WO2019105234A1 - 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

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WO2019105234A1
WO2019105234A1 PCT/CN2018/115615 CN2018115615W WO2019105234A1 WO 2019105234 A1 WO2019105234 A1 WO 2019105234A1 CN 2018115615 W CN2018115615 W CN 2018115615W WO 2019105234 A1 WO2019105234 A1 WO 2019105234A1
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alkyl
group
compound
pharmaceutically acceptable
halogen
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PCT/CN2018/115615
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English (en)
French (fr)
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朱加望
宋智泉
龙冬
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201880063551.9A priority Critical patent/CN111148742B/zh
Priority to EP18884390.8A priority patent/EP3719010B1/en
Priority to KR1020207009121A priority patent/KR102603436B1/ko
Priority to JP2020518441A priority patent/JP7259850B2/ja
Priority to US16/652,274 priority patent/US11332457B2/en
Publication of WO2019105234A1 publication Critical patent/WO2019105234A1/zh
Priority to US16/879,204 priority patent/US11261170B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • 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
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • 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
    • 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D215/38—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a class of aromatic compounds, as well as processes for the preparation of such compounds and intermediates thereof.
  • the invention also relates to the use of such compounds for the manufacture of a medicament for the prevention or treatment of a disease or condition associated with a peroxisome proliferator-activated receptor (PPAR).
  • PPAR peroxisome proliferator-activated receptor
  • Nonalcoholic fatty liver disease is a type of clinical pathological syndrome with liver histological changes similar to alcoholic liver disease but no history of excessive drinking, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH). And its associated cirrhosis, where NASH is an important intermediate stage in the progression of NAFLD.
  • SFL simple fatty liver
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic steatohepatitis
  • NASH nonalcoholic steatohepatitis
  • Non-alcoholic fatty liver disease can directly lead to decompensated cirrhosis, hepatocellular carcinoma and transplanted liver recurrence, and can also affect the progression of other chronic liver diseases, and participate in the onset of type 2 diabetes and atherosclerosis.
  • Metabolic syndrome-related malignancies, atherosclerotic cardiovascular and cerebrovascular diseases, and cirrhosis are important factors influencing the quality of life and life expectancy of patients with nonalcoholic fatty liver disease.
  • NASH has become one of the most important cirrhotic precancerous lesions after chronic viral hepatitis and alcoholic liver disease, and it is a common cause of abnormal serum transaminase in healthy people.
  • Nonalcoholic fatty liver disease is a new challenge in the field of contemporary medicine.
  • the development of drugs for the treatment of nonalcoholic fatty liver disease has important clinical significance.
  • Peroxisome proliferator-activated receptor is a member of the nuclear receptor superfamily superfamily and plays a key role in regulating metabolic homeostasis, inflammation, cell growth and differentiation.
  • PPAR agonists have been used as lipid-lowering drugs and oral hypoglycemic agents in type 2 diabetes, and recent studies have found that such agonists have liver protective functions.
  • PPAR ⁇ is highly expressed in hepatocytes and plays a role in regulating fatty acid transport and ⁇ -oxidation.
  • PPAR ⁇ can also regulate the gluconeogenesis process and inflammatory response. Similar to PPAR ⁇ , PPAR ⁇ regulates glucose utilization and lipoprotein metabolism in the liver and has significant anti-inflammatory activity.
  • PPAR ⁇ & ⁇ dual agonists have the potential to address a variety of biological problems involved in the pathogenesis of NASH, or a broader range of metabolic and cardiovascular problems.
  • the present invention provides a compound containing a 2-phenoxyacetic acid structure as a PPAR ⁇ & ⁇ double agonist, which has excellent double agonistic activity against PPAR ⁇ & ⁇ , and better physicochemical properties (e.g., solubility, physical and/or chemical stability). Improved pharmacokinetic properties (eg improved bioavailability, appropriate half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc. Excellent properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite thereof Or a prodrug wherein the compound has the structure of formula (I):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, halogen, -OH, -SH, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halogen C 1-6 Alkyl, C 2-5 alkenyl, -O-[(C 1-6 alkylene)-O] n -(C 1-6 alkyl), -S-(C 1-6 alkyl), - NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , 3-10 membered heterocyclic group;
  • R 3 is bonded to R 4 to form a C 3-6 cycloalkyl group or a 3-10 membered heterocyclic group;
  • X is selected from the group consisting of ethylene, vinylidene and C 3-6 cycloalkylene, and optionally, the ethylene, vinylidene and C 3-6 cycloalkylene groups are each independently one or more Selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3-10 membered heterocyclic, C 6 a substituent of a -14 aryl group and a 5-14 membered heteroaryl group;
  • Y is selected from the group consisting of a bond, N and CR 6 ;
  • W is selected from N, S and C;
  • R 5 and R 6 are each independently selected from H, halogen, -OH, -SH, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-5 alkenyl, -S (O) m -(C 1-6 alkyl), -O-[(C 1-6 alkylene)-O] n -(C 1-6 alkyl), -OC 3-6 cycloalkyl, -O-3-6 membered heterocyclic group, -S(O) m -C 3-6 cycloalkyl, -S(O) m -3-10 membered heterocyclic group, -NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , 3-10 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, optionally wherein said C The 1-6 alkyl group, the cycloalkyl group, the heterocyclic group, the
  • n is an arbitrary integer from 0 to 10;
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, Solvate, N-oxide, isotopically labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.
  • Another aspect of the application provides the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof, Use of a metabolite, prodrug or mixture thereof, pharmaceutical composition, or kit product for the manufacture of a medicament for the prevention or treatment of a disease or condition associated with a peroxisome proliferator-activated receptor (PPAR).
  • PPAR peroxisome proliferator-activated receptor
  • Another aspect of the application provides the compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof, A metabolite, prodrug or mixture thereof, pharmaceutical composition, or kit product for use in preventing or treating a disease or condition associated with PPAR.
  • Another aspect of the present application provides a method of preventing or treating a disease or condition associated with PPAR comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt, ester, or stereo thereof Isomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, prodrugs or mixtures thereof, pharmaceutical compositions, or kit products.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled
  • a compound, metabolite or prodrug or a pharmaceutical composition of the invention for a reagent for activating PPAR in a cell.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled A compound, metabolite or prodrug or a pharmaceutical composition of the invention for use in activating PPAR in a cell.
  • Another aspect of the invention provides a method of activating a PPAR in a cell comprising administering the cell to an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, The step of contacting the polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or a pharmaceutical composition of the invention.
  • alkylene denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has from 1 to 12, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched aliphatic hydrocarbon group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, positive) Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) Substituting (e.g., halogen) (wherein the group is referred to as "haloalkyl”) (e.g., CH 2 F, CHF 2 , CF 3 , CCl 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, sec. Butyl or tert-butyl).
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical comprising one double bond and having, for example, 2 to 5 carbon atoms ("C 2-5 alkenyl").
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • alkenylene group include a vinylidene group, a propenylene group, and the like.
  • the compounds of the invention may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • cycloalkyl or “cycloalkane” as used herein refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, 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] anthracenyl, decalinyl, etc.), which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cyclohepty
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclo) Butyl, cyclopentyl or cyclohexyl), which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as methyl substituted cyclopropyl.
  • heterocyclyl means having, for example, from 3 to 10 (suitably from 3 to 8, more suitably from 3 to 6) ring atoms, at least one of which The ring atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie having one or more double bonds and/or three in the ring) Key) a cyclic group.
  • a "3-10 membered heterocyclic group” has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (eg, 1, 2) One, three or four) saturated or partially unsaturated heterocyclic groups independently selected from the heteroatoms of N, O and S.
  • heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( Dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl.
  • the heterocyclic group may be optionally substituted by one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • heterocyclylene refers to having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring atoms, wherein at least one ring atom is selected from a heteroatom of N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) of C or partially unsaturated (ie having one or more double and/or triple bonds in the ring) divalent ring Shape group.
  • a "3-10 membered heterocyclylene” has 2 to 9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (eg, 1, 2, 3 or 4) saturated or partially unsaturated heterocyclylenes independently selected from the heteroatoms of N, O and S.
  • heterocyclylene groups include, but are not limited to, ethylene oxide, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, sub-di Dioxolinyl, pyrrolidinyl, pyrrolidinone, imidazolidinyl, pyridazolidinyl, pyridinoline, tetrahydropyranyl, piperidinyl, morpholine Base, dithianyl, sulfazolinyl, piperazinyl or trithianyl.
  • the heterocyclylene group can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • (sub)aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C 6-14 (sub)aryl means an aromatic group containing from 6 to 14 carbon atoms, such as (phenylene) or (methylene)naphthyl.
  • the (i)aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • (sub)heteroaryl refers to a monocyclic or polycyclic aromatic ring system having, for example, 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and it contains at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), and additionally In each case it may be benzofused.
  • the (sub)heteroaryl group is selected from the group consisting of (i)thienyl, (i)furanyl, (sub)pyrrolyl, (i)oxazolyl, (sub)thiazolyl, (sub)imidazolyl, (Asia) Pyrazolyl, (i)isoxazolyl, (i)isothiazolyl, (sub)oxadiazolyl, (sub)triazolyl, (sub)thiadiazolyl, etc., and their benzo derivative Or (i)pyridinyl, (i)pyridazinyl, (i)pyrimidinyl, (i)pyrazinyl, (i)triazinyl, and the like, and their benzo derivatives.
  • halogen as used herein includes F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
  • the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the 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 hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the 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 hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • 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.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • suitable contain a compound of the present invention isotopes include (but are not limited to) isotopes of hydrogen (e.g., deuterium (2 H), tritium (3 H)); isotopes of carbon (e.g.
  • Chlorine isotope eg 36 Cl
  • fluorine isotopes eg 18 F
  • iodine isotopes eg 123 I and 125 I
  • nitrogen isotopes eg 13 N and 15 N
  • oxygen isotopes eg 15 O
  • phosphorus isotope eg 32 P
  • sulfur isotope eg 35 S
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to a patient in need thereof
  • the compound of the invention, or a metabolite or residue thereof, can be provided directly or indirectly after the drug.
  • a “compound of the invention” it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts, and other similar salts.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • N-oxides are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize heterocyclic and tertiary amines.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)” It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. 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, which is incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound thereof a metabolite or prodrug wherein the compound has the structure of formula (I):
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, halogen, -OH, -SH, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, halogen C 1-6 Alkyl, C 2-5 alkenyl, -O-[(C 1-6 alkylene)-O] n -(C 1-6 alkyl), -S-(C 1-6 alkyl), - NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , 3-10 membered heterocyclic group;
  • R 3 is bonded to R 4 to form a C 3-6 cycloalkyl group or a 3-10 membered heterocyclic group;
  • X is selected from the group consisting of ethylene, vinylidene and C 3-6 cycloalkylene, and optionally, the ethylene, vinylidene and C 3-6 cycloalkylene groups are each independently one or more Selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3-10 membered heterocyclic, C 6 a substituent of a -14 aryl group and a 5-14 membered heteroaryl group;
  • Y is selected from the group consisting of a bond, N and CR 6 ;
  • W is selected from N, S and C;
  • R 5 and R 6 are each independently selected from H, halogen, -OH, -SH, cyano, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-5 alkenyl, -S (O) m -(C 1-6 alkyl), -O-[(C 1-6 alkylene)-O] n -(C 1-6 alkyl), -O-(C 3-6 ring Alkyl), -O-(3-6 membered heterocyclyl), -S(O) m -(C 3-6 cycloalkyl), -S(O) m -(3-10 membered heterocyclyl) , -NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , 3-10 membered heterocyclic group, C 6-14 aryl group and 5-14 membered heteroaryl And optionally wherein said C 1-6 alkyl, cycloalkyl, heterocycl
  • n is an arbitrary integer from 0 to 10.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, halo, C 1-6 alkyl, halo C 1-6 alkyl and —O—[(C 1 -6 alkylene)-O] n -(C 1-6 alkyl), wherein n is any integer from 0 to 10, preferably n is any integer from 0 to 5, more preferably n is 0, 1. 2 or 3; preferably, R 1 and R 2 are methyl; in a more preferred embodiment, R 1 , R 2 , R 3 and R 4 are methyl;
  • X is selected from the group consisting of ethylene, vinylidene and cyclopropylene, and the ethylene, vinylidene and cyclopropylene are each independently optionally one or two selected from halogen. Substituted with a C 1-6 alkyl substituent. In a more preferred embodiment, X is a vinylidene group.
  • Y is selected from the group consisting of a bond and CR 6 ;
  • W is selected from the group consisting of N and S.
  • R 5 and R 6 are each independently selected from H, halo, -OH, C 1-6 alkyl, C 3-6 cycloalkyl, -S(O) m - (C 1- 6 alkyl), -O-[(C 1-6 alkylene)-O] n -(C 1-6 alkyl), -O-(C 3-6 cycloalkyl), -O-(3 -6 membered heterocyclic group), -NH 2 , -NH-(C 1-6 alkyl), -N(C 1-6 alkyl) 2 and 3-6 membered heterocyclic group, wherein said C 1-
  • the 6 alkyl group, the C 3-6 cycloalkyl group and the 3-6 membered heterocyclic group are optionally one or more selected from the group consisting of halogen, -OH, -OC 1-3 alkyl, -SH, -SC 1-3 Substituted by a substituent of an alkyl group, -NH 2
  • R 5 and R 6 are each independently selected from the group consisting of H, F, Cl, -OH, C 1-3 alkyl, cyclopropyl, -S(O) m - (C 1-3 Alkyl), -O-[(C 1-2 alkylene)-O] n -(C 1-3 alkyl), -O-(C 5-6 cycloalkyl), -O-(5- a substituent of a 6-membered heterocyclic group, -NH 2 , -NH-(C 1-6 alkyl), -N(C 1-3 alkyl) 2 and a 5-6 membered heterocyclic group, wherein C 1-3 alkyl, C 1-6 alkyl, cyclopropyl, C 5-6 cycloalkyl and 5-6 membered heterocyclyl are optionally selected from 1-3 selected from F, Cl, -OH and -Substituent substitution of OCH 3 ; m is 0, 1 or 2, and
  • R 5 is selected from H and -O-[(C 1-2 alkylene)-O] n -(C 1-3 alkyl), n is 0, 1 or 2; preferably , n is 0;
  • R 6 is selected from the group consisting of H, F, Cl, -OH, C 1-3 alkyl, -SCH 3 , -O-[(C 1-2 alkylene)-O] n - ( C 1-3 alkyl), -N(C 1-3 alkyl) 2 and 5-6 membered heterocycloalkyl, wherein said C 1-3 alkyl and 5-6 membered heterocycloalkyl are optionally Substituted by 1-3 substituents selected from the group consisting of F, Cl, -OH and -OCH 3 ; n is 0, 1 or 2; preferably, n is 0 or 1.
  • the compounds of the invention have the structure of Formula (I)-1, Formula (I)-2, or Formula (I)-3:
  • W, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined in formula (I);
  • R 7 is selected from the group consisting of H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3-10 membered heterocyclic ring a group, a C 6-14 aryl group and a 5-14 membered heteroaryl group; preferably, R 7 is selected from the group consisting of H, halogen and C 1-6 alkyl; more preferably, R 7 is H or methyl;
  • R 8 and R 9 are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), a 3-10 membered heterocyclic group, a C 6-14 aryl group and a 5-14 membered heteroaryl group; preferably, R 8 and R 9 are each independently selected from the group consisting of H, halogen and C 1-6 alkyl; more preferably , R 8 and R 9 are H;
  • the compounds of the invention have the structure of formula (II) or formula (III):
  • X is selected from the group consisting of vinylidene and C 3-6 cycloalkylene
  • R 5 is selected from the group consisting of H and -O-(C 1-3 alkyl);
  • R 6 is selected from the group consisting of H, F, Cl, -OH, C 1-3 alkyl, -SCH 3 , -O-[(C 1-2 alkylene)-O] n -(C 1-3 alkyl) And -N(C 1-3 alkyl) 2 and 5-6 membered heterocycloalkyl, wherein said C 1-3 alkyl group and 5-6 membered heterocycloalkyl group are optionally selected from 1 to 3 Substituents of F, Cl, -OH and -OCH 3 are substituted; n is 0, 1 or 2; preferably, n is 0 or 1.
  • the compounds of the invention have the structure of formula (II-1) or formula (III-1):
  • R 7 is selected from the group consisting of H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3-10 membered heterocyclic ring a C 6-14 aryl group, a 5-14 membered heteroaryl group; preferably, R 7 is selected from the group consisting of H, halogen and C 1-6 alkyl; more preferably, R 7 is H or methyl.
  • R 5 is selected from the group consisting of H and -O-(C 1-3 alkyl);
  • R 6 is selected from the group consisting of H, F, Cl, -OH, C 1-3 alkyl, -SCH 3 , -O-[(C 1-2 alkylene)-O] n -(C 1-3 alkyl) And -N(C 1-3 alkyl) 2 and 5-6 membered heterocycloalkyl, wherein said C 1-3 alkyl group and 5-6 membered heterocycloalkyl group are optionally selected from 1 to 3 Substituted with a substituent of F, Cl, -OH and -OCH 3 ; n is 0, 1 or 2; preferably, n is 0 or 1;
  • R 7 is H or methyl.
  • the compounds of the invention have the structure of formula (II-2) or formula (III-2):
  • R 5 is selected from the group consisting of H and -O-(C 1-3 alkyl);
  • R 6 is selected from the group consisting of H, F, Cl, -OH, C 1-3 alkyl, -SCH 3 , -O-[(C 1-2 alkylene)-O] n -(C 1-3 alkyl) And -N(C 1-3 alkyl) 2 and 5-6 membered heterocycloalkyl, wherein said C 1-3 alkyl group and 5-6 membered heterocycloalkyl group are optionally selected from 1 to 3 Substituted with a substituent of F, Cl, -OH and -OCH 3 ; n is 0, 1 or 2; preferably, n is 0 or 1;
  • the compounds of the invention have the structure of formula (II-3) or formula (III-3):
  • R 8 and R 9 are each independently selected from H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl a 3-10 membered heterocyclic group, a C 6-14 aryl group, a 5-14 membered heteroaryl group; preferably, R 8 and R 9 are each independently selected from the group consisting of H, halogen and C 1-6 alkyl; Preferably, R 8 and R 9 are H.
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled a compound, metabolite or prodrug, wherein the compound is selected from the group consisting of:
  • Another object of the present invention is to provide a process for the preparation of the above compounds, comprising the steps of:
  • V represents halogen or a C 1-3 alkyl sulfonate group optionally substituted by halogen (for example, a triflate group);
  • Z is selected from the group consisting of H, Cl, Br, I and -P(O) (OEt) 2 .
  • R 7 is selected from the group consisting of H, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3-10 membered heterocyclic ring a C 6-14 aryl group, a 5-14 membered heteroaryl group; preferably, R 7 is selected from the group consisting of H, halogen and C 1-6 alkyl.
  • the method of preparing a compound of the invention comprises the steps of:
  • V represents a halogen or a C 1-3 alkyl sulfonate group optionally substituted by a halogen (for example, a triflate group), and Z is selected from the group consisting of H, Cl, Br, I, and -P(O).
  • R 7 is selected from H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, -O-(C 1-6 alkyl), 3 a 10-membered heterocyclic group, a C 6-14 aryl group, a 5-14 membered heteroaryl group; preferably, R 7 is selected from the group consisting of H, halogen and C 1-6 alkyl.
  • the first step phenol a and compound b are substituted to form ether intermediate c.
  • a condensation reaction for example, a similar method according to the method disclosed in Synthesis 1626 (2003), Wittig reaction reported by Bizet et al. (Journal of Fluorine Chemistry, 2013, 56- 61), similar methods of Wittig-Horner reaction reported by Johnson et al. (Heterocycles, 2006, 2165-2170) or Aldol condensation reaction method reported by Wang et al
  • the first step is carried out under the action of a base selected from the group consisting of organic or inorganic bases including, but not limited to, cesium carbonate, potassium carbonate and potassium t-butoxide.
  • the second step is carried out under the action of an organic base, including an organic base, an inorganic base or a condensation reagent, including but not limited to sodium t-butoxide, triethylamine, DIPEA, pyridine or DMAP.
  • the inorganic base includes, but is not limited to, NaH, NaOH, Na 2 CO 3 or K 2 CO 3 .
  • the condensation reagents include, but are not limited to, DCC, DIC, EDC, BOP, PyAOP, and PyBOP.
  • the method of preparing a compound of the invention comprises the steps of:
  • Step 3 - Step 1 Compound e deprotection group gives compound (I)-1.
  • the method of preparing a compound of the invention comprises the steps of:
  • Step 3-2a Compound e is subjected to a reduction reaction to give compound f.
  • the reaction is carried out under Pd/C catalysis.
  • Steps -2bb Compound f deprotection affords compound (I)-2.
  • the method of preparing a compound of the invention comprises the steps of:
  • p is selected from any integer from 1 to 4.
  • Step 3 - 3a Compound e undergoes a ring-forming reaction to form compound g.
  • Steps -3b Compound g deprotection affords compound (I)-3.
  • the third -1, third -2b or third -3b step is carried out under the action of an acid selected from the group consisting of organic or inorganic acids including, but not limited to, hydrochloric acid or trifluorocarbon Acetic acid.
  • tert-butyl group in the SM1 ester group can be replaced with other protecting groups having the same function, which are removed in a subsequent step to finally obtain an acid product such as benzyl or p-methoxybenzyl. a group, a benzyloxy group, a substituted silicon group, and the like.
  • the above steps can be carried out in an organic solvent.
  • the organic solvent may be a reaction solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane). Etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) , nitriles (such as acetonitrile, etc.) and their mixed solvents.
  • a reaction solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hex
  • the compounds of the invention may also be prepared in a variety of ways known to those skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by 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 employed and suitable for effecting the conversion.
  • Those skilled in the art of organic synthesis should be aware that the functional groups present on the molecule should be consistent with the proposed transformation. This will sometimes require the following determination: modify the order of the synthetic steps or route another specific method route relative to one method to obtain the desired compound of the invention.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the first aspect of the invention or an isomer thereof, a pharmaceutically acceptable salt or ester, a hydrate, a solvate, any crystal form or racemate thereof , or their metabolite forms, or mixtures thereof, and one or more pharmaceutically acceptable carriers.
  • the medicinal excipients described herein refer to the excipients and auxiliaries used in the production of pharmaceuticals and formulation formulations, which refer to the reasonable evaluation of safety in addition to the active ingredients, and are included in the pharmaceutical preparations. Substance. Pharmaceutical excipients can be used for prototyping, acting as a carrier, improving stability, and also having important functions such as solubilization, solubilization, slow release and release, and are important ingredients that may affect the quality, safety and effectiveness of drugs. According to its source, it can be divided into natural materials, semi-synthetic materials and total synthetic materials.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, antioxidants, chelating agents, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, filter aid, release retardant, etc.
  • solvent propellant
  • solubilizer cosolvent
  • emulsifier colorant
  • binder disintegrant
  • filler filler
  • lubricant wetting agent
  • osmotic pressure regulator stabilizer
  • Glidants osmotic pressure regulator
  • flavoring agents preservatives
  • suspending agents coating materials
  • fragrances anti
  • Specific pharmaceutical excipients include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate, cellulose. , aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like.
  • the pharmaceutical composition may be administered in any form as long as it achieves prevention, alleviation, prevention or cure of symptoms of a human or animal patient.
  • various suitable dosage forms can be prepared depending on the route of administration.
  • the pharmaceutical composition When administered orally, the pharmaceutical composition can be formulated into any orally acceptable preparation including, but not limited to, tablets, capsules, granules, pills, syrups, oral solutions, oral suspensions, and oral emulsions. Wait. Oral suspensions are usually prepared by admixing the active ingredient with suitable emulsifying and suspending agents. Optionally, some sweeteners, fragrances or colorants may also be added to the above oral formulation forms.
  • the pharmaceutical compositions When administered transdermally or topically, the pharmaceutical compositions may be in the form of a suitable ointment, lotion or lozenge, wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers which 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; and carriers which can be used for lotions or elixirs include, but are not limited to, minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can also be administered in the form of an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may also be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • kits product comprising the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide thereof , isotopically labeled compounds, metabolites, prodrugs or mixtures thereof, or pharmaceutical compositions, and optional pharmaceutical instructions.
  • Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or Use of the mixture or the pharmaceutical composition of the present invention for the preparation of a medicament for preventing or treating a disease associated with a peroxisome proliferator-activated receptor (PPAR).
  • PPAR peroxisome proliferator-activated receptor
  • Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or A mixture or a pharmaceutical composition of the present invention for use in preventing or treating a disease associated with a peroxisome proliferator-activated receptor (PPAR).
  • PPAR peroxisome proliferator-activated receptor
  • Another object of the present invention is to provide a method for preventing or treating a disease associated with a peroxisome proliferator-activated receptor (PPAR), the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or Pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs, or mixtures thereof, or pharmaceutical compositions of the invention.
  • PPAR peroxisome proliferator-activated receptor
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled
  • a compound, metabolite or prodrug or a pharmaceutical composition of the invention for a reagent for activating PPAR in a cell.
  • the agent is for use in an in vivo method.
  • the agent is for use in an in vitro method.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled A compound, metabolite or prodrug or a pharmaceutical composition of the invention for use in activating PPAR in a cell.
  • Compounds, metabolites or prodrugs or pharmaceutical compositions of the invention are used in in vivo methods.
  • the compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled Compounds, metabolites or prodrugs or pharmaceutical compositions of the invention are used in in vitro methods.
  • Another aspect of the invention provides a method of activating a PPAR in a cell comprising administering the cell to an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, The step of contacting the polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or a pharmaceutical composition of the invention.
  • 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 peroxisome proliferator-activated receptor (PPAR)-associated disease is a liver disease, for example selected from the group consisting of liver fibrosis or fatty liver disease.
  • the disease or condition is nonalcoholic fatty liver disease (NAFLD), such as simple fatty liver (SFL) or nonalcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • SFL simple fatty liver
  • NASH nonalcoholic steatohepatitis
  • the "cell” is a cell line or a cell from a subject.
  • effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition. The amount of administration and the administration regimen of the pharmaceutical composition can be readily determined by one of ordinary skill in the clinical arts.
  • the composition or compound of the present invention is generally administered once a day to once every three days, preferably once a day, and the total amount of administration is from 0.01 to 1000 mg per time.
  • the dosage of the treatment varies, depending on the considerations, such as the age, sex and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the extent of tissue damage; the symptoms Duration; and other variables that can be adjusted by each physician.
  • the desired dose can be administered one or more times to achieve the desired result.
  • the pharmaceutical composition according to the invention may also be provided in unit dosage form.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or the progression of one or more symptoms of such a condition or condition, or preventing such A condition or condition or one or more symptoms of such condition or condition.
  • “Individual” or “subject” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • the MS was measured using an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Thin layer chromatography was performed using a GF 254 (0.4-0.5 nm) silica gel plate from Yantai.
  • the reaction was monitored by thin layer chromatography (TLC) or LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, solvents.
  • TLC thin layer chromatography
  • LC-MS LC-MS using a developing solvent system including, but not limited to, dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and petroleum ether and ethyl acetate systems, solvents.
  • the volume ratio is adjusted depending on the polarity of the compound, or is adjusted by adding triethylamine or the like.
  • the eluent system includes, but is not limited to, a dichloromethane and methanol system, and a n-hexane and ethyl acetate system.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine or the like.
  • the temperature of the reaction is room temperature (20 ° C to 30 ° C) unless otherwise specified in the examples.
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Tiber Chemical.
  • the compound 1-2 (140 mg, 0.29 mmol) was dissolved in DCM (4.5 mL), and the mixture was cooled in ice-water bath for 10 min, and TFA (1.5 mL) was added dropwise for 1 h, and the reaction was monitored by LC-MS. The reaction mixture was concentrated and purified by column chromatography.
  • Compound TM2 was synthesized in a manner similar to that described in the first step to the second step of Example 2, except that in the first step of Example 3, 2-1 was used instead of 1-1 of the first step in Example 2. The step yield was 38%.
  • the second step preparation of 2-chloro-3-acetylquinoline (3-3)
  • Second and third steps two-step synthesis of (E)-2-(4-(3-(2-methoxyquinolin-3-yl)-3-oxo-1-propen-1-yl)-2 ,6-dimethylphenoxy)-2-methylpropionic acid (TM4)
  • Compound TM4 was synthesized in a manner similar to that described in the first step to the second step of Example 2 except that in the second step of Example 5, 4-2 was used instead of the compound of the first step in Example 2.
  • the total yield of the three steps is 25%.
  • Example 6 A method similar to that described in the first to third steps of Example 5 was used except that in the first step, the sodium methoxide was used instead of the sodium methoxide compound in the first step of Example 5 in Example 6.
  • the compound TM5 was synthesized in a three-step total yield of 20%.
  • the compound TM7 was synthesized in a manner similar to that described in the first to third steps of Example 7, except that in the first step, the trifluoroacetylacetone was used in place of the acetylacetonate compound in the first step of Example 7.
  • the total yield of the three steps is 21%.
  • Compound TM8 was synthesized in a manner similar to that described in the first step to the third step of Example 5 except that in the first step, the tetrahydropyrrole was used in place of sodium methoxide in the first step of Example 5. The yield was 44%.
  • Compound TM10 was synthesized in a manner similar to that described in the second to fourth steps of Example 4 except that in the third step of Example 11, the step 3-2 was replaced with 10-3 in the second step of Example 4. The total yield of the three steps is 25%.
  • Example 12 The first step to the third step of Example 5 were used except that in the first step, in Example 12, (R)-3-hydroxypyrrolidine was used in place of the sodium methoxide compound of the first step in Example 5. A similar method was used to synthesize the compound TM53 in a total yield of 39%.
  • the first step to the third step of Example 5 were used except that in the first step, the (S)-3-hydroxypyrrolidine was used in place of the sodium methoxide compound in the first step of Example 5.
  • a similar method was used to synthesize compound TM54 with a total yield of 46%.
  • Example 14 The same procedure as described in the first step to the third step of Example 5 was carried out except that in the first step, the 4-methylpiperidine hydrochloride was replaced with the sodium methoxide compound of the first step in Example 5 in Example 14. Method The compound TM25 was synthesized in a total yield of 26% in three steps.
  • the first step to the third step of Example 5 was employed except that in the first step, the (M)-amino-1,2-propanediol was replaced with the sodium methoxide compound of the first step in Example 5 in Example 16.
  • the compound TM11 was synthesized in a similar manner as described in the step, with a total yield of 5% in three steps.
  • Example 17 Except for the first step in Example 17, the sodium methoxide was used in place of the sodium methoxide compound of the first step in Example 5, and NMP was substituted for methanol, using a similar procedure as described in the first to third steps of Example 5. Method The compound TM13 was synthesized in a three-step total yield of 17%.
  • the compound TM29 was synthesized in a manner similar to that described in the first step to the fourth step of Example 4 except that the first step of Example 18 was carried out by substituting 29-1 for the 3-1 compound of the first step of Example 4. The total yield of the four steps is 7%.
  • Compound TM28 was synthesized in a manner similar to that described in the first step to the third step of Example 5, except that the first step in Example 19 was carried out by substituting 28-1 for the 4-1 compound of the first step of Example 5. The total yield of the three steps is 30%.
  • the compound TM27 was synthesized in a manner similar to that described in the first to fourth steps of Example 4 except that the first step in Example 20 was carried out by substituting 27-1 for the 3-1 compound of the first step of Example 4. , the total yield of four steps is 22%.
  • Compound TM26 was synthesized in a manner similar to that described in the first to third steps of Example 5, except that the first step in Example 21 was followed by the use of 26-1 in place of the 4-1 compound of the first step of Example 5. The total yield of the three steps is 32%.
  • Test Example 1 Transient activation test of compound on PPAR ⁇ of HEK293 cells
  • Plasmid pcDNA3.1(+)-GAL4-hPPAR ⁇ , customized to Nanjing Kehao Biotechnology Co., Ltd.
  • Liposomes PGL4.35, customized to Nanjing Kehao Biotechnology Co., Ltd.
  • Cells Human embryonic kidney cells HEK293, purchased from ATCC.
  • Transfection reagent Lipofectamine Reagent 3000, purchased from Invitrogen.
  • Detection kit Bright Glo TM Luciferase Assay System, purchased from Promega.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum at 37 ° C, 5% CO 2 . 3 ⁇ 10 5 /ml cells were plated in each well of a 6-well plate. When the cell confluence reached 50%-80%, 5 ⁇ g of liposome PGL4.35 and 5 ⁇ g of expression plasmid pcDNA3.1(+)- were added. GAL4-hPPAR ⁇ harvested 24 hours after transfection, cells were plated in 96 well plates after transfection into cells and various concentrations of compounds of the present application, for 24 hours, Bright Glo TM luciferase Assay System reagent, luciferase activity was detected.
  • luciferase activity is increased, and induction of luciferase activity indicates that the compound of the present application is a PPAR alpha agonist.
  • compound 50 of the present application value HEK293 cells transfected EC calculated using GraphPad software, results shown in Table 1.
  • the compounds of the present application have a strong agonistic effect on PPAR ⁇ : the EC 50 of the test compounds are all less than 2 ⁇ M.
  • Test Example 2 Transient activation test of compound on PPAR ⁇ of HEK293 cells
  • Plasmid pcDNA3.1(+)-GAL4-hPPAR ⁇ , customized to Nanjing Kehao Biotechnology Co., Ltd.
  • Liposomes PGL4.35, customized to Nanjing Kehao Biotechnology Co., Ltd.
  • Cells Human embryonic kidney cells HEK293, purchased from ATCC.
  • Transfection reagent Lipofectamine Reagent 3000, purchased from Invitrogen.
  • Detection kit Bright Glo TM Luciferase Assay System, purchased from Promega.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal calf serum, and cultured at 37 ° C under 5% CO 2 . In a 6-well plate, 3 ⁇ 10 5 /ml cells were plated in each well. When the cell confluence reached 50%-80%, 5 ⁇ g of liposome PGL4.35 and 5 ⁇ g of expression plasmid pcDNA3.1 (+) were added. -GAL4-hPPAR ⁇ was harvested 24 hours after transfection, and the transfected cells were plated in 96-well plates and added with different concentrations of the compound of the present application, incubated for 24 hours, and added with Bright Glo TM Luciferase Assay System reagent for luciferase activity.
  • luciferase activity is increased, and induction of luciferase activity indicates that the compound of the present application is a PPAR ⁇ agonist.
  • compound 50 of the present application value HEK293 cells transfected EC calculated using GraphPad software (Table 2).
  • the compounds of the present application have significant agonistic effects on PPAR ⁇ : the EC 50 of the test compounds are all less than 10 ⁇ M.
  • hepatocyte HepG2 purchased from ATCC
  • human embryonic kidney cell HEK293 purchased from ATCC.
  • Detection reagent CellTiter Luminescent Cell Viability Assay, purchased from Promega.
  • HepG2 and HEK293 cells were cultured in DMEM/F12 medium containing 10% fetal bovine serum, respectively. Appropriate cells were plated into 96-well plates, and after overnight incubation in the incubator, the medium was removed and incubated for 3 days in complete medium containing the compound of the present application. On the fourth day, the detection reagent CellTiter Glo was added to each well, and the relative luminescence unit (RLU) of each well was detected by chemiluminescence. The CC 50 values of the compounds of the present application against HepG2 and HEK293 cells, respectively, were calculated using GraphPad software. The results are shown in Table 3.
  • the compound of the present invention has a CC 50 toxicity to HepG2 cells and HEK293 cells of the order of ⁇ M. All test compounds were less cytotoxic to HepG2 cells and HEK293 cells.
  • Test Example 4 In vitro safety test
  • Example 2 8.24
  • Example 3 >10
  • Example 4 >10
  • Example 5 >10
  • Example 6 >10
  • Example 8 >10
  • Example 9 >10
  • Example 10 >10
  • Example 17 >10
  • Example 18 >10
  • Example 19 >10
  • Example 21 >10
  • the compounds of the present invention all have an IC 50 for hERG of more than 8 ⁇ M. Therefore, the compound of the present invention has no significant inhibitory effect on hERG, and has no safety hazard leading to prolongation of the QT interval of the heart.

Abstract

本发明涉及一类芳香族化合物，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。本发明还涉及所述化合物用于制备预防或治疗与PPAR相关疾病的药物的用途。

Description

芳香族化合物及其药物组合物和用途 技术领域
本发明涉及一类芳香族化合物，以及该类化合物及其中间体的制备方法。本发明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，PPARα&δ双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
本发明提供用作为PPARα&δ双激动剂的含有2-苯氧基乙酸结构的化合物，其具有优异的对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)、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。
本发明的一个方面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式(I)的结构：
Figure PCTCN2018115615-appb-000001
其中：
R 1、R 2、R 3和R 4各自独立地选自H、卤素、-OH、-SH、氰基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-S-(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基；
或者，R 3与R 4连接形成C 3-6环烷基或3-10元杂环基；
X选自亚乙基、亚乙烯基和C 3-6亚环烷基，任选地，所述亚乙基、亚乙烯基和C 3-6亚环烷基各自独立地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基和5-14元杂芳基的取代基取代；
Y选自键、N和C-R 6；
W选自N、S和C；
R 5和R 6各自独立地选自H、卤素、-OH、-SH、氰基、硝基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-S(O) m-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-O-C 3-6环烷基、-O-3-6元杂环基、-S(O) m-C 3-6环烷基、-S(O) m-3-10元杂环基、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基，任选地，其中所述C 1-6烷基、环烷基、杂环基、C 6-14芳基和5-14元杂芳基各自独立地被一个或多个卤素、-OH、-OC 1-6烷基、卤代C 1-6烷基、-O-卤代C 1-6烷基、-SH、-SC 1-6烷基、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2的取代基取代；
m为0-2的任意整数，n为0-10的任意整数；
本发明的另一方面提供药物组合物，其含有预防或治疗有效量的本发明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、代谢物或前药以及一种或多种药学上可接受的载体。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。
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。
本发明的另一方面提供本发明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发明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。
本发明的另一方面提供本发明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发明的药物组合物，其用于激活细胞中PPAR。
本发明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发明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发明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“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
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。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“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有例如2-5个碳原子(“C 2-5烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。
如本文中所使用，术语“亚烯基”意指具有一个或多个碳-碳双键的直链或支链二价碳链(-CR＝CR'-，其中R和R'各自独立地是氢或其它取代基)。亚烯基的实例包括亚乙烯基、亚丙烯基等。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
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“杂环基”、“杂环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有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，“3-10元杂环基”是具有2-9个(如2、3、4、5、6、7、8或9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“亚杂环基”是指具有例如3-10个(适合地具有3-8个，更适合地具有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)二价环状基团。例如，“3-10元亚杂环基”是具有2-9个(如2、3、4、5、6、7、8或9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亚杂环基。亚杂环基的实例包括但不限于：亚环氧乙烷基、亚氮丙啶基、亚氮杂环丁基(azetidinyl)、亚氧杂环丁基(oxetanyl)、亚四氢呋喃基、亚二氧杂环戊烯基(dioxolinyl)、亚吡咯烷基、亚吡咯烷酮基、亚咪唑烷基、亚吡唑烷基、亚吡咯啉基、亚四氢吡喃基、亚哌啶基、亚吗啉基、亚二噻烷基(dithianyl)、亚硫吗啉基、亚哌嗪基或亚三噻烷基(trithianyl)。所述亚杂环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“(亚)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，如本文中所使用，术语“C 6-14(亚)芳基”意指含有6至14个碳原子的芳族基团，诸如(亚)苯基或(亚)萘基。(亚)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“(亚)杂芳基”指单环或多环芳族环系，其具有例如5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，(亚)杂芳基选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“卤素”包括F、Cl、Br或I。
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。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，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。适合包含入本发明的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，本发明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酮-烯醇互变异构体、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 PCTCN2018115615-appb-000002
实楔形
Figure PCTCN2018115615-appb-000003
或虚楔形
Figure PCTCN2018115615-appb-000004
描绘本发明的化合物的碳-碳键。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，否则本发明的化 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。本发明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。
本发明涵盖本发明的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，本发明的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。在本发明中，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发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的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。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的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发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的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,pp 748-750；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。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的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，本发明包括本发明的化合物的代谢物，包括通过使本发明的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。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的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本发明的化合物。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)。本发明的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)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的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，由此形成本发明的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，本发明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式(I)的结构：
Figure PCTCN2018115615-appb-000005
其中：
R 1、R 2、R 3和R 4各自独立地选自H、卤素、-OH、-SH、氰基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-S-(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基；
或者，R 3与R 4连接形成C 3-6环烷基或3-10元杂环基；
X选自亚乙基、亚乙烯基和C 3-6亚环烷基，任选地，所述亚乙基、亚乙烯基和C 3-6亚环烷基各自独立地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基和5-14元杂芳基的取代基取代；
Y选自键、N和C-R 6；
W选自N、S和C；
R 5和R 6各自独立地选自H、卤素、-OH、-SH、氰基、硝基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-S(O) m-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-O-(C 3-6环烷基)、-O-(3-6元杂环基)、-S(O) m-(C 3-6环烷基)、-S(O) m-(3-10元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基，任选地，其中所述C 1-6烷基、环烷基、杂环基、C 6-14芳基和5-14元杂芳基各自独立地被一个或多个卤素、-OH、-OC 1-6烷基、卤代C 1-6烷基、-O-卤代C 1-6烷基、-SH、-SC 1-6烷基、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2的取代基取代；
m为0-2中的任意整数，n为0-10中的任意整数。
在优选的实施方案中，R 1、R 2、R 3和R 4各自独立地选自H、卤素、C 1-6烷基、卤代C 1-6烷基和-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)，其中n为0-10中的任意整数，优选n为0-5中的任意整数，更优选n为0、1、2或3；优选地，R 1和R 2为甲基；在更优选的实施方案中，R 1、R 2、R 3和R 4为甲基；
在优选的实施方案中，X选自亚乙基、亚乙烯基和亚环丙基，所述亚乙基、亚乙烯基和亚环丙基各自独立任选地被一个或两个选自卤素和C 1-6烷基的取代基取代。在更优选的 实施方案中，X为亚乙烯基。
在优选的实施方案中，Y选自键和C-R 6；
在优选的实施方案中，W选自N和S。
在优选的实施方案中，R 5和R 6各自独立地选自H、卤素、-OH、C 1-6烷基、C 3-6环烷基、-S(O) m-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-O-(C 3-6环烷基)、-O-(3-6元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2和3-6元杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-6元杂环基任选地被一个或多个选自卤素、-OH、-OC 1-3烷基、-SH、-SC 1-3烷基、-NH 2、-NH-(C 1-3烷基)和-N(C 1-3烷基) 2的取代基取代；m为0、1或2，n为0，1，2，3，4，或5。在更优选的实施方案中，R 5和R 6各自独立地选自H、F、Cl、-OH、C 1-3烷基、环丙基、-S(O) m-(C 1-3烷基)、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-O-(C 5-6环烷基)、-O-(5-6元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-3烷基) 2和5-6元杂环基的取代基取代，其中所述C 1-3烷基、C 1-6烷基、环丙基、C 5-6环烷基和5-6元杂环基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；m为0、1或2，n为0或1。
在优选的实施方案中，R 5选自H和-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)，n为0、1或2；优选地，n为0；
在优选的实施方案中，R 6选自H、F、Cl、-OH、C 1-3烷基、-SCH 3、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-N(C 1-3烷基) 2和5-6元杂环烷基，其中所述C 1-3烷基和5-6元杂环烷基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；n为0、1或2；优选地，n为0或1。
在部分实施方案中，本发明的化合物具有式(I)-1、式(I)-2或式(I)-3的结构：
Figure PCTCN2018115615-appb-000006
其中，W、Y、R 1、R 2、R 3、R 4、R 5、R 6如式(I)所定义；
R 7选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基和5-14元杂芳基；优选地，R 7选自H、卤素和C 1-6烷基；更优选地，R 7为H或甲基；
R 8、R 9分别独立地选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基和5-14元杂芳基；优选地，R 8、R 9分别独立地选自H、卤素和C 1-6烷基；更优选地，R 8、R 9为H；
p＝1或2，更优选地，p＝1。
在部分实施方案中，本发明的化合物具有式(II)或式(III)的结构：
Figure PCTCN2018115615-appb-000007
其中，X、R 5、R 6如式(I)所定义。
在优选的实施方案中，
X选自亚乙烯基和C 3-6亚环烷基；
R 5选自H和-O-(C 1-3烷基)；
R 6选自H、F、Cl、-OH、C 1-3烷基、-SCH 3、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-N(C 1-3 烷基) 2和5-6元杂环烷基，其中所述C 1-3烷基和5-6元杂环烷基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；n为0、1或2；优选地，n为0或1。
在部分实施方案中，本发明的化合物具有式(II-1)或式(III-1)的结构：
Figure PCTCN2018115615-appb-000008
R 7选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基；优选地，R 7选自H、卤素和C 1-6烷基；更优选地，R 7为H或甲基。
在优选的实施方案中，
R 5选自H和-O-(C 1-3烷基)；
R 6选自H、F、Cl、-OH、C 1-3烷基、-SCH 3、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-N(C 1-3烷基) 2和5-6元杂环烷基，其中所述C 1-3烷基和5-6元杂环烷基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；n为0、1或2；优选地，n为0或1；
R 7为H或甲基。
在部分实施方案中，本发明的化合物具有式(II-2)或式(III-2)的结构：
Figure PCTCN2018115615-appb-000009
R 5和R 6如式(I)所定义；其中，p选自1-4中的任一整数，优选地，p＝1或2，更优选地，p＝1。
在优选的实施方案中，
R 5选自H和-O-(C 1-3烷基)；
R 6选自H、F、Cl、-OH、C 1-3烷基、-SCH 3、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-N(C 1-3烷基) 2和5-6元杂环烷基，其中所述C 1-3烷基和5-6元杂环烷基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；n为0、1或2；优选地，n为0或1；
p＝1。
在部分实施方案中，本发明化合物具有式(II-3)或式(III-3)的结构：
Figure PCTCN2018115615-appb-000010
其中，R 8、R 9分别独立地选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基；优选地，R 8、R 9分别独立地选自H、卤素和C 1-6烷基；更优选地，R 8、R 9为H。
本发明涵盖对各个实施方案进行任意组合所得的化合物。
在优选的实施方案中，本发明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 PCTCN2018115615-appb-000011
Figure PCTCN2018115615-appb-000012
制备方法
本发明的另一目的在于提供了上述化合物的制备方法，包括以下步骤：
Figure PCTCN2018115615-appb-000013
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)；Z选自H、Cl、Br、I和-P(O)(OEt) 2。R 7选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基；优选地，R 7选自H、卤素和C 1-6烷基。
在部分实施方案中，本发明化合物的制备方法包括以下步骤：
Figure PCTCN2018115615-appb-000014
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)，Z选自H、Cl、Br、I和-P(O)(OEt) 2，R 7选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基；优选地，R 7选自H、卤素和C 1-6烷基。
第一步：酚a与化合物b进行取代反应生成醚中间体c。
第二步：中间体c与化合物d进行缩合反应得到烯中间体e(例如可根据Synthesis 1626(2003)中公开的方法、Bizet等报导的Wittig反应类似方法(Journal of Fluorine Chemistry,2013,56-61)、Johnson等报导的Wittig-Horner反应类似方法(Heterocycles,2006,2165-2170)或者Wang等报导的Aldol缩合反应方法(Chemical Communications,2016,2811-2814)等)。
在本发明的一个实施方案中，第一步在碱作用下进行，所述碱选自有机碱或无机碱，包括但不限于碳酸铯、碳酸钾和叔丁醇钾。
在本发明的一个实施方案中，第二步在有机碱、无机碱或缩合试剂的作用下进行，所述有机碱包括但不限于叔丁醇钠、三乙胺、DIPEA、吡啶或DMAP。所述无机碱包括但不限于NaH、NaOH、Na 2CO 3或K 2CO 3。所述缩合试剂包括但不限于DCC、DIC、EDC、BOP、PyAOP和PyBOP。
在部分实施方案中，本发明化合物的制备方法包括以下步骤：
Figure PCTCN2018115615-appb-000015
第三-1步：化合物e脱保护基生成化合物(I)-1。
在部分实施方案中，本发明化合物的制备方法包括以下步骤：
Figure PCTCN2018115615-appb-000016
第三-2a步：化合物e经过还原反应生成化合物f，优选地，所述反应在Pd/C催化下进行。
第三-2b步：化合物f脱保护基生成化合物(I)-2。
在部分实施方案中，本发明化合物的制备方法包括以下步骤：
Figure PCTCN2018115615-appb-000017
其中，p选自1-4中的任意整数。
第三-3a步：化合物e经过成环反应生成化合物g。
第三-3b步：化合物g脱保护基生成化合物(I)-3。
根据本发明的一个实施方案，第三-1步、第三-2b步或第三-3b步在酸作用下进行，所述酸选自有机酸或无机酸，包括但不限于盐酸或三氟乙酸。
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，SM1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，本发明的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。本发明的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本发明的所需化合物。
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本发明中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发明所定义。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
本发明还提供一种药物组合物，其含有本发明第一方面所述的化合物或其异构体、药学可接受的盐或酯、水合物、溶剂化物、它们的任意晶型或消旋物，或它们的代谢物形式，或它们的混合物，以及一种或多种药用上可接受的载体。
本文中所述药用辅料是指生产药品和调配处方时，使用的的赋形剂和附加剂，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、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
本发明的另一目的在于提供本发明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、代谢物或前药、或者它们的混合物或者本发明的药物组合物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)相关疾病的药物中的用途。
本发明的另一目的在于提供本发明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、代谢物或前药、或者它们的混合物或者本发明的药物组合物，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。
本发明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)相关疾病的方法，所述方法包括向有此需要的个体施用有效量的本发明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、代谢物或前药、或者它们的混合物，或者本发明的药物组合物。
本发明的另一方面提供本发明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发明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。在一些优选的实施方案中，所述试剂用于体内方法中。在一些优选的实施方案中，所述试剂用于体外方法中。
本发明的另一方面提供本发明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发明的药物组合物，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发明的药物组合物用于体内方法中。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发明的药物组合物用于体外方法中。
本发明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发明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发明的药物组合物接触的步骤。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。
在本发明的一个实施方案中，所述过氧化物酶体增殖物激活受体(PPAR)为PPARα和/或PPARδ。
在本发明的一个实施方案，所述与过氧化物酶体增殖物激活受体(PPAR)相关疾病为肝脏疾病，例如选自肝纤维变性或脂肪性肝病。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)，例如单纯性脂肪肝(SFL)或非酒精性脂肪性肝炎(NASH)。
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。本发明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发明的药物组合物。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
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。本发明中“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。
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
AcCl 乙酰氯 LAH 四氢铝锂
Ac 2O 乙酸酐 CH 3MgBr 甲基溴化镁
AlCl 3 三氯化铝 LC-MS 液相色谱-质谱联用
aq. 水溶液 LDA 二异丙基氨基锂
Boc 叔丁氧基羰基 MeCN 乙腈
CF 3SO 3H 三氟甲磺酸 MeOH 甲醇
DCM 二氯甲烷 MeONa 甲醇钠
DIPEA 二异丙基乙基胺 NaBH 4 硼氢化钠
BBr 3 三溴化硼 NMP N-甲基吡咯烷酮
DMF N,N-二甲基甲酰胺 Cs 2CO 3 碳酸铯
DMP 戴斯-马丁氧化剂 Na 2CO 3 碳酸钠
DMSO 二甲基亚砜 NaOH 氢氧化钠
EA 乙酸乙酯 KOH 氢氧化钾
Et 3N 三乙胺 Na 2SO 4 硫酸钠
EtOAc 乙酸乙酯 m-CPBA 间氯过氧苯甲酸
EtOH 乙醇 Pd/C 钯碳
K 2CO 3 碳酸钾 NaSMe 甲硫醇钠
TFA 三氟乙酸 Py 吡啶
H 2 氢气 SOCl 2 氯化亚砜
HBr 溴化氢 rt 室温
HCl 氯化氢 THF 四氢呋喃
H 2O 水 TLC 薄层色谱法
实施例1:2-(4-甲酰基-2,6-二甲基苯基)-2-甲基丙酸叔丁酯(Int 1)的制备
Figure PCTCN2018115615-appb-000018
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,1.67mmol)，升温至100℃反应30min，往体系中滴加2-溴代异丁酸叔丁酯(297g,1.33mmol)，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，将水相用乙酸乙酯萃取，合并有机相，加无水硫酸钠干燥，过滤并浓缩滤液，将粗产品经硅胶柱层析纯化得化合物Int 1(31g)，收率16％.
实施例2：(E)-2-(4-(3-(苯并[b]噻吩-2-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM1)的制备
Figure PCTCN2018115615-appb-000019
第一步：(E)-2-(4-(3-(苯并[b]噻吩-2-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(1-2)的制备
将化合物1-1(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)，反应过夜，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，经柱层析纯化得到目标产物2-2(160mg)，收率45％。
第二步：(E)-2-(4-(3-(苯并[b]噻吩-2-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM1)的制备
将化合物1-2(140mg,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TM1(67mg)，收率54％。
MS m/z(ESI):395[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.97(s,1H),8.75(s,1H),8.12-8.02(m,2H),7.93(d,J＝16.0Hz,1H),7.68(d,J＝16.0Hz,1H),7.62(s,2H),7.59-7.47(m,2H),2.25(s,6H),1.41(s,6H).
实施例3:(E)-2-(4-(3-(喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM2)的制备
Figure PCTCN2018115615-appb-000020
除在实施例3中第一步用2-1代替实施例2中的第一步的1-1外，采用与实施例2第一步至第二步所描述的类似方法合成化合物TM2，两步收率38％。
MS m/z(ESI):390[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.95(s,1H),9.48(d,J＝2.0Hz,1H),9.28(d,J＝2.0Hz,1H),8.22(d,J＝4.0Hz,1H),8.14(d,J＝4.0Hz,1H),8.00(d,J＝16.0Hz,1H),7.98-7.92(m,1H),7.81-7.71(m,2H),7.64(s,2H),2.25(s,6H),1.41(s,6H).
实施例4:(E)-2-(4-(3-(2-氯喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM3)的制备
Figure PCTCN2018115615-appb-000021
第一步：1-(2-氯喹啉-3-基)乙醇(3-2)的制备
将化合物CH 3MgBr(1M)(196mL,196mmol)溶于THF(125mL)中，冰水浴降温10min，用THF(550mL)溶解2-氯-3-甲酰基喹啉(25g,130mmol)滴加至反应体系，搅拌反应4h。LC-MS监测反应无继续转化的趋势后将反应液倒入饱和氯化铵水溶液中，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，得到目标产物3-2(28g)，未经纯化直接用于下一步反应。
第二步：2-氯-3-乙酰基喹啉(3-3)的制备
将化合物3-2(28g,130mmol)溶于DCM(560mL)中，冰水浴降温15min，分批加入DMP(83g,196mmol))，反应2h，LC-MS监测反应完全。将反应液倒入亚硫酸钠水溶液中，垫硅藻土过滤，滤液用DCM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，经柱层析纯化得到目标产物3-3(18.5g)，收率69％。
第三、四步：两步合成(E)-2-(4-(3-(2-氯喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM3)
除在实施例4中第三步用3-3代替实施例2中的第一步的1-1化合物外，采用与实施例2中第一步至第二步所描述的类似方法合成化合物TM3，两步总收率26％。
MS m/z(ESI):404[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.96(s,1H),8.71(s,1H),8.15(d,J＝4.0Hz,1H),8.06(d,J＝4.0Hz,1H),7.98-7.92(m,1H),7.80-7.72(m,1H),7.50(s,2H),7.45(d,J＝16.0Hz,1H),7.27(d,J＝16.0Hz,1H),2.18(s,6H),1.37(s,6H).
实施例5:(E)-2-(4-(3-(2-甲氧基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM4)的制备
Figure PCTCN2018115615-appb-000022
第一步：2-甲氧基-3-乙酰基喹啉(4-2)的制备
将化合物4-1(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，经柱层析纯化得到目标产物4-2(270mg)，收率92％。
第二、三步：两步合成(E)-2-(4-(3-(2-甲氧基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM4)
除在实施例5中第二步用4-2代替实施例2中的第一步的1-1化合物外，采用与实施例2中第一步至第二步所描述的类似方法合成化合物TM4，三步总收率25％。
MS m/z(ESI):420[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.96(s,1H),8.72(s,1H),8.02(d,J＝4.0Hz,1H),7.85(d,J＝4.0Hz,1H),7.81-7.74(m,1H),7.55-7.48(m,1H),7.47(d,J＝16.0Hz,1H),7.46(s,2H),7.34(d,J＝16.0Hz,1H),4.05(s,3H),2.19(s,6H),1.38(s,6H).
实施例6:(E)-2-(4-(3-(2-(2-甲氧基乙氧基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM5)的制备
Figure PCTCN2018115615-appb-000023
除在实施例6中第一步用2-甲氧基乙醇钠代替实施例5中的第一步的甲醇钠化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM5，三步总收率20％。
MS m/z(ESI):464[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.99(s,1H),8.59(s,1H),8.05(d,J＝4.0Hz,1H),7.83(d,J＝4.0Hz,1H),7.80-7.75(m,1H),7.55-7.48(m,3H),7.45(s,2H),4.68-4.62(m,2H),3.77-3.71(m,2H),3.25(s,3H),2.17(s,6H),1.36(s,6H).
实施例7:(E)-2-(4-(3-(2-甲基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM6)的制备
Figure PCTCN2018115615-appb-000024
第一步：2-甲基-3-乙酰基喹啉(6-2)的制备
将化合物6-1(1.0g,8.25mmol)溶于水(20mL))中，然后加入乙酰丙酮(826mg,8.25mmol)，回流反应5h，LC-MS监测反应完全。将反应液倒入冰水中，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，经柱层析纯化得到目标产物6-2(780mg)，收率51％。
第二、三步：两步合成(E)-2-(4-(3-(2-甲基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM6)
除在实施例7中第二步用6-2代替实施例2中的第一步的1-1化合物外，采用与实施例2第一步至第二步所描述的类似方法合成化合物TM6，两步总收率18％。
MS m/z(ESI):420[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.97(s,1H),8.69(s,1H),8.08(d,J＝4.0Hz,1H),8.00(d,J＝4.0Hz,1H),7.88-7.80(m,1H),7.68-7.60(m,1H),7.51(s,2H),7.49(d,J＝16.0Hz,1H),7.43(d,J＝16.0Hz,1H),2.72(s,3H),2.20(s,6H),1.38(s,6H).
实施例8:(E)-2-(4-(3-(2-三氟甲基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM7)的制备
Figure PCTCN2018115615-appb-000025
除在实施例8中第一步用三氟乙酰丙酮代替实施例7中的第一步的乙酰丙酮化合物外，采用与实施例7中第一步至第三步所描述的类似方法合成化合物TM7，三步总收率21％。
MS m/z(ESI):458[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.97(s,1H),8.86(s,1H),8.28-8.20(m,2H),8.10-8.00(m,1H),7.95-7.85(m,1H),7.48(s,2H),7.44(d,J＝16.0Hz,1H),7.28(d,J＝16.0Hz,1H),2.17(s,6H),1.37(s,6H).
实施例9:(E)-2-(4-(3-(2-二甲氨基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM9)的制备
Figure PCTCN2018115615-appb-000026
第一步：2-二甲氨基-3-乙酰基喹啉(9-2)的制备
将化合物9-1(516mg,2.5mmol)溶于DMF(5mL)中，加入二甲胺盐酸盐(200mg,2.5mmol)、碳酸钾(1042mg,7.5mmol)，60℃下加热反应4h。加水、乙酸乙酯萃取，有机相饱和食盐水洗2次，干燥浓缩有机相，柱层析分离得到目标产物9-2(452mg)，收率84％。
第二步：(E)-2-(4-(3-(2-二甲氨基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸叔丁酯(9-3)的制备
将化合物9-2(100mg,0.47mmol)、Int1(136mg,0.47mmol)溶于10mL无水乙醇中，冰浴下滴加10％的氢氧化钠溶液(0.13mL,0.35mmol)，反应4h。TLC监控反应完全，浓缩反应液，加二氯甲烷溶解过滤，母液浓缩制备板分离，得到目标产物9-3(154mg)，收率53％。
第三步：(E)-2-(4-(3-(2-二甲氨基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM9)的制备
将9-3(154mg,0.31mmol)溶于5mL二氯甲烷中，加入三氟乙酸(1mL)，室温搅拌2h。浓缩反应液，加水冻干，得到目标产物TM9(109mg)，收率80％。
MS m/z(ESI):433[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.58(s,1H),7.96-7.94(m,1H),7.87(s,1H),7.79-7.76(s,1H),7.69(d,J＝16.0Hz,1H),7.51(s,2H),7.45-7.42(s,1H),7.33(d,J＝16.0Hz,1H),3.12(s,6H),2.20(s,6H),1.38(s,6H).
实施例10:(E)-2-(4-(3-(2-(1-吡咯烷基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM8)的制备
Figure PCTCN2018115615-appb-000027
除在实施例10中第一步用四氢吡咯代替实施例5中的第一步的甲醇钠外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM8，总收率44％。
MS m/z(ESI):459[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.71(s,1H),8.07-8.05(m,1H),8.01(d,J＝8.0Hz,1H),7.88-7.84(m,1H),7.71(d,J＝16.0Hz,1H),7.52(s,3H),7.33(d,J＝16.0Hz,1H),3.54(s,4H),2.20(s,6H),1.99(s,4H),1.39(s,6H).
实施例11:(E)-2-(4-(3-(2-(吗啉-4-基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM10)的制备
Figure PCTCN2018115615-appb-000028
第一步：2-(吗啉-4-基)-3-甲酰基喹啉(10-2)的制备
将化合物10-1(1.0g,5.2mmol)溶于DMF(15mL)中，加入吗啉(1.4g,15.7mmol)、碳酸钾(3.6g,26.1mmol)，90℃下加热反应4小时。加水、乙酸乙酯萃取，有机相饱和食盐水洗2次，干燥浓缩有机相，柱层析分离得到目标产物10-2(750mg)收率59.5％。
第二步：1-(2-(吗啉-4-基)喹啉-3-基)-乙醇(10-3)的制备
将化合物CH3MgBr(1M)(4.7mL,4.7mmol),溶于THF(5mL)中，冰水浴降温10min，用THF(10mL)溶解10-2(750mg,3.1mmol)滴加至反应体系，搅拌反应2h。LC-MS监测反应无继续转化的趋势，将反应液倒入饱和氯化铵水溶液中，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，得到目标产物10-2(800mg crude)，未经纯化直接用于下一步反应。
第三、四、五步：三步合成(E)-2-(4-(3-(2-(吗啉-4-基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM10)
除在实施例11中第三步用10-3代替实施例4中的第二步的3-2化合物外，采用与实施例4中第二步至第四步所描述的类似方法合成化合物TM10，三步总收率25％。
MS m/z(ESI):475[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.97(s,1H),8.40(s,1H),7.93(d,J＝8.0Hz,1H),7.80-7.68(m,2H),7.62(d,J＝16.0Hz,1H),7.50(s,2H),7.45-7.35(m,2H),3.70-3.50(m,4H),3.40-3.30(m,4H),2.20(s,6H),1.38(s,6H).
实施例12:(E)-2-(4-(3-(2-(S)-(3-羟基吡咯烷-1-基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM53)的制备
Figure PCTCN2018115615-appb-000029
除在实施例12中第一步用(R)-3-羟基吡咯烷代替实施例5中的第一步的甲醇钠化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM53，总收率39％。
MS m/z(ESI):475[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.40(s,1H),7.86(d,J＝8.0Hz,2H),7.67-7.65(m,2H),7.60(d,J＝16.0Hz,1H),7.52(s,2H),7.34-7.30(m,2H),4.33(s,1H),3.62(s,2H),3.47(s,2H),3.12(s,1H),2.20(s,6H),1.98-1.86(m,2H),1.38(s,6H).
实施例13:(E)-2-(4-(3-(2-(R)-(3-羟基吡咯烷-1-基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM54)的制备
Figure PCTCN2018115615-appb-000030
除在实施例13中第一步用(S)-3-羟基吡咯烷代替实施例5中的第一步的甲醇钠化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM54,总收率46％。
MS m/z(ESI):475[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.44(s,1H),7.87(d,J＝8.0Hz,1H),7.72-7.67(m,2H),7.62(d,J＝16.0Hz,1H),7.52(s,2H),7.34-7.30(m,2H),4.34(s,1H),3.64(s,2H),3.50(s,2H),3.14(s,1H),2.20(s,6H),1.98-1.87(m,2H),1.38(s,6H).
实施例14:(E)-2-(4-(3-(2-(4-羟基哌啶-1-基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM25)的制备
Figure PCTCN2018115615-appb-000031
除在实施例14中第一步用4-羟基哌啶盐酸盐代替实施例5中的第一步的甲醇钠化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM25，三步总收率26％。
MS m/z(ESI):489[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.92(s,1H),8.33(s,1H),7.89(d,J＝16.0Hz,1H),7.72-7.64(m,2H),7.61(d,J＝16.0Hz,1H),7.48(s,2H),7.38-7.31(m,2H),4.71(d,J＝2.0Hz,1H),3.75-3.60(m,3H),3.15-3.10(m,2H),2.19(s,6H),1.80-1.70(m,2H),1.50-1.30(m,8H).
实施例15:(E)-2-(4-(3-(2-羟基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM12)的制备
Figure PCTCN2018115615-appb-000032
将化合物TM4(15mg,0.04mmol)溶于DCM(3mL)，冰水浴降温10min，加入三溴化硼的二氯甲烷溶液(1mL)，反应30min，LC-MS监测无继续转化趋势。浓缩反应液经柱层析纯化得到目标产物TM12(5mg)，收率35％。
MS m/z(ESI):406[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.13(s,1H),8.46(s,1H),7.87(d,J＝4.0Hz,1H),7.69(d,J＝16.0Hz,1H),7.65-7.60(m,1H),7.69(d,J＝16.0Hz,1H),7.44-7.36(m,3H),7.28-7.22(m,1H),2.11(s,6H),1.37(s,6H).
实施例16:(E)-2-(4-(3-(2-(R)-(2,3-二羟基丙氨基)喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM11)的制备
Figure PCTCN2018115615-appb-000033
除在实施例16中第一步用(R)-3-氨基-1,2-丙二醇代替实施例5中的第一步的甲醇钠化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM11，三步总收率5％。
MS m/z(ESI):479[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:9.20(s,1H),9.05-8.98(m,1H),8.01(d,J＝16.0Hz,1H),7.89(d,J＝4.0Hz,1H),7.72-7.62(m,2H),7.56(s,2H),7.52(d,J＝4.0Hz,1H),7.26(t,J＝7.2Hz,1H),5.10(d,J＝2.0Hz,1H),4.80(t,J＝4.0Hz,1H),3.85-3.65(m,3H),3.35-3.30(m,2H),2.28(s,6H),1.37(s,6H).
实施例17:(E)-2-(4-(3-(2-甲硫基喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM13)的制备
Figure PCTCN2018115615-appb-000034
除在实施例17中第一步用甲硫醇钠代替实施例5中的第一步的甲醇钠化合物，NMP代替甲醇外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM13，三步总收率17％。
MS m/z(ESI):436[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.97(s,1H),8.97(s,1H),8.09(d,J＝3.6Hz,1H),7.95(d,J＝8.4Hz,1H),7.90-7.82(m,1H),7.68(d,J＝16.0Hz,1H),7.64-7.52(m,4H),2.58(s,3H),2.22(s,6H),1.39(s,6H).
实施例18:(E)-2-(4-(3-(2-氯-7-甲氧基-喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM29)的制备
Figure PCTCN2018115615-appb-000035
除在实施例18中第一步用29-1代替实施例4中的第一步的3-1化合物外，采用与实施例4中第一步至第四步所描述的类似方法合成化合物TM29，四步总收率7％。
MS m/z(ESI):454[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:8.64(s,1H),8.07(d,J＝9.2Hz,1H),7.50-7.41(m,4H),7.40-7.36(m,1H),7.28(d,J＝16.0Hz,1H),3.97(s,3H),2.22(s,6H),1.33(s,6H).
实施例19:(E)-2-(4-(3-(2,7-二甲氧基-喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM28)的制备
Figure PCTCN2018115615-appb-000036
除在实施例19中第一步用28-1代替实施例5中的第一步的4-1化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM28，三步总收率30％。
MS m/z(ESI):450[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.94(s,1H),8.50(s,1H),7.94(d,J＝8.0Hz,1H),7.55-7.35(m,4H),7.25-7.20(m,1H),7.17-7.10(m,1H),4.06(s,3H),3.94(s,3H),2.22(s,6H),1.38(s,6H).
实施例20:((E)-2-(4-(3-(2-氯-6-甲氧基-喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM27)的制备
Figure PCTCN2018115615-appb-000037
除在实施例20中第一步用27-1代替实施例4中的第一步的3-1化合物外，采用与实施例4中第一步至第四步所描述的类似方法合成化合物TM27，四步总收率22％。
MS m/z(ESI):454[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.96(s,1H),8.55(s,1H),7.97(d,J＝8Hz,1H),7.60-7.52(m,2H),7.50(s,2H),7.44(d,J＝16.0Hz,1H),7.27(d,J＝16.0Hz,1H),3.92(s,3H),2.18(s,6H),1.37(s,6H).
实施例21:(E)-2-(4-(3-(2,6-二甲氧基-喹啉-3-基)-3-氧代-1-丙烯-1-基)-2,6-二甲基苯氧基)-2-甲基丙酸(TM26)的制备
Figure PCTCN2018115615-appb-000038
除在实施例21中第一步用26-1代替实施例5中的第一步的4-1化合物外，采用与实施例5中第一步至第三步所描述的类似方法合成化合物TM26，三步总收率32％。
MS m/z(ESI):450[M+H] +
1HNMR(400MHz,DMSO-d 6)δ:12.95(s,1H),8.42(s,1H),7.78(d,J＝8.0Hz,1H),7.50-7.40(m,5H),7.36(d,J＝16.0Hz,1H),4.01(s,3H),3.87(s,3H),2.19(s,6H),1.38(s,6H).
药理学测试
试验例1：化合物对HEK293细胞PPARα的瞬转激活试验
试剂：
质粒：pcDNA3.1(+)-GAL4-hPPARα，定制于南京科佰生物科技有限公司。
脂质体：PGL4.35，定制于南京科佰生物科技有限公司。
细胞：人胚胎肾细胞HEK293，购自于ATCC。
转染试剂：Lipofectamine Reagent 3000，购自于Invitrogen。
检测试剂盒：Bright Glo TMLuciferase Assay System，购自于Promega。
检测方法：
将HEK293细胞在含有10％胎牛血清的DMEM培养基中，在37℃，5％CO 2条件下进行培养。在6孔板中每孔铺入3×10 5/ml细胞，当细胞汇合度达50％-80％时，加入5μg的脂质体PGL4.35和5μg的表达质粒pcDNA3.1(+)-GAL4-hPPARα转染24小时后收获细胞，在96孔板铺入转染后的细胞并加入不同浓度的本申请化合物，孵育24小时，加入Bright Glo TMLuciferase Assay System试剂进行荧光素酶活性检测。在质粒转染并用化合物处理的细胞中，荧光素酶活性增加，荧光素酶活性的诱发表明本申请的化合物是PPARα激动剂。用GraphPad软件计算得到本申请化合物对转染后的HEK293细胞的EC 50值，结果见表1。
表1：对HEK293细胞PPARα的瞬转激活作用
化合物 EC 50(nM)
实施例2 1211.46
实施例3 1933.28
实施例4 277.91
实施例5 28.32
实施例6 52.81
实施例7 751.92
实施例8 691.69
实施例9 307.29
实施例10 76.95
实施例11 584.93
实施例17 122.57
实施例18 8.62
实施例19 1.33
实施例20 459.85
实施例21 5.40
由表1的试验数据可见，本申请的化合物对PPARα均具有较强的激动作用：试验化合物的EC 50均小于2μM。
试验例2：化合物对HEK293细胞PPARδ的瞬转激活试验
试剂：
质粒：pcDNA3.1(+)-GAL4-hPPARδ，定制于南京科佰生物科技有限公司。
脂质体：PGL4.35，定制于南京科佰生物科技有限公司。
细胞：人胚胎肾细胞HEK293，购自于ATCC。
转染试剂：Lipofectamine Reagent 3000，购自于Invitrogen。
检测试剂盒：Bright Glo TMLuciferase Assay System，购自于Promega。
检测方法：
将HEK293细胞培养在含有10％胎牛血清的DMEM培养基中，在37℃，5％CO 2条件下进行培养。在6孔板中，每孔中铺入3×10 5/ml细胞，当细胞汇合度达50％-80％时，加入5μg的脂质体PGL4.35和5μg的表达质粒pcDNA3.1(+)-GAL4-hPPARδ转染24小时后收获细胞，在96孔板铺入转染后的细胞并加入不同浓度的本申请化合物，孵育24小时，加入Bright Glo TMLuciferase Assay System试剂进行荧光素酶活性检测。在质粒转染并用化合物处理的细胞中，荧光素酶活性增加，荧光素酶活性的诱发表明本申请的化合物是PPARδ激动剂。用GraphPad软件计算得到本申请化合物对转染后的HEK293细胞的EC 50值，结果见表2。
表2：HEK293细胞PPARδ的瞬转激活作用
化合物 EC 50(nM)
实施例2 6130.95
实施例4 3441.71
实施例5 555.77
实施例6 373.60
实施例9 6699.54
实施例10 2510.76
实施例11 4426.63
实施例18 809.57
实施例19 795.87
实施例21 674.55
由表2的试验数据可见，本申请的化合物对PPARδ均具有明显的激动作用：试验化合物的EC 50均小于10μM。
试验例3：化合物对HepG2&Hek293细胞毒性试验
试剂：
细胞：人肝细胞HepG2，购自于ATCC；人胚胎肾细胞HEK293：购自于ATCC。
检测试剂：CellTiter
Figure PCTCN2018115615-appb-000039
Luminescent Cell Viability Assay，购自于Promega。
检测方法：
分别将HepG2和HEK293细胞在含有10％胎牛血清的DMEM/F12培养基中进行培养。向96孔板中铺入适量细胞，培养箱中过夜培养后，移除培养基，加入含有本申请化合物的完全培养基孵育3天。第四天向每孔中加入检测试剂CellTiter Glo，化学发光检测各孔的相对发光单位(RLU)。用GraphPad软件计算得到本申请化合物分别对HepG2和HEK293细胞的CC 50值，结果见表3。
表3：化合物对HepG2&HEK293细胞毒性作用
Figure PCTCN2018115615-appb-000040
由表3试验数据可知，本发明的化合物对HepG2细胞和HEK293细胞毒性的CC 50为μM级。所有试验化合物对HepG2细胞和HEK293细胞毒性的细胞毒性均较低。
试验例4：体外安全性试验
采用Predictor TMhERG荧光偏振测定法，检测待测化合物对hERG钾离子通道的作用。试验结果如表4中所示：
表4：hERG试验结果
化合物 IC 50(μM)
实施例2 8.24
实施例3 >10
实施例4 >10
实施例5 >10
实施例6 >10
实施例8 >10
实施例9 >10
实施例10 >10
实施例17 >10
实施例18 >10
实施例19 >10
实施例21 >10
由表4的结果可见，本发明的化合物对于hERG的IC 50均大于8μM。因此，本发明的化合物对hERG无明显的抑制作用，无导致心脏QT间期延长的安全性隐患。
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 (16)

  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、代谢物或前药，其中所述化合物具有式(I)的结构：
    Figure PCTCN2018115615-appb-100001
    其中：
    R 1、R 2、R 3和R 4各自独立地选自H、卤素、-OH、-SH、氰基、C 1-6烷基、C 3-6环烷基、卤代C 1-6烷基、C 2-5烯基、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-S-(C 1-6烷基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基；
    或者，R 3与R 4连接形成C 3-6环烷基或3-10元杂环基；
    X选自亚乙基、亚乙烯基和C 3-6亚环烷基，任选地，所述亚乙基、亚乙烯基和C 3-6亚环烷基各自独立地被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基和5-14元杂芳基的取代基取代；
    Y选自键、N和C-R 6；
    W选自N、S和C；
    R 5和R 6各自独立地选自H、卤素、-OH、-SH、氰基、硝基、C 1-6烷基、C 3-6环烷基、C 2-5烯基、-S(O) m-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-O-(C 3-6环烷基)、-O-(3-6元杂环基)、-S(O) m-(C 3-6环烷基)、-S(O) m-(3-10元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2、3-10元杂环基、C 6-14芳基和5-14元杂芳基，任选地，其中所述C 1-6烷基、环烷基、杂环基、C 6-14芳基和5-14元杂芳基各自独立地被一个或多个卤素、-OH、-OC 1-6烷基、卤代C 1-6烷基、-O-卤代C 1-6烷基、-SH、-SC 1-6烷基、-NH 2、-NH-(C 1-6烷基)和-N(C 1-6烷基) 2的取代基取代；
    m为0-2中的任意整数，n为0-10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、代谢物或前药，其中，
    R 1、R 2、R 3和R 4各自独立地选自H、卤素、C 1-6烷基、卤代C 1-6烷基和-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)，其中n为0-10中的任意整数，优选地，n为0-5中的任意整数，更优选地，n为0、1、2或3；
    优选地，R 1和R 2为甲基；
    更优选地，R 1、R 2、R 3和R 4为甲基。
  3. 权利要求1或2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，其中，
    X选自亚乙基、亚乙烯基和亚环丙基，所述亚乙基、亚乙烯基和亚环丙基各自独立任选地被一个或两个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基的取代基取代；优选地，X选自亚乙烯基；
    Y选自键和C-R 6；
    W选自N和S。
  4. 权利要求1至3中任意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、代谢物或前药，其中，
    R 5和R 6各自独立地选自H、卤素、-OH、C 1-6烷基、C 3-6环烷基、-S(O) m-(C 1-6烷基)、-O-[(C 1-6亚烷基)-O] n-(C 1-6烷基)、-O-(C 3-6环烷基)、-O-(3-6元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-6烷基) 2和3-6元杂环基，其中所述C 1-6烷基、C 3-6环烷基和3-6元杂环基任选地被一个或多个选自卤素、-OH、-OC 1-3烷基、-SH、-SC 1-3烷基、-NH 2、-NH-(C 1-3烷基)和-N(C 1-3烷基) 2的取代基取代；m为0、1或2，n为0，1，2，3，4，或5；
    优选地，R 5和R 6各自独立地选自H、F、Cl、-OH、C 1-3烷基、环丙基、-S(O) m-(C 1-3烷基)、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-O-(C 5-6环烷基)、-O-(5-6元杂环基)、-NH 2、-NH-(C 1-6烷基)、-N(C 1-3烷基) 2和5-6元杂环基，其中所述C 1-3烷基、C 1-6烷基、环丙基、C 5-6环烷基和5-6元杂环基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；m为0、1或2，n为0、1或2；
    优选地，R 5选自H和-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)，n为0、1或2；优选地，n为0；
    优选地，R 6选自H、F、Cl、-OH、C 1-3烷基、-SCH 3、-O-[(C 1-2亚烷基)-O] n-(C 1-3烷基)、-N(C 1-3烷基) 2和5-6元杂环烷基，其中所述C 1-3烷基和5-6元杂环烷基任选地被1-3个选自F、Cl、-OH和-OCH 3的取代基取代；n为0、1或2；优选地，n为0或1。
  5. 权利要求1至4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、代谢物或前药，其中所述化合物具有式(II)或式(III)的结构：
    Figure PCTCN2018115615-appb-100002
  6. 权利要求1至5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、代谢物或前药，其中所述化合物具有式(II-1)或式(III-1)的结构：
    Figure PCTCN2018115615-appb-100003
    其中，R 7选自H、卤素、C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基、-O-(C 1-6烷基)、3-10元杂环基、C 6-14芳基、5-14元杂芳基；优选地，R 7选自H、卤素和C 1-6烷基；更优选地，R 7为H或甲基。
  7. 权利要求1至6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、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2018115615-appb-100004
    Figure PCTCN2018115615-appb-100005
  8. 药物组合物，其包含预防或治疗有效量的权利要求1-7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载体。
  9. 药盒产品，其含有权利要求1-7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8的药物组合物，以及任选的药品说明书。
  10. 权利要求1-7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8的药物组合物、或权利要求9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，例如选自肝纤维变性或脂肪性肝病；优选地，所述疾病或病症为非酒精性脂肪性肝病(NAFLD)，例如单纯性脂肪肝(SFL)或非酒精性脂肪性肝炎(NASH)。
  11. 权利要求1-7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8的药物组合物、或权利要求9所述的药盒产品用于制备试剂的用途，所述试剂用于激活细胞中的PPAR；
    优选地，所述PPAR为PPARα和/或PPARδ。
  12. 权利要求1-7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8的药物组合物、或权利要求9所述的药盒产品，其用于预防或治疗与PPAR相关的疾病或病症；
    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，例如选自肝纤维变性或脂肪性肝病；优选地，所述疾病或病症为NAFLD，例如SFL或NASH。
  13. 权利要求1-7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8的药物组合物、或权利要求9所述的药盒产品，其用于激活细胞中的PPAR；
    优选地，所述PPAR为PPARα和/或PPARδ。
  14. 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权利要求1-7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8的药物组合物、或权利要求9所述的药盒产品；
    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，例如选自肝纤维变性或脂肪性肝病；优选地，所述疾病或病症为NAFLD，例如SFL或NASH。
  15. 一种激活细胞中PPAR的方法，其包括将所述细胞与有效量的权利要求1-7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8的药物组合物、或权利要求9所述的药盒产品接触的步骤；
    优选地，所述PPAR为PPARα和/或PPARδ。
  16. 制备权利要求1-7中任一项的化合物的方法，其包括以下步骤：
    Figure PCTCN2018115615-appb-100006
    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)；Z选自H、Cl、Br、I和-P(O)(OEt) 2。
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