基。典型的基团包括乙烯基或烯丙基。术语“(C 2-C 6)烯基”是指直链或支链的含有2-6个碳原子，至少有一个碳碳双键的基团，如乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(Z)-1-己烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基和(E)-1,3-己二烯基。“取代烯基”是指烯基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c 与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。 The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon double bond. Typical groups include vinyl or allyl. The term "(C 2 -C 6 )alkenyl" refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond, such as vinyl, propenyl, 2-propenyl , (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl , 2,3-Dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (Z)-1-hexenyl, (E)-2 -Pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3 -Hexenyl, (E)-3-hexenyl and (E)-1,3-hexadienyl. "Substituted alkenyl" means that one or more positions in the alkenyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring may be optionally substituted.
术语“炔基”是指直链或支链烃基含有2-18个碳原子，至少一个碳碳三键的取代基。典型的基团包括乙炔基。术语“(C 2-C 6)炔基”是指直链或支链的含有2-6个碳原子，至少有一个碳碳三键的基团，如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、3-己炔基。“取代炔基”是指炔基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。典型的取代基可以任选取代。 The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2-18 carbon atoms and at least one carbon-carbon triple bond substituent. Typical groups include ethynyl. The term "(C 2 -C 6 )alkynyl" refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2 -Propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl. "Substituted alkynyl" means that one or more positions in the alkynyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. Typical substituents can be optionally substituted.
术语“环烷基”是指完全饱和的环状烃类化合物基团，包括1、2、3或4个环，每个环中含有3-8个碳原子(如C3-C8环烷基)。“取代环烷基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。 The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group, including 1, 2, 3 or 4 rings, each containing 3-8 carbon atoms (such as C3-C8 cycloalkyl) . "Substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include spiro ring, bridged ring or fused ring substituents, especially spirocyclic alkyl, spirocycloalkenyl, spirocyclic heterocycle (not including heteroaromatic ring), bridged cycloalkyl, bridged cycloalkenyl, Bridged heterocyclic ring (excluding heteroaromatic ring), fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
术语“环烯基”是指部分不饱和的环状烃类化合物基团，包括1-4个环，每个环中含有3-8个碳原子。典型的环烯基如环丁烯基、环戊烯基、环己烯基等等。“取代环烯基”是指环烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环或稠环取代基，尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。 The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon compound group, including 1-4 rings, each containing 3-8 carbon atoms. Typical cycloalkenyl groups are cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. "Substituted cycloalkenyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include spirocyclic or fused ring substituents, especially spirocyclic alkyl, spirocyclic alkenyl, spirocyclic heterocycle (excluding heteroaromatic rings), fused ring alkyl, fused cycloalkenyl, fused ring hetero Cyclic or fused-ring aromatic ring groups, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic and heterocyclic aryl groups may be optionally substituted.
术语“杂环基”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环，7-11元双环，或8-16元三环系统)，其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1，2，3或4个杂原子，这些杂原子选自氮原子、氧原子或硫原子，其中氮原子或硫原子可以被氧化，氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基团可以是取代的或者非取代的，当被取代时，取代基优选为一个或多个一下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to 4-7 membered monocyclic ring, 7-11 membered bicyclic ring, or 8-16 membered tricyclic ring system), At least one heteroatom is present in a ring with at least one carbon atom. Each heterocyclic ring containing heteroatoms can have 1, 2, 3 or 4 heteroatoms. These heteroatoms are selected from nitrogen atoms, oxygen atoms or sulfur atoms. The nitrogen or sulfur atoms can be oxidized, and the nitrogen atoms can also be Is quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom residue of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine Group, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Inyl, 4-piperidinone, tetrahydropyranyl, morpholino, thiomorpholino, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3-dioxanyl and Tetrahydro-1,1-dioxythiophene, etc. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more atoms above are further connected to other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups; the heterocyclic group may be substituted or unsubstituted. When substituted, The substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, Halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxy and carboxylate.
术语“芳基”是指芳香环状烃类化合物基团，具有1、2、3、4或5个环，尤其指单环 和双环基团，如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等)，芳基基团的芳香环可由单键联接(如联苯)，或稠合(如萘、蒽等等)。“取代的芳基”是指芳基中的一个或多个位置被取代，尤其是1-3个取代基，可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团：如氢，氘，卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、腈基、硝基、氧(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e,P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e,NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中在此出现的R a可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者说R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基，尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基，上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。 The term "aryl" refers to an aromatic cyclic hydrocarbon compound group having 1, 2, 3, 4 or 5 rings, especially monocyclic and bicyclic groups such as phenyl, biphenyl or naphthyl. Where there are two or more aromatic rings (bicyclic, etc.), the aromatic ring of the aryl group can be connected by a single bond (such as biphenyl) or fused (such as naphthalene, anthracene, etc.). "Substituted aryl" means that one or more positions in the aryl group are substituted, especially 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (for example, single halogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Nitrile, nitro, oxygen (such as =0), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e ,NR d C (=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P( = O) 2 R e, wherein R a occurring here can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring, R b, R c, and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom can form a heterocyclic ring; R e can independently represent hydrogen, deuterium, alkyl, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic or aromatic ring. The above-mentioned typical substituents may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclic group or fused ring aromatic ring group, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic group and heterocyclic aromatic The group can be optionally substituted.
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, where the heteroatoms are selected from oxygen, nitrogen and sulfur. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably 5-membered or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , Furyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazole and tetrazolyl, etc. "Heteroaryl" may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, and alkoxy , Haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkane Sulfur group, oxo group, carboxyl group and carboxylate group.
术语“卤素”或“卤”是指氯、溴、氟、碘。The term "halogen" or "halo" refers to chlorine, bromine, fluorine, and iodine.
术语“氨基”是指-NH 2。 The term "amino" refers to -NH 2 .
术语“卤代”是指被卤素取代。The term "halo" refers to substitution by halogen.
术语“烷氧基”是指直链或支链烷氧基，如“C1-C6烷氧基”，其是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。术语“氘代烷氧基”具有类似的含义，是指“烷氧基”中的一个或多个或全部氢被氘取代所得基团，如“C1-C6氘代烷氧基”。The term "alkoxy" refers to a straight-chain or branched alkoxy group, such as "C1-C6 alkoxy", which refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, without limitation Ground includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like. Preferably it is a C1-C4 alkoxy group. The term "deuterated alkoxy" has a similar meaning and refers to a group obtained by replacing one or more or all of the hydrogens in the "alkoxy" with deuterium, such as "C1-C6 deuterated alkoxy".
术语“酯基”是指带有结构的-COOR基团，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，前述各基团如上文所定义。The term "ester group" refers to a -COOR group with a structure, wherein R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, Aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above.
术语“羰基”是指-C(O)R，其中R可以代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，前述各基团如上文所定义。The term "carbonyl" refers to -C(O)R, where R can represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or For substituted aryl, heterocycle, or substituted heterocycle, the aforementioned groups are as defined above.
术语“羧基”是指-COOH。The term "carboxy" refers to -COOH.
术语“酰胺基”是指带有结构的-CONRR"基团，其中R和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，前述各基团如上文所定义。R和R"在二烷基胺片段中可以相同或不同。The term "amido" refers to a -CONRR" group with a structure, wherein R and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or Substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, and each of the foregoing groups is as defined above. R and R" may be the same or different in the dialkylamine segment.
术语“磺酰胺基”是指带有结构的-SO 2NRR"基团，其中R和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，前述各基团如上文所定义。R和R"在二烷基胺片段中可以相同或不同。 The term "sulfonamido" refers to a -SO 2 NRR" group with a structure, where R and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above. R and R" may be the same or different in the dialkylamine segment.
术语“脲基”是指-NRC(O)NR'R",其中R、R'和R"可以独立的代表氢、烷基或取代的烷基、环烷基或取代的环烷基、环烯基或取代的环烯基、芳基或取代的芳基、杂环或取代的杂环，前述各基团如上文所定义。R、R'和R"在二烷基胺片段中可以相同或不同。The term "ureido" refers to -NRC(O)NR'R", where R, R'and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, ring Alkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, each of the aforementioned groups is as defined above. R, R'and R" may be the same or different in the dialkylamine segment.
术语“氨基酸”是指同时含有氨基和羧基的一类化合物，可按照氨基连在碳链上的不同位置而分为α-，β-，γ-氨基酸等。包含但不局限于甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、苯丙氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、蛋氨酸、天冬酰胺、谷氨酰胺、苏氨酸、天冬氨酸、谷氨酸、赖氨酸、精氨酸和组氨酸等。The term "amino acid" refers to a class of compounds containing both amino and carboxyl groups, which can be divided into α-, β-, γ-amino acids and the like according to the different positions of the amino groups on the carbon chain. Including but not limited to glycine, alanine, valine, leucine, isoleucine, phenylalanine, proline, tryptophan, serine, tyrosine, cysteine, methionine, Asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine and histidine, etc.
术语“-O-氨基酸”是指氨基酸的酸根和O形成酯基结构。The term "-O-amino acid" means that the acid radical of the amino acid and O form an ester structure.
术语“任选……被……取代”包括取代或未取代的情况。The term "optionally substituted by..." includes substituted or unsubstituted.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position. Those skilled in the art should understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. The substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
术语“一个或多个”指1、2、3、4、5、6、7、8、9、10、11或12个。The term "one or more" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom with a dissatisfying valence state has enough hydrogen atoms to supplement its valence state.
化合物Compound
在本发明所述的化合物中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14、A 1、A 2、A 3和A 4中任一个分别为如下所述具体化合物中所对应的基团。 In the compound of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 Any one of A 1 , A 2 , A 3 and A 4 is the corresponding group in the specific compound described below.
在另一优选例中，所述化合物优选为实施例中所制备的化合物。In another preferred embodiment, the compound is preferably the compound prepared in the embodiment.
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The salts that the compounds of the present invention may form also belong to the scope of the present invention. Unless otherwise specified, the compounds in the present invention are understood to include their salts. The term "salt" as used herein refers to a salt in the acid or basic form formed with an inorganic or organic acid and a base. In addition, when the compound of the present invention contains a basic fragment, it includes but is not limited to pyridine or imidazole, and when it contains an acidic fragment, including but not limited to carboxylic acid, the zwitterion ("internal salt") that may be formed is contained in Within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, they can be used in separation or purification steps in the preparation process. The compound of the present invention may form a salt. For example, the compound can be obtained by reacting with a certain amount of acid or base, such as an equivalent amount of acid or base, and salting out in the medium, or freeze-dried in an aqueous solution.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。The basic fragments contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids that can form salts include acetate (such as acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, and benzoate. , Benzene sulfonate, hydrogen sulfate, borate, butyrate, citrate, camphor salt, camphor sulfonate, cyclopentane propionate, diglycolate, dodecyl sulfate, Ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, isethionate (E.g. 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salt, pectinate, persulfate, phenylpropionate (such as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfate (such as formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, etc.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐，和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。The acidic fragments that some compounds of the present invention may contain, including but not limited to carboxylic acids, may form salts with various organic or inorganic bases. Typical salts formed by bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed by organic bases (such as organic amines), such as benzathine and bicyclohexyl Amine, Hypamine (a salt formed with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Base amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecular alkyl halides (such as methyl, ethyl, propyl and butyl chloride, bromide and iodide), dialkyl sulfate (E.g., dimethyl sulfate, diethyl, dibutyl and dipentyl sulfate), long chain halides (such as chlorides and bromides of decyl, dodecyl, tetradecyl and tetradecyl And iodides), aralkyl halides (such as benzyl and phenyl bromides) and so on.
本发明中化合物的前药及溶剂化物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、 或溶剂化物。本发明的化合物包括溶剂化物，如水合物。The prodrugs and solvates of the compounds of the present invention are also covered. The term "prodrug" herein refers to a compound that undergoes metabolism or chemical transformation through a chemical process to produce the compound, salt, or solvate of the present invention when treating related diseases. The compounds of the present invention include solvates such as hydrates.
本发明中的化合物、盐或溶剂化物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imine ethers). All these tautomers are part of the invention.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。All stereoisomers of compounds (for example, those asymmetric carbon atoms that may exist due to various substitutions), including their enantiomeric forms and diastereomeric forms, fall within the scope of the present invention. The independent stereoisomers of the compound in the present invention may not coexist with other isomers (for example, as a pure or substantially pure optical isomer with special activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or part of them. The chiral center of the present invention has two configurations, S or R, defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or separation of crystallization by derivatization into diastereomers, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to traditional methods, such as salt formation with an optically active acid and recrystallization.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。In the compound of the present invention, the weight content of the compound obtained by successive preparation, separation and purification is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), as described in the text Listed. Here, such "very pure" compounds of the invention are also part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configuration isomers of the compounds of the present invention are within the scope of coverage, whether in mixture, pure or very pure form. The definition of the compound of the present invention includes two olefin isomers, cis (Z) and trans (E), as well as cis and trans isomers of carbocyclic and heterocyclic rings.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,也有说明，其全部内容纳入参考文献之列。 Specific functional groups and chemical term definitions are described in detail below. For purposes of the present invention, the chemical elements with the Periodic Table of the Elements, CAS version , of Chemistry and Physics, 75 th Ed same as defined in Handbook.. The definition of specific functional groups is also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and the entire contents are included in the list of references.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, and exogenous Spin the mixture and other mixtures. In addition, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and their mixtures are included in the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1，或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers can contain various isomer ratios. For example, a mixture of only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by those skilled in the art and ratios that are mixtures of more complex isomers are also within the scope of the present invention.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示意图中及(或)示例中的方案可以制备。 The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in fact, it usually occurs when one or more atoms are replaced by atoms whose atomic weight or mass number is different. Examples of isotopes of compounds that can be included in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 O, respectively. , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention . Certain isotope-labeled compounds of the present invention, such as radioisotopes of 3 H and 14 C, are also among them, which are useful in tissue distribution experiments of drugs and substrates. Tritium, namely 3 H and carbon-14, namely 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie 2 H, have advantages in certain therapies due to its good metabolic stability, such as increasing the half-life or reducing the dosage in the body, so it can be given priority in some cases. Isotopically-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the scheme disclosed in the schematic diagram and/or the example.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If you want to design the synthesis of a specific enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis, or derivatized with a chiral adjuvant, separating the resulting diastereomeric mixture, and then removing the chiral adjuvant. The pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form a diastereomeric salt with it, and then through separation crystallization or chromatography, etc. After separation by conventional means, the pure enantiomers are obtained.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的，例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention can be combined with any number of substituents or functional groups to expand their coverage. Generally, whether the term "substituted" appears before or after the term "optional", the general formula including substituents in the formula of the present invention refers to the replacement of hydrogen radicals with designated structural substituents. When a plurality of positions in a specific structure are substituted by a plurality of specific substituents, each position of the substituents may be the same or different. The term "substitution" as used herein includes all permissible substitution of organic compounds. Broadly speaking, the permissible substituents include acyclic, cyclic, branched unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any permitted organic compound as described above to supplement its valence. In addition, the present invention is not intended to limit the permitted substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is good in the treatment of diseases in the form of stable compounds, such as infectious diseases or proliferative diseases. Here, the term "stable" refers to a compound that is stable and can be tested for a long enough time to maintain the structural integrity of the compound, preferably for a long enough time to be effective, and is used herein for the above purpose.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds and their pharmaceutically acceptable salts involved in the application, as well as the prodrugs that can be transformed into the structure of the compounds and their pharmaceutically acceptable salts involved in the application, are also included in the claims of the application. in.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时， 原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compound of general formula (I) can be combined with other drugs known to treat or improve similar conditions. In the case of combined administration, the original drug administration mode and dosage can remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered with one or more other drugs at the same time, a pharmaceutical composition containing one or more known drugs and the compound of formula I can be preferably used. The combination of drugs also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dose of the compound of formula I or the known drug may be lower than the dose of the compound used alone.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：胆汁酸受体(FXR)激动剂(如Obeticholic acid、tropifexor、GS-9674)、过氧化物酶体增殖物激活受体(PPAR)激动剂(如Elafibranor，saroglitazar、Remogliflozin Etabonate)、甲状腺激素受体(THR β)激动剂(如MGL-3196)、二酰甘油-O-酰基转移酶(DGAT)抑制剂(如Pradigastat、PF-06865571)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976、PF-05221304)、半胱天冬酶抑制剂(如Emricasan)、平滑受体(SMO)抑制剂(如Vismodegib)、半乳糖凝结素抑制剂(如GR-MD-02)、C-C趋化因子受体2型和5型的双重拮抗剂(如Cenicriviroc)、已酮糖激酶(KHK)抑制剂(PF-06835919)、胰高血糖素样肽-1(GLP-1)受体激动剂(如利拉鲁肽、semaglutide)、抗赖氨酰氧化酶样蛋白-2(LOXL2)单抗(如simtuzumab)、胆酸和花生四烯酸的复合物Aramchol等。 Drugs or active ingredients that can be used in combination with the compound of formula (I) include but are not limited to: bile acid receptor (FXR) agonists (such as Obeticholic acid, tropifexor, GS-9674), peroxidase Proliferator-activated receptor (PPAR) agonists (such as Elafibranor, saroglitazar, Remogliflozin Etabonate), thyroid hormone receptor (THR β ) agonists (such as MGL-3196), diacylglycerol-O-acyltransferase (DGAT) Inhibitors (such as Pradigastat, PF-06865571), acetyl-coenzyme A carboxylase (ACC) inhibitors (such as GS-0976, PF-05221304), caspase inhibitors (such as Emricasan), smooth receptor (SMO) ) Inhibitors (such as Vismodegib), galectin inhibitors (such as GR-MD-02), dual antagonists of CC chemokine receptor types 2 and 5 (such as Cenicriviroc), ketose kinase (KHK) Inhibitor (PF-06835919), glucagon-like peptide-1 (GLP-1) receptor agonist (such as liraglutide, semaglutide), anti-lysyl oxidase-like protein-2 (LOXL2) monoclonal antibody (Such as simtuzumab), Aramchol, a complex of cholic acid and arachidonic acid.
本申请所涉及的炎症、心血管疾病、感染、免疫性疾病、代谢性疾病或癌症包括(但并不限于)：原发性硬化(PBC)、原发性硬化性胆囊炎(PSC)、胆汁淤积症、自身免疫肝炎、病毒性肝炎(如乙肝)、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)或肝纤维化；动脉硬化症、血脂障碍、高胆固醇血症或高甘油三酯血症；I型糖尿病、II型糖尿病或肥胖；肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、血癌、骨癌、肾癌、胃癌、肝癌或大肠癌。Inflammation, cardiovascular disease, infection, immune disease, metabolic disease or cancer involved in this application include (but not limited to): primary sclerosis (PBC), primary sclerosing cholecystitis (PSC), bile Stasis, autoimmune hepatitis, viral hepatitis (such as hepatitis B), alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or liver fibrosis; arteriosclerosis, dyslipidemia, high cholesterol Hyperemia or hypertriglyceridemia; type I diabetes, type II diabetes or obesity; lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, blood cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, or colorectal cancer.
术语“共振体”是指同一化合物分子的极限结构式,原子核相对位置不变,只是电子(一般是π电子和未共用电子对)排列不同。The term "resonant body" refers to the limit structural formula of the same compound molecule. The relative position of the nucleus remains unchanged, but the arrangement of electrons (usually π electrons and unshared electron pairs) is different.
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。The term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention and an acid or a base suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of this invention with acids. Acids suitable for salt formation include but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
另一类优选的盐是本发明化合物与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、 碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。Another type of preferred salt is the salt formed by the compound of the present invention with a base, such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine.
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。The term "solvate" refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio. "Hydrate" refers to a complex formed by coordination of the compound of the present invention with water.
术语“前药分子”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式(I)一类化合物，或式(I)一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。The term "prodrug molecule" includes itself which may be biologically active or inactive. When taken by a proper method, it undergoes metabolism or chemical reaction in the human body to transform into a compound of formula (I), or A salt or solution composed of a compound of formula (I). The prodrugs include (but are not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone ester, sulfoxide ester, amino compound, carbamate, azo compound of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020100888-appb-000013
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid). , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween)
Figure PCTCN2020100888-appb-000013
), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和 硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectant, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
所述药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂，或控释型或缓释型或纳米制剂。The dosage form of the pharmaceutical composition includes (but is not limited to): injection, tablet, capsule, aerosol, suppository, film, dripping pill, topical liniment, or controlled release or sustained release or nano formulation .
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。The composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。The dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, spray and inhalant. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗肿瘤药物) 联合给药。The compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is the pharmaceutically effective dosage considered to be administered. For a 60kg body weight, the daily The administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skill range of a skilled physician.
与现有技术相比，本发明具有以下主要优点：Compared with the prior art, the present invention has the following main advantages:
1)本发明化合物对PPAR受体有多重激动作用、具有更好药效学性能和更好的安全性能。1) The compound of the present invention has multiple agonistic effects on PPAR receptors, has better pharmacodynamic performance and better safety performance.
2)本发明化合物具有更好的药代动力学性质，如更高的最大血药浓度和/或药物血浆暴露量。2) The compound of the present invention has better pharmacokinetic properties, such as higher maximum blood drug concentration and/or drug plasma exposure.
3)本发明化合物具有显著减轻非酒精性脂肪肝炎(NASH)的药效作用。3) The compound of the present invention has the pharmacodynamic effect of significantly reducing non-alcoholic steatohepatitis (NASH).
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples usually follow the conventional conditions such as Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions described in the manufacturer The suggested conditions. Unless otherwise stated, percentages and parts are calculated by weight.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) and liquid mass spectrometry (LC-MS).
NMR是使用Bruker AVANCE-400核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。 NMR is detected by Bruker AVANCE-400 nuclear magnetic instrument. The solvent for determination includes deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol ( CD 3 OD), etc., the internal standard uses tetramethylsilane (TMS), and the chemical shift is measured in units of parts per million (ppm).
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。Liquid mass spectrometry (LC-MS) is detected by Waters SQD2 mass spectrometer.
HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100x 3.0mm色谱柱)。HPLC measurement uses Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100x 3.0mm chromatographic column).
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the TLC uses 0.15-0.20mm, and the preparative thin layer chromatography uses 0.4mm-0.5mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized by using or according to literature reported in the field.
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。Except for special instructions, all reactions in the present invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is all degrees Celsius.
实施例1Example 1
(E)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯的制备 (E)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl)phenoxy)phenyl)-3-(3-methoxy-5- (Methoxy-d 3 )phenyl) methyl acrylate preparation
Figure PCTCN2020100888-appb-000014
Figure PCTCN2020100888-appb-000014
第一步：3-羟基-5-(甲氧基-d 3)苯甲醛的制备 Step 1: Preparation of 3-hydroxy-5-(methoxy-d 3 )benzaldehyde
在500mL的圆底烧瓶中依次加入3,5-二羟基苯甲醛(5.6g，40.54mmol)、碳酸钾(7.5g，54.27mmol)和N,N-二甲基甲酰胺(100mL)。在冰浴下(0-5℃)，用 30分钟滴加对甲苯磺酸-d 3-甲酯(6.85g，36.20mmol)的N,N-二甲基甲酰胺(50mL)溶液。反应液随后在0-5℃反应1小时，再升至室温反应18小时。得到的混合物加水(200mL)淬灭，然后用盐酸调pH至2再用乙酸乙酯(100mL×4)萃取。合并的有机相用饱和食盐水洗涤，再无水硫酸镁干燥后过滤。滤液减压浓缩，所得粗品通过硅胶柱层析纯化得到目标化合物(2.1g，收率37.4％)。 In a 500 mL round bottom flask, 3,5-dihydroxybenzaldehyde (5.6 g, 40.54 mmol), potassium carbonate (7.5 g, 54.27 mmol) and N,N-dimethylformamide (100 mL) were sequentially added. In an ice bath (0-5°C), a solution of p-toluenesulfonic acid-d 3 -methyl ester (6.85 g, 36.20 mmol) in N,N-dimethylformamide (50 mL) was added dropwise over 30 minutes. The reaction solution was then reacted at 0-5°C for 1 hour, and then raised to room temperature for 18 hours. The resulting mixture was quenched with water (200 mL), then adjusted to pH 2 with hydrochloric acid, and extracted with ethyl acetate (100 mL×4). The combined organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the target compound (2.1 g, yield 37.4%).
LC-MS:m/z 154(M-H) -。 LC-MS: m/z 154(MH) - .
第二步：3-甲氧基-5-(甲氧基-d 3)苯甲醛的制备 Step 2: Preparation of 3-methoxy-5-(methoxy-d 3 )benzaldehyde
在50mL的圆底烧瓶中依次加入3-羟基-5-(甲氧基-d 3)苯甲醛(2.1g，13.53mmol)、碳酸钾(2.8g，20.30mmol)和N,N-二甲基甲酰胺(20mL)。在冰浴，滴加碘甲烷(2.3g，16.24mmol)。滴加完毕，反应液升至室温反应2小时，随后加水(50mL)淬灭后用乙酸乙酯(50mL×4)萃取。合并的有机相用饱和食盐水洗涤，然后用无水硫酸镁干燥后过滤，滤液减压浓缩得到目标化合物(粗产品2.2g，粗产率96.1％)。 Add 3-hydroxy-5-(methoxy-d 3 )benzaldehyde (2.1g, 13.53mmol), potassium carbonate (2.8g, 20.30mmol) and N,N-dimethyl in a 50mL round bottom flask. Formamide (20 mL). In an ice bath, iodomethane (2.3 g, 16.24 mmol) was added dropwise. After the addition was completed, the reaction solution was raised to room temperature to react for 2 hours, then quenched with water (50 mL) and extracted with ethyl acetate (50 mL×4). The combined organic phase was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (crude product 2.2 g, crude yield 96.1%).
1H NMR(400MHz，DMSO-d 6)δ9.93(s,1H),7.07(d,J＝2.4Hz,2H),6.83(t,J＝2.4Hz,1H),3.82(s,3H)。 1 H NMR(400MHz, DMSO-d 6 )δ9.93(s,1H), 7.07(d,J=2.4Hz,2H), 6.83(t,J=2.4Hz,1H), 3.82(s,3H) .
第三步：(E)-2-(4-羟基苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸的制备 The third step: Preparation of (E)-2-(4-hydroxyphenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl)acrylic acid
在25mL的圆底烧瓶中依次加入3-甲氧基-5-(甲氧基-d 3)苯甲醛(2.2g，13.00mmol)、对羟基苯乙酸(1.98g，13.00mmol)和乙酸酐(4.4mL)，随后滴加入三乙胺(1.9mL)。滴加完毕，反应液加热至135℃反应4小时，然后冷却至室温。反应液中滴加盐酸水溶液(20％wt，9.5mL)，加完后在室温搅拌30分钟后过滤。滤饼用水淋洗，然后加入到预先配置好的氢氧化钠(2.7g)水溶液中(14.5mL)，并在室温搅拌1小时。得到的混合物过滤，向所得滤液中滴加盐酸水溶液(20％wt，14.5mL)。滴加完毕，反应液在室温搅拌30分钟后过滤。滤饼用水淋洗后在60℃真空干燥4小时。将所得粗品用乙醇和水中重结晶得到目标化合物(1.9g，收率48.2％)。 In a 25mL round-bottomed flask were added 3-methoxy-5-(methoxy-d 3 )benzaldehyde (2.2g, 13.00mmol), p-hydroxyphenylacetic acid (1.98g, 13.00mmol) and acetic anhydride ( 4.4 mL), and then triethylamine (1.9 mL) was added dropwise. After the addition was completed, the reaction solution was heated to 135°C for 4 hours and then cooled to room temperature. An aqueous hydrochloric acid solution (20% wt, 9.5 mL) was added dropwise to the reaction solution, and after the addition, the mixture was stirred at room temperature for 30 minutes and then filtered. The filter cake was rinsed with water, and then added to the pre-prepared sodium hydroxide (2.7g) aqueous solution (14.5mL), and stirred at room temperature for 1 hour. The obtained mixture was filtered, and an aqueous hydrochloric acid solution (20% wt, 14.5 mL) was added dropwise to the obtained filtrate. After the addition was completed, the reaction solution was stirred at room temperature for 30 minutes and filtered. The filter cake was rinsed with water and dried under vacuum at 60°C for 4 hours. The obtained crude product was recrystallized from ethanol and water to obtain the target compound (1.9 g, yield 48.2%).
LC-MS:m/z 304(M+H) +。 LC-MS: m/z 304(M+H) + .
第四步：(E)-2-(4-羟基苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯的制备 Step 4: Preparation of (E)-2-(4-hydroxyphenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl) methyl acrylate
在50mL的圆底烧瓶中依次加入(E)-2-(4-羟基苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸(1.9g，6.26mmol)和甲醇(18mL)，随后滴加浓硫酸(0.5mL)。滴加完毕反应液加热回流反应24小时，然后降至室温。所得混合物真空浓缩除去部分溶剂，然后加乙酸乙酯(50mL)萃取。有机相用水(50mL)洗涤。水相合并后，再用乙酸乙酯(30mL)萃取。所有有机相合并，依次用饱和碳酸氢钠水溶液(20mL)和饱和食盐水(50mL)洗涤，经过无水硫酸镁干燥后过滤。滤液真空浓缩得目标化合物(1.8 g，90.5％)。 (E)-2-(4-hydroxyphenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl)acrylic acid (1.9g, 6.26 mmol) and methanol (18 mL), followed by concentrated sulfuric acid (0.5 mL) dropwise. After the dropwise addition, the reaction solution was heated and refluxed for 24 hours, and then cooled to room temperature. The resulting mixture was concentrated in vacuo to remove part of the solvent, and then extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL). After the aqueous phases were combined, they were extracted with ethyl acetate (30 mL). All organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (50 mL) in turn, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the target compound (1.8 g, 90.5%).
LC-MS:m/z 318(M+H) +。 LC-MS: m/z 318(M+H) + .
第五步：(E)-2-(4-(4-甲酰基苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯的制备 The fifth step: (E)-2-(4-(4-formylphenoxy)phenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl)methacrylate Preparation of ester
在50mL的圆底烧瓶中依次加入(E)-2-(4-羟基苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯(1.8g，5.67mmol)、对氟苯甲醛(0.74g，5.96mmol)、碳酸钾(1.57g，11.34mmol)和二甲基亚砜(10mL)。得到的反应液加热至100℃反应4小时，然后冷至室温再用水(50mL)淬灭后用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水洗涤，然后用无水硫酸镁干燥后过滤，滤液浓缩得目标化合物(2.2g，粗收率92.0％)，无需纯化直接用于下一步反应。 Add (E)-2-(4-hydroxyphenyl)-3-(3-methoxy-5-(methoxy-d 3 )phenyl) methyl acrylate (1.8 g, 5.67 mmol), p-fluorobenzaldehyde (0.74 g, 5.96 mmol), potassium carbonate (1.57 g, 11.34 mmol) and dimethyl sulfoxide (10 mL). The resulting reaction solution was heated to 100°C to react for 4 hours, then cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain the target compound (2.2 g, crude yield 92.0%), which was directly used in the next reaction without purification.
第六步：(E)-2-(4-(4-((Z)-(2,4-二氧代噻唑烷-5-亚基)亚基)苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯的制备 The sixth step: (E)-2-(4-(4-((Z)-(2,4-dioxothiazolidine-5-ylidene) subunit)phenoxy)phenyl)-3- Preparation of (3-methoxy-5-(methoxy-d 3 )phenyl) methyl acrylate
在50mL的装有分水器的圆底烧瓶中依次加入(E)-2-(4-(4-甲酰基苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯(2.2g，5.22mmol)、2,4-噻唑烷二酮(688mg，5.87mmol)、苯甲酸(864mg，7.07mmol)和甲苯(14mL)，随后滴加哌啶(667mg，7.83mmol)。滴加完毕反应液加热回流分水4小时，然后冷至室温。所得混合物真空浓缩除去溶剂，然后加入甲苯(4mL)和甲醇(12mL)。得到的混合物在60℃搅拌2小时，然后降至室温并依次在室温搅拌16小时、在冰浴搅拌1小时后过滤。滤饼用甲醇淋洗，经真空干燥得到目标化合物(2.2g，收率81.0％)。 Add (E)-2-(4-(4-formylphenoxy)phenyl)-3-(3-methoxy-5-(formyl) in a 50mL round-bottom flask equipped with a water trap. (Oxy-d 3 )phenyl)methyl acrylate (2.2g, 5.22mmol), 2,4-thiazolidinedione (688mg, 5.87mmol), benzoic acid (864mg, 7.07mmol) and toluene (14mL), followed by Piperidine (667mg, 7.83mmol) was added dropwise. After the dropwise addition, the reaction solution was heated to reflux and separated water for 4 hours, and then cooled to room temperature. The resulting mixture was concentrated in vacuo to remove the solvent, and then toluene (4 mL) and methanol (12 mL) were added. The resulting mixture was stirred at 60°C for 2 hours, then lowered to room temperature and stirred at room temperature for 16 hours, stirred in an ice bath for 1 hour, and filtered. The filter cake was rinsed with methanol and dried under vacuum to obtain the target compound (2.2 g, yield 81.0%).
LC-MS:m/z 521(M+H) +。 LC-MS: m/z 521(M+H) + .
第七步：(E)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯的制备 The seventh step: (E)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl)phenoxy)phenyl)-3-(3-methoxy Preparation of methyl-5-(methoxy-d 3 )phenyl) acrylate
在100mL的三口烧瓶中依次加入(E)-2-(4-(4-((Z)-(2,4-二氧代噻唑烷-5-亚基)亚基)苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸甲酯(2.2g，4.23mmol)、甲酸铵(16g，254mmol)、Pt/C(10％wt，943mg，含水65％)和乙酸(66mL)。反应液加热至115℃反应9小时，然后降温至室温后过滤。滤饼用乙酸淋洗，滤液真空浓缩除去部分溶剂后用二氯甲烷(50mL×2)萃取。合并的有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤，经无水硫酸镁干燥后过滤。滤液减压浓缩，残留物经硅胶柱层析得到粗产品。粗产品用无水乙醇重结晶得到目标化合物(1.06g，收率48.0％)。 Add (E)-2-(4-(4-((Z)-(2,4-dioxothiazolidine-5-ylidene) subunit) phenoxy) phenyl in a 100 mL three-necked flask )-3-(3-Methoxy-5-(methoxy-d 3 )phenyl) methyl acrylate (2.2g, 4.23mmol), ammonium formate (16g, 254mmol), Pt/C (10%wt , 943mg, 65% water) and acetic acid (66mL). The reaction solution was heated to 115°C to react for 9 hours, then cooled to room temperature and filtered. The filter cake was rinsed with acetic acid, and the filtrate was concentrated in vacuo to remove part of the solvent and then extracted with dichloromethane (50 mL×2). The combined organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a crude product. The crude product was recrystallized with absolute ethanol to obtain the target compound (1.06 g, yield 48.0%).
LC-MS:m/z 523(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(brs,1H),7.73(s,1H),7.30(d,J＝8.4Hz,2H),7.22(d,J＝8.8Hz,2H),7.04(d,J＝8.8Hz,2H), 6.99(d,J＝8.4Hz,2H),6.43(t,J＝2.4Hz,1H),6.29(d,J＝2.4Hz,2H),4.93(dd,J＝4.4Hz和9.2Hz,1H),3.74(s,3H),3.59(s,3H),3.39(dd,J＝4.4Hz和14.4Hz,1H),3.15(dd,J＝9.2Hz和14.4Hz,1H)。 LC-MS: m/z 523(M+H) + . 1 H NMR(400MHz, DMSO-d 6 )δ12.06(brs,1H), 7.73(s,1H), 7.30(d,J=8.4Hz,2H), 7.22(d,J=8.8Hz,2H) ,7.04(d,J=8.8Hz,2H), 6.99(d,J=8.4Hz,2H), 6.43(t,J=2.4Hz,1H), 6.29(d,J=2.4Hz,2H), 4.93 (dd, J = 4.4 Hz and 9.2 Hz, 1H), 3.74 (s, 3H), 3.59 (s, 3H), 3.39 (dd, J = 4.4 Hz and 14.4 Hz, 1H), 3.15 (dd, J = 9.2 Hz and 14.4 Hz, 1H).
实施例2Example 2
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl )Phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000015
Figure PCTCN2020100888-appb-000015
第一步：3,5-双(甲氧基-d 3)苯甲醛的制备 Step 1: Preparation of 3,5-bis(methoxy-d 3 )benzaldehyde
在100mL的圆底烧瓶中依次加入3,5-二羟基苯甲醛(4g，28.96mmol)、对甲苯磺酸-d 3-甲酯(12g，63.70mmol)、碳酸钾(12g，86.88mmol)和N,N-二甲基甲酰胺(50mL)。反应液加热至65℃反应32小时，冷至室温后用水(300mL)淬灭，然后用乙酸乙酯(100mL×2)萃取。合并的有机相用饱和食盐水(100mL×2)洗涤，经过无水硫酸镁干燥后过滤。滤液减压浓缩得到目标化合物(粗产品4.67g)，无需提纯直接用于下一步反应。 In a 100mL round-bottomed flask were added 3,5-dihydroxybenzaldehyde (4g, 28.96mmol), p-toluenesulfonic acid-d 3 -methyl ester (12g, 63.70mmol), potassium carbonate (12g, 86.88mmol) and N,N-Dimethylformamide (50 mL). The reaction solution was heated to 65°C to react for 32 hours, cooled to room temperature and quenched with water (300 mL), and then extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the target compound (crude product 4.67 g), which was directly used in the next reaction without purification.
1H NMR(400MHz，DMSO-d 6)δ9.93(s,1H),7.07(d,J＝2.4Hz,2H),6.83(t,J＝2.4Hz,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 7.07 (d, J=2.4 Hz, 2H), 6.83 (t, J=2.4 Hz, 1H).
第二步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-羟基苯基)丙烯酸的制备 Step 2: Preparation of (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-hydroxyphenyl)acrylic acid
在25mL的圆底烧瓶中依次加入3,5-双(甲氧基-d 3)苯甲醛(4.5g，26.13mmol)、 对羟基苯乙酸(3.98g，26.13mmol)和乙酸酐(9mL)，随后在30℃以下向反应液中滴加三乙胺(3.8mL)。滴加完毕，反应液加热至135℃反应3.5小时，然后冷却至室温，随后滴加盐酸水溶液(20％wt，20mL)。滴加完毕反应液搅拌30分钟后过滤。滤饼用水淋洗后加入到预先配置好的氢氧化钠(5.5g)的水溶液中(30mL)。得到的混合物搅拌1小时后过滤。滤液中滴加盐酸水溶液(20％wt，30mL)。滴加完毕反应液搅拌30分钟后过滤。滤饼用水淋洗后在60℃真空干燥4小时得到粗品。粗品用乙醇和水重结晶得到目标化合物(3.64g)。 Add 3,5-bis(methoxy-d 3 )benzaldehyde (4.5g, 26.13mmol), p-hydroxyphenylacetic acid (3.98g, 26.13mmol) and acetic anhydride (9mL) in a 25mL round-bottomed flask. Then, triethylamine (3.8 mL) was added dropwise to the reaction solution below 30°C. After the addition was completed, the reaction solution was heated to 135°C for 3.5 hours, then cooled to room temperature, and then an aqueous hydrochloric acid solution (20% wt, 20 mL) was added dropwise. After dripping, the reaction solution was stirred for 30 minutes and filtered. The filter cake was rinsed with water and added to a pre-prepared aqueous solution (30 mL) of sodium hydroxide (5.5 g). The resulting mixture was stirred for 1 hour and then filtered. An aqueous hydrochloric acid solution (20% wt, 30 mL) was added dropwise to the filtrate. After dripping, the reaction solution was stirred for 30 minutes and filtered. The filter cake was rinsed with water and dried in vacuum at 60°C for 4 hours to obtain a crude product. The crude product was recrystallized from ethanol and water to obtain the target compound (3.64 g).
LC-MS:m/z 307(M+H) +。 LC-MS: m/z 307(M+H) + .
第三步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-羟基苯基)丙烯酸甲酯的制备 The third step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-hydroxyphenyl) methyl acrylate
在50mL的圆底烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-羟基苯基)丙烯酸(1.8g，5.87mmol)和甲醇(15mL)，随后滴加浓硫酸(0.4mL)。滴加完毕反应液加热回流反应23小时，然后降至室温。所得混合物真空浓缩除去部分溶剂，然后加乙酸乙酯(50mL)萃取。有机相用水(50mL)洗涤。水相合并后，再用乙酸乙酯(30mL)萃取。所有有机相合并，依次用饱和碳酸氢钠水溶液(20mL)和饱和食盐水(50mL)洗涤，经过无水硫酸镁干燥后过滤。滤液真空浓缩得目标化合物(1.95g，定量收率)。 Add (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-hydroxyphenyl)acrylic acid (1.8g, 5.87mmol) in a 50mL round bottom flask successively And methanol (15 mL), then concentrated sulfuric acid (0.4 mL) was added dropwise. After the dropwise addition, the reaction solution was heated to reflux for 23 hours, and then cooled to room temperature. The resulting mixture was concentrated in vacuo to remove part of the solvent, and then extracted with ethyl acetate (50 mL). The organic phase was washed with water (50 mL). After the aqueous phases were combined, they were extracted with ethyl acetate (30 mL). All organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (50 mL) in turn, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the target compound (1.95 g, quantitative yield).
LC-MS:m/z 321(M+H) +。 LC-MS: m/z 321(M+H) + .
第四步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-甲酰基苯氧基)苯基)丙烯酸甲酯的制备 The fourth step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-formylphenoxy)phenyl) methyl acrylate
在50mL的圆底烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-羟基苯基)丙烯酸甲酯(1.9g，5.93mmol)、对氟苯甲醛(0.77g，6.23mmol)、碳酸钾(1.64g，11.86mmol)和二甲基亚砜(10mL)。得到的反应液加热至100℃反应20小时，然后冷至室温再用水(25mL)淬灭。得到的混合物过滤，滤饼用水淋洗后在60℃真空干燥5小时得到粗品，所得粗品经硅胶柱层析纯化得到目标化合物(1.99g，79.0％)。 Add (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-hydroxyphenyl) acrylate (1.9g, 5.93) to a 50mL round-bottomed flask. mmol), p-fluorobenzaldehyde (0.77 g, 6.23 mmol), potassium carbonate (1.64 g, 11.86 mmol) and dimethyl sulfoxide (10 mL). The resulting reaction solution was heated to 100°C to react for 20 hours, then cooled to room temperature and quenched with water (25 mL). The obtained mixture was filtered, the filter cake was rinsed with water and then vacuum dried at 60° C. for 5 hours to obtain a crude product, which was purified by silica gel column chromatography to obtain the target compound (1.99 g, 79.0%).
LC-MS:m/z 425(M+H) +。 LC-MS: m/z 425(M+H) + .
第五步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((Z)-(2,4-二氧代噻唑烷-5-亚基)甲基)苯氧基)苯基)丙烯酸甲酯的制备 The fifth step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((Z)-(2,4-dioxothiazole) (Alk-5-ylidene) methyl) phenoxy) phenyl) methyl acrylate
在50mL的装有分水器的圆底烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-甲酰基苯氧基)苯基)丙烯酸甲酯(1.9g，4.48mmol)、2,4-噻唑烷二酮(0.59g，5.04mmol)、苯甲酸(0.74g，6.07mmol)和甲苯(12mL)，随后滴加哌啶(0.57g，6.71mmol)。滴加完毕反应液加热回流分水3小时，然后冷至室温。 所得混合物真空浓缩除去溶剂，然后加入甲苯(4mL)和甲醇(12mL)。得到的混合物在60℃搅拌2小时，然后降至室温并依次在室温搅拌16小时、在冰浴搅拌1小时后过滤。滤饼用甲醇淋洗，经真空干燥得到目标化合物(1.84g，收率78.5％)。 Add (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-formylbenzene) to a 50mL round bottom flask equipped with a water trap. Oxy)phenyl)methyl acrylate (1.9g, 4.48mmol), 2,4-thiazolidinedione (0.59g, 5.04mmol), benzoic acid (0.74g, 6.07mmol) and toluene (12mL), followed by drops Add piperidine (0.57 g, 6.71 mmol). After dripping, the reaction solution was heated to reflux and separated water for 3 hours, and then cooled to room temperature. The resulting mixture was concentrated in vacuo to remove the solvent, and then toluene (4 mL) and methanol (12 mL) were added. The resulting mixture was stirred at 60°C for 2 hours, then lowered to room temperature and stirred at room temperature for 16 hours, stirred in an ice bath for 1 hour, and filtered. The filter cake was rinsed with methanol and dried under vacuum to obtain the target compound (1.84 g, yield 78.5%).
LC-MS:m/z 524(M+H) +。 LC-MS: m/z 524(M+H) + .
第六步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备 The sixth step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5- (Yl)methyl)phenoxy)phenyl)methyl acrylate
在100mL的三口烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((Z)-(2,4-二氧代噻唑烷-5-亚基)甲基)苯氧基)苯基)丙烯酸甲酯(1.8g，3.44mmol)、甲酸铵(13g，206mmol)、Pt/C(10％wt，0.77g，含水65％)和乙酸(54mL)。反应液加热至115℃反应15小时，然后降温至室温后过滤。滤饼用乙酸淋洗，滤液真空浓缩除去部分溶剂后用二氯甲烷(80mL×2)萃取。合并的有机相依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤，经无水硫酸镁干燥后过滤。滤液减压浓缩，残留物经硅胶柱层析得到粗产品。粗产品用无水乙醇重结晶得到目标化合物(1.08g，收率59.8％)。 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((Z)-(2,4- Dioxothiazolidine-5-ylidene) methyl) phenoxy) phenyl) methyl acrylate (1.8g, 3.44mmol), ammonium formate (13g, 206mmol), Pt/C (10%wt, 0.77g) , 65% water) and acetic acid (54 mL). The reaction solution was heated to 115°C to react for 15 hours, then cooled to room temperature and filtered. The filter cake was rinsed with acetic acid, and the filtrate was concentrated in vacuo to remove part of the solvent and then extracted with dichloromethane (80 mL×2). The combined organic phase was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain a crude product. The crude product was recrystallized with absolute ethanol to obtain the target compound (1.08 g, yield 59.8%).
LC-MS:m/z 526(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(brs,1H),7.73(s,1H),7.30(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.99(d,J＝8.8Hz,2H),6.42(t,J＝2.0Hz,1H),6.29(d,J＝2.4Hz,2H),4.93(dd,J＝4.4Hz和8.8Hz,1H),3.74(s,3H),3.39(dd,J＝4.4Hz和14.4Hz,1H),3.15(dd,J＝8.8Hz和14.4Hz,1H)。 LC-MS: m/z 526(M+H) + . 1 H NMR(400MHz, DMSO-d 6 )δ12.06(brs,1H), 7.73(s,1H), 7.30(d,J=8.4Hz,2H), 7.22(d,J=8.4Hz,2H) ,7.04(d,J=8.4Hz,2H), 6.99(d,J=8.8Hz,2H), 6.42(t,J=2.0Hz,1H), 6.29(d,J=2.4Hz,2H), 4.93 (dd, J=4.4Hz and 8.8Hz, 1H), 3.74 (s, 3H), 3.39 (dd, J=4.4Hz and 14.4Hz, 1H), 3.15 (dd, J=8.8Hz and 14.4Hz, 1H) .
实施例3Example 3
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸的制备 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl )Phenoxy)phenyl)acrylic acid
Figure PCTCN2020100888-appb-000016
Figure PCTCN2020100888-appb-000016
第一步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸的制备 The first step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5- (Yl)methyl)phenoxy)phenyl)acrylic acid
在25mL的圆底烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4- 二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯(0.88g，1.67mmol)、氢氧化锂一水合物(200mg，4.76mmol)、四氢呋喃(4mL)和水(3mL)。反应液在室温反应24小时，然后加水淬灭(10mL)，随后用乙酸乙酯(10mL×3)萃取。水相用盐酸调pH至1后过滤，滤饼用水洗后干燥得粗品。所得粗品经硅胶柱层析柱纯化得目标化合物(0.66g，收率77.1％)。 Add (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxo) to a 25mL round bottom flask in sequence Thiazolidine-5-yl)methyl)phenoxy)phenyl)methyl acrylate (0.88g, 1.67mmol), lithium hydroxide monohydrate (200mg, 4.76mmol), tetrahydrofuran (4mL) and water (3mL) . The reaction solution was reacted at room temperature for 24 hours, then quenched with water (10 mL), and then extracted with ethyl acetate (10 mL×3). The pH of the aqueous phase is adjusted to 1 with hydrochloric acid and then filtered, the filter cake is washed with water and dried to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain the target compound (0.66 g, yield 77.1%).
LC-MS:m/z 512(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.75(brs,1H),12.06(brs,1H),7.70(s,1H),7.29(d,J＝8.8Hz,2H),7.20(d,J＝8.8Hz,2H),7.03(d,J＝8.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.41(t,J＝2.0Hz,1H),6.28(d,J＝2.0Hz,2H),4.93(dd,J＝4.4Hz和9.2Hz,1H),3.39(dd,J＝4.4Hz和14.0Hz,1H),3.14(dd,J＝9.2Hz和14.4Hz,1H)。 LC-MS: m/z 512(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.75 (brs, 1H), 12.06 (brs, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.8Hz, 2H), 7.03 (d, J = 8.4Hz, 2H), 6.98 (d, J = 8.4Hz, 2H), 6.41 (t, J = 2.0Hz, 1H), 6.28 (d, J = 2.0Hz, 2H), 4.93 (dd, J = 4.4 Hz and 9.2 Hz, 1H), 3.39 (dd, J = 4.4 Hz and 14.0 Hz, 1H), 3.14 (dd, J = 9.2 Hz and 14.4 Hz, 1H) .
按照实施例3所述同样的方法使用不同的起始原料合成了以下化合物：The following compounds were synthesized according to the same method described in Example 3 using different starting materials:
实施例4Example 4
(E)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)-3-(3-甲氧基-5-(甲氧基-d 3)苯基)丙烯酸 (E)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl)phenoxy)phenyl)-3-(3-methoxy-5- (Methoxy-d 3 )phenyl)acrylic acid
Figure PCTCN2020100888-appb-000017
Figure PCTCN2020100888-appb-000017
LC-MS:m/z 509(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.75(brs,1H),12.06(brs,1H),7.70(s,1H),7.29(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.41(t,J＝2.4Hz,1H),6.28(d,J＝2.4Hz,2H),4.93(dd,J＝4.4Hz,9.2Hz,1H),3.59(s,3H),3.39(dd,J＝4.4,14.0Hz,1H),3.14(dd,J＝9.2Hz,14.0Hz,1H)。 LC-MS: m/z 509(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.75 (brs, 1H), 12.06 (brs, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4Hz, 2H), 7.03 (d, J = 8.4Hz, 2H), 6.98 (d, J = 8.4Hz, 2H), 6.41 (t, J = 2.4Hz, 1H), 6.28 (d, J = 2.4Hz, 2H), 4.93 (dd, J = 4.4 Hz, 9.2 Hz, 1H), 3.59 (s, 3H), 3.39 (dd, J = 4.4, 14.0 Hz, 1H), 3.14 (dd, J = 9.2 Hz ,14.0Hz,1H).
实施例5Example 5
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯的制备 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5- d) Preparation of methyl)phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000018
Figure PCTCN2020100888-appb-000018
第一步：(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯的制备 The first step: (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5- -5-d) methyl) phenoxy) phenyl) methyl acrylate
在50mL的圆底烧瓶中依次加入(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯(1.3g，2.47mmol)、三乙胺(751mg，7.42mmol)和甲醇-d 1(13mL)。反应液在0℃反应19小时，随后在冰浴下将反应液滴加到HCl水溶液(1M，200mL)中。得到的混合物搅拌后过滤，滤饼水洗后干燥得目标化合物(1.3g，定量收率)。 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxo Thiazolidine-5-yl)methyl)phenoxy)phenyl)methyl acrylate (1.3 g, 2.47 mmol), triethylamine (751 mg, 7.42 mmol) and methanol-d 1 (13 mL). The reaction solution was reacted at 0°C for 19 hours, and then the reaction solution was added dropwise to an aqueous HCl solution (1M, 200 mL) under an ice bath. The obtained mixture was stirred and filtered, and the filter cake was washed with water and dried to obtain the target compound (1.3 g, quantitative yield).
LC-MS:m/z 527(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(s,1H),7.73(s,1H),7.30(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.04(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.74(s,3H),3.38(d,J＝14.1Hz,1H),3.14(d,J＝14.1Hz,1H)。 LC-MS: m/z 527(M+H) + . 1 H NMR(400MHz, DMSO-d 6 ) δ12.06(s,1H), 7.73(s,1H), 7.30(d,J=8.6Hz,2H), 7.21(d,J=8.6Hz,2H) ,7.04(d,J=8.6Hz,2H), 6.99(d,J=8.6Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.74 (s, 3H), 3.38 (d, J=14.1 Hz, 1H), 3.14 (d, J=14.1 Hz, 1H).
实施例5A和5BExamples 5A and 5B
(R,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯和(S,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯的制备 (R,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl- 5-d)Methyl)phenoxy)phenyl)methyl acrylate and (S,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-( Preparation of 4-((2,4-dioxothiazolidine-5-yl-5-d)methyl)phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000019
Figure PCTCN2020100888-appb-000019
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯(1.2g,2.28mmol)溶于甲醇(50mL)中，然后使用SFC进行分离(色谱柱CHIRALPAK AD-H 20×250mm,5um(Daicel)，流动相CO2/MeOH/ACN＝55/22.5/22.5，检测波长214nm)得到两个光学纯的异构体。 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5- d)Methyl)phenoxy)phenyl)methyl acrylate (1.2g, 2.28mmol) was dissolved in methanol (50mL), and then separated by SFC (column CHIRALPAK AD-H 20×250mm, 5um (Daicel) , Mobile phase CO2/MeOH/ACN=55/22.5/22.5, detection wavelength 214nm) to obtain two optically pure isomers.
实施例5AExample 5A
(R,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基) 苯氧基)苯基)丙烯酸甲酯:旋光度[α] D＝+73.6°(c＝0.2，20℃，dioxane)。LC-MS:m/z527(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(s,1H),7.73(s,1H),7.30(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.04(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.74(s,3H),3.38(d,14.1Hz,1H),3.14(d,14.1Hz,1H)。 (R,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl- 5-d) Methyl) phenoxy) phenyl) methyl acrylate: optical rotation [α] D = +73.6° (c = 0.2, 20° C., dioxane). LC-MS: m/z 527(M+H) + . 1 H NMR(400MHz, DMSO-d 6 ) δ12.06(s,1H), 7.73(s,1H), 7.30(d,J=8.6Hz,2H), 7.21(d,J=8.6Hz,2H) ,7.04(d,J=8.6Hz,2H), 6.99(d,J=8.6Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.74 (s, 3H), 3.38 (d, 14.1 Hz, 1H), 3.14 (d, 14.1 Hz, 1H).
实施例5BExample 5B
(S,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯:旋光度[α] D＝-72.5°(c＝0.2，20℃，dioxane)。LC-MS:m/z527(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(s,1H),7.73(s,1H),7.30(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.04(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.74(s,3H),3.38(d,14.1Hz,1H),3.14(d,14.1Hz,1H)。 (S,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl- 5-d) Methyl)phenoxy)phenyl)methyl acrylate: optical rotation [α] D = -72.5° (c=0.2, 20°C, dioxane). LC-MS: m/z 527(M+H) + . 1 H NMR(400MHz, DMSO-d 6 ) δ12.06(s,1H), 7.73(s,1H), 7.30(d,J=8.6Hz,2H), 7.21(d,J=8.6Hz,2H) ,7.04(d,J=8.6Hz,2H), 6.99(d,J=8.6Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.74 (s, 3H), 3.38 (d, 14.1 Hz, 1H), 3.14 (d, 14.1 Hz, 1H).
按照实施例5所述同样的方法使用不同的起始原料合成了以下化合物：The following compounds were synthesized according to the same method described in Example 5 using different starting materials:
实施例6Example 6
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5- d)Methyl)phenoxy)phenyl)acrylic acid
Figure PCTCN2020100888-appb-000020
Figure PCTCN2020100888-appb-000020
LC-MS:m/z 513(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.74(brs,1H),12.06(brs,1H),7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 513(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.74 (brs, 1H), 12.06 (brs, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J=8.6Hz,2H), 7.03(d,J=8.6Hz,2H), 6.98(d,J=8.6Hz,2H), 6.41(t,J=2.2Hz,1H), 6.28(d,J= 2.2Hz, 2H), 3.38 (d, J=14.2Hz, 1H), 3.12 (d, J=14.2Hz, 1H).
实施例6A和6BExamples 6A and 6B
(R,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸和(S,E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸 (R,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl- 5-d)Methyl)phenoxy)phenyl)acrylic acid and (S,E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4- ((2,4-dioxothiazolidine-5-yl-5-d)methyl)phenoxy)phenyl)acrylic acid
Figure PCTCN2020100888-appb-000021
Figure PCTCN2020100888-appb-000021
实施例6A：异构体AExample 6A: Isomer A
LC-MS:m/z 513(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.74(brs,1H),12.06(brs,1H),7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 513(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.74 (brs, 1H), 12.06 (brs, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J=8.6Hz,2H), 7.03(d,J=8.6Hz,2H), 6.98(d,J=8.6Hz,2H), 6.41(t,J=2.2Hz,1H), 6.28(d,J= 2.2Hz, 2H), 3.38 (d, J=14.2Hz, 1H), 3.12 (d, J=14.2Hz, 1H).
实施例6B：异构体BExample 6B: Isomer B
LC-MS:m/z 513(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.74(brs,1H),12.06(brs,1H),7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 513(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.74 (brs, 1H), 12.06 (brs, 1H), 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J=8.6Hz,2H), 7.03(d,J=8.6Hz,2H), 6.98(d,J=8.6Hz,2H), 6.41(t,J=2.2Hz,1H), 6.28(d,J= 2.2Hz, 2H), 3.38 (d, J=14.2Hz, 1H), 3.12 (d, J=14.2Hz, 1H).
实施例7Example 7
(E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯(E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d)methyl) Phenoxy) phenyl) methyl acrylate
Figure PCTCN2020100888-appb-000022
Figure PCTCN2020100888-appb-000022
LC-MS:m/z 521(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.05(s,1H),7.73(s,1H),7.29(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.73(s,3H),3.58(s,6H),3.38(d,J＝14.1Hz,1H),3.13(d,J＝14.1Hz,1H)。 LC-MS: m/z 521(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 7.73 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H) ,7.03(d,J=8.4Hz,2H), 6.98(d,J=8.4Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.73 (s, 3H), 3.58 (s, 6H), 3.38 (d, J=14.1 Hz, 1H), 3.13 (d, J=14.1 Hz, 1H).
实施例7A和7BExamples 7A and 7B
(R,E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯和(S,E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸甲酯(R,E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d)methyl Yl)phenoxy)phenyl)methyl acrylate and (S,E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-diox Thiazolidine-5-yl-5-d)methyl)phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000023
Figure PCTCN2020100888-appb-000023
实施例7A：异构体AExample 7A: Isomer A
LC-MS:m/z 521(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.05(s,1H),7.73(s,1H),7.29(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.73(s,3H),3.58(s,6H),3.38(d,J＝14.1Hz,1H),3.13(d,J＝14.1Hz,1H)。 LC-MS: m/z 521(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 7.73 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H) ,7.03(d,J=8.4Hz,2H), 6.98(d,J=8.4Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.73 (s, 3H), 3.58 (s, 6H), 3.38 (d, J=14.1 Hz, 1H), 3.13 (d, J=14.1 Hz, 1H).
实施例7B：异构体BExample 7B: Isomer B
LC-MS:m/z 521(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.05(s,1H),7.73(s,1H),7.29(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.42(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.73(s,3H),3.58(s,6H),3.38(d,J＝14.1Hz,1H),3.13(d,J＝14.1Hz,1H)。 LC-MS: m/z 521(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 7.73 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H) ,7.03(d,J=8.4Hz,2H), 6.98(d,J=8.4Hz,2H), 6.42(t,J=2.2Hz,1H), 6.28(d,J=2.2Hz,2H), 3.73 (s, 3H), 3.58 (s, 6H), 3.38 (d, J=14.1 Hz, 1H), 3.13 (d, J=14.1 Hz, 1H).
实施例8Example 8
(E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸(E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d)methyl) Phenoxy) phenyl) acrylic
Figure PCTCN2020100888-appb-000024
Figure PCTCN2020100888-appb-000024
LC-MS:m/z 507(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝ 8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.58(s,6H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 507(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.6Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 3.58 (s, 6H), 3.38 (d, J=14.2 Hz, 1H), 3.12 (d, J=14.2 Hz, 1H).
实施例8A和8BExamples 8A and 8B
(R,E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸和(S,E)-3-(3,5-双甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基)苯氧基)苯基)丙烯酸(R,E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d)methyl Yl)phenoxy)phenyl)acrylic acid and (S,E)-3-(3,5-bismethoxyphenyl)-2-(4-(4-((2,4-dioxothiazole) Alk-5-yl-5-d)methyl)phenoxy)phenyl)acrylic acid
Figure PCTCN2020100888-appb-000025
Figure PCTCN2020100888-appb-000025
实施例8A：异构体AExample 8A: Isomer A
LC-MS:m/z 507(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.58(s,6H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 507(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.6Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 3.58 (s, 6H), 3.38 (d, J=14.2 Hz, 1H), 3.12 (d, J=14.2 Hz, 1H).
实施例8B：异构体BExample 8B: Isomer B
LC-MS:m/z 507(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.70(s,1H),7.29(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),7.03(d,J＝8.6Hz,2H),6.98(d,J＝8.6Hz,2H),6.41(t,J＝2.2Hz,1H),6.28(d,J＝2.2Hz,2H),3.58(s,6H),3.38(d,J＝14.2Hz,1H),3.12(d,J＝14.2Hz,1H)。 LC-MS: m/z 507(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.70 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.6Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.41 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 2.2 Hz, 2H), 3.58 (s, 6H), 3.38 (d, J=14.2 Hz, 1H), 3.12 (d, J=14.2 Hz, 1H).
实施例9Example 9
(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基-d)苯氧基)苯基)丙烯酸甲酯的制备(E)-3-(3,5-Dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d)methyl- d) Preparation of phenoxy) phenyl) methyl acrylate
Figure PCTCN2020100888-appb-000026
Figure PCTCN2020100888-appb-000026
第一步：(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基 -d)苯氧基)苯基)丙烯酸甲酯的制备The first step: (E)-3-(3,5-dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5-d ) Preparation of methyl-d) phenoxy) phenyl) methyl acrylate
在100mL高压釜中依次加入methyl(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((Z)-(2,4-二氧代噻唑烷-5-亚基)甲基)苯氧基)苯基)丙烯酸甲酯(0.5g，0.97mmol)、干铂碳(10％wt，75mg)和乙酸-d 4(15mL)。反应液在氘气氛围下(0.8MPa)加热至100℃反应36小时。得到的混合物通过硅藻土过滤，滤液减压浓缩得到目标化合物。 Add methyl(E)-3-(3,5-dimethoxyphenyl)-2-(4-(4-((Z)-(2,4-dioxothiazolidine) into the 100mL autoclave in sequence -5-ylidene)methyl)phenoxy)phenyl)methyl acrylate (0.5 g, 0.97 mmol), dry platinum carbon (10% wt, 75 mg) and acetic acid-d 4 (15 mL). The reaction solution was heated to 100°C for 36 hours under a deuterium atmosphere (0.8 MPa). The resulting mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the target compound.
LC-MS:m/z 522(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.74(s,1H),7.30(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.13(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.43(t,J＝2.2Hz,1H),6.29(d,J＝2.2Hz,2H),3.74(s,3H),3.59(s,6H),3.37(s,0.5H),3.12(s,0.5H)。 LC-MS: m/z 522(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.74 (s, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 6.43 (t, J = 2.2 Hz, 1H), 6.29 (d, J = 2.2 Hz, 2H), 3.74 (s, 3H), 3.59 (s, 6H), 3.37 (s, 0.5H), 3.12 (s, 0.5H).
按照实施例9所述同样的方法使用不同的起始原料合成了以下化合物：The following compounds were synthesized according to the same method described in Example 9 using different starting materials:
实施例10Example 10
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基-5-d)甲基-d)苯氧基)苯基)丙烯酸甲酯 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl-5- d) Methyl-d) phenoxy) phenyl) methyl acrylate
Figure PCTCN2020100888-appb-000027
Figure PCTCN2020100888-appb-000027
LC-MS:m/z 528(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.73(s,1H),7.29(d,J＝8.6Hz,2H),7.21(d,J＝8.6Hz,2H),7.04(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.42(t,J＝2.2Hz,1H),6.29(d,J＝2.2Hz,2H),3.74(s,3H),3.37(s,0.5H),3.08(s,0.5H)。 LC-MS: m/z 528(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.73 (s, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6Hz, 2H), 6.97 (d, J = 8.6 Hz, 2H), 6.42 (t, J = 2.2 Hz, 1H), 6.29 (d, J = 2.2 Hz, 2H), 3.74 (s, 3H), 3.37 (s, 0.5H), 3.08 (s, 0.5H).
实施例11Example 11
(E)-3-3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备(E)-3-3,5-Dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl)phenoxy)benzene Preparation of methyl acrylate
Figure PCTCN2020100888-appb-000028
Figure PCTCN2020100888-appb-000028
第一步：(E)-3-(3,5,-二甲氧基苯基)-2-(4-羟基苯基)丙烯酸的制备The first step: the preparation of (E)-3-(3,5,-dimethoxyphenyl)-2-(4-hydroxyphenyl)acrylic acid
在30℃以下将三乙胺(91g，0.90mol)滴加到3,5-二甲氧基苯甲醛(150g，0.90mol)和对羟基苯乙酸(137g，0.90mol)的乙酸酐(300mL)溶液中。滴加完后，反应液加热至125℃反应14小时然后冷却至室温。向反应液中滴加20％的盐酸溶液(666mL)，加完后搅拌30分钟再过滤。滤饼用水(1.5L)淋洗，然后加入到预先配置好的氢氧化钠溶液中(氢氧化钠184.3g，水990mL)，搅拌1小时后过滤。向所得滤液中滴加20％的盐酸溶液988mL，加完搅拌30分钟后过滤，滤饼用水(1.5L)淋洗，然后在60℃真空干燥16小时。所得粗品用乙醇重结晶得到目标化合物(143.5g。收率52.9％)。Add triethylamine (91g, 0.90mol) dropwise to 3,5-dimethoxybenzaldehyde (150g, 0.90mol) and acetic anhydride (300mL) of p-hydroxyphenylacetic acid (137g, 0.90mol) below 30°C In solution. After the addition, the reaction solution was heated to 125°C for 14 hours and then cooled to room temperature. A 20% hydrochloric acid solution (666 mL) was added dropwise to the reaction solution, and after the addition, it was stirred for 30 minutes and then filtered. The filter cake was rinsed with water (1.5L), then added to the pre-prepared sodium hydroxide solution (184.3g sodium hydroxide, 990mL water), stirred for 1 hour and filtered. 988 mL of 20% hydrochloric acid solution was added dropwise to the obtained filtrate, and after stirring for 30 minutes, it was filtered. The filter cake was rinsed with water (1.5 L), and then vacuum dried at 60° C. for 16 hours. The obtained crude product was recrystallized from ethanol to obtain the target compound (143.5 g. Yield 52.9%).
LC-MS:m/z 301(M+H) +。 LC-MS: m/z 301(M+H) + .
第二步：(E)-3-(3,5,-二甲氧基苯基)-2-(4-羟基苯基)丙烯酸甲酯的制备Step 2: Preparation of (E)-3-(3,5,-dimethoxyphenyl)-2-(4-hydroxyphenyl)methyl acrylate
在室温下，将浓硫酸(28mL)滴加到(E)-3-(3,5,-二甲氧基苯基)-2-(4-羟基苯基)丙烯酸(120g，0.4mol)的甲醇(840mL)溶液中。滴加加完后，反应液加热回流反应25小时后降至室温。混合物减压浓缩除去部分溶剂，然后加水(840mL)搅拌1小时再过滤。滤饼用水(800mL)淋洗，然后在60℃真空干燥8小时得目标化合物(127.5g，定量收率)。At room temperature, add concentrated sulfuric acid (28mL) dropwise to (E)-3-(3,5,-dimethoxyphenyl)-2-(4-hydroxyphenyl)acrylic acid (120g, 0.4mol) Methanol (840 mL) solution. After the addition was completed, the reaction solution was heated to reflux for 25 hours and then cooled to room temperature. The mixture was concentrated under reduced pressure to remove part of the solvent, and then water (840 mL) was added and stirred for 1 hour and then filtered. The filter cake was rinsed with water (800 mL), and then vacuum dried at 60° C. for 8 hours to obtain the target compound (127.5 g, quantitative yield).
LC-MS:m/z 335(M+H) +。 LC-MS: m/z 335(M+H) + .
第三步：(E)-3-(3,5,-二甲氧基苯基)-2-(4-(4-甲酰基苯氧基)苯基)丙烯 酸甲酯的制备The third step: Preparation of methyl (E)-3-(3,5,-dimethoxyphenyl)-2-(4-(4-formylphenoxy)phenyl)acrylic acid
在1L的三口烧瓶中依次加入化合物(E)-3-(3,5,-二甲氧基苯基)-2-(4-羟基苯基)丙烯酸甲酯(120g，0.38mol)、对氟苯甲醛(49.7g，0.40mol)、碳酸钾(105.5g，0.76mol)和二甲基亚砜(600mL)。反应液加热至100℃反应4小时后冷至室温，然后滴加水(1.5L)后搅拌16小时再过滤。滤饼用水(1.2L)淋洗，然后在60℃真空干燥5小时得目标化合物(149.6g，收率93.6％)。In a 1L three-necked flask, add compound (E)-3-(3,5,-dimethoxyphenyl)-2-(4-hydroxyphenyl)methyl acrylate (120g, 0.38mol), p-fluoro Benzaldehyde (49.7 g, 0.40 mol), potassium carbonate (105.5 g, 0.76 mol) and dimethyl sulfoxide (600 mL). The reaction solution was heated to 100°C to react for 4 hours and then cooled to room temperature, and then water (1.5L) was added dropwise and stirred for 16 hours and then filtered. The filter cake was rinsed with water (1.2 L), and then vacuum dried at 60° C. for 5 hours to obtain the target compound (149.6 g, yield 93.6%).
LC-MS:m/z 419(M+H) +。 LC-MS: m/z 419(M+H) + .
第四步：(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-亚基)甲基)苯氧基)苯基)丙烯酸甲酯的制备The fourth step: (E)-3-(3,5-dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-ylidene)methyl )Phenoxy)phenyl)methyl acrylate
在2L的装有分水器的三口烧瓶中依次加入化合物(E)-3-(3,5,-二甲氧基苯基)-2-(4-(4-甲酰基苯氧基)苯基)丙烯酸甲酯(120g，0.29mol)、2,4-噻唑烷二酮(37.8g，0.32mol)、苯甲酸(47.5g，0.43mol)和甲苯(750mL)。随后在搅拌下，向反应液中滴加哌啶(36.7g，0.43mol)。滴加完后，反应加热至110℃回流分水5小时。反应液冷至室温，然后加入甲醇(750mL)后加热回流2小时。所得混合物冷却，再在冰浴下搅拌30分钟后过滤。滤饼用甲醇(350mL)淋洗，然后在50℃真空干燥3小时得目标化合物(101.4g，收率68.3％)。Add the compound (E)-3-(3,5,-dimethoxyphenyl)-2-(4-(4-formylphenoxy)benzene into a 2L three-necked flask equipped with a water trap. Methyl) acrylate (120 g, 0.29 mol), 2,4-thiazolidinedione (37.8 g, 0.32 mol), benzoic acid (47.5 g, 0.43 mol) and toluene (750 mL). Subsequently, under stirring, piperidine (36.7 g, 0.43 mol) was added dropwise to the reaction solution. After the addition, the reaction was heated to 110°C and refluxed for 5 hours. The reaction solution was cooled to room temperature, then methanol (750 mL) was added and heated to reflux for 2 hours. The resulting mixture was cooled, stirred in an ice bath for 30 minutes, and filtered. The filter cake was rinsed with methanol (350 mL), and then vacuum dried at 50° C. for 3 hours to obtain the target compound (101.4 g, yield 68.3%).
LC-MS:m/z 518(M+H) +。 LC-MS: m/z 518(M+H) + .
第五步：(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备The fifth step: (E)-3-(3,5-dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5-yl)methyl) Preparation of phenoxy)phenyl)methyl acrylate
在5L的三口烧瓶中依次加入化合物(E)-3-(3,5-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-亚基)甲基)苯氧基)苯基)丙烯酸甲酯(100g，0.19mol)、甲酸铵(731g，11.59mol)、Pt/C(30g，含水50％)和乙酸(3L)。反应液加热至115℃反应14小时，然后降温至室温后过滤。滤饼用乙酸淋洗，将合并的滤液缓慢滴加到12L水中，然后在室温搅拌16小时后过滤。滤饼用水淋洗，然后在45℃真空干燥4小时。将所得粗品用无水乙醇重结晶得目标化合物(48.4g。收率48.2％)。In a 5L three-necked flask was added compound (E)-3-(3,5-dimethoxyphenyl)-2-(4-(4-((2,4-dioxothiazolidine-5- Subunit) methyl) phenoxy) phenyl) methyl acrylate (100 g, 0.19 mol), ammonium formate (731 g, 11.59 mol), Pt/C (30 g, 50% water), and acetic acid (3L). The reaction solution was heated to 115°C for 14 hours, then cooled to room temperature and filtered. The filter cake was rinsed with acetic acid, and the combined filtrate was slowly added dropwise to 12 L of water, and then stirred at room temperature for 16 hours and then filtered. The filter cake was rinsed with water and then vacuum dried at 45°C for 4 hours. The obtained crude product was recrystallized with absolute ethanol to obtain the target compound (48.4 g. Yield 48.2%).
LC-MS:m/z 520(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ12.06(brs,1H),7.74(s,1H),7.30(d,J＝8.8Hz,2H),7.21(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.99(d,J＝8.8Hz,2H),6.43(t,J＝2.4Hz,1H),6.29(d,J＝2.4Hz,2H),4.93(dd,J＝4.0Hz和9.2Hz,1H),3.74(s,3H),3.59(s,6H),3.39(dd,J＝4.4Hz,14.4Hz,1H),3.14(dd,J＝8.8Hz,14.4Hz,1H)。 LC-MS: m/z 520(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ12.06 (brs, 1H), 7.74 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H) ,7.04(d,J=8.4Hz,2H), 6.99(d,J=8.8Hz,2H), 6.43(t,J=2.4Hz,1H), 6.29(d,J=2.4Hz,2H), 4.93 (dd, J = 4.0 Hz and 9.2 Hz, 1H), 3.74 (s, 3H), 3.59 (s, 6H), 3.39 (dd, J = 4.4 Hz, 14.4 Hz, 1H), 3.14 (dd, J = 8.8 Hz, 14.4 Hz, 1H).
实施例12Example 12
(E)-3-(3,5-双(甲氧基-d 3)苯基)-2-(4-(4-((2,4-二氧代-3-((特戊酰基氧基)甲基)噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备 (E)-3-(3,5-bis(methoxy-d 3 )phenyl)-2-(4-(4-((2,4-dioxo-3-((pivaloyloxy (Yl)methyl)thiazolidine-5-yl)methyl)phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000029
Figure PCTCN2020100888-appb-000029
在0℃下将氢化钠(8mg，0.21mmol)加入到(E)-3-(3,5-d 6-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯(100mg，0.19mmol)的N,N-二甲基甲酰胺(2mL)溶液中。得到的混合物在0℃搅拌10min，随后滴加特戊酸氯甲酯(34mg，0.23mmol)的N,N-二甲基甲酰胺(1mL)溶液。滴加完毕反应液升至室温，随后在室温反应18小时。得到的混合物用水(5mL)淬灭后用乙酸乙酯萃取。合并的有机相用饱和食盐水洗涤后无水硫酸钠干燥，然后过滤。滤液减压浓缩，得到的粗品经制备色谱纯化后得到目标化合物(40mg，收率33％)。 Sodium hydride (8mg, 0.21mmol) was added to (E)-3-(3,5-d 6 -dimethoxyphenyl)-2-(4-(4-((2,4 -Dioxthiazolidine-5-yl)methyl)phenoxy)phenyl)methyl acrylate (100 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at 0°C for 10 min, and then a solution of chloromethyl pivalate (34 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. After the addition, the reaction solution was raised to room temperature, and then reacted at room temperature for 18 hours. The resulting mixture was quenched with water (5 mL) and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by preparative chromatography to obtain the target compound (40 mg, yield 33%).
LC-MS:m/z 640(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.73(s,1H),7.29(d,J＝8.4Hz,2H),7.21(d,J＝8.8Hz,2H),7.03(d,J＝8.4Hz,2H),6.96(d,J＝8.8Hz,2H),6.42(t,J＝2.4Hz,1H),6.28(d,J＝2.4Hz,2H),5.42(s,2H),5.10(dd,J＝4.4,8.0Hz,1H),3.73(s,3H),3.42(dd,J＝4.8,14.4Hz,1H),3.22(dd,J＝8.4,14.4Hz,1H),1.08(s,9H)。 LC-MS: m/z 640(M+H) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.73 (s, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.4Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.42 (t, J = 2.4 Hz, 1H), 6.28 (d, J = 2.4 Hz, 2H), 5.42 (s, 2H), 5.10 (dd,J=4.4,8.0Hz,1H),3.73(s,3H),3.42(dd,J=4.8,14.4Hz,1H),3.22(dd,J=8.4,14.4Hz,1H),1.08( s,9H).
实施例13Example 13
(E)-2-(4-(4-((3-((二叔丁氧基磷酰氧基)甲基)2,4-二羰基噻唑烷-5-基)甲基)苯氧基)苯基)-3-(3,5-双(甲氧基-d 3)-苯基)丙烯酸甲酯的制备 (E)-2-(4-(4-((3-((Di-tert-butoxyphosphoryloxy)methyl)2,4-dicarbonylthiazolidine-5-yl)methyl)phenoxy )Phenyl)-3-(3,5-bis(methoxy-d 3 )-phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000030
Figure PCTCN2020100888-appb-000030
在0℃下将加入氢化钠(8mg，0.21mmol)加入到(E)-3-(3,5-d 6-二甲氧基苯基)-2-(4-(4-((2,4-二氧代噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯(100mg，0.19mmol)的N,N-二甲基甲酰胺(2mL)溶液中。得到的混合物在0℃搅拌10min，随后滴加二叔丁基氯甲基磷酸酯(59mg，0.23mmol)的N,N-二甲基甲酰胺(1mL)溶液。加完后反应液升至55℃反应6小时，然后加水淬灭。得到的混合物减压浓缩，残余物经制备色谱纯化后得到目标化合物(25mg，收率18％)。 Add sodium hydride (8mg, 0.21mmol) to (E)-3-(3,5-d 6 -dimethoxyphenyl)-2-(4-(4-((2, 4-dioxothiazolidine-5-yl)methyl)phenoxy)phenyl)methyl acrylate (100 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at 0°C for 10 min, and then a solution of di-tert-butylchloromethyl phosphate (59 mg, 0.23 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. After the addition, the reaction solution was raised to 55°C for 6 hours, and then quenched with water. The obtained mixture was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain the target compound (25 mg, yield 18%).
LC-MS:m/z 770(M+Na) +。 1H NMR(400MHz，DMSO-d 6)δ7.73(s,1H),7.32(d, J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.98(d,J＝8.8Hz,2H),6.42(t,J＝2.0Hz,1H),6.28(d,J＝2.0Hz,2H),5.18(d,J＝7.6Hz,2H),5.11(dd,J＝4.4,8.8Hz,1H),3.74(s,3H),3.49(dd,J＝4.8,14.0Hz,1H),3.14(dd,J＝9.2,14.4Hz,1H),1.41(d,J＝2.0Hz,18H)。 LC-MS: m/z 770(M+Na) + . 1 H NMR (400MHz, DMSO-d 6 ) δ 7.73 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.4Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 6.42 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 2H), 5.18 (d, J = 7.6 Hz , 2H), 5.11 (dd, J = 4.4, 8.8 Hz, 1H), 3.74 (s, 3H), 3.49 (dd, J = 4.8, 14.0 Hz, 1H), 3.14 (dd, J = 9.2, 14.4 Hz, 1H), 1.41 (d, J=2.0 Hz, 18H).
实施例14Example 14
3-(3,5-双(甲氧基-d 3)-苯基)-2-(4-(4-((2,4-二羰基-3-(磷酰氧甲基)噻唑烷-5-基)甲基)苯氧基)苯基)丙烯酸甲酯的制备 3-(3,5-bis(methoxy-d 3 )-phenyl)-2-(4-(4-((2,4-dicarbonyl-3-(phosphoryloxymethyl)thiazolidine- Preparation of 5-yl)methyl)phenoxy)phenyl)methyl acrylate
Figure PCTCN2020100888-appb-000031
Figure PCTCN2020100888-appb-000031
在室温下将三氟乙酸(0.25mL)加入到(E)-2-(4-(4-((3-((二叔丁氧基磷酰氧基)甲基)2,4-二羰基噻唑烷-5-基)甲基)苯氧基)苯基)-3-(3,5-二甲氧基-d 6-苯基)丙烯酸甲酯(10mg，0.013mmol)的二氯甲烷(0.25mL)溶液中。加完后反应液室温反应2小时，然后减压浓缩。残余物经制备色谱纯化得到目标化合物。 Add trifluoroacetic acid (0.25mL) to (E)-2-(4-(4-((3-((di-tert-butoxyphosphoryloxy)methyl)2,4-dicarbonyl at room temperature Thiazolidine-5-yl)methyl)phenoxy)phenyl)-3-(3,5-dimethoxy-d 6 -phenyl)methyl acrylate (10mg, 0.013mmol) in dichloromethane ( 0.25mL) solution. After the addition, the reaction solution was reacted at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was purified by preparative chromatography to obtain the target compound.
LC-MS:m/z 636(M+H) +。 1H NMR(400MHz，DMSO-d 6)δ7.73(s,1H),7.32(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),7.04(d,J＝8.8Hz,2H),6.99(d,J＝8.4Hz,2H),6.41(t,J＝2.0Hz,1H),6.28(d,J＝2.0Hz,2H),5.18(dd,J＝2.4,7.6Hz,2H),5.04(dd,J＝4.4,9.6Hz,1H),3.73(s,3H),3.50(dd,J＝4.4,14.0Hz,1H),3.10(dd,J＝10.0,14.0Hz,1H)。 31P NMR(162MHz,DMSO-d 6)δ-3.57(s). LC-MS: m/z 636(M+H) + . 1 H NMR(400MHz, DMSO-d 6 )δ7.73(s,1H), 7.32(d,J=8.4Hz,2H), 7.21(d,J=8.4Hz,2H), 7.04(d,J= 8.8Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.41 (t, J = 2.0 Hz, 1H), 6.28 (d, J = 2.0 Hz, 2H), 5.18 (dd, J = 2.4, 7.6Hz, 2H), 5.04 (dd, J = 4.4, 9.6 Hz, 1H), 3.73 (s, 3H), 3.50 (dd, J = 4.4, 14.0 Hz, 1H), 3.10 (dd, J = 10.0, 14.0 Hz,1H). 31 P NMR (162MHz, DMSO-d 6 ) δ-3.57(s).
生物学测试评价Biological test evaluation
以下生物学测试例进一步描述解释本发明，但这些实例并非意味着限制本发明的范围The following biological test examples further describe and explain the present invention, but these examples are not meant to limit the scope of the present invention
测试实施例1 HEK293细胞中化合物对PPARγ的激动活性测试Test Example 1 Test of the agonistic activity of the compound on PPARγ in HEK293 cells
实验步骤Experimental steps
1.1准备细胞悬液及种板1.1 Prepare cell suspension and seed plate
a)所有细胞按照ATCC推荐方案培养。在HEK293细胞对数生长期测试。a) All cells are cultured in accordance with the ATCC recommended protocol. Tested in the logarithmic growth phase of HEK293 cells.
b)去除培养瓶中培养基b) Remove the medium in the culture flask
c)PBS漂洗细胞c) PBS rinse cells
d)在培养瓶中加入TrypLE(胰酶替代物)消化分散细胞。完全培养基洗涤细胞一次。d) Add TrypLE (trypsin substitute) to the culture flask to digest the scattered cells. Wash the cells once with complete medium.
e)吸取并用PBS洗涤细胞2次去除酚红指示剂，重新于培养液中并调整至合适浓度。e) Aspirate and wash the cells twice with PBS to remove the phenol red indicator, and re-in the culture medium and adjust to a suitable concentration.
f)只有细胞活性>90％才能继续用于测试。f) Only cell viability >90% can continue to be used for testing.
g)将HEK293细胞按照6*10 6个/ml接种于100mm培养皿中。 g) Inoculate HEK293 cells in a 100mm petri dish at 6*10 6 cells/ml.
h)5％CO 2 37℃培养16小时。 h) Incubate at 37°C with 5% CO 2 for 16 hours.
1.2细胞转染1.2 Cell transfection
a)取出Trans-IT试剂盒平衡至室温；a) Take out the Trans-IT kit and equilibrate to room temperature;
b)滴入Trans-IT试剂并和Opti-MEM(Invitrogen)混匀，注意避免试剂接触管壁。翻转混匀，室温孵育5min。DNA加入至混合试剂中，翻转混匀，室温孵育20min。b) Drop the Trans-IT reagent and mix it with Opti-MEM (Invitrogen), taking care to avoid the reagent contacting the tube wall. Invert and mix, and incubate at room temperature for 5 min. Add DNA to the mixed reagent, turn to mix, and incubate at room temperature for 20 minutes.
i.所有质粒使用贮存浓度为0.5mg/mli. The storage concentration of all plasmids is 0.5mg/ml
ii.对于PPAR测试:分别加入7.5μg GAL4-PPARγ质粒和2.5μg pGL4.35荧光酶质粒ii. For PPAR test: add 7.5μg GAL4-PPARγ plasmid and 2.5μg pGL4.35 luciferase plasmid respectively
c)加入试剂混合液至100mm培养皿中。c) Add the reagent mixture to a 100mm petri dish.
d)5％CO 2 37℃培养5-6小时。 d) Incubate at 37°C with 5% CO 2 for 5-6 hours.
1.3化合物处理1.3 Compound treatment
a)使用Echo550转移25nl/孔化合物稀释液至384孔反应板。a) Use Echo550 to transfer 25nl/well of compound dilution to a 384-well reaction plate.
b)在384孔反应板中按照18000个细胞/孔接种HEK239T细胞。b) Inoculate HEK239T cells in a 384-well reaction plate at 18,000 cells/well.
c)5％CO 2 37℃培养16-20小时。 c) Incubate at 37°C with 5% CO 2 for 16-20 hours.
1.4读值1.4 reading
a)取出Steady-Glo TM荧光检测试剂平衡至室温； a) Take out Steady-Glo TM fluorescence detection reagent and equilibrate to room temperature;
b)取出384孔反应板平衡至室温；b) Take out the 384-well reaction plate and equilibrate to room temperature;
c)按照25μl/孔在384孔反应板中加入Steady-Glo TM荧光检测试剂； c) Add Steady-Glo TM fluorescence detection reagent to the 384-well reaction plate according to 25μl/well;
d)振荡器上振荡测试版(避光)5min。d) Oscillate the test board on the oscillator (protected from light) for 5 minutes.
e)使用Envision 2104读板机读取荧光数值。e) Use Envision 2104 plate reader to read the fluorescence value.
实验结果Experimental results
表1Table 1
Figure PCTCN2020100888-appb-000032
Figure PCTCN2020100888-appb-000032
Figure PCTCN2020100888-appb-000033
Figure PCTCN2020100888-appb-000033
从表1可以看出：本发明化合物具有很好的PPARγ激动活性。It can be seen from Table 1 that the compound of the present invention has good PPARγ agonistic activity.
测试实施例2化合物对PPARα的激动活性测试Test Example 2 Test of the agonistic activity of the compound on PPARα
实验步骤Experimental steps
将组氨酸标记的PPARα(配体结合结构域，25nM蛋白质)与25nM生物素标记的PGC1α共激活蛋白和0.4μg荧光受体(抗组氨酸抗体偶联珠)在含有20mM Hepes/NaOH(pH 7.4)、80mM NaCl，0.08％Tween 20、0.8mM DTT和0.08％BSA的孵育缓冲液中混合。将混合物在22℃下预温育30分钟，包括温育缓冲液(基础对照)、参比激动剂(阳性对照组)和不同浓度测试化合物组。此后，加入荧光供体(链霉抗生物素蛋白偶联珠)。在22℃温育120分钟后，使用酶标仪在λ ex＝680nm和λ em＝520和620nm处测量信号。结果表示为对GW7647 的对照响应的百分比。在实验中以几种浓度进行测试以产生浓度-响应曲线，由此计算其EC 50值。 The histidine-labeled PPARα (ligand binding domain, 25nM protein) and 25nM biotin-labeled PGC1α co-activator protein and 0.4μg fluorescent receptor (anti-histidine antibody-conjugated beads) were combined with 20mM Hepes/NaOH ( pH 7.4), 80 mM NaCl, 0.08% Tween 20, 0.8 mM DTT and 0.08% BSA in an incubation buffer. The mixture was pre-incubated at 22°C for 30 minutes, including incubation buffer (basic control), reference agonist (positive control group), and test compound groups with different concentrations. After that, a fluorescent donor (streptavidin-coupled beads) was added. After incubating at 22°C for 120 minutes, the signal was measured at λ ex =680 nm and λ em =520 and 620 nm using a microplate reader. The results are expressed as a percentage of the control response to GW7647. Several concentrations were tested in the experiment to generate a concentration-response curve, from which the EC 50 value was calculated.
实验结果：本发明化合物具有很好的PPARα激动活性。Experimental results: The compound of the present invention has good PPARα agonistic activity.
测试实施例3口服灌胃给予大鼠体内药代动力学研究Test Example 3 Pharmacokinetics study of oral administration in rats
试剂：Reagents:
肝素钠：1％肝素钠抗凝试管，干净EP管中加入15ul 1％肝素钠溶液湿润管壁，60℃鼓风干燥厢烘干，冷冻放置备用。Heparin sodium: 1% heparin sodium anticoagulation test tube, add 15ul 1% heparin sodium solution to the clean EP tube to moisten the tube wall, dry it in a blast drying chamber at 60℃, and place it in a frozen storage for later use.
试验步骤：experiment procedure:
1.大鼠试验前先适应饲养一周，自由摄取饮食。1. Before the experiment, the rats should be adapted to rearing for one week and freely take in food.
2.称量体重，随机分为4组，每组4只大鼠。2. Weigh the weight and divide them into 4 groups randomly, each with 4 rats.
3.实验开始前12-16h，所有动物禁食，饮水不限。3. 12-16h before the start of the experiment, all animals are fasted with unlimited drinking water.
4.供试品DMSO/PEG400(5/95)配制成溶液，配置好的药物储存在4℃或当天配置当天使用。4. The test product DMSO/PEG400 (5/95) is prepared into a solution, and the prepared drug is stored at 4°C or used on the day of preparation.
5.所有动物，按照分组，分别口服给予相应供试品。5. All animals, according to the group, were given the corresponding test products orally.
6.于给药前和给药后第0.25，0.5，0.75，1，2，3，4，6，8，12和24小时经大鼠眼球后静脉丛取静脉血0.3mL，置1％肝素钠抗凝试管中。6. At 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, and 24 hours before and after administration, 0.3 mL of venous blood was taken from the rat’s posterior venous plexus, and 1% heparin was placed Sodium anticoagulation test tube.
7.每只动物收集200μL的血样转移到冰冻的肝素化EP管中，0℃12000rpm离心30s。将50μL的血浆用冰冻的吸管迅速的转移到盛有450μL预冷的乙腈的EP管内，对样本去蛋白处理。在一分钟内将混合物旋转混合然后在干冰上冷冻。7. Collect 200 μL of blood samples from each animal and transfer them to frozen heparinized EP tubes, and centrifuge at 12000 rpm at 0°C for 30 seconds. Use a frozen pipette to quickly transfer 50 μL of plasma into an EP tube containing 450 μL of pre-cooled acetonitrile, and deproteinize the sample. The mixture was swirled to mix within a minute and then frozen on dry ice.
8.采用LC/MS/MS法分别测定大鼠给药后不同时间点血浆中的对应化合物。8. The LC/MS/MS method was used to determine the corresponding compounds in the plasma of rats at different time points after administration.
实验结果Experimental results
本发明化合物在大鼠体内体现出较好的代谢性质，血浆暴露量AUC和最大血药浓度C max都表现良好。 The compound of the present invention exhibits better metabolic properties in rats, and both the plasma exposure amount AUC and the maximum blood drug concentration C max perform well.
表2Table 2
Figure PCTCN2020100888-appb-000034
Figure PCTCN2020100888-appb-000034
Figure PCTCN2020100888-appb-000035
Figure PCTCN2020100888-appb-000035
从表2可以看出：It can be seen from Table 2:
1)本发明化合物相对于参照化合物11具有更好的药代动力学性质，如更高的最大血药浓度和药物血浆暴露量。1) Compared with the reference compound 11, the compound of the present invention has better pharmacokinetic properties, such as higher maximum blood drug concentration and drug plasma exposure.
2)化合物5A和5B的最大血药浓度分别是参照化合物11的1.59和1.44倍。2) The maximum blood concentration of compound 5A and 5B are 1.59 and 1.44 times of the reference compound 11, respectively.
3)化合物5A和5B的药物血浆暴露量AUC 0-t分别是参照化合物11的1.22和1.58倍。 3) The drug plasma exposure AUC 0-t of compounds 5A and 5B are 1.22 and 1.58 times that of the reference compound 11, respectively.
测试实施例4化合物在C57BL/6小鼠经STZ-HFD饲料诱导的NASH模型中的治疗性药效试验Therapeutic efficacy test of the compound of Example 4 in the NASH model induced by STZ-HFD feed in C57BL/6 mice
实验动物：Experimental animals:
雄性C57BL/6小鼠，21只，4周龄。21 male C57BL/6 mice, 4 weeks old.
模型建立：Model establishment:
新生鼠在出生48h后皮下注射链脲佐菌素(Streptozotocin,STZ)，建立糖尿病小鼠。哺育四周后挑选糖尿病雄鼠21只(空腹血糖＞10mmol/L)。依据体重和血糖分为3组，开始高脂饲料(HFD)喂养。Newborn mice were injected subcutaneously with streptozotocin (STZ) 48 hours after birth to establish diabetic mice. After four weeks of feeding, 21 diabetic male mice were selected (fasting blood glucose>10mmol/L). Divided into 3 groups according to body weight and blood sugar, and started feeding on high-fat diet (HFD).
实验流程：experiment process:
HFD(正常)饲养六周，第三周开始给药口服每日一次(p.o，q.d)，给药体积10ml/kg，共给药4周。HFD (normal) was fed for six weeks, and the drug was administered orally once a day (p.o, q.d) at the beginning of the third week, and the administration volume was 10ml/kg for a total of 4 weeks.
实验结果：Experimental results:
实验所得小鼠病理组织学变化如图1-4所示。The histopathological changes of the experimental mice are shown in Figure 1-4.
从图1可以看出：实施例化合物5A和5B，特别是5B显著降低脂肪变性病理评分。It can be seen from Figure 1 that the Example Compounds 5A and 5B, especially 5B, significantly reduced the pathological score of steatosis.
从图2可以看出：实施例化合物5B降低炎性病理评分。It can be seen from Figure 2 that Example Compound 5B reduces the inflammatory pathology score.
从图3可以看出：实施例化合物5A和5B显著降低气球样病理评分。It can be seen from Figure 3 that Example Compounds 5A and 5B significantly reduced the balloon-like pathology score.
从图4可以看出：实施例化合物5A和5B，特别是5B显著降低非酒精性脂肪变性病理评分。It can be seen from Figure 4 that the Example Compounds 5A and 5B, especially 5B, significantly reduced the non-alcoholic steatosis pathology score.
因此，本发明化合物5A和5B对STZ和高脂饲料(HFD)诱导的非酒精性脂肪肝炎具有良好的治疗效果。Therefore, the compounds 5A and 5B of the present invention have a good therapeutic effect on non-alcoholic steatohepatitis induced by STZ and high-fat diet (HFD).
测试实施例5化合物在HFD-CHOL诱导的实验兔NASH模型中的治疗药效学试验The therapeutic pharmacodynamic test of the compound of Test Example 5 in the experimental rabbit NASH model induced by HFD-CHOL
实验动物：Experimental animals:
新西兰大白兔20只，体重2.0kg。20 New Zealand white rabbits weighing 2.0 kg.
模型建立：Model establishment:
动物检疫后入组实验，模型动物每天给予高脂高胆固醇饲料，每天每只定量给予100g，持续8周。After the animals were quarantined, they were enrolled in the experiment. The model animals were given high-fat and high-cholesterol feed every day, and each animal was given 100g per day for 8 weeks.
实验流程：experiment process:
模型第5周开始给予化合物治疗，一天一次口服给予(p.o，q.d)，持续4周。The model was given compound treatment at the 5th week and was orally administered once a day (p.o, q.d) for 4 weeks.
实验结果：Experimental results:
实验所得动物病理组织学变化如图5-8所示。The histopathological changes of the experimental animals are shown in Figure 5-8.
从图5可以看出：实施例化合物5B显著降低脂肪变性病理评分。It can be seen from Figure 5: Example Compound 5B significantly reduces the pathological score of steatosis.
从图6可以看出：实施例化合物5B显著降低气球样病理评分。It can be seen from Figure 6 that Example Compound 5B significantly reduced the balloon-like pathology score.
从图7可以看出：实施例化合物5B显著降低非酒精性脂肪变性病理评分。It can be seen from Figure 7 that Example Compound 5B significantly reduces the pathological score of non-alcoholic steatosis.
从图8可以看出：实施例化合物5B显著降低肝脏纤维化病理评分。It can be seen from Figure 8 that Example Compound 5B significantly reduces the pathological score of liver fibrosis.
因此，本发明化合物5B对HFD-CHOL诱导的非酒精性脂肪肝炎具有良好的治疗效果。Therefore, the compound 5B of the present invention has a good therapeutic effect on HFD-CHOL-induced non-alcoholic steatohepatitis.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

  1. 具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：The thiazolidinedione compound with the structure of formula (I), or its enantiomers, diastereomers, resonators, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or prodrug molecules thereof :
    Figure PCTCN2020100888-appb-100001
    Figure PCTCN2020100888-appb-100001
    式中：Where:
    R 1是氢、氘或-CH 2R 24； R 1 is hydrogen, deuterium or -CH 2 R 24 ;
    R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13和R 14相同或不同，且独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、酯基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 17、-(CH 2) nO(CH 2) mR 17、-(CH 2) nSR 17、-(CH 2) nCOR 17、-(CH 2) nC(O)OR 17、-(CH 2) nS(O) mR 17、-(CH 2) nNR 17R 18、-(CH 2) nC(O)NR 17R 18、-(CH 2) nC(O)NHR 18、-(CH 2) nNR 18C(O)R 17和-(CH 2) nNR 18S(O) mR 17；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 17、-(CH 2) nSR 17、-(CH 2) nCOR 17、-(CH 2) nC(O)OR 17、-(CH 2) nS(O) mR 17、-(CH 2) nNR 18R 17、-(CH 2) nC(O)NR 18R 17、-(CH 2) nC(O)NHR 18、-(CH 2) nNR 18C(O)R 17、-(CH 2) nNR 18S(O) mR 17； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are the same or different, and are independently selected from substituted or unsubstituted Substitution of the following groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogen Substituted C1-C6 alkoxy, halogen, amino, nitro, hydroxy, ester, cyano, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 17 , -(CH 2 ) n O(CH 2 ) m R 17 , -(CH 2 ) n SR 17 , -(CH 2 ) n COR 17 , -(CH 2 ) n C(O)OR 17 ,- (CH 2 ) n S(O) m R 17 , -(CH 2 ) n NR 17 R 18 , -(CH 2 ) n C(O)NR 17 R 18 , -(CH 2 ) n C(O)NHR 18 , -(CH 2 ) n NR 18 C(O)R 17 and -(CH 2 ) n NR 18 S(O) m R 17 ; wherein the substitution independently refers to one or more selected from the group Substituent substitution: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, Nitro, hydroxyl, cyano, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 17 , -(CH 2 ) n SR 17 , -(CH 2 ) n COR 17 , -(CH 2 ) n C(O)OR 17 , -(CH 2 ) n S(O) m R 17 , -(CH 2 ) n NR 18 R 17 , -(CH 2 ) n C(O)NR 18 R 17 , -(CH 2 ) n C(O)NHR 18 , -(CH 2 ) n NR 18 C(O)R 17 , -(CH 2 ) n NR 18 S(O) m R 17 ;
    A 1选自C、CH或CD； A 1 is selected from C, CH or CD;
    A 2、A 3和A 4分别独立地选自CR 15或CR 15R 16； A 2 , A 3 and A 4 are each independently selected from CR 15 or CR 15 R 16 ;
    R 15和R 16相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、酯基、-(CH 2) nC(O)OR 17、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 19、-(CH 2) nSR 19、-(CH 2) nCOR 19、-(CH 2) nC(O)OR 19、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 15 and R 16 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, -(CH 2 ) n C(O)OR 17 , cyano, C3 -C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the following group: hydrogen, deuterium, C1-C18 alkyl , Deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkane Group, heterocyclic group, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 19 , -(CH 2 ) n COR 19 , -(CH 2 ) n C (O)OR 19 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C(O)R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
    R 17和R 18相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6 烷氧基、氨基、羟基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、-(CH 2) nOR 19、-(CH 2) nSR 20、-(CH 2) nCOR 20、-(CH 2) nC(O)OR 20、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 17 and R 18 are the same or different, and are each independently selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl ; Wherein the substitution independently refers to the substitution of one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1- C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 20 , -(CH 2 ) n COR 20 , -(CH 2 ) n C(O)OR 20 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C( O) R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
    R 19和R 20相同或不同，且各自独立地选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、氨基、羟基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基、羰基、羧基、酰胺基、磺酰胺基、脲基； R 19 and R 20 are the same or different, and are each independently selected from the following substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl , C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, amino, hydroxyl, ester, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, Heteroaryl; wherein said substitution independently refers to substitution by one or more substituents selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halo C1-C18 alkyl , C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen, amino, nitro, hydroxyl, cyano, ester, C3-C8 cycloalkyl, heterocyclic, C6-C14 aryl, hetero Aryl, carbonyl, carboxyl, amide, sulfonamide, urea group;
    R 24是-OH、-O-氨基酸、-OP(O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH) 2、-OP(＝O)(OH)OP(＝O)(OH)OP(＝O)(OH) 2、-OP(O)(X 1R 25)(X 2R 26)、-OP(O)(X 1R 25)(X 3R 28R 29)、-OCH 2P(O)(X 1R 25)(X 2R 26)、-OCH 2P(O)(X 1R 25)(X 3R 28R 29)、-P(O)(OH) 2、-P(O)(X 1R 25)(X 2R 26)、-OC(O)-R 27或者-OC(O)O-R 27； R 24 is -OH, -O-amino acid, -OP(O)(OH) 2 , -OP(=O)(OH)OP(=O)(OH) 2 , -OP(=O)(OH)OP (=O)(OH)OP(=O)(OH) 2 , -OP(O)(X 1 R 25 )(X 2 R 26 ), -OP(O)(X 1 R 25 )(X 3 R 28 R 29 ), -OCH 2 P(O)(X 1 R 25 )(X 2 R 26 ), -OCH 2 P(O)(X 1 R 25 )(X 3 R 28 R 29 ), -P( O)(OH) 2 , -P(O)(X 1 R 25 )(X 2 R 26 ), -OC(O)-R 27 or -OC(O)OR 27 ;
    X 1、X 2分别独立地是氧或者硫； X 1 and X 2 are each independently oxygen or sulfur;
    X 3是氮； X 3 is nitrogen;
    R 25、R 26、R 27、R 28和R 29独立地选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基，或者R 25和R 26与相邻的X 1、X 2和P结合形成取代5-16元杂环基；其中，所述取代独立地指被选自下组的一个或多个取代基取代：氘、C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、C3-C8环烷基、杂环基、C6-C14芳基、卤代C6-C14芳基、杂芳基、卤素、氨基、硝基、-COR 30、-COOR 30、-OCOOR 30、氰基、羟基、酰胺基、磺酰胺基； R 25 , R 26 , R 27 , R 28 and R 29 are independently selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl , Heterocyclyl, C6-C14 aryl, heteroaryl, or R 25 and R 26 combine with adjacent X 1 , X 2 and P to form a substituted 5-16 membered heterocyclic group; wherein the substitution is independently Refers to being substituted by one or more substituents selected from the following group: deuterium, C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6 -C14 aryl, halogenated C6-C14 aryl, heteroaryl, halogen, amino, nitro, -COR 30 , -COOR 30 , -OCOOR 30 , cyano, hydroxyl, amide, sulfonamide;
    R 30选自取代或未取代的下组基团：氢、C1-C18烷基、氘代C1-C18烷基、C3-C8环烷基、C3-C8环烯基、C6-C14芳基、氨基、杂环基，其中所述取代独立地指被选自下组的一个或多个取代基取代：C1-C18烷基、C6-C14芳基； R 30 is selected from the following group of substituted or unsubstituted groups: hydrogen, C1-C18 alkyl, deuterated C1-C18 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C14 aryl, Amino and heterocyclyl, wherein said substitution independently refers to being substituted by one or more substituents selected from the following group: C1-C18 alkyl, C6-C14 aryl;
    m独立为0、1或2的整数；且m is independently an integer of 0, 1 or 2; and
    n独立为0、1、2、3、4或5的整数；n is independently an integer of 0, 1, 2, 3, 4 or 5;
    Figure PCTCN2020100888-appb-100002
    独立为单键或双键；
    Figure PCTCN2020100888-appb-100003
    表示单键；
    Figure PCTCN2020100888-appb-100002
    Independent as single bond or double bond;
    Figure PCTCN2020100888-appb-100003
    Represents a single key;
    所述“杂环基”为含1-4个选自N、O、S的杂原子的4-7元单杂环、7-11元双杂环或 8-16元三杂环；The "heterocyclic group" is a 4-7 membered monocyclic ring, 7-11 membered bicyclic ring or 8-16 membered tricyclic ring containing 1-4 heteroatoms selected from N, O, and S;
    所述“杂芳基”为含1-4个选自N、O、S的杂原子的5-14元杂芳环；The "heteroaryl group" is a 5-14 membered heteroaromatic ring containing 1-4 heteroatoms selected from N, O, S;
    附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有一个是氘代的或者氘。 The additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
  2. 根据权利要求1所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子，其特征在于，附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有两个是氘代的或者氘。 The thiazolidinedione compound having the structure of formula (I) according to claim 1, or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, hydrate or solvate The compound or its prodrug molecule is characterized in that the additional condition is that when R 1 is hydrogen, at least two of A 1 -A 4 and R 1 -R 14 are deuterated or deuterated.
  3. 根据权利要求1所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子，其特征在于，其为通式(II)所示的化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：The thiazolidinedione compound having the structure of formula (I) according to claim 1, or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, hydrate or solvate Compound, or its prodrug molecule, characterized in that it is a compound represented by general formula (II), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, hydrate Or solvate, or its prodrug molecule:
    Figure PCTCN2020100888-appb-100004
    Figure PCTCN2020100888-appb-100004
    R 1-R 14、A 1-A 4如权利要求1所述； R 1 -R 14 , A 1 -A 4 are as claimed in claim 1;
    附加条件是：当R 1是氢时，A 1-A 4、R 1-R 14至少有一个是氘代的或者氘。 The additional condition is: when R 1 is hydrogen, at least one of A 1 -A 4 and R 1 -R 14 is deuterated or deuterated.
  4. 根据权利要求1所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子，其特征在于，其为通式(III)所示的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：The thiazolidinedione compound having the structure of formula (I) according to claim 1, or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, hydrate or solvate Compound, or its prodrug molecule, characterized in that it is a thiazolidinedione compound represented by the general formula (III), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable The salt, hydrate or solvate of, or its prodrug molecule:
    Figure PCTCN2020100888-appb-100005
    Figure PCTCN2020100888-appb-100005
    式中：Where:
    R 15、R 16、R 21和R 23独立地选自氢或氘； R 15 , R 16 , R 21 and R 23 are independently selected from hydrogen or deuterium;
    R 22选自取代或未取代的下组基团：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳基；其中所述取代独立地指被选自下组的一个或多个取代基取代：氢、氘、C1-C18烷基、氘代C1-C18烷基、卤代C1-C18烷基、C1-C6烷氧基、卤代C1-C6烷氧基、卤素、氨基、硝基、羟基、氰基、酯基、C3-C8环烷基、杂环基、C6-C14芳基、杂芳 基、-(CH 2) nOR 19、-(CH 2) nSR 19、-(CH 2) nCOR 19、-(CH 2) nC(O)OR 19、-(CH 2) nS(O) mR 19、-(CH 2) nNR 19R 20、-(CH 2) nC(O)NR 19R 20、-(CH 2) nC(O)NHR 20、-(CH 2) nNR 20C(O)R 19、-(CH 2) nNR 20S(O) mR 19； R 22 is selected from the following group of substituted or unsubstituted groups: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, deuterated C1 -C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl; wherein said substitution independently refers to one selected from the group Or multiple substituent substitutions: hydrogen, deuterium, C1-C18 alkyl, deuterated C1-C18 alkyl, halogenated C1-C18 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, halogen , Amino, nitro, hydroxy, cyano, ester, C3-C8 cycloalkyl, heterocyclyl, C6-C14 aryl, heteroaryl, -(CH 2 ) n OR 19 , -(CH 2 ) n SR 19 , -(CH 2 ) n COR 19 , -(CH 2 ) n C(O)OR 19 , -(CH 2 ) n S(O) m R 19 , -(CH 2 ) n NR 19 R 20 , -(CH 2 ) n C(O)NR 19 R 20 , -(CH 2 ) n C(O)NHR 20 , -(CH 2 ) n NR 20 C(O)R 19 , -(CH 2 ) n NR 20 S(O) m R 19 ;
    R 1-R 14、R 19、R 20、m和n如权利要求1所述； R 1 -R 14 , R 19 , R 20 , m and n are as claimed in claim 1;
    附加条件是：当R 1是氢时，R 1-R 16、R 19-R 23至少有一个是氘代的或者氘。 The additional condition is that when R 1 is hydrogen, at least one of R 1 -R 16 and R 19 -R 23 is deuterated or deuterated.
  5. 根据权利要求1所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子，其特征在于，其为通式(IV)所示的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子：The thiazolidinedione compound having the structure of formula (I) according to claim 1, or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable salt, hydrate or solvate Compound, or its prodrug molecule, characterized in that it is a thiazolidinedione compound represented by the general formula (IV), or its enantiomer, diastereomer, resonance form, crystal form, pharmaceutically acceptable The salt, hydrate or solvate of, or its prodrug molecule:
    Figure PCTCN2020100888-appb-100006
    Figure PCTCN2020100888-appb-100006
    式中：Where:
    R 12和R 13独立地选自下组：C1-C6烷氧基、氘代C1-C6烷氧基； R 12 and R 13 are independently selected from the following group: C1-C6 alkoxy, deuterated C1-C6 alkoxy;
    R 22选自下组：氢、氘、C1-C18烷基、氘代C1-C18烷基； R 22 is selected from the group consisting of hydrogen, deuterium, C1-C18 alkyl, and deuterated C1-C18 alkyl;
    R 1-R 11、R 14-R 16和R 23独立地选自氢或氘。 R 1 -R 11 , R 14 -R 16 and R 23 are independently selected from hydrogen or deuterium.
  6. 根据权利要求1-5任一所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子，其特征在于，所述化合物选自下组：The thiazolidinedione compound with the structure of formula (I) according to any one of claims 1-5, or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, hydration The compound or solvate or its prodrug molecule is characterized in that the compound is selected from the following group:
    Figure PCTCN2020100888-appb-100007
    Figure PCTCN2020100888-appb-100007
    Figure PCTCN2020100888-appb-100008
    Figure PCTCN2020100888-appb-100008
    Figure PCTCN2020100888-appb-100009
    Figure PCTCN2020100888-appb-100009
    Figure PCTCN2020100888-appb-100010
    Figure PCTCN2020100888-appb-100010
    Figure PCTCN2020100888-appb-100011
    Figure PCTCN2020100888-appb-100011
    Figure PCTCN2020100888-appb-100012
    Figure PCTCN2020100888-appb-100012
  7. 一种药物组合物，其特征在于，含有药学上可接受的载体和一种或多种权利要求1-6任一所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、 晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable carrier and one or more thiazolidinedione compounds with the structure of formula (I) according to any one of claims 1-6, or a combination thereof Enantiomers, diastereomers, resonators, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or prodrug molecules thereof.
  8. 根据权利要求7所述的药物组合物，其特征在于，还含有预防和/或治疗选自下组的疾病的药物：心血管疾病、代谢性疾病、感染、免疫性疾病、炎症、癌症。The pharmaceutical composition according to claim 7, characterized in that it further contains drugs for preventing and/or treating diseases selected from the group consisting of cardiovascular diseases, metabolic diseases, infections, immune diseases, inflammations, and cancers.
  9. 权利要求1-6任一所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子的用途，其特征在于，用于制备药物组合物，所述药物组合物用于预防和/或治疗选自下组的疾病：炎症、心血管疾病、感染、免疫性疾病、代谢性疾病、癌症。The thiazolidinedione compound with the structure of formula (I) according to any one of claims 1-6, or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, and hydrates thereof Or the use of a solvate or a prodrug molecule thereof, characterized in that it is used to prepare a pharmaceutical composition for the prevention and/or treatment of diseases selected from the group consisting of inflammation, cardiovascular disease, and infection , Immune diseases, metabolic diseases, cancer.
  10. 权利要求1-6任一所述的具有式(I)结构的噻唑烷二酮类化合物、或其对映体、非对映体、共振体、晶型、药学上可接受的盐、水合物或溶剂合物、或其前药分子的用途，其特征在于，用于制备为过氧化物酶体增殖剂激活受体(PPAR)激动剂的药物组合物。The thiazolidinedione compound with the structure of formula (I) according to any one of claims 1-6, or its enantiomers, diastereomers, resonance forms, crystal forms, pharmaceutically acceptable salts, and hydrates thereof Or the use of a solvate or a prodrug molecule thereof is characterized in that it is used to prepare a pharmaceutical composition that is a peroxisome proliferator activated receptor (PPAR) agonist.
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