WO2021169769A1 - 芳香族化合物及其药物组合物和用途 - Google Patents

芳香族化合物及其药物组合物和用途 Download PDF

Info

Publication number
WO2021169769A1
WO2021169769A1 PCT/CN2021/075433 CN2021075433W WO2021169769A1 WO 2021169769 A1 WO2021169769 A1 WO 2021169769A1 CN 2021075433 W CN2021075433 W CN 2021075433W WO 2021169769 A1 WO2021169769 A1 WO 2021169769A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
stereoisomer
alkyl
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/CN2021/075433
Other languages
English (en)
French (fr)
Inventor
陈寿军
谢佳
宋智泉
田强
宋宏梅
薛彤彤
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN202180007741.0A priority Critical patent/CN114901641A/zh
Publication of WO2021169769A1 publication Critical patent/WO2021169769A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2

Definitions

  • This application belongs to the field of pharmaceuticals, and specifically relates to a class of aromatic compounds, pharmaceutical compositions containing such compounds, and methods for preparing such compounds and intermediates thereof.
  • the application also relates to the use of such compounds for preparing drugs for preventing or treating diseases or disorders related to peroxisome proliferator activated receptor (PPAR).
  • PPAR peroxisome proliferator activated receptor
  • Non-alcoholic fatty liver disease is a type of clinical pathological syndrome with liver histological changes similar to alcoholic liver disease, but without a history of excessive drinking, including simple fatty liver (SFL), non-alcoholic steatohepatitis (NASH) ) And related liver cirrhosis, in which NASH is an important intermediate stage of NAFLD progression.
  • SFL simple fatty liver
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the prevalence of NAFLD/NASH is gradually increasing.
  • NAFLD has now become one of the most common liver diseases.
  • the prevalence of NAFLD in general adults in the United States is 10-40% (average 20%), and NASH is 2-5% (average 3%).
  • the prevalence of NAFLD is higher in special populations such as obesity, diabetes, and chronically elevated serum alanine aminotransferase (ALT), and the onset of NAFLD is becoming younger
  • Non-alcoholic fatty liver disease can directly lead to decompensated liver cirrhosis, hepatocellular carcinoma and recurrence of transplanted liver, it can also affect the progress of other chronic liver diseases, and participate in the pathogenesis of type 2 diabetes and atherosclerosis. Metabolic syndrome-related malignancies, arteriosclerotic cardiovascular and cerebrovascular diseases and liver cirrhosis are important factors affecting the quality of life and life expectancy of patients with non-alcoholic fatty liver disease. At present, NASH has become one of the important pre-cirrhotic lesions second only to chronic viral hepatitis and alcoholic liver disease, and is a common cause of abnormal serum transaminase in the healthy population.
  • Non-alcoholic fatty liver disease is a new challenge in the contemporary medical field, and the development of drugs to treat non-alcoholic fatty liver-related diseases has important clinical significance.
  • Peroxisome proliferator-activated receptor is a member of the nuclear receptor transcription factor superfamily, which plays a key role in regulating metabolic homeostasis, inflammation, cell growth and differentiation.
  • PPAR agonists are used as lipid-lowering drugs and oral hypoglycemic agents in type II diabetes. Recent studies have found that such agonists have liver protective functions.
  • PPAR ⁇ is highly expressed in liver cells, and mainly plays a role in regulating fatty acid transport and ⁇ -oxidation.
  • PPAR ⁇ can also regulate the process of glycogenogenesis and inflammation. Similar to PPAR ⁇ , PPAR ⁇ can regulate the utilization of glucose and lipoprotein metabolism in the liver, and has significant anti-inflammatory activity.
  • PPAR agonists may solve a variety of biological problems involved in the pathogenesis of NASH, or broader metabolic and cardiovascular problems.
  • This application provides compounds containing 2-phenoxyacetic acid structure for use as PPAR agonists, especially having excellent dual agonist activity to PPAR ⁇ & ⁇ , and better physical and chemical properties (such as solubility, physical and/or chemical stability) , Improved pharmacokinetic properties (such as improved bioavailability, appropriate half-life and duration of action) and/or improved safety (lower toxicity and/or fewer side effects, wider therapeutic window) And other more excellent properties.
  • this application provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolic A substance or prodrug, wherein the compound has the structure of general formula (I):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio; alternatively, R 1 Together with R 2 and the carbon atom to which they are connected, form a C 3-6 cycloalkyl group, and R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy And C 1-6 alkylthio;
  • X is -CH 2 CH 2 -;
  • R 6 and R 6 ' are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl and aryloxy groups;
  • R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and aryl;
  • the ring A connected to Y is selected from:
  • R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl
  • n is any integer from 0-6.
  • the application provides a pharmaceutical composition, which contains a preventive or therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, or polymorph thereof Compounds, solvates, N-oxides, isotopically-labeled compounds, metabolites, prodrugs or mixtures thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the application provides a kit product, which contains the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, or solvate thereof.
  • kit product which contains the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, or solvate thereof.
  • Another aspect of the application provides the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, Use of metabolites, prodrugs or mixtures thereof, pharmaceutical compositions, or kit products in the preparation of drugs for the prevention or treatment of diseases or disorders related to PPAR.
  • Another aspect of the application provides the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled compound, Metabolites, prodrugs or mixtures thereof, pharmaceutical compositions, or kit products, which are used to prevent or treat diseases or disorders related to PPAR.
  • Another aspect of the present application provides a method for preventing or treating diseases or disorders related to PPAR, which comprises administering an effective amount of the compound or a pharmaceutically acceptable salt, ester, or three-dimensional compound thereof to a subject in need thereof.
  • the application provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopes thereof.
  • the application provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopes thereof A labeled compound, metabolite or prodrug or a pharmaceutical composition as described herein, which is used to activate PPAR in a cell.
  • the application provides a method for activating PPAR in a cell, which comprises combining the cell with an effective amount of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer The step of contacting the body, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug, or the pharmaceutical composition described herein.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon group.
  • the alkyl group has 1 to 12, for example, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched aliphatic hydrocarbon group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n- Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable Substitution with a group (such as halogen) (in this case, the group is called "haloalkyl”) (for example, -CH 2 F, -CHF 2 , -CF 3 ,
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon group of 1 to 4 carbon atoms (ie methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary Butyl or tert-butyl).
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.2.1] octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclonony
  • the cycloalkyl It has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, Cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • alkoxy refers to an alkyl-O- group, where the alkyl group is as previously described.
  • the alkoxy group may contain 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms.
  • suitable alkoxy groups include methoxy, ethoxy, and isopropoxy.
  • the alkyl group of the alkoxy group is connected to the adjacent moiety through an oxygen atom.
  • alkylthio refers to an alkyl-S- group, where the alkyl group is as previously described.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio and the like.
  • heterocyclyl and “heterocycloalkyl” refer to having 3-6 ring atoms, in which at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are A saturated (ie, heterocycloalkyl) or partially unsaturated (ie, having one or more double bonds and/or triple bonds in the ring) cyclic group of C.
  • “3-6 membered heterocycloalkyl” has 2-5 (such as 2, 3, 4, or 5) ring carbon atoms and one or more (such as 1, 2, 3, or 4) ring carbon atoms.
  • heterocycloalkyl groups include, but are not limited to: oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl (dioxolinyl), pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl , Piperazinyl or trithianyl (trithianyl).
  • the heterocycloalkyl group may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-14 aryl means an aromatic group containing 6 to 14 carbon atoms, such as 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aryloxy refers to an -O-aryl group, where the aryl group is as previously described. For example: -O-phenyl and so on.
  • substitution means that one or more (for example, one, two, three or four) hydrogens on the specified atom are replaced by a selection from the indicated group, provided that no more than the specified atom is present in the In the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Optional substitution of selected substituents. If the nitrogen of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5, or 10 under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • This article also relates to a pharmaceutically acceptable isotope-labeled compound, which is the same as the compound described herein, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the predominant atomic mass in nature or Atomic substitution of mass number.
  • isotopes suitable for inclusion in the compound include, but are not limited to, isotopes of hydrogen (such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon (such as 11 C, 13 C, and 14 C); Isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (e.g.
  • isotopes of nitrogen e.g. 13 N and 15 N
  • isotopes of oxygen e.g. 15 O, 17 O and 18 O
  • phosphorus isotopes e.g. 32 P
  • sulfur isotopes e.g. 35 S
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (for example, one, two, three, or four) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual The diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds described herein may exist as a mixture of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like.
  • Solid wedge Virtual wedge Depicts the covalent bonds of the compound.
  • the use of a solid line to depict the bond to an asymmetric carbon atom is intended to indicate that it includes all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of real or imaginary wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist. When present in a racemic mixture, use real and imaginary wedges to define relative stereochemistry, rather than absolute stereochemistry.
  • the compounds are intended to be stereoisomers (including cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, geometric It exists in the form of isomers, rotamers, conformational isomers, atropisomers and mixtures thereof.
  • the compounds described herein can exhibit more than one type of isomerism, and are composed of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • This document also relates to all possible crystalline forms or polymorphs of the compound, which can be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions herein may exist in free form for treatment, or, when appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, after they are administered to patients in need thereof,
  • the compounds described herein or their metabolites or residues can be provided directly or indirectly. Therefore, when “compounds described herein" are referred to herein, it is also intended to encompass the aforementioned various derivative forms of the compounds.
  • the pharmaceutically acceptable salts of the compounds described herein include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts.
  • esters means an ester derived from each compound of the general formula in this application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form described herein) Compound).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the free acid or alcohol form described herein
  • the compounds described herein can also be esters themselves.
  • the compound described herein may exist in the form of a solvate (preferably a hydrate), wherein the compound contains a polar solvent as a structural element of the compound's crystal lattice, in particular, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the compound's crystal lattice, in particular, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.
  • N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines can form N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxide such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane to oxidize heterocycles and tertiary amines.
  • the application also relates to metabolites of the compound, that is, substances formed in the body when the compound is administered. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present application also relates to metabolites of the compound, including compounds prepared by contacting the compound with a mammal for a time sufficient to produce its metabolites.
  • the application further relates to prodrugs of the compounds, which are certain derivatives of the compounds that may themselves have less or no pharmacological activity, which can be cleaved by, for example, hydrolysis when administered into or on the body Into the compound with the desired activity.
  • prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo.
  • prodrugs can be replaced by certain parts known to those skilled in the art as "pro-moiety (for example, “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))", for example. It is prepared by the appropriate functional groups present in the compound.
  • This application also relates to said compounds containing protecting groups.
  • protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compound.
  • This can be achieved by conventional protecting groups, such as those described in T.W.Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, and these references are incorporated herein by reference.
  • the protecting group can be removed at an appropriate subsequent stage.
  • the application provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds , Metabolite or prodrug, wherein the compound has the structure of general formula (I):
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio; alternatively, R 1 Together with R 2 and the carbon atom to which they are connected, form a C 3-6 cycloalkyl group, and R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-6 alkyl, and C 1-6 alkoxy And C 1-6 alkylthio;
  • X is -CH 2 CH 2 -;
  • R 6 and R 6 ' are each independently selected from H, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-6 alkyl, -OC 3-6 cycloalkyl and aryloxy groups;
  • R 7 is selected from H, C 1-6 alkyl, C 3-6 cycloalkyl and aryl;
  • the ring A connected to Y is selected from:
  • R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl
  • n is any integer from 0-6.
  • the application provides a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof , Isotope-labeled compounds, metabolites or prodrugs,
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A and n are as defined in the general formula (I).
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, fluorine, chlorine, bromine, and iodine , C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylthio; alternatively, R 1 and R 2 together with the carbon atom to which they are connected form a C 3-6 cycloalkyl group, R 3 , R 4 and R 5 are each independently selected from H, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkylthio.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, fluorine, chlorine, bromine, and iodine , Methyl, ethyl, n-propyl, isopropyl, C 1-4 alkoxy and C 1-4 alkylthio.
  • R 1 and R 2 are methyl; R 3 and R 4 are each independently selected from methyl and chlorine; each R 5 is independently Ground is selected from H, chlorine, methyl, methoxy and methylthio.
  • R 1 , R 2 , R 3 and R 4 are methyl; each R 5 is independently selected from H, chloro, methyl , Methoxy and methylthio.
  • n is 0, 1, 2 or 3.
  • n 1 or 2.
  • Y is -(CR 6 R 6 ')-, and R 6 and R 6 'are as defined above; preferably, R 6 and R 6' Each is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, -OH, -OC 1-4 alkyl, -OC 3-6 cycloalkyl and aryloxy; preferably, R 6 is H; R 6 'is selected from -OH and -OC 1-4 alkyl; more preferably, R 6 is H; R 6' is -OH.
  • Y is -CH(OH)-.
  • R 8 is selected from H, C 1-4 alkyl and C 3-6 cycloalkyl.
  • R 8 is H or methyl
  • R 8 is H.
  • the ring A connected to Y is selected from:
  • R 8 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl; preferably, R 8 is H or methyl; more preferably, R 8 is H.
  • R 1 and R 2 are methyl; R 3 and R 4 are each independently selected from methyl and chlorine; each R 5 is independently selected from H, chlorine, methyl, methoxy and methylthio.
  • R 1 and R 2 are methyl; R 3 and R 4 are each independently selected from methyl and chlorine.
  • the compound encompasses compounds obtained by arbitrarily combining the various embodiments.
  • the application provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds , Metabolites or prodrugs, wherein the compound is selected from:
  • the application provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled A compound, metabolite or prodrug, wherein the compound:
  • the application provides compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds , Metabolite or prodrug, wherein the compound:
  • This application also relates to stereoisomers of the following compounds:
  • the optical rotation direction of the stereoisomer detected under the following optical rotation detection conditions is left-handed: detection temperature: 20° C., detection wavelength 589.3 nm, solvent is methanol, and concentration is 100 mg/mL.
  • the specific rotation of the stereoisomer [ ⁇ ] D 20 -9.5° ⁇ 1°.
  • the specific rotation [ ⁇ ] D 20 of the stereoisomer is -9.5° ⁇ 0.9°, -9.5° ⁇ 0.8°, -9.5° ⁇ 0.7°, -9.5° ⁇ 0.6°, -9.5° ⁇ 0.5°, -9.5° ⁇ 0.4°, -9.5° ⁇ 0.3°, -9.5° ⁇ 0.2° or -9.5° ⁇ 0.1°.
  • the retention time of the stereoisomer under the following liquid phase conditions is 5.8 min ⁇ 1 min, for example, 5.8 min ⁇ 0.9 min, 5.8 min ⁇ 0.8 min, 5.8 min ⁇ 0.7 min, 5.8 min ⁇ 0.6min, 5.8min ⁇ 0.5min, 5.8min ⁇ 0.4min, 5.8min ⁇ 0.3min, 5.8min ⁇ 0.2min or 5.8min ⁇ 0.1min:
  • the optical rotation direction of the stereoisomer detected under the following optical rotation detection conditions is right-handed: detection temperature: 20° C., detection wavelength 589.3 nm, solvent is methanol, and concentration is 100 mg/mL.
  • the specific rotation of the stereoisomer [ ⁇ ] D 20 +9.7° ⁇ 1°.
  • the specific rotation [ ⁇ ] D 20 of the stereoisomer is +9.7° ⁇ 0.9°, +9.7° ⁇ 0.8°, +9.7° ⁇ 0.7°, +9.7° ⁇ 0.6°, + 9.7° ⁇ 0.5°, +9.7° ⁇ 0.4°, +9.7° ⁇ 0.3°, +9.7° ⁇ 0.2° or +9.7° ⁇ 0.1°.
  • the retention time of the stereoisomer under the following liquid phase conditions is 3.5 min ⁇ 1 min, for example, 3.5 min ⁇ 0.9 min, 3.5 min ⁇ 0.8 min, 3.5 min ⁇ 0.7 min, 3.5 min ⁇ 0.6min, 3.5min ⁇ 0.5min, 3.5min ⁇ 0.4min, 3.5min ⁇ 0.3min, 3.5min ⁇ 0.2min or 3.5min ⁇ 0.1min:
  • this application relates to a preparation method of the above-mentioned compound, including the following steps:
  • V represents halogen or a C 1-3 alkylsulfonate group optionally substituted by halogen (for example, a triflate group);
  • R 1 , R 2 , R 3 , R 4 , R 5 , ring A and n are all as defined in general formula I.
  • the preparation method includes the following steps:
  • the first step the acetate derivative (a) and the phenol derivative (b) undergo a substitution reaction under alkaline conditions to prepare intermediate (c);
  • the base is selected from organic bases or inorganic bases, including but not limited to Cs 2 CO 3 , K 2 CO 3 , t BuOK, NaH, etc.;
  • the base is selected from organic bases or inorganic bases, and the organic bases include but are not limited to tertiary Sodium butoxide, TEA, DIPEA, Pyridine or DMAP, the inorganic base includes but not limited to NaH, NaOH, KOH, Na 2 CO 3 or K 2 CO 3 ;
  • intermediate (e) undergoes ester hydrolysis under acidic or alkaline conditions to prepare intermediate (f);
  • acidic reagents include but are not limited to trifluoroacetic acid, hydrochloric acid, etc.;
  • alkaline reagents include but are not limited to NaOH, KOH, LiOH, etc.;
  • the fourth step Intermediate (f) undergoes hydrogenolysis to obtain a product (formula (II)); the hydrogenolysis conditions include but are not limited to Pd/C and H 2 .
  • the above steps can all be carried out in organic solvents.
  • the organic solvent may be a reaction solvent commonly used in the art, such as but not limited to N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane Etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) , Nitriles (such as acetonitrile, etc.) and their mixed solvents.
  • reaction solvent commonly used in the art, such as but not limited to N,N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane Etc.),
  • the compound can also be prepared in a variety of ways known to those skilled in the field of organic synthesis.
  • the compound can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include, but are not limited to, those described above.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the conversion.
  • Those skilled in the field of organic synthesis should understand that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the judgment of modifying the sequence of the synthesis steps or choosing another specific method route relative to one method route to obtain the desired compound.
  • the application also provides a pharmaceutical composition, which contains a preventive or therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, or polymorph thereof.
  • a pharmaceutical composition which contains a preventive or therapeutically effective amount of the compound described herein, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, or polymorph thereof.
  • the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the pharmaceutical excipients mentioned in this article refer to the excipients and additives used in the production of drugs and formulating prescriptions. They refer to those that have been reasonably evaluated in terms of safety in addition to the active ingredients and are included in the pharmaceutical preparations. substance.
  • Pharmaceutical excipients can be used to shape, act as carriers, improve stability, and also have important functions such as solubilization, solubilization, and slow and controlled release. They are important ingredients that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural products, semi-synthetic products and fully-synthetic products.
  • solvents for oral administration, injection, mucosal, transdermal or topical administration, nasal or oral inhalation administration, and ocular administration.
  • Specific pharmaceutical excipients include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, alginate, calcium silicate, calcium phosphate, cellulose , Aqueous syrup, methylcellulose, polyvinylpyrrolidone, alkyl p-hydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, etc.
  • the pharmaceutical composition can be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms in human or animal patients.
  • various suitable dosage forms can be prepared according to the route of administration.
  • the pharmaceutical composition When administered orally, the pharmaceutical composition can be made into any orally acceptable preparation form, including but not limited to tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions and oral emulsions Wait. Oral suspensions are usually used by mixing the active ingredients with suitable emulsifiers and suspending agents. Optionally, some sweeteners, fragrances or coloring agents can be added to the above oral preparation forms.
  • the pharmaceutical composition When applied transdermally or topically, the pharmaceutical composition can be made into an appropriate ointment, lotion or liniment form, in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax, and water; carriers that can be used for lotions or liniments include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of injection, including injection, sterile powder for injection and concentrated solution for injection.
  • usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • kit product which contains the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N- Oxide, isotope-labeled compound, metabolite, prodrug or mixture thereof, or pharmaceutical composition, and optional package insert.
  • Another object of the application is to provide the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels
  • PPAR peroxisome proliferator activated receptor
  • Another object of the application is to provide the compounds described herein or their pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels Compounds, metabolites or prodrugs, or their mixtures, or the pharmaceutical compositions described herein, or kit products, which are used to prevent or treat peroxisome proliferator-activated receptor (PPAR) related diseases Or illness.
  • PPAR peroxisome proliferator-activated receptor
  • Another object of the present application is to provide a method for preventing or treating diseases or disorders associated with peroxisome proliferator-activated receptor (PPAR), the method comprising administering to an individual in need thereof an effective amount of the described herein
  • PPAR peroxisome proliferator-activated receptor
  • Another aspect of the application provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels thereof
  • the compounds, metabolites or prodrugs described herein, or the pharmaceutical compositions or kit products described herein, are used for the preparation of reagents for activating PPAR in cells.
  • the agent activates PPAR in cells in vivo, in vitro or ex vivo.
  • Another aspect of the application provides the compounds described herein or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopic labels thereof
  • the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope-labeled activates PPAR in cells in vivo, in vitro or in vitro.
  • Another aspect of the application provides a method for activating PPAR in a cell, which comprises combining the cell with an effective amount of the compound described herein or a pharmaceutically acceptable salt, ester, stereoisomer, or tautomer , Polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs, or the pharmaceutical compositions described herein, or the steps of contacting the kit product.
  • the method is performed in vivo. In some preferred embodiments, the method is performed in vitro.
  • the peroxisome proliferator activated receptor is PPAR ⁇ and/or PPAR ⁇ .
  • the disease or disorder associated with peroxisome proliferator-activated receptor is liver disease and/or bile duct disease, such as liver fibrosis, fatty liver disease, cirrhosis, or, for example, cholangitis .
  • the disease or condition is non-alcoholic fatty liver disease (NAFLD), biliary cirrhosis, and sclerosing cholangitis.
  • NAFLD non-alcoholic fatty liver disease
  • biliary cirrhosis biliary cirrhosis
  • sclerosing cholangitis sclerosing cholangitis
  • the disease or condition is simple fatty liver (SFL) or non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, primary sclerosing cholangitis.
  • SFL simple fatty liver
  • NASH non-alcoholic steatohepatitis
  • primary biliary cirrhosis primary sclerosing cholangitis.
  • the "cell” is a cell line or a cell derived from a subject.
  • the term "effective amount” as used herein refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the dosage and administration schedule of the pharmaceutical composition can be easily determined by a person of ordinary skill in the clinical field.
  • the composition or compound described herein is generally administered twice a day to once every 3 days, preferably once a day, and the total amount of administration is 0.01-1000 mg/time.
  • the dose of treatment varies, depending on the considerations, such as: the age, gender and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; the symptomatic Duration; and other variables that can be adjusted by individual physicians.
  • the desired dose can be administered in one or more times to obtain the desired result.
  • the pharmaceutical composition according to the description herein can also be provided in a unit dosage form.
  • prevention refers to the use of blocking, reducing, inhibiting, preventing and/or delaying a disease or condition or symptom (for example, respiratory disease and symptom, infection or autoimmune disease) in a subject's body
  • a disease or condition or symptom for example, respiratory disease and symptom, infection or autoimmune disease
  • treatment refers to a method performed in order to obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviating symptoms, narrowing the scope of the disease, stabilizing (ie, not worsening) the state of the disease, delaying or slowing down the development of the disease after the subject is sick, To improve or alleviate the state of the disease, and alleviate the symptoms (regardless of part or all), “treatment” can also refer to prolonging the survival period compared to the expected survival period (if not receiving treatment).
  • “Individual” or “subject” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • the term "non-human animals” as used herein includes all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • Thin-layer chromatography purification uses GF254 (0.4 ⁇ 0.5nm) silica gel plate produced in Yantai.
  • the reaction is monitored by thin-layer chromatography (TLC) or LC-MS.
  • the developing solvent system used includes but not limited to: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent
  • the volume ratio is adjusted according to the polarity of the compound, or adjusted by adding triethylamine.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the stationary phase.
  • the eluent system includes but is not limited to the dichloromethane and methanol system and the n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 30°C).
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company, or Terbo Chemical.
  • TM2 (35g) was synthesized by the same method as in Example 2, and a pair of enantiomers TM2-1 (14.4g) and TM2-2 (14.8g) of compound TM2 were obtained by chiral resolution.
  • the split conditions are as follows:
  • CHO-K1 PPAR ⁇ Protein Interaction Cell Line genetically engineered from Chinese hamster ovary cell CHO-K1, 3 strains in total, namely CHO-K1 PPAR ⁇ Protein Interaction Cell Line, CHO-K1 PPAR ⁇ Protein Interaction Cell Line and CHO-K1 PPAR ⁇ Protein Interaction Cell Line, derived from DiscoverX.
  • Detection kit Detection Kit, derived from DiscoverX.
  • the cell test method of protein interaction tests the nuclear receptor agonistic activity of PPAR ⁇ , ⁇ and ⁇ .
  • Cell culture separately Three different cell lines of CHO-K1 PPAR ⁇ , ⁇ , and ⁇ Protein Interaction were resuscitated and cultured overnight. The cells were digested and counted, 20 ⁇ L of cell suspension was added to a 384-well white microtiter plate, and cultured in a medium containing carbon adsorption-dextran stripped serum at 37° C. and 5% CO 2.
  • the compounds were tested for their agonistic activity on the three nuclear receptors PPAR ⁇ , ⁇ , and ⁇ , and the determination results are shown in Tables 1-3.
  • Table 1 shows that, compared with GFT505, the compounds TM2 and TM2-2 have stronger agonistic activity on PPAR ⁇ in the in vitro cell viability assay.
  • Table 2 shows that compounds TM2, TM2-2 and GFT505 have comparable agonistic activities to PPAR ⁇ in the in vitro cell viability assay.
  • Table 3 shows that, compared with GFT505, the agonistic activity of compound TM2 and its isomer TM2-2 on PPAR ⁇ in the in vitro cell viability assay has increased, and the agonistic activity of TM2-2 has a more significant increase.
  • the compounds TM2 and TM2-2 have agonistic activity on PPAR ⁇ , ⁇ and ⁇ , among which they have stronger agonistic activity on PPAR ⁇ .
  • TM2 and TM2-2 have agonistic activity against PPAR ⁇ , ⁇ and ⁇ .
  • PPAR ⁇ has better selectivity.
  • the agonistic activity of compound TM2 on PPAR ⁇ increased by 17 times, and the affinity of TM2-2 on PPAR ⁇ increased by 26 times; the agonistic activity of compound TM2 and TM2-2 on PPAR ⁇ was equivalent to that of GFT505; the agonistic activity of compound TM2 on PPAR ⁇ The activity is comparable to GFT505, and the agonistic activity of compound TM2-2 is stronger than that of GFT505.
  • GFT505 is a clinically researched PPAR receptor agonist drug, the structure is shown in the figure below, and it is synthesized according to the existing technology:
  • HEK293T cells stably transfected with hERG gene were used for the experiment.
  • the manual patch clamp whole-cell patch clamp technique was used to study the effect of compounds on hERG channel current, calculate the concentration effect curve, and evaluate the risk of ventricular repolarization toxicity.
  • each voltage stimulation includes the following 5 stages: stage A, keep the cell membrane clamp potential -80mV for 0.5s; stage B, give the cell -50mV repolarization voltage Take baseline tail current measurement for 0.5s; in stage C, give the cell a +50mV depolarization voltage for 2.5s; in stage D, repolarize to -50mV to elicit hERG tail current for 4s; stage E, restore the clamping potential- 80mV for 0.5s.
  • the entire stimulation process is 8s, and each voltage stimulation is repeated at an interval of 2s, that is, each stimulation cycle is 10s.
  • the compound is administered using a perfusion drug delivery system (under room temperature), and a negative control (extracellular fluid containing 0.1% DMSO), 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, 30 ⁇ M and 100 ⁇ M concentration of compound solutions, the liquid in channels 1-6 is sequentially applied to the cells by gravity perfusion (when positive drugs are detected, add 0.3% DMSO extracellular solution, 50nM, 100nM, 200nM, 400nM and 800nM Terfenadine test solution).
  • the negative control hERG tail current was stably recorded in the extracellular fluid for no less than 3 minutes.
  • Compound or positive control is administered by perfusion. When the amplitude of hERG tail current changes less than 5%, the drug effect is considered to reach a steady state. If the current does not reach a steady state within 6 minutes, the concentration compound detection is also ended.
  • the inhibition rate of the test compound on hERG current is calculated according to the following equation:
  • Inhibition rate (1-inhibition current/control current) ⁇ 100%
  • the inhibition rate (mean ⁇ standard deviation) of the hERG current at various concentrations of the test compound was obtained, and then the data was fitted using GraphPad Prism5 (version: 5.01) software to obtain the IC 50 value.
  • the IC 50 of compound TM2 on hERG current was 121.03 ⁇ 22.41 ⁇ M, indicating that the compound had no inhibitory effect on hERG channels within the concentration range tested in this test.
  • Test operation The test selects 5 strains of Salmonella typhimurium mutant strains, namely TA97a, TA98, TA100, TA102 and TA1535 as standard test strains.
  • the experiment adopts the plate incorporation method, and is carried out under two treatment conditions with the addition of in vitro metabolic activation system (+S9) and without addition of in vitro metabolic activation system (-S9).
  • this test uses DMSO as the solvent, with or without the addition of the in vitro metabolic activation system, and the compound is set in 5 concentration groups for each test strain, respectively 5000 ⁇ g/dish and 2000 ⁇ g/ Dish, 800 ⁇ g/dish, 320 ⁇ g/dish and 128 ⁇ g/dish, meanwhile, solvent control group and positive control group are set in parallel.
  • concentration groups including vehicle control and positive control
  • the increase in the number of back-mutant colonies did not reach the threshold (2 times or 3 times), but there was a concentration response relationship. Or the increase in the number of back-mutant colonies is equal to or greater than the respective threshold (2 times or 3 times), but there is no concentration response relationship.
  • the test results can be judged as suspicious results.
  • the compound TM2 at 5000, 2000, 800, 320 and 128 ⁇ g/dish is not mutagenic to all the tested strains, that is, the Ames test result is negative .
  • CHL Chinese hamster lung fibroblasts
  • Test operation This test uses DMSO as the test solvent control.
  • the positive control and the concentration used were ethyl methanesulfonate 1000 ⁇ g/mL (-S9, 3h), 500 ⁇ g/mL (-S9, 24h) and injection cyclophosphamide 5 ⁇ g/mL (+S9, 3h).
  • the metabolic activation system is SD rat liver homogenate induced by the combination of phenobarbital and ⁇ -naphthoflavone (S9).
  • Three treatment conditions were set up in the experiment, namely 3 hours without the addition of the in vitro metabolic activation system, 3 hours without the addition of the in vitro metabolic activation system, and 24 hours without the addition of the in vitro metabolic activation system.
  • the highest concentration of the compound in these three treatment conditions is set to 250 ⁇ g/mL.
  • the compound has 5 concentrations, respectively 250 ⁇ g/mL, 100 ⁇ g/mL, 40 ⁇ g/mL, 16 ⁇ g/mL and 6.4 ⁇ g/mL; the solvent control and the positive control group are set in parallel, and each concentration is set to 2 Parallel cell culture.
  • colchicamine final concentration 0.1 ⁇ g/mL was used for 2 hours to block the cells in the mid-division period. Cells were harvested 24 hours after administration, cell count, cytotoxicity analysis and slide preparation were performed.
  • 3 concentrations were selected for each treatment condition, including vehicle control for microscopy, at least 300 metaphase cells were observed; positive control for microscopy, at least 100 metaphase cells were observed to analyze chromosomal aberrations.
  • 1Data calculation The total number of structural aberrations should be calculated for each culture flask cell according to the following categories: the total number of counted cells, the total number of aberrant cells, the total number of aberrant chromosomes, and the total number of fissures; 2Statistical processing: using Microsoft Excel 2013 Calculated and analyzed with SPSS 13.0 software, compared the formation rate of chromosomal aberration cells in the drug treatment group (including the positive control group) and the vehicle control group, and used Fisher's exact (Fisher Exact) probability method to identify significant differences. The positive control group and the vehicle control group were compared in pairs. When P ⁇ 0.05, the difference was considered significant. The compound group and the vehicle control group are first compared with each other.
  • the compound TM2 at 40, 100 and 250 ⁇ g/mL did not cause significant aberrations in the chromosome structure of CHL cells. Elevated, non-mutagenic to CHL mammalian cells cultured in vitro. The result of the chromosome aberration test was negative.

Abstract

本申请公开了一种芳香族化合物及其药物组合物的用途，含有所述化合物的药物组合物，以及该类化合物及其中间体的制备方法。本申请还公开了所述化合物用于制备预防或治疗肝脏疾病和/或胆管疾病相关疾病或病症的药物用途。

Description

芳香族化合物及其药物组合物和用途
本申请是以CN申请号为202010130024.4，申请日为2020年2月28日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请属于制药领域，具体涉及一类芳香族化合物，含有该类化合物的药物组合物，以及该类化合物及其中间体的制备方法。本申请还涉及该类化合物用于制备预防或治疗与过氧化物酶体增殖物激活受体(PPAR)相关的疾病或病症的药物的用途。
背景技术
非酒精性脂肪性肝病(NAFLD)是一类肝组织学改变与酒精性肝病相似，但无过量饮酒史的临床病理综合征，包括单纯性脂肪肝(SFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化，其中NASH是NAFLD进展的重要中间阶段。随着胰岛素抵抗及其相关的多元代谢综合征的高发，NAFLD/NASH的患病率逐渐升高。在发达国家和地区，NAFLD现已成为最常见的肝病之一。美国普通成人NAFLD的患病率为10～40％(平均20％)，NASH为2～5％(平均3％)。在肥胖、糖尿病以及血清丙氨酸转氨酶(ALT)慢性升高者等特殊人群中NAFLD的患病率更高，并且NAFLD的起病渐趋低龄化。
非酒精性脂肪性肝病除可直接导致失代偿期肝硬化、肝细胞癌和移植肝复发外，还可影响其他慢性肝病的进展，并参与2型糖尿病和动脉粥样硬化的发病。代谢综合征相关恶性肿瘤、动脉硬化性心脑血管疾病以及肝硬化为影响非酒精性脂肪性肝病患者生活质量和预期寿命的重要因素。当前NASH已成为仅次于慢性病毒性肝炎、酒精性肝病的重要肝硬化前期病变之一，并为健康体检人群血清转氨酶异常的常见病因，NASH的有效防治可望阻止慢性肝病进展，减少肝硬化和肝病相关残疾和死亡的发生。非酒精性脂肪性肝病是当代医学领域的新挑战，治疗非酒精性脂肪肝相关疾病的药物开发具有重要的临床意义。
过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor,PPAR)是核内受体转录因子超家族成员，在调节代谢体内平衡、炎症、细胞生长和分化中扮演着关键角色。PPAR激动剂在II型糖尿病中被用作降脂药和口服降血糖药，近年来的研究发现这类激动剂具有肝保护功能。PPARα在肝细胞中有很高的表达，主要起着调节脂肪酸转运和β-氧化的作用。另外，PPARα还能调节糖质新生过程和炎症反应。与PPARα相似，PPARδ能够调控肝脏中葡萄糖的利用和脂蛋白代谢,并具有显著的抗炎活性。基于对PPARα和PPARδ功能的研究，PPAR激动剂有可能解决在NASH发病机制中所涉 及的多种生物学问题，或者更广泛的的代谢和心血管问题。
发明内容
本申请提供用作为PPAR激动剂的含有2-苯氧基乙酸结构的化合物，尤其是具有优异的对PPARα&δ的双激动活性、更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)和/或改善的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等更优异的性质。
在一个方面，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有通式(I)的结构：
Figure PCTCN2021075433-appb-000001
其中：
R 1、R 2、R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；或者，R 1和R 2与它们相连的碳原子一起形成C 3-6环烷基，R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；
X为-CH 2CH 2-；
Y选自-(CR 6R 6’)-和-C(＝N-OR 7)-；
R 6和R 6’各自独立地选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基和芳氧基；
R 7选自H、C 1-6烷基、C 3-6环烷基和芳基；
与Y相连的环A选自：
Figure PCTCN2021075433-appb-000002
R 8选自H、C 1-6烷基和C 3-6环烷基；
n为0-6中的任意整数。
在另一方面，本申请提供药物组合物，其含有预防或治疗有效量的本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物以及一种或多种药学上可接受的辅料。所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
在另一方面，本申请提供一种药盒产品，其含有本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，或者本文所述的药物组合物，以及任选的药品说明书。
本申请的另一方面提供所述化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物、药物组合物、或药盒产品在制备用于预防或治疗与PPAR相关的疾病或病症的药物中的用途。
本申请的另一方面提供所述化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物、药物组合物、或药盒产品，其用于预防或治疗与PPAR相关的疾病或病症。
本申请的另一方面提供一种预防或治疗与PPAR相关的疾病或病症的方法，其包括向有此需要的受试者施用有效量的所述化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物、药物组合物、或药盒产品。
在另一方面，本申请提供本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物用于试剂的用途，所述试剂用于激活细胞中PPAR。
在另一方面，本申请提供本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物，其用于激活细胞中PPAR。
在另一方面，本申请提供激活细胞中PPAR的方法，其包括将所述细胞与有效量的本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物接触的步骤。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下 术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃基。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的脂肪族烃基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基(如卤素)取代(此时该基团被称作“卤代烷基”)(例如-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃基(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“环烷基”或“环烷烃基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指含3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“烷氧基”指烷基-O-基团，其中烷基如前所述。烷氧基可包含1至约12个碳原子，优选1至约6个碳原子。合适的烷氧基的非限制性实例包括甲氧基、乙氧基和异丙氧基。烷氧基的烷基通过氧原子与相邻部分连接。
如本文中所使用，术语“烷硫基”指烷基-S-基团，其中烷基如前所述。C 1-6烷硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基、己硫基等。
如本文中所使用，术语“杂环基”、“杂环烷基”是指具有3-6个环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-6元杂环烷基”是具有2-5个(如2、3、4或5个)环碳原子和一个或多个(例如1个、2个、3个或4个)独立地选自N、O和S的杂原子的饱和或部分不饱和杂环基。杂环烷基的实例包括但不限于：环氧乙烷基、氮丙啶基、氮杂环丁基(azetidinyl)、氧杂环丁基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。所述杂环烷基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，术语“C 6-14芳基”意指含有6至14个碳原子例如含有6至10个碳原子的芳族基团， 诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语"芳氧基"是指-O-芳基基团，其中芳基如前所述。例如：-O-苯基等。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被……取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组基团，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本文还涉及药学上可接受的同位素标记的化合物，其与本文所述的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入所述化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本文所述的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有 这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2021075433-appb-000003
实楔形
Figure PCTCN2021075433-appb-000004
或虚楔形
Figure PCTCN2021075433-appb-000005
描绘所述化合物的共价键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则所述化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本文所述的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本文还涉及所述化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本文中某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。所述药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本文所述的化合物或其代谢物或残余物。因此，当在本文中提及“本文所述的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本文所述化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。适合的碱加成盐由形成药学可接受盐的碱来形成。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本文所述化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本文所述化合物)。本文所述化合物本身也可以是酯。
本文所述的化合物可以溶剂合物(优选水合物)的形式存在，其中所述化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。 本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
本申请还涉及所述化合物的代谢物，即在给药所述化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本申请还涉及所述化合物的代谢物，包括通过使所述化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本申请进一步涉及所述化合物的前药，其为自身可具有较小药理学活性或无药理学活性的所述化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的所述化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。所述前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代是化合物中存在的适当官能团来制备。
本申请还涉及含有保护基的所述化合物。在制备所述化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成所述化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
具体实施方式
化合物
在一些实施方案中，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中 所述化合物具有通式(I)的结构：
Figure PCTCN2021075433-appb-000006
其中：
R 1、R 2、R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；或者，R 1和R 2与它们相连的碳原子一起形成C 3-6环烷基，R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；
X为-CH 2CH 2-；
Y选自-(CR 6R 6’)-和-C(＝N-OR 7)-；
R 6和R 6’各自独立地选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基和芳氧基；
R 7选自H、C 1-6烷基、C 3-6环烷基和芳基；
与Y相连的环A选自：
Figure PCTCN2021075433-appb-000007
R 8选自H、C 1-6烷基和C 3-6环烷基；
n为0-6中的任意整数。
在部分实施方案中，本申请提供式(II)的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，
Figure PCTCN2021075433-appb-000008
其中，R 1、R 2、R 3、R 4、R 5、环A和n如通式(I)所定义。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 1、R 2、R 3、R 4和R 5各 自独立地选自H、氟、氯、溴、碘、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；或者，R 1和R 2与它们相连的碳原子一起形成C 3-6环烷基，R 3、R 4和R 5各自独立地选自H、氟、氯、溴、碘、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 1、R 2、R 3、R 4、R 5各自独立地选自H、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、C 1-4烷氧基和C 1-4烷硫基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 1和R 2为甲基；R 3和R 4各自独立地选自甲基和氯；各R 5独立地选自H、氯、甲基、甲氧基和甲硫基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 1、R 2、R 3和R 4为甲基；各R 5独立地选自H、氯、甲基、甲氧基和甲硫基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，n为0、1、2或3。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，n为1或2。
在部分实施方案中，本申请提供的式(I)化合物中，Y为-(CR 6R 6’)-，R 6和R 6’定义如前文所述；优选地，R 6和R 6’各自独立地选自H、C 1-4烷基、C 3-6环烷基、C 3-6杂环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基和芳氧基；优选地，R 6为H；R 6‘选自-OH和-OC 1-4烷基；更优选地，R 6为H；R 6‘为-OH。
在部分实施方案中，本申请提供的式(I)化合物中，Y为-CH(OH)-。
在部分实施方案中，本申请提供的式(I)化合物中，Y为-C(＝N-OR 7)-，R 7定义如前文所述；优选地，R 7选自H、C 1-4烷基、C 3-6环烷基和芳基(例如C 6-10芳基)；优选地，R 7选自H和C 1-4烷基；更优选地，R 7为H。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 8选自H、C 1-4烷基和C 3-6环烷基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 8为H或甲基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，R 8为H。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，与Y相连的环A选自：
Figure PCTCN2021075433-appb-000009
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，
Figure PCTCN2021075433-appb-000010
选自：
Figure PCTCN2021075433-appb-000011
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，
Figure PCTCN2021075433-appb-000012
选自：
Figure PCTCN2021075433-appb-000013
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，
Figure PCTCN2021075433-appb-000014
选自：
Figure PCTCN2021075433-appb-000015
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，与Y相连的
Figure PCTCN2021075433-appb-000016
选自：
Figure PCTCN2021075433-appb-000017
其中，R 8选自H、C 1-6烷基和C 3-6环烷基；优选地，R 8为H或甲基；更优选地，R 8为H。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，
Figure PCTCN2021075433-appb-000018
选自：
Figure PCTCN2021075433-appb-000019
R 1和R 2为甲基；R 3和R 4各自独立地选自甲基和氯；各R 5独立地选自H、氯、甲基、甲氧基和甲硫基。
在部分实施方案中，本申请提供的式(I)或式(II)化合物中，
Figure PCTCN2021075433-appb-000020
选自：
Figure PCTCN2021075433-appb-000021
R 1和R 2为甲基；R 3和R 4各自独立地选自甲基和氯。
所述化合物涵盖对各个实施方案进行任意组合所得的化合物。
在部分实施方案中，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2021075433-appb-000022
Figure PCTCN2021075433-appb-000023
在部分优选实施方案中，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物：
Figure PCTCN2021075433-appb-000024
在部分实施方案中，本申请提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物：
Figure PCTCN2021075433-appb-000025
本申请还涉及下述化合物的立体异构体：
Figure PCTCN2021075433-appb-000026
在一些实施方案中，所述立体异构体在下述旋光度检测条件下检测得到的旋光方向为左旋：检测温度：20℃，检测波长589.3nm，溶剂为甲醇，浓度为100mg/mL。在一些实施方案中，所述立体异构体的比旋光度[α] D 20＝-9.5°±1°。在一些实施方案中，所述立体异构体的比旋光度[α] D 20为-9.5°±0.9°、-9.5°±0.8°、-9.5°±0.7°、-9.5°±0.6°、-9.5°±0.5°、-9.5°±0.4°、-9.5°±0.3°、-9.5°±0.2°或-9.5°±0.1°。在一些实施方案中，所述立体异构体在下述液相条件下的保留时间为5.8min±1min，例如，5.8min±0.9min、5.8min±0.8min、5.8min±0.7min、5.8min±0.6min、5.8min±0.5min、5.8min±0.4min、5.8min±0.3min、5.8min±0.2min或5.8min±0.1min：
色谱柱：CHIRALPAK IC(IG00CD-KJ016)；
色谱柱尺寸：0.46cm I.D.×15cm L；
进样量：1μL；
流动相：Hexane/EtOH/HAC＝85/15/0.1(V/V/V)；
流速：1.0ml/min；
检测波长：UV 254nm；以及
柱温：35℃。
在另一些实施方案中，所述立体异构体在下述旋光度检测条件下检测得到的旋光方向为右旋：检测温度：20℃，检测波长589.3nm，溶剂为甲醇，浓度为100mg/mL。在一些实施方案中，所述立体异构体比旋光度[α] D 20＝+9.7°±1°。在一些实施方案中，所述立体异构体比旋光度[α] D 20为+9.7°±0.9°、+9.7°±0.8°、+9.7°±0.7°、+9.7°±0.6°、+9.7°±0.5°、+9.7°±0.4°、+9.7°±0.3°、+9.7°±0.2°或+9.7°±0.1°。在一些实施方案中，所述立体异构体在下述液相条件下的保留时间为3.5min±1min，例如，3.5min±0.9min、3.5min±0.8min、3.5min±0.7min、3.5min±0.6min、3.5min±0.5min、3.5min±0.4min、3.5min±0.3min、3.5min±0.2min或3.5min±0.1min：
色谱柱：CHIRALPAK IC(IG00CD-KJ016)；
色谱柱尺寸：0.46cm I.D.×15cm L；
进样量：1μL；
流动相：Hexane/EtOH/HAC＝85/15/0.1(V/V/V)；
流速：1.0ml/min；
检测波长：UV 254nm；以及
柱温：35℃。
制备方法
在另一个方面，本申请涉及上述化合物的制备方法，包括以下步骤：
Figure PCTCN2021075433-appb-000027
其中，V表示卤素或任选地被卤素取代的C 1-3烷基磺酸酯基(例如三氟甲磺酸酯基)；
R 1、R 2、R 3、R 4、R 5、环A和n均如通式I所定义。
在部分实施方案中，所述制备方法包括以下步骤：
第一步：乙酸酯衍生物(a)与苯酚衍生物(b)在碱性条件下发生取代反应制得中间体(c)；所述碱选自有机碱或无机碱，包括但不限于Cs 2CO 3、K 2CO 3、 tBuOK、NaH等；
第二步：中间体(c)与化合物(d)在碱性条件下发生缩合反应制得中间体(e)；所述碱选自有机碱或无机碱，所述有机碱包括但不限于叔丁醇钠、TEA、DIPEA、Pyridine或DMAP，所述无机碱包括但不限于NaH、NaOH、KOH、Na 2CO 3或K 2CO 3；
第三步：中间体(e)在酸性或碱性条件下发生酯水解反应制得中间体(f)；酸性试剂包括但不限于三氟醋酸、盐酸等；碱性试剂包括但不限于NaOH、KOH、LiOH等；
第四步：中间体(f)发生氢解反应制得产物(式(Ⅱ))；氢解条件包括但不限于Pd/C和H 2等。
本领域技术人员会明白，可根据需要调整各个步骤的顺序，例如可在脱除叔丁基保护后进行氢化或成环反应。本领域技术人员也会明白，中间体c酯基中的叔丁基可以替换为其它具有同等功能的保护基团，在后续步骤中被脱除从而最终得到酸产物，例如苄基、对甲氧基苄基、苄氧酰基和取代的硅基等。
以上步骤均可在有机溶剂中进行。所述有机溶剂可以是本领域常用的反应溶剂，例如但不限于N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、饱和烃类(例如环己烷、己烷等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醚类(例如四氢呋喃、乙醚、二噁烷、1,2-二甲氧基乙烷等)、腈类(例如乙腈等)和它们的混合溶剂等。
另外，所述化合物还可以由有机合成领域的技术人员已知的多种方式制备。所述化合 物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)上文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。有机合成领域的技术人员应了解，分子上存在的官能团应与所提出的转化一致。这有时将需要以下判断：修改合成步骤的顺序或相对于一种方法路线选择另一特定方法路线以获得所需化合物。
还应认识到，本领域中设计任何合成途径的另一主要考虑因素是正确选择用于保护所述化合物中存在的反应性官能团的保护基团。向受过训练的相关人士描述许多替代方案的权威说明为Greene等人(Protective Groups in Organic Synthesis，第4版，Wiley-Interscience(2006))。
除非另外说明，上述路线中化合物的取代基如本文所定义。本领域技术人员会明白，根据期望获得的产物结构，可省略以上路线中的一个或多个步骤。本领域技术人员也可根据需要适当地调整反应步骤的顺序。
药物组合物和药盒产品
在另一方面，本申请还提供药物组合物，其含有预防或治疗有效量的本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物以及一种或多种药学上可接受的辅料。所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本文中所述药用辅料是指生产药品和调配处方时，使用的赋形剂和附加剂，是指除活性成分外，在安全性方面已进行了合理的评估，并且包含在药物制剂中的物质。药用辅料可用于赋型、充当载体、提高稳定性，还可具有增溶、助溶、缓控释等重要功能，是可能会影响到药品的质量、安全性和有效性的重要成分。根据其来源可分为天然物、半合成物和全合成物。根据其作用与用途可分为：溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、湿润剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏着剂、抗氧剂、螯合剂、渗透促进剂、pH调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂等；根据其给药途径可分为口服、注射、黏膜、经皮或局部给药、经鼻或口腔吸入给药和眼部给药等。具体的药用辅料包含水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等。
所述药物组合物可以以任意形式施用，只要其实现预防、减轻、防止或者治愈人类或 动物患者的症状。例如，可根据给药途径制成各种适宜的剂型。
当口服用药时，所述药物组合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊剂、颗粒剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等。口服混悬剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。任选地，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当经皮或局部施用时，所述药物组合物可制成适当的软膏、洗剂或搽剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或搽剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
所述药物组合物还可以注射剂形式用药，包括注射液、注射用无菌粉末与注射用浓溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
本申请还提供一种药盒产品，其含有本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，或者药物组合物，以及任选的药品说明书。
治疗方法和用途
本申请的另一目的在于提供本文所述的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物，或者本文所述的的药物组合物，或者药盒产品，在制备用于预防或治疗与过氧化物酶体增殖物激活受体(PPAR)相关疾病或病症的药物中的用途。
本申请的另一目的在于提供本文所述的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物，或者本文所述的药物组合物，或者药盒产品，其用于预防或治疗与过氧化物酶体增殖物激活受体(PPAR)相关疾病或病症。
本申请的另一目的在于提供预防或治疗与过氧化物酶体增殖物激活受体(PPAR)相关疾病或病症的方法，所述方法包括向有此需要的个体施用有效量的本文所述的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药、或者它们的混合物，或者本文所述的药物组合物，或者药盒产品。
本申请的另一方面提供本文所述的化合物或其药学上可接受的盐、酯、立体异构体、 互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物，或者药盒产品，用于制备试剂的用途，所述试剂用于激活细胞中PPAR。在一些优选的实施方案中，所述试剂在体内、体外或离体激活细胞中PPAR。
本申请的另一方面提供本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物，或者药盒产品，其用于激活细胞中PPAR。
在一些优选的实施方案中，所述化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本文所述的药物组合物，或者药盒产品在体内、体外或离体激活细胞中PPAR。
本申请的另一方面提供激活细胞中PPAR的方法，其包括将所述细胞与有效量的本文所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，或者本文所述的药物组合物，或者药盒产品接触的步骤。
在一些优选的实施方案中，所述方法在体内进行。在一些优选的实施方案中，所述方法在体外进行。
在一个实施方案中，所述过氧化物酶体增殖物激活受体(PPAR)为PPARα和/或PPARδ。
在一个实施方案，所述与过氧化物酶体增殖物激活受体(PPAR)相关疾病或病症为肝脏疾病和/或胆管疾病，例如肝纤维变性、脂肪性肝病、肝硬化，或者例如胆管炎。
在一些优选的实施方案中，所述疾病或病症为非酒精性脂肪性肝病(NAFLD)、胆汁性肝硬化、硬化性胆管炎。
在一些优选的实施方案中，所述疾病或病症为单纯性脂肪肝(SFL)或非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化、原发性硬化性胆管炎。
在一些优选的实施方案中，所述“细胞”为细胞系或来自受试者的细胞。如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。本文所述的组合物或化合物一般为每天两次至每3天给药1次，优选每天 给药1次，并且给药总量0.01～1000mg/次。一般地，治疗的剂量是变化的，这取决于所考虑的事项，例如：待治疗患者的年龄、性别和一般健康状况；治疗的频率和想要的效果的性质；组织损伤的程度；症状的持续时间；以及可由各个医师调整的其它变量。可以以一次或多次施用想要的剂量，以获得想要的结果。也可以以单位剂量形式提供根据本文所述的药物组合物。
除非另外说明，术语“预防”是指，用于阻断、减少、抑制、防止和/或延迟疾病或病症或症状(例如，呼吸系统疾病和症状、感染或自身免疫性疾病)在对象体内的发生而实施的方法，降低所述对象中感染性疾病患病发生率的方法。
如本文中所使用的，术语“治疗”是指，为了获得有益或所需临床结果而实施的方法。为了本发明的目的，有益或所需的临床结果包括但不限于，所述对象患病后减轻症状、缩小疾病范围、稳定(即，不再恶化)疾病的状态，延迟或减缓疾病的发展，改善或减轻疾病的状态、和缓解症状(无论部分或全部)，“治疗”还可以指，与期望的存活期相比(如果未接受治疗)，延长存活期。
如本文所使用的“个体”或“受试者”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本文所用术语“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
以下列举实施例和试验例，进而详细地说明本发明，但它们不限制本发明的范围，另外在不脱离本发明的范围下可进行变化。
NMR的测定使用Bruker核磁共振仪，生产商：Bruker，型号：AVANCE III HD 400。
MS的测定使用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
制备高效液相色谱法使用岛津LC-8A制备液相色谱仪(YMC,ODS,250×20mm色谱柱)。
薄层色谱法纯化采用的是烟台产GF 254(0.4～0.5nm)硅胶板。
反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系包括但不限于：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系和石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，或者加入三乙胺等进行调节。
柱色谱法一般使用青岛海洋200～300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺等进行调节。
如实施例中无特殊说明，则反应的温度为室温(20℃～30℃)。
实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company或者特伯化学等公司。
如本文中所使用的缩写具有以下含义：
缩写 含义 缩写 含义
DMP 戴斯-马丁氧化剂 Na 2SO 4 硫酸钠
Oxone 过氧单磺酸钾 Na 2SO 3 亚硫酸钠
IBX 2-碘酰基苯甲酸 HCl 氯化氢
Jones 琼斯氧化剂 TFA 三氟乙酸
PDC 重铬酸吡啶 CF 3SO 3H 三氟甲磺酸
PCC 氯铬酸吡啶盐 HCOOH 甲酸
TEA 三乙胺 MeOH 甲醇
DIPEA N,N-二异丙基乙胺 EtOH 乙醇
DMAP 4-二甲氨基吡啶 MeCN 乙腈
Pyridine 吡啶 Et 2O 乙醚
NaH 氢化钠 THF 四氢呋喃
NaOH 氢氧化钠 Acetone 丙酮
KOH 氢氧化钾 DCM 二氯甲烷
LiOH 氢氧化锂 DMF N,N-二甲基甲酰胺
Na 2CO 3 碳酸钠 NMP N-甲基吡咯烷酮
K 2CO 3 碳酸钾 DMSO 二甲基亚砜
Cs 2CO 3 碳酸铯 EtOAc 乙酸乙酯
NaOMe 甲醇钠 LC-MS 液相色谱-质谱联用
tBuOK 叔丁醇钾 NMR 核磁共振仪
LDA 二异丙基氨基锂 HPLC 高效液相色谱
H 2 氢气 TLC 薄层色谱法
Pd/C 钯碳    
实施例1:2-(4-甲酰基-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(Int 1)的制备
Figure PCTCN2021075433-appb-000028
将SM1 3,5-二甲基-4-羟基苯甲醛(100g,0.67mol)溶于DMF(800mL)中，加入碳酸铯(543g,1.67mol)，升温至100℃反应30min，往体系中滴加2-溴代异丁酸叔丁酯(297g,1.33mol)，滴加完毕后再升温至120℃反应8h，LC-MS监测反应无继续转化的趋势。将反应液倒入冰水中，分层，收集水相。水相用乙酸乙酯萃取，合并有机相。有机相加无水硫酸钠干燥，过滤并浓缩滤液，得粗产品。将粗产品经硅胶柱层析纯化得化合物Int 1(31g)。MS m/z(ESI):293.0[M+H] +。
实施例2:
2-(4-(3-羟基-3-(2-甲氧基喹啉-3-基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM2)的制备
Figure PCTCN2021075433-appb-000029
第一步：化合物2-2的制备
将化合物2-1(300mg,1.46mmol)溶于甲醇(5mL)中，然后加入甲醇钠(5M)(1.46mL,7.30mmol)，LC-MS监测反应完全。将反应液倒入冰水中，用3N HCl水溶液调节至pH 2，乙酸乙酯萃取，合并有机相。有机相用饱和食盐水溶液洗涤1次，硫酸钠干燥，过滤浓缩，经硅胶柱层析纯化得到目标产物(2-2)(270mg)。
MS m/z(ESI):202.2[M+H] +。
第二步：化合物2-3的制备
将化合物2-2(150mg,0.74mmol)、Int 1(216mg,0.74mmol)溶于乙醇(20mL)中，冰水浴降温10min，滴加10％NaOH(0.35mL)，反应16h，LC-MS监测反应无继续转化的趋势。加入水和乙酸乙酯萃取，合并有机相，有机相用饱和食盐水溶液洗涤1次，硫酸钠干燥，过滤浓缩，经硅胶柱层析纯化得到目标产物(2-3)(160mg)。
MS m/z(ESI):476.3[M+H] +。
第三步：化合物2-4的制备
将化合物2-3(138mg,0.29mmol)溶于DCM(4.5mL)中，冰水浴降温10min，滴加TFA(1.5mL)，反应1h，LC-MS监测反应完全。浓缩反应液，经柱层析纯化得到目标产物(2-4)(67mg)。
MS m/z(ESI):420.2[M+H] +。
第四步：化合物TM2的制备
将化合物2-4(4.5g,10.73mmol)加到MeOH(45mL)中，搅拌下加入10％Pd/C(450mg)，反应体系经氢气置换3次后在室温反应16h，经LC-MS监测反应完全。反应液经硅藻土过滤，滤液浓缩后过硅胶柱(洗脱剂体系：DCM/MeOH＝0-5％)和制备型HPLC(流动相：甲酸，乙腈/水)纯化得化合物TM2(1.4g)。
MS m/z(ESI):424.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),8.25(s,1H),7.90(d,J＝7.2Hz,1H),7.75(d,J＝8.4Hz,1H),7.61(t,J＝8.0Hz,1H),7.41(t,J＝8.0Hz,1H),6.80(s,2H),5.40(br,1H),4.87–4.81(m,1H),3.97(s,3H),2.70–2.55(m,2H),2.10(s,6H),2.07–1.97(m,1H),1.85–1.73(m,1H),1.32(s,6H).
实施例3:(S)-2-(4-(3-羟基-3-(2-甲氧基喹啉-3-基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸和(R)-2-(4-(3-羟基-3-(2-甲氧基喹啉-3-基)丙基)-2,6-二甲基苯氧基)-2-甲基丙酸的制备
Figure PCTCN2021075433-appb-000030
采用与实施例2同样的方法合成TM2(35g)，经手性拆分得到化合物TM2的一对对映异构体TM2-1(14.4g)和TM2-2(14.8g)。拆分条件如下：
柱子：CHIRALPAK IC(IG00CD-KJ016)，柱子尺寸：0.46cm I.D.×15cm L，进样量：1ul，流动相：Hexane/EtOH/HAC＝85/15/0.1(V/V/V)，流速：1.0ml/min，检测波长：UV 254nm，柱温：35℃。
TM2-1保留时间为(t 1＝3.466min)，TM2-2保留时间为(t 2＝5.777min)。
TM2-1的比旋光度检测条件：检测温度：20℃，检测波长589.3nm，[α]：+9.7°，(甲醇，C＝100mg/mL)。
TM2-2的比旋光度检测条件：检测温度：20℃，检测波长589.3nm，[α]：-9.5°，(甲醇，C＝100mg/mL)。
TM2-1:
MS m/z(ESI):424.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.80(s,1H),8.25(s,1H),7.90(dd,J  1＝8.0Hz,J 2＝1.2Hz,1H),7.75(d,J＝8.4Hz,1H),7.64-7.58(m,1H),7.45-7.38(m,1H),6.80(s,2H),5.40(d,J＝4.4Hz,1H),4.90–4.81(m,1H),3.98(s,3H),2.70–2.55(m,2H),2.10(s,6H),2.07–1.97(m,1H),1.85–1.73(m,1H),1.32(s,6H).
TM2-2:
MS m/z(ESI):424.1[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ12.80(s,1H),8.25(s,1H),7.90(dd,J  1＝8.0Hz,J 2＝0.8Hz,1H),7.77(d,J＝8.0Hz,1H),7.64-7.58(m,1H),7.45-7.38(m,1H),6.80(s,2H),5.40(d,J＝4.0Hz,1H),4.87–4.81(m,1H),3.98(s,3H),2.70–2.55(m,2H),2.10(s,6H),2.07–1.97(m,1H),1.85–1.73(m,1H),1.32(s,6H).
药理学测试
实验例1：化合物在细胞水平上对PPARα、δ和γ的激活试验
细胞：由中国仓鼠卵巢细胞CHO-K1基因工程改造而得，共3株，分别是
Figure PCTCN2021075433-appb-000031
CHO-K1 PPARα Protein Interaction Cell Line,
Figure PCTCN2021075433-appb-000032
CHO-K1 PPARδ Protein Interaction Cell Line和
Figure PCTCN2021075433-appb-000033
CHO-K1 PPARγ Protein Interaction Cell Line，源自于DiscoverX。
检测试剂盒：
Figure PCTCN2021075433-appb-000034
Detection Kit，源自于DiscoverX。
1.试验方法
采用
Figure PCTCN2021075433-appb-000035
蛋白相互作用的细胞试验方法对PPARα、δ和γ的核受体激动活性进行测试。
1)细胞培养：分别将
Figure PCTCN2021075433-appb-000036
CHO-K1 PPARα、δ、γProtein Interaction的3种不同细胞株进行复苏，过夜培养。将细胞进行消化、计数，取20μL细胞悬液加入384孔白色微孔板中，于37℃，5％CO 2条件下，在含有碳吸附-葡聚糖剥离血清的培养基中培养。
2)化合物孵育：加入5μL不同浓度的5×待测化合物于384孔板细胞中，使其终浓度分别为30μM、10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM(对应化合物GFT505、TM2)，或者，使其终浓度分别为10μM、3.33μM、1.11μM、0.37μM、0.123μM、0.041μM、0.014μM、0.0046μM、0.0015μM、0.0005μM(对应化合物TM2-2)，DMSO终浓度为1％，于37℃，5％CO 2条件下进行孵育。
3)信号检测：待测化合物与细胞孵育6h后，加入12.5μL(50％v/v)PathHunter检测试剂，室温孵育1h后，用PerkinElmer Envision TM多功能酶标仪检测化学发光单位值(RLU)。
4)数据分析：运用CBIS软件(ChemInnovation，CA)进行数据分析，使用以下公式计算不同浓度下化合物的活性百分比：活性百分比％＝(测试样品RLU-溶媒对照RLU)/(最大激活RLU-溶媒对照RLU)×100％，通过曲线拟合计算不同浓度化合物对PPARα、δ、γ不同靶点活性的EC 50值。
2.试验结果
测试了化合物对PPARα、δ、γ3个核受体的激动活性，测定结果见表1-3。
表1 化合物对PPARα的激动活性
化合物编号 EC 50(μM)
GFT505 0.317
TM2 0.018
TM2-2 0.012
由表1的数据显示，相比于GFT505，化合物TM2与TM2-2在体外细胞活性测定中对PPARα具有更强的激动活性。
表2 化合物对PPARδ的激动活性
化合物编号 EC 50(μM)
GFT505 0.111
TM2 0.126
TM2-2 0.092
由表2的数据显示，化合物TM2、TM2-2和GFT505在体外细胞活性测定中对PPARδ的激动活性相当。
表3 化合物对PPARγ的激动活性
化合物编号 EC 50(μM)
GFT505 0.594
TM2 0.237
TM2-2 0.168
由表3的数据显示，与GFT505相比，化合物TM2及其异构体TM2-2在体外细胞活性测定中对PPARγ的激动活性均有提高，而TM2-2的激动活性提高幅度更为显著。
综上，在体外细胞活性测定中，化合物TM2与TM2-2对PPARα、δ和γ都具有激动活性，其中对PPARα具有更强的激动活性，相比于PPARδ和PPARγ，TM2与TM2-2对PPARα具有更好的选择性。相比于GFT505，化合物TM2对PPARα的激动活性提高了17倍，TM2-2对PPARα的亲和力提高了26倍；化合物TM2和TM2-2对PPARδ的激动活性与GFT505相当；化合物TM2对PPARγ的激动活性与GFT505相当，化合物TM2-2的激动活性比GFT505更强。
注明：GFT505为临床在研PPAR受体激动剂药物，结构如下图所示，根据现有技术合成：
Figure PCTCN2021075433-appb-000037
实验例2：化合物对hERG电流的影响研究
本试验采用稳定转染hERG基因的HEK293T细胞进行试验，用手动膜片钳全细胞膜片钳技术来研究化合物对hERG通道电流的影响，计算浓度效应曲线，并评价其引发心室复极毒性的风险。
1.试验方法
1)细胞培养：细胞复苏、传代后于实验前4～8小时接种于24孔板(预先放置12mm盖玻片圆片)中，进行细胞种板。检测前取出盖玻片圆片，用细胞外液清洗后浸泡待测。
2)电压刺激方案和电流记录：采用全细胞记录模式，每个电压刺激包括以下5个阶段：A阶段，保持细胞膜钳制电位-80mV持续0.5s；B阶段，给予细胞-50mV复极化电压用作基线尾电流测量，持续0.5s；C阶段，给予细胞+50mV去极化电压，持续2.5s；D阶段，复极化至-50mV引出hERG尾电流，持续4s；E阶段，恢复钳制电位-80mV，持续0.5s。整个刺激过程为8s，每次电压刺激完成后间隔2s重复，即每个刺激周期为10s。
3)给药过程：化合物给药使用灌流给药系统(室温条件下进行)，分别在1-6号加样通道加入阴性对照(含0.1％DMSO的细胞外液)、1μM、3μM、10μM、30μM和100μM浓度的化合物溶液，通过重力灌流将1-6号通道中的液体依次作用于细胞(检测阳性药物时，分别在1-6号加样通道加入含0.3％DMSO细胞外液、50nM、100nM、200nM、400nM及800nM浓度Terfenadine待测溶液)。阴性对照hERG尾电流在细胞外液中稳定记录不小于3min。灌流给予化合物或阳性对照，当hERG尾电流幅值变化＜5％时，认为药物作用达到稳态。若电流在6分钟内未达到稳态，则亦结束该浓度化合物检测。
4)数据采集与分析：数据采集和分析使用Patchmaster(version：2X65)软件采集后使用Igor Pro(version：6.3.7.2)、EXCEL2007分析。尾电流值计算方法为D段电流峰值减去B段电流均值。选取加入化合物前电流处于稳态的sweep尾电流作为对照电流。选取加入化合物后电流处于稳态的sweep尾电流值，作为抑制电流。
待测化合物对hERG电流的抑制率依据以下方程进行计算：
抑制率＝(1-抑制电流/对照电流)×100％
依据上述计算方法得到待测化合物多个浓度对hERG电流的抑制率(平均值±标准差)后，使用GraphPad Prism5(version：5.01)软件对数据进行拟合，得到IC 50值。
2.试验结果
在本试验条件下，化合物TM2对hERG电流的IC 50为121.03±22.41μM，表明本试验检测浓度范围内化合物对hERG通道无抑制作用。
实验例3：化合物细菌回复突变试验
在添加和不添加体外代谢活化系统的条件下，采用5株组氨酸营养缺陷型鼠伤寒沙门氏菌突变型菌株(TA97a、TA98、TA100、TA102和TA1535)检测化合物的诱变性，预测其遗传危害和潜在致癌作用的可能性。
1.试验方法
1)试验操作：试验选择5株鼠伤寒沙门氏菌突变型菌株，分别是TA97a、TA98、TA100、TA102和TA1535作为标准测试菌株。试验采用平皿掺入法，分别在添加体外代谢活化系统(+S9)和不添加体外代谢活化系统(-S9)两种处理条件下进行。根据预试验的结果，本试验以DMSO为溶媒，在添加或不添加体外代谢活化系统两种处理条件下，化合物在每种测试菌株中均设置5个浓度组，分别是5000μg/皿、2000μg/皿、800μg/皿、320μg/皿和128μg/皿，同时均平行设置溶媒对照组和阳性对照组。每个浓度组(包括溶媒对照和阳性对照)同时设3个平行平皿。
2)结果判定：测试菌株中至少有一种菌株，在添加或不添加体外代谢活化系统时，供试品组的回复突变菌落数与相应溶媒对照组回复突变菌落数相比，超出一定的数量范围(即测试菌株TA1535的供试品组回复突变菌落数均值等于或大于溶媒对照组平均数值的3倍，其它测试菌株的供试品组回复突变菌落数均值等于或大于溶媒对照组平均值的2倍)，并伴有浓度-反应关系，或者在某一测试点(菌株或浓度)回复突变菌落数存在可重复性的明显增加，试验结果即可判定为阳性。
回复突变菌落数的增加值没有达到域值(2倍或3倍)以上，但有浓度反应关系。或者回复突变菌落数的增加值等于或大于各自的域值(2倍或3倍)以上，但没有浓度反应关系。试验结果均可判定为可疑结果。
3)数据处理和统计分析：采用Microsoft Excel 2013求取各组回复突变菌落数均数及标准差，并计算各组回复突变菌落数与相对应溶媒对照组的比值。
2.试验结果
本试验条件下，在添加或不添加体外代谢活化系统两种处理条件下，5000、2000、800、320和128μg/皿的化合物TM2对所有测试菌株均无致突变性，即Ames试验结果为阴性。
实验例4：化合物体外哺乳动物细胞染色体畸变试验
利用体外培养的中国仓鼠肺成纤维细胞(CHL)，检测化合物是否会引起体外哺乳动物细胞发生染色体畸变，以评价供试品致突变的可能性。
1.试验方法
1)试验操作：本试验以DMSO为试验的溶媒对照。阳性对照及使用浓度为甲磺酸乙酯1000μg/mL(-S9，3h)、500μg/mL(-S9，24h)和注射用环磷酰胺5μg/mL(+S9，3h)。代谢活化系统为苯巴比妥和β-萘黄酮联合诱导的SD大鼠肝脏匀浆(S9)。试验共设三种处理条件，分别为添加体外代谢活化系统3小时、不添加体外代谢活化系统3小时和不添加体外代谢活化系统24小时。根据预试验的结果，化合物在这3种处理条件的最高浓度均设为250μg/mL。每种处理条件，化合物均设5个浓度，分别为250μg/mL、100μg/mL、40μg/mL、16μg/mL和6.4μg/mL；平行设置溶媒对照及阳性对照组，每个浓度设2个平行细胞培养物。收获前以秋水仙胺(终浓度0.1μg/mL)作用2小时以阻断细胞于分裂中期。给药后24小时收获细胞，进行细胞计数、分析细胞毒性和制片。根据细胞毒性分析结果，每个处理条件选择3个浓度，包括溶媒对照进行镜检，至少观察300个中期相细胞；阳性对照进行镜检，至少观察100个中期相细胞以分析染色体畸变。
2)结果评价：化合物所诱发的染色体结构畸变数具有统计学意义的增加(P<0.05)，并有浓度-效应相关性；或化合物在任何一个浓度条件下，引起染色体结构畸变数具有统计学意义的增加(P<0.05)，并有可重复性。以上两种情况均可判定为阳性结果。如果任何化合物浓度组的染色体畸变细胞率与溶媒对照组相比没有显著增加，则可认为该化合物为阴性。
3)数据处理和统计分析：①数据计算：每一培养瓶细胞应根据以下分类计算结构畸变总数：计数细胞总数、畸变细胞总数、畸变染色体总数、裂隙总数；②统计学处理：采用Microsoft Excel 2013与SPSS 13.0软件进行计算分析，比较给药组(包括阳性对照组)与溶媒对照组的染色体畸变细胞形成率，使用Fisher氏确切(Fisher Exact)概率法鉴定显著性差异。阳性对照组和溶媒对照组进行两两比较，当P<0.05时，认为差异具有显著性。化合物组与溶媒对照组首先进行多重比较，如P≥0.05，认为差异没有显著性；如P<0.05，继续开展供试品每一浓度与溶媒对照组的两两比较，得到的P值用Bonferroni方法进行校正(即P值乘以样本数，本试验样本数为3)，校正后P值<0.05时，认为差异具有显著性。
2.试验结果
在本试验条件下，不添加体外代谢活化系统暴露约3、24小时及添加体外代谢活化系统暴露约3小时，40、100和250μg/mL的化合物TM2未引起CHL细胞染色体结构畸变率有意义的升高，对体外培养的CHL哺乳动物细胞无致突变性。染色体畸变试验结 果为阴性。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (19)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中所述化合物具有通式(I)的结构：
    Figure PCTCN2021075433-appb-100001
    其中：
    R 1、R 2、R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；或者，R 1和R 2与它们相连的碳原子一起形成C 3-6环烷基，R 3、R 4、R 5各自独立地选自H、卤素、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；
    X为-CH 2CH 2-；
    Y选自-(CR 6R 6’)-和-C(＝N-OR 7)-；
    R 6和R 6’各自独立地选自H、C 1-6烷基、C 3-6环烷基、C 3-6杂环烷基、-OH、-OC 1-6烷基、-OC 3-6环烷基和芳氧基；
    R 7选自H、C 1-6烷基、C 3-6环烷基和芳基；
    与Y相连的环A选自：
    Figure PCTCN2021075433-appb-100002
    R 8选自H、C 1-6烷基和C 3-6环烷基；
    n为0-6中的任意整数。
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中，
    Y为-(CR 6R 6’)-；R 6和R 6’各自独立地选自H、C 1-4烷基、C 3-6环烷基、C 3-6杂环烷基、-OH、-OC 1-4烷基、-OC 3-6环烷基和芳氧基；优选地，R 6为H，R 6’选自-OH和-OC 1-4烷基；更优选地，R 6为H，R 6‘为-OH；
    优选地，Y为-CH(OH)-。
  3. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中，
    Y为-C(＝N-OR 7)-，
    R 7选自H、C 1-4烷基、C 3-6环烷基和芳基；优选地，R 7选自H和C 1-4烷基；更优选地，R 7为H。
  4. 权利要求1-3任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中，
    R 1、R 2、R 3、R 4、R 5各自独立地选自H、氟、氯、溴、碘、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；或者，R 1和R 2与它们相连的碳原子一起形成C 3-6环烷基，R 3、R 4和R 5各自独立地选自H、氟、氯、溴、碘、C 1-6烷基、C 1-6烷氧基和C 1-6烷硫基；优选地，R 1、R 2、R 3、R 4、R 5各自独立地选自H、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、C 1-4烷氧基和C 1-4烷硫基；优选地，R 1和R 2为甲基；R 3和R 4各自独立地选自甲基和氯；各R 5独立地选自H、氯、甲基、甲氧基和甲硫基；更优选地，R 1、R 2、R 3和R 4为甲基；各R 5独立地选自H、氯、甲基、甲氧基和甲硫基；
    n为0、1、2或3；优选地，n为1或2。
  5. 权利要求1至4任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中，与Y相连的A选自：
    Figure PCTCN2021075433-appb-100003
  6. 权利要求1至5任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中，与Y相连的
    Figure PCTCN2021075433-appb-100004
    选自：
    Figure PCTCN2021075433-appb-100005
    各R 5如权利要求1或4中所定义；
    优选地，
    Figure PCTCN2021075433-appb-100006
    选自：
    Figure PCTCN2021075433-appb-100007
    优选地，
    Figure PCTCN2021075433-appb-100008
    选自：
    Figure PCTCN2021075433-appb-100009
  7. 权利要求1至6任一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，具有式(II)所示结构，
    Figure PCTCN2021075433-appb-100010
    其中，R 1、R 2、R 3、R 4、R 5、环A和n如权利要求1至6任一项所定义。
  8. 权利要求1至7中任意一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中所述化合物选自：
    Figure PCTCN2021075433-appb-100011
    Figure PCTCN2021075433-appb-100012
  9. 权利要求1至8中任意一项所述的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，其中所述化合物选自：
    Figure PCTCN2021075433-appb-100013
    Figure PCTCN2021075433-appb-100014
  10. 下述化合物的立体异构体：
    Figure PCTCN2021075433-appb-100015
  11. 权利要求10所述的立体异构体，其在下述旋光度检测条件下检测得到的旋光方向为左旋：检测温度：20℃，检测波长589.3nm，溶剂为甲醇，浓度为100mg/mL；
    优选地，其比旋光度[α] D 20＝-9.5°±1°(例如，-9.5°±0.9°、-9.5°±0.8°、-9.5°±0.7°、-9.5°±0.6°、-9.5°±0.5°、-9.5°±0.4°、-9.5°±0.3°、-9.5°±0.2°或-9.5°±0.1°)。
  12. 权利要求10或11所述的立体异构体，其在下述液相条件下的保留时间为5.8min±1min(例如，5.8min±0.9min、5.8min±0.8min、5.8min±0.7min、5.8min±0.6min、5.8min±0.5min、5.8min±0.4min、5.8min±0.3min、5.8min±0.2min或5.8min±0.1min)：
    色谱柱：CHIRALPAK IC(IG00CD-KJ016)；
    色谱柱尺寸：0.46cm I.D.×15cm L；
    进样量：1μL；
    流动相：Hexane/EtOH/HAC＝85/15/0.1(V/V/V)；
    流速：1.0ml/min；
    检测波长：UV 254nm；以及
    柱温：35℃。
  13. 权利要求10所述的立体异构体，其在下述旋光度检测条件下检测得到的旋光方向为右旋：检测温度：20℃，检测波长589.3nm，溶剂为甲醇，浓度为100mg/mL；
    优选地，其比旋光度[α] D 20＝+9.7°±1°(例如，+9.7°±0.9°、+9.7°±0.8°、+9.7°±0.7°、+9.7°±0.6°、+9.7°±0.5°、+9.7°±0.4°、+9.7°±0.3°、+9.7°±0.2°或+9.7°±0.1°)。
  14. 权利要求10或13所述的立体异构体，其在下述液相条件下的保留时间为3.5min±1min(例如，3.5min±0.9min、3.5min±0.8min、3.5min±0.7min、3.5min±0.6min、3.5min±0.5min、3.5min±0.4min、3.5min±0.3min、3.5min±0.2min或3.5min±0.1min)：
    色谱柱：CHIRALPAK IC(IG00CD-KJ016)；
    色谱柱尺寸：0.46cm I.D.×15cm L；
    进样量：1μL；
    流动相：Hexane/EtOH/HAC＝85/15/0.1(V/V/V)；
    流速：1.0ml/min；
    检测波长：UV 254nm；以及
    柱温：35℃。
  15. 药物组合物，其包含预防或治疗有效量的权利要求1至14中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，以及一种或多种药学上可接受的辅料。
  16. 药盒产品，其含有权利要求1至14中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物，或者权利要求10的药物组合物，以及任选的药品说明书。
  17. 权利要求1至14中任一项的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物、权利要求15的药物组合物、或权利要求16所述的药盒产品在制备用于预防或治疗与过氧化物酶体增殖物激活受体(PPAR)相关的疾病或病症的药物中的用途；
    优选地，所述PPAR为PPARα和/或PPARδ；
    优选地，所述疾病或病症为肝脏疾病和/或胆管疾病，例如选自肝纤维变性、脂肪性肝病、肝硬化、胆管炎；优选地，所述疾病或病症为非酒精性脂肪性肝病(NAFLD)、胆汁性肝硬化、硬化性胆管炎，例如单纯性脂肪肝(SFL)或非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化、原发性硬化性胆管炎。
  18. 一种预防或治疗与PPAR相关的疾病或病症的方法，其包括向有此需要的受试者施用预防或治疗有效量的权利要求1至14中任一项的化合物或其药学可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物、前药或其混合物、权利要求15的药物组合物、或权利要求16所述的药盒产品的步骤；
    优选地，所述PPAR为PPARα和/或PPARδ；
    优选地，所述疾病或病症为肝脏疾病和/或胆管疾病，例如选自肝纤维变性、脂肪性肝病、肝硬化、胆管炎；优选地，所述疾病或病症为非酒精性脂肪性肝病(NAFLD)、胆汁性肝硬化、硬化性胆管炎，例如单纯性脂肪肝(SFL)或非酒精性脂肪性肝炎(NASH)、原发性胆汁性肝硬化、原发性硬化性胆管炎；
    优选地，所述受试者为人或非人哺乳动物。
  19. 制备式(II)化合物的方法，其包括以下步骤：
    Figure PCTCN2021075433-appb-100016
    其中，V为卤素或任选地被卤素取代的C 1-3烷基磺酸酯基；R 1、R 2、R 3、R 4、R 5、环A和n如权利要求1至7中任一项所定义。
PCT/CN2021/075433 2020-02-28 2021-02-05 芳香族化合物及其药物组合物和用途 WO2021169769A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180007741.0A CN114901641A (zh) 2020-02-28 2021-02-05 芳香族化合物及其药物组合物和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010130024.4 2020-02-28
CN202010130024 2020-02-28

Publications (1)

Publication Number Publication Date
WO2021169769A1 true WO2021169769A1 (zh) 2021-09-02

Family

ID=77490664

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/075433 WO2021169769A1 (zh) 2020-02-28 2021-02-05 芳香族化合物及其药物组合物和用途

Country Status (2)

Country Link
CN (1) CN114901641A (zh)
WO (1) WO2021169769A1 (zh)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1349525A (zh) * 1999-04-28 2002-05-15 阿文蒂斯药物德国有限公司 作为ppar受体配体的二芳基酸衍生物
WO2003072099A1 (en) * 2002-02-21 2003-09-04 Eli Lilly And Company Peroxisome proliferator activated receptor modulators
WO2005040102A2 (en) * 2003-10-28 2005-05-06 Dr. Reddy's Laboratories Ltd. Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them
CN1728992A (zh) * 2002-12-19 2006-02-01 希格马托制药工业公司 具有降低血清葡萄糖和降低血清脂质活性的α－苯硫基羧酸和α－苯氧基羧酸的用途
WO2008087365A2 (fr) * 2006-12-29 2008-07-24 Genfit Derives de 1,3-diphenylpropane substitues, preparations et utilisations
WO2008087367A2 (fr) * 2006-12-29 2008-07-24 Genfit Derives de (phenylthiazolyl)-phenyl-propan-1-one et de (phenyloxazodyl)-phenyl-propan-1-one substitues, preparations et utilisations
CN101506138A (zh) * 2006-06-21 2009-08-12 基恩菲特 取代的1，3-二苯基丙烷衍生物、它们的制备及用途
CN101605775A (zh) * 2006-12-29 2009-12-16 基恩菲特公司 取代的3-苯基-1-(苯基噻吩基)丙-1-酮类以及3-苯基-1-(苯基呋喃基)丙-1-酮类的衍生物、制备以及用途
WO2019105234A1 (zh) * 2017-11-30 2019-06-06 四川科伦博泰生物医药股份有限公司 芳香族化合物及其药物组合物和用途

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1349525A (zh) * 1999-04-28 2002-05-15 阿文蒂斯药物德国有限公司 作为ppar受体配体的二芳基酸衍生物
WO2003072099A1 (en) * 2002-02-21 2003-09-04 Eli Lilly And Company Peroxisome proliferator activated receptor modulators
CN1728992A (zh) * 2002-12-19 2006-02-01 希格马托制药工业公司 具有降低血清葡萄糖和降低血清脂质活性的α－苯硫基羧酸和α－苯氧基羧酸的用途
WO2005040102A2 (en) * 2003-10-28 2005-05-06 Dr. Reddy's Laboratories Ltd. Novel compounds and their use as antidiabetic and hypolipidemic agents, process for their preparation and pharmaceutical compositions containing them
CN101506138A (zh) * 2006-06-21 2009-08-12 基恩菲特 取代的1，3-二苯基丙烷衍生物、它们的制备及用途
WO2008087365A2 (fr) * 2006-12-29 2008-07-24 Genfit Derives de 1,3-diphenylpropane substitues, preparations et utilisations
WO2008087367A2 (fr) * 2006-12-29 2008-07-24 Genfit Derives de (phenylthiazolyl)-phenyl-propan-1-one et de (phenyloxazodyl)-phenyl-propan-1-one substitues, preparations et utilisations
CN101605775A (zh) * 2006-12-29 2009-12-16 基恩菲特公司 取代的3-苯基-1-(苯基噻吩基)丙-1-酮类以及3-苯基-1-(苯基呋喃基)丙-1-酮类的衍生物、制备以及用途
WO2019105234A1 (zh) * 2017-11-30 2019-06-06 四川科伦博泰生物医药股份有限公司 芳香族化合物及其药物组合物和用途

Also Published As

Publication number Publication date
CN114901641A (zh) 2022-08-12

Similar Documents

Publication Publication Date Title
EP3392244A1 (en) Cyclopropylamines as lsd1 inhibitors
JP5277256B2 (ja) ｍａｘｉ−Ｋチャネル開口薬としてのピリミジン、ピリジン及びトリアジン誘導体
WO2014198880A1 (en) 2-(2-aminophenoxy)-3-chloronaphthalene-1,4-dione compounds having orexin 2 receptor agonist activity
EP4289843A1 (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
EP3029024A1 (en) 2-(2-aminophenoxy)-3-chloronaphthalene-1,4-dione compounds having orexin 2 receptor agonist activity
US11261170B2 (en) Aromatic compound, pharmaceutical composition and use thereof
US8247404B2 (en) Derivatives of 2-oxoalkyl-1-piperazin-2-one, preparation method thereof and therapeutic use of same
JP2022510425A (ja) パーキンソン病を治療するためのデカルボキシラーゼ阻害剤
JP2018538355A (ja) ベンズアミド誘導体
WO2013192610A2 (en) Pro-drugs of riluzole and their method of use for the treatment of amyotrophic lateral sclerosis
WO2021169769A1 (zh) 芳香族化合物及其药物组合物和用途
US20220363664A1 (en) Heterocyclic compounds as modulators of mglur7
EP4029858A1 (en) Pyrimidine compound and preparation method therefor
US9545387B2 (en) Composition and kit comprising piperazine derivatives and metformin, and use thereof in the treatment of diabetes
EP4003955A1 (en) Inhibitors of human atgl
EP3447045B1 (en) 1-(1-hydroxy-2,3-dihydro-1h-inden-5-yl)-urea derivatives and related compounds kcnq 2-5 channel activators for treating dysuria
CN109456274B (zh) 苯并咪唑类衍生物、其制备方法及其作为药物的用途
WO2023145873A1 (ja) リゾホスファチジルセリン類似体、及びリゾホスファチジルセリン類似体を含む線維症を治療又は予防するための医薬組成物
US20220332714A1 (en) P2x3 and/or p2x2/3 receptor antagonist, pharmaceutical composition containing same, and use thereof
WO2023091565A1 (en) Nsd2-targeted chemical degraders and compositions and methods of use thereof
WO2023160672A1 (en) Compounds and compositions for treating conditions associated with lpa receptor activity
WO2019141095A1 (zh) 脒类和胍类衍生物、其制备方法及其在医药上的应用
CN104650030A (zh) 芳香多环羧酸衍生物
EP2953625A1 (en) Novel functionalized 4-(phenoxymethyl(-1,3-dioxolane analogs exhibiting cytochrome p450 inhibition and their method of use

Legal Events

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

Ref document number: 21761291

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21761291

Country of ref document: EP

Kind code of ref document: A1