WO2017071653A1 - N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途 - Google Patents

N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途 Download PDF

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WO2017071653A1
WO2017071653A1 PCT/CN2016/103810 CN2016103810W WO2017071653A1 WO 2017071653 A1 WO2017071653 A1 WO 2017071653A1 CN 2016103810 W CN2016103810 W CN 2016103810W WO 2017071653 A1 WO2017071653 A1 WO 2017071653A1
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substituted
unsubstituted
group
alkyl
compound
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PCT/CN2016/103810
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French (fr)
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徐华强
易伟
李佳
李静雅
施晶晶
赵关关
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中国科学院上海药物研究所
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Priority to CN201680062258.1A priority Critical patent/CN108349887A/zh
Publication of WO2017071653A1 publication Critical patent/WO2017071653A1/zh

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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of medicinal chemistry, and in particular, designs N-benzyl-5/6-formylaminopurine-2-carboxylic acid derivatives and uses thereof.
  • TZD peroxisome proliferator-activated receptor gamma
  • PPAR ⁇ peroxisome proliferator-activated receptor gamma
  • TZD full agonist thiazolidinedione
  • Avandia and Aiketo have brought about the treatment of type 2 diabetes.
  • TZDs are full agonists of PPAR ⁇ , although the ability of TZDs to activate PPAR ⁇ is consistent with its regulation of insulin sensitization (ie, anti-diabetic effects), long-term use of TZDs has many potential side effects such as obesity, weight gain, edema, heart enlargement, and Cause heart failure and so on. These side effects are also thought to be primarily associated with the complete activation of PPAR ⁇ by TZDs. Therefore, the development of oral hypoglycemic drugs with good curative effect and low toxic side effects has become an urgent need in the medical field, and it is also a research hotspot in the academic and pharmaceutical industries today.
  • the target of the compound of the present invention is PPAR ⁇ which is a target of TZD drug action.
  • PPAR ⁇ which is a target of TZD drug action.
  • the agent not only retains its insulin sensitization, but also reduces the side effects caused by the full agonist of PPAR ⁇ .
  • a first aspect of the invention provides a compound of formula I, an optical isomer, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof,
  • Each R 0 is independently selected from the group consisting of: Halogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted C 3 - C 8 cycloalkyl, -OH, -NO 2 , -CN; wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C a 3- haloalkyl group, and a phenyl group;
  • n is a positive integer of 1-4;
  • R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl; substituted or unsubstituted C 3 -C 10 cycloalkyl; ZY- and R 5 (R 6 )N-; Substituted as having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl;
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkyl-carbonyl, substituted or unsubstituted C 1 -C 10 alkane An oxy-carbonyl group, or a substituted or unsubstituted C 5 -C 20 aryl group; wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, carboxyl, -OH, -NH 2 , and phenyl;
  • Z is selected from the group consisting of a substituted or unsubstituted C 5 -C 20 aryl group, a substituted or unsubstituted C 3 -C 20 heteroaryl group, and a substituted or unsubstituted 5-20 membered heterocyclic group; Substituted as having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and phenyl;
  • Y is a C 1 -C 10 alkylene group which is unsubstituted, substituted or unsubstituted, wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 2 -C 4 Alkenyl
  • R 2 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 2 -C 6 alkene , substituted or unsubstituted C 3 -C 8 cycloalkyl, -NO 2 , -CN, -OH, substituted or unsubstituted C 1 -C 6 alkyl-carbonyl, or substituted or unsubstituted C 1 - C 6 alkoxycarbonyl; wherein substituted means having one or more substituents selected from the group: halo, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, and phenyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 5 -C 20 aryl, R 9 - C(O)-, cyano, formamide, and tetrazole; wherein the substitution means having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl , carboxyl group, -OH, -NH 2 , and phenyl group.
  • Each R 4 is each independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 20 aryl, -NO 2 , -CN, -OH, R 9 -C(O)-, R 10 (R 11 )N-, or C 5 -C 20 aryl-C(O)-N(R 10 )R 11 -; There are one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, carboxyl, -OH, -NH 2 ,
  • R 9 is selected from the group consisting of hydroxy, fluorenyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy and R 10 (R 11 )N-; wherein There are one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, and phenyl.
  • R 10 and R 11 are each independently hydrogen, C 1 -C 10 alkyl or C 1 -C 10 haloalkyl;
  • n is an integer from 0 to 5.
  • n is an integer from 1 to 5.
  • n is a positive integer of 1-2.
  • the heteroaryl group is 4-10 members, preferably 5-7 members, and contains 1-3 hetero atoms selected from N, O, S.
  • 1 or 2 R 0 are
  • the compound has the structure of formula Ic or Id:
  • R 1 , R 2 , R 3 , R 4 , and m are as defined above,
  • R 7 and R 8 are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C a 2- C 8 alkynyl group, a substituted or unsubstituted C 3 -C 8 cycloalkyl group, -OH, -NO 2 , -CN; wherein the substitution is one or more substituents selected from the group consisting of the following groups : halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and phenyl.
  • the ZY- group is selected from the group consisting of substituted or unsubstituted (5-20 membered heterocyclyl)-(C 1 -C 10 alkylene)-, substituted or unsubstituted C 5 -C 20 aryl, substituted or unsubstituted (C 5 -C 20 aryl)-(C 1 -C 10 alkylene)-, substituted or unsubstituted (5-20 membered heteroaryl)-(C 1 -C 10 alkylene)-.
  • the halogen includes F, Cl, Br or I.
  • the halogen includes F, Cl, or Br.
  • the compound has the structure of formula I-1:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the compound has the structure of Formula Ia and Formula Ib:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted containing 1-3 5-10 membered heterocyclic C 1 -C 6 alkylene selected from heteroatoms in N, S and O, substituted or unsubstituted C 5 -C 10 aryl, substituted or unsubstituted C 5 - C 10 aryl C 1 -C 6 alkylene, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, S and O, or R 5 (R 6 ) N-, wherein R 2 and R 3 are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-carbonyl, C 1 -C 6 alkoxy-carbonyl, C 5 -C 10 Aryl; and/or
  • R 2 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, CF 3 ,- NO 2 , -CN, hydroxy, C 1 -C 6 alkyl-carbonyl or C 1 -C 6 alkoxycarbonyl; and/or
  • R 3 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 5 -C 20 aryl, C 1 -C 6 alkoxy-C(O)-, carboxyl, cyano, formamide, tetrazolium; and/or
  • R 4 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, CF 3 ,- NO 2 , -CN, hydroxy, carboxy, ester, amino or substituted amino, C 1 -C 6 alkyl-carbonyl or C 1 -C 6 alkoxy-carbonyl, C 3 -C 10 cycloalkyl or C 5 -C 10 aryl, C 3 -C 10 cycloalkyl or C 5 -C 10 arylcarbonyl;
  • n 1 or 2
  • R 1 is selected from the group consisting of benzyl, phenyl, pyridin-4-ylmethyl, pyridin-4-ylethyl, 1-phenylethyl, methoxycarbonylbenzyl, or Carboxybenzyl; and/or
  • R 2 is selected from the group consisting of H, or halogen
  • R 3 is selected from the group consisting of carboxy, cyano, formamide, tetrazole, methyl ester; and/or
  • R 4 is selected from the group consisting of H, halogen, methyl, methoxy, cyclopropyl, CF 3 , -NO 2 , -CN, hydroxy, carboxy, ester, amino or substituted amino, acetyl, phenyl or Substituted phenyl;
  • R 1 , R 2 , R 3 , and R 4 are specific groups corresponding to the specific compounds in the examples.
  • the prodrug of the compound of formula I is an ester compound.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • a second aspect of the invention provides the use of a compound of formula I, an optical isomer, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament or formulation,
  • the formulation is for (i) preparing a PPAR gamma selective modulator; and/or (ii) treating and/or preventing a disease modulated by a PPAR gamma agonist.
  • the disease is selected from the group consisting of diabetes, non-insulin dependent diabetes, elevated blood pressure, elevated lipids, metabolic syndrome of cholesterol levels, or a combination thereof.
  • the medicament or formulation further has one or more characteristics selected from the group consisting of:
  • the "weak activation ability" refers to a ratio (M1/M0) of the test group measurement value M1 to the control reference value M0 of ⁇ 0.75, preferably ⁇ 0.6, more preferably ⁇ 0.5, more preferably Ground ⁇ 0.4, optimally ⁇ 0.3, wherein the compound of the control group is rosiglitazone.
  • the "strong binding ability" refers to a ratio (C1/C0) of the test group measurement value C1 to the control reference value C0 of >0.9, preferably >1, more preferably >1.15, more preferably > 1.25, optimally > 1.35, wherein the compound of the control group is rosiglitazone.
  • the "the ability of the weak preadipocyte 3T3-L1 to transform into an adipocyte” means that the ratio of the test group measured value T1 to the control reference value T0 (T1/T0) ⁇ 0.5, preferably ⁇ 0.25, more preferably ⁇ 0.1, more preferably ⁇ 0.06, wherein the compound of the control group is rosiglitazone.
  • a third aspect of the invention provides a pharmaceutical composition comprising:
  • the pharmaceutical composition contains a therapeutically effective amount or a safe and effective amount of a compound of formula I, an optical isomer, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.0001 to 99% by weight (preferably 0.01 to 90% by weight, more preferably 0.1 to 80% by weight) of the component (i) to the total of the pharmaceutical composition. Weight meter.
  • the pharmaceutical composition is used to prepare a PPAR gamma selective modulator.
  • the pharmaceutical composition is for treating and/or preventing a disease modulated by a PPAR gamma agonist (eg, diabetes, non-insulin dependent diabetes, elevated blood pressure, elevated lipid and cholesterol levels) Metabolic syndrome).
  • a disease modulated by a PPAR gamma agonist eg, diabetes, non-insulin dependent diabetes, elevated blood pressure, elevated lipid and cholesterol levels
  • Metabolic syndrome eg, diabetes, non-insulin dependent diabetes, elevated blood pressure, elevated lipid and cholesterol levels
  • a fourth aspect of the invention provides a method of preparing a compound, the method comprising the steps of:
  • R 1 , R 2 , R 3 and R 4 are as defined in the first aspect of the invention.
  • the method further comprises the steps of:
  • R 1 , R 4 are as defined in the first aspect of the invention.
  • R 3 is R 9 -C(O)- and R 9 is a substituted or unsubstituted C 1 -C 6 alkoxy group;
  • R 3 is R 9 -C(O)- and R 9 is a hydroxyl group.
  • the method further comprises the steps of:
  • R 1 , R 3 , R 4 are as defined in the first aspect of the invention.
  • R 2 is H
  • R 2 is halogen
  • the method further includes the steps of:
  • R 1 and R 4 are as defined in the first aspect of the invention, and R 2 is halogen;
  • R 3 is R 9 -C(O)- and R 9 is a substituted or unsubstituted C 1 -C 6 alkoxy group;
  • R 3 is R 9 -C(O)- and R 9 is a hydroxyl group.
  • the inert solvent is selected from the group consisting of DMF, dichloromethane, tetrahydrofuran or a combination thereof.
  • the base is selected from the group consisting of sodium carbonate, sodium hydride, sodium hydroxide, sodium t-butoxide, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, hydrogencarbonate. Potassium, triethylamine, diisopropylethylamine, DBU, DMAP, morpholine, pyridine, or a combination thereof.
  • the reaction temperature is 0-100 ° C, preferably 0-60 ° C, more preferably 10-40 ° C.
  • the reaction time is from 2 to 24 h, preferably from 4 to 12 h, more preferably from 5 to 8 h.
  • the inert solvent is selected from the group consisting of water, methanol, THF, ethanol, or a combination thereof.
  • the base is selected from the group consisting of sodium carbonate, sodium hydride, sodium hydroxide, sodium t-butoxide, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, Potassium hydrogencarbonate, triethylamine, diisopropylethylamine, DBU, DMAP, morpholine, pyridine, or a combination thereof.
  • the reaction temperature is 0-100 ° C, preferably 0-60 ° C, more preferably 10-40 ° C.
  • the reaction time is 2 to 24 h, preferably 4 to 12 h, more preferably 5 to 8 h.
  • the inert solvent is selected from the group consisting of DCM, DMF, or a combination thereof.
  • the halogenating agent is selected from the group consisting of NBS, NCS, NIS, 1-fluoro-2,6-dichloropyridine trifluoromethanesulfonate, 1 - chloromethyl-4-fluoro-1,4-diazonium dicyclo 2.2.2 octane bis(tetrafluoroborate), or a combination thereof.
  • the reaction temperature is 0-100 ° C, preferably 0-60 ° C, more preferably 10-40 ° C.
  • the reaction time is 2 to 24 h, preferably 4 to 12 h, more preferably 5 to 8 h.
  • the inert solvent is selected from the group consisting of water, methanol, THF, ethanol, or a combination thereof.
  • the base is selected from the group consisting of sodium carbonate, sodium hydride, sodium hydroxide, sodium t-butoxide, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, Potassium hydrogencarbonate, triethylamine, diisopropylethylamine, DBU, DMAP, morpholine, pyridine, or a combination thereof.
  • the reaction temperature is 0-100 ° C, preferably 0-60 ° C, more preferably 10-40 ° C.
  • the reaction time is 2 to 24 h, preferably 4 to 12 h, more preferably 5 to 8 h.
  • the compound I1-2 is prepared by the following method:
  • R 2 and R 3 are as defined in the first aspect of the invention.
  • R 1 is ZY- and is substituted or unsubstituted (C 5 -C 20 aryl)-(C 1 -C 10 alkylene)-.
  • the inert solvent is selected from the group consisting of DCM, DMF, acetonitrile, or a combination thereof.
  • the base is selected from the group consisting of sodium carbonate, sodium hydride, sodium hydroxide, sodium t-butoxide, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, and Isopropylethylamine, DBU, DMAP, morpholine, pyridine, or a combination thereof.
  • the amide condensing agent is selected from the group consisting of HATU, HBTU, HCTU, PyBop, Bop, TBTU, TSTU, TNTU, EDCI, DCC, or a combination thereof.
  • reaction temperature is 0-100 ° C, preferably 0-60 ° C, more preferably 10-40 ° C.
  • reaction time is from 2 to 24 h, preferably from 4 to 12 h, more preferably from 5 to 8 h.
  • a fifth aspect of the invention provides a method for treating PPAR ⁇ in vitro, comprising the steps of:
  • the compound of formula I produces a weak activation of PPAR ⁇ .
  • the PPAR gamma in step (a), is located on a live PPAR gamma expressing cell, such as a mammalian cell.
  • the method is non-therapeutic and non-diagnostic.
  • a sixth aspect of the invention provides a method for treating and/or preventing a disease modulated by a PPAR gamma agonist, the method comprising:
  • the compound of the formula I according to the first aspect of the invention or the pharmaceutical composition of the third aspect of the invention is administered to a subject in need thereof.
  • the disease is selected from the group consisting of diabetes, non-insulin dependent diabetes, elevated blood pressure, metabolic syndrome with elevated lipid and cholesterol levels, or a combination thereof.
  • the object comprises a person.
  • the subject comprises a non-human mammal.
  • the non-human mammal comprises a rodent such as a mouse or a rat.
  • the administration dose is 10-10000 mg/kg/day, preferably 500-10000 mg/kg/day, more preferably 1000-10000 mg/kg/day.
  • the application frequency is 1-5 times/day, preferably 1-2 times/day.
  • the administration comprises one or more cycles, each cycle being from 2 to 30 days, preferably from 3 to 7 days.
  • the present inventors synthesized a series of N-benzyl-5/6-formylaminopurine-2-carboxylic acid derivatives which are capable of retaining its insulin sensitizing property. In addition, it can reduce the side effects caused by PPAR ⁇ full agonist, so it can be used as a PPAR ⁇ selection regulator. On the basis of this, the inventors completed the present invention.
  • substituted or unsubstituted means that the group may be unsubstituted or that H in the group is one or more (eg 1-10, preferably 1-5) More preferably 1-3, optimally 1-2) substituents are substituted.
  • substituted or “substituted” means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the group consisting of: Halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • substituents selected from the group consisting of: Halogen, hydroxy, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl.
  • C 1 -C 10 alkyl refers to straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl Butyl, sec-butyl, tert-butyl, or the like;
  • C 1 -C 3 alkyl means a straight or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, N-propyl, isopropyl, or the like.
  • C 3 -C 10 cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or Similar group.
  • C 1 -C 10 alkylene refers to a divalent hydrocarbon radical having from 1 to 10 carbon atoms, for example, a methylene, ethylene, propylene, butylene, or the like.
  • C 2 -C 8 alkenyl refers to a straight or branched alkenyl group having 2-8 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
  • C 2 -C 8 alkynyl group means a straight or branched alkynyl chain having 2-8 carbon atoms, e.g. ethynyl, propynyl, or the like.
  • C 1 -C 10 alkyl-carbonyl refers to a group having the structure "-CO-(C 1 -C 10 alkyl)", such as methyl acyl, ethyl acyl, propyl acyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • C 1 -C 10 alkoxy-carbonyl refers to a group having a (C 1 -C 10 alkyl)-O-CO- structure, such as CH 3 -O-CO-, C 2 H. 5- O-CO-, C 3 H 8 -O-CO-, (CH 3 ) 2 CH-O-CO-, nC 4 H 9 -O-CO-, tC 4 H 9 -O-CO-, or Similar group.
  • C 5 -C 20 aryl refers to a monovalent aromatic carbocyclic group of 5 to 20 (preferably 5 to 14) carbon atoms which has a monocyclic (eg phenyl) or fused ring. (eg naphthyl or anthracenyl), if the point of attachment is on an aromatic carbon source, the fused ring may be non-aromatic (eg 2-benzoxazolone, 2H-1,4-benzoxazine-3 (4H) -keto-7-yl, etc.).
  • Preferred aryl groups include phenyl and naphthyl.
  • the term includes substituted or unsubstituted forms wherein the substituents are as defined above.
  • C 3 -C 20 heteroaryl refers to an aromatic group having 3 to 20 carbon atoms and 1 to 4 (preferably 1 to 3) hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur,
  • Such heteroaryl groups may be monocyclic (such as pyridyl or furyl) or fused (such as indolizinyl or benzothienyl), wherein the fused ring may be non-aromatic and/or Contains a heteroatom as long as the point of attachment is through an aromatic heteroaryl atom.
  • Preferred heteroaryl groups include pyridinyl, pyrrolyl, indolyl, thienyl and furanyl. The term includes substituted or unsubstituted heteroaryl.
  • C 5 -C 20 heterocyclyl refers to a saturated, partially saturated or unsaturated group (but not aromatic), having a single or fused ring (including spiro and bridged ring systems a system having 5 to 20 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen.
  • fused ring system one or more of the rings may be a cycloalkyl, aryl or heteroaryl group, as long as The point of attachment passes through a non-aromatic ring.
  • the term includes substituted or unsubstituted heterocyclic groups.
  • halogen means fluoro, chloro, bromo, or iodo, preferably fluoro, chloro and bromo.
  • halo refers to a group substituted by the same or different one or more of the above halogen atoms, and may be partially or fully halogenated, such as trifluoromethyl, pentafluoroethyl, heptafluoro. Isopropyl, or a similar group.
  • C 1 -C 3 haloalkyl refers to a straight or branched alkyl group having from 1 to 3 carbon atoms in which hydrogen is substituted by one or more halogens, for example, a halomethyl group. , haloethyl, halopropyl, haloisopropyl, or the like.
  • the compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures And pure or partially pure compounds are included within the scope of the invention.
  • the invention includes all isomeric forms of the compounds.
  • room temperature means 4-40 ° C, preferably 20-25 ° C.
  • the invention provides a compound of formula I, an optical isomer, hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof.
  • Each R 0 is independently selected from the group consisting of: Halogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted C 3 - C 8 cycloalkyl, -OH, -NO 2 , -CN; wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C a 3- haloalkyl group, and a phenyl group;
  • n is a positive integer of 1-4;
  • R 1 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl; substituted or unsubstituted C 3 -C 10 cycloalkyl; ZY- and R 5 (R 6 )N-; Substituted as having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl;
  • R 5 and R 6 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkyl-carbonyl, substituted or unsubstituted C 1 -C 10 alkane An oxy-carbonyl group, or a substituted or unsubstituted C 5 -C 20 aryl group; wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, carboxyl, -OH, -NH 2 , and phenyl;
  • Z is selected from the group consisting of a substituted or unsubstituted C 5 -C 20 aryl group, a substituted or unsubstituted C 3 -C 20 heteroaryl group, and a substituted or unsubstituted 5-20 membered heterocyclic group; Substituted as having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and phenyl;
  • Y is a non-substituted or unsubstituted C1-10 alkylene group, wherein the substitution is one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, and C 2 -C 4 alkene base;
  • R 2 is selected from the group consisting of H, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 2 -C 6 alkene , substituted or unsubstituted C 3 -C 8 cycloalkyl, -NO 2 , -CN, -OH, substituted or unsubstituted C 1 -C 6 alkyl-carbonyl, or substituted or unsubstituted C 1 - C 6 alkoxycarbonyl; wherein substituted means having one or more substituents selected from the group: halo, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, and phenyl;
  • R 3 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted C 5 -C 20 aryl, R 9 - C(O)-, cyano, formamide, and tetrazole; wherein the substitution means having one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl , carboxyl group, -OH, -NH 2 , and phenyl group.
  • Each R 4 is each independently selected from the group consisting of halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 20 aryl, -NO 2 , -CN, -OH, R 9 -C(O)-, R 10 (R 11 )N-, or C 5 -C 20 aryl-C(O)-N(R 10 )R 11 -; There are one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, carboxyl, -OH, -NH 2 ,
  • R 9 is selected from the group consisting of hydroxy, fluorenyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy and R 10 (R 11 )N-; wherein There are one or more substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, and phenyl.
  • R 10 and R 11 are each independently hydrogen, C 1 -C 10 alkyl or C 1 -C 10 haloalkyl;
  • n is an integer from 0 to 5.
  • n is an integer from 1 to 5.
  • n is a positive integer of 1-2.
  • 1 or 2 R 0 are
  • the compound of formula I is:
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the invention includes all stereoisomers of the compound.
  • the invention includes all tautomers of the compounds.
  • the invention also includes deuterated compounds resulting from the substitution of any one or more of the hydrogen atoms of the compound by its stable isotope oxime.
  • the compound of the formula (I) of the present invention can be produced by a method as described herein, however, the conditions of the preparation method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited. The following description of the examples.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at a reaction temperature of 0 to 100 ° C (preferably, 0 to 60 ° C, more preferably 10 to 40 ° C).
  • the reaction time is usually 2 to 24 hours, preferably 4 to 12 hours.
  • the base used in the reaction includes, but is not limited to, sodium hydride, sodium hydroxide, sodium t-butoxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine. Diisopropyl B Amine, DBU, DMAP, morpholine, or pyridine.
  • the amide condensing agents used in the reaction include, but are not limited to, HATU, HBTU, HCTU, PyBop, Bop, TBTU, TSTU, TNTU, EDCI, or DCC.
  • Halogenating reagents used in the reaction include, but are not limited to, NBS, NCS, NIS, 1-fluoro-2,6-dichloropyridine trifluoromethanesulfonate, or 1-chloromethyl-4-fluoro-1 , 4-diazonium dicyclo 2.2.2 octane bis (tetrafluoroborate).
  • the compounds of formula I of the present invention can be prepared by the following schemes and exemplary methods described in the Examples and related publications used by those skilled in the art.
  • the methods of preparing the compounds of Formula I-1 of the present invention may include, but are not limited to, the following schemes.
  • Step 1 In the presence of a base such as diisopropylethylamine, DMAP, triethylamine, in the presence of an amide condensing agent (such as HATU, HBTU, HCTU) in an inert solvent (eg DCM, DMF)
  • a base such as diisopropylethylamine, DMAP, triethylamine
  • an amide condensing agent such as HATU, HBTU, HCTU
  • an inert solvent eg DCM, DMF
  • Step 2 Under the action of a base (such as sodium carbonate, sodium hydride), in a inert solvent (such as DMF), the compound I1-2 is reacted with the compound-substituted benzyl bromide at a certain temperature (for example, 0-60 ° C), thereby obtaining Compound I1-3.
  • a base such as sodium carbonate, sodium hydride
  • a inert solvent such as DMF
  • Step 3 Under the action of a halogenating reagent (such as NBS, NCS), the compound I1-3 is halogenated at a certain temperature (such as 0-60 ° C) in an inert solvent (such as DCM, DMF) to obtain a compound I1. -4.
  • a halogenating reagent such as NBS, NCS
  • the compound I1-3 is halogenated at a certain temperature (such as 0-60 ° C) in an inert solvent (such as DCM, DMF) to obtain a compound I1.
  • Step 4 Under the action of a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide, in an inert solvent (such as water, methanol, THF), the compound I1-4 is at a certain temperature (for example, 0-100 ° C) A hydrolysis reaction is carried out to obtain a compound I-1.
  • a base such as sodium hydroxide, lithium hydroxide or potassium hydroxide
  • an inert solvent such as water, methanol, THF
  • R 2 is H
  • Step 4 i.e., in Formula I1-4, Formula In I-1
  • R 2 is a halogen
  • R 3 is R 9 -C(O)- and R 9 is substituted or unsubstituted C 1 -C 6 alkoxy
  • R 3 is R 9 -C(O)- and R 9 is a hydroxyl group
  • R 1 and R 4 are as defined in the specification.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.
  • the "active ingredient” as used herein means a compound of the formula I, an optical isomer, a hydrate, a solvate thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof.
  • the "active ingredient" and pharmaceutical compositions of the present invention are useful as PPAR gamma selective modulators.
  • the disease is selected from the group consisting of diabetes, non-insulin dependent diabetes, elevated blood pressure, metabolic syndrome with elevated lipid and cholesterol levels, or a combination thereof.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • the compounds of the preferred embodiments of the invention may be administered as separate active agents or in combination with one or more other agents useful in the treatment of diabetes.
  • the use of the compounds of the preferred embodiments of the invention in combination with known therapeutic agents is also effective, and combinations of currently known compounds and other therapeutic agents for treating diabetes are within the scope of the preferred embodiments.
  • therapeutic agents for treating diabetes include, but are not limited to, the following: Wendia, Aiketo, and the like.
  • the compounds of the preferred embodiments are also effective when administered simultaneously with a therapeutic agent for treating diabetes.
  • the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the accepted modes of administration of agents having similar effects.
  • the actual amount of the compound (i.e., active ingredient) of the preferred embodiment is determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. .
  • the drug can be administered multiple times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.
  • the therapeutically effective dose may generally be a total daily dose administered to a patient in a single administration or in divided doses, for example, from about 0.001 to about 1000 mg/kg body weight per day, preferably from about 1.0 to about 30 per day. Mg/kg body weight.
  • a Dosage unit composition can include its dosage factor to form a daily dose. The choice of dosage form will depend on various factors such as the mode of administration and the bioavailability of the drug substance.
  • the compounds of the preferred embodiments can be administered as a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous). Or subcutaneous).
  • the preferred mode of administration is oral, and a convenient daily dose can be adjusted depending on the degree of bitterness.
  • the compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or any other suitable compositions.
  • Another preferred mode of administration of the preferred embodiment compounds is inhalation. This is an effective method of delivering a therapeutic agent directly to the respiratory tract (see, e.g., U.S. Patent No. 5,607,915).
  • Suitable pharmaceutically acceptable carriers or excipients include, for example, treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , Methylcellulose sodium, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • treatment and drug delivery modifiers and accelerators such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starches, gelatin, cellulose , Methylcellulose sodium, carboxymethylcellulose, glucose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting wax, ion exchange resin, and the like, and combinations of any two or more thereof.
  • the liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Preferred liquid carriers, particularly carriers for injectable solutions include water, saline, aqueous dextrose and ethylene glycol.
  • Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
  • pharmaceutically acceptable salt refers to a non-toxic acid or alkaline earth metal salt of a compound of formula I. These salts can be prepared in situ by final isolation and purification of the compound of formula I, or by separately reacting a suitable organic or inorganic acid or base with a basic or acidic functional group.
  • Representative salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate , camphorate, camphor sulfonate, digluconate, cyclopentane propionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerol phosphate, hemisulfate, heptanoic acid Salt, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate , 2-naphthyl sulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, sul
  • the nitrogen-containing basic group can be quaternized by the following reagents: alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide; dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Base halides such as benzyl and phenethyl bromide. A water soluble or oil soluble or dispersible product is thus obtained.
  • alkyl halides such as methyl, ethyl, propyl, butyl chloride, bromide and iodide
  • dialkyl sulfate Such as dimethyl, diethyl, dibutyl and dipentyl sulfate
  • long chain halides
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, and citric acid.
  • the base addition salt can be prepared in situ upon final isolation and purification of the compound of formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a hydroxide, carbonate or carbonate of a pharmaceutically acceptable metal cation. Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including However, it is not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • the term "pharmaceutically acceptable prodrug” refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • pharmaceutically acceptable prodrug refers to a prodrug of a compound of those preferred embodiments, which is rapidly converted in vivo to a parent compound of the above formula, for example, hydrolyzed in blood.
  • the invention also provides the use of the compounds of formula I described.
  • the compound of formula I is for use in the preparation of a PPAR gamma selective modulator; the PPAR gamma selective modulator comprises an effective amount of a compound of formula I or a pharmaceutically acceptable thereof salt.
  • the compound of formula I is for use in the manufacture of a pharmaceutical composition for the treatment and/or prevention of a disease modulated by a PPAR gamma agonist.
  • the disease includes, but is not limited to, diabetes, non-insulin dependent diabetes, elevated blood pressure, increased metabolic syndrome of lipid and cholesterol levels.
  • the compound of formula I has one or more characteristics selected from the group consisting of:
  • the "weak activation ability” refers to a ratio (M1/M0) of the test group measurement value M1 to the control reference value M0 of ⁇ 0.75, preferably ⁇ 0.6, more preferably ⁇ 0.5, more preferably Ground ⁇ 0.4, optimally ⁇ 0.3.
  • the "strong binding ability" refers to a ratio (C1/C0) of the test group measurement value C1 to the control reference value C0 of >0.9, preferably >1, more preferably >1.15, more preferably Ground > 1.25, optimally > 1.35.
  • the "the ability of the weak preadipocyte 3T3-L1 to transform into an adipocyte” means that the ratio of the test group measured value T1 to the control reference value T0 (T1/T0) ⁇ 0.5, preferably ⁇ 0.25, more preferably ⁇ 0.1, more preferably ⁇ 0.06.
  • the compound of the present invention can be used as a potent PPAR ⁇ selection regulator
  • the synthesis method is mild, the operation is simple and easy, the yield is high, and the derivatization is easy, and it is suitable for industrial scale production;
  • Preparation 22 (yield 48%) was carried out by the procedure of Preparation 15 using 4-fluorobenzyl bromide instead of 3-chloro-4-fluorobenzyl bromide.
  • Preparation 24 (yield 71%) was carried out by the procedure of Preparation 15 using 4-isopropylbenzyl bromide instead of 3-chloro-4-fluorobenzyl bromide.
  • Preparation 26 (yield 68%) was carried out by the procedure of Preparation 15 using 4-trifluoromethoxybenzyl bromide instead of 3-chloro-4-fluorobenzyl bromide.
  • Cos-7 cells were purchased from ATCC, were cultured in 10% FBS without antibiotics DMEM, 37 °C, 5% CO 2 incubator. When the cells were inoculated into a 24-well plate in a logarithmic growth phase and the cells were fused about 70%, the plasmid was co-transfected according to the lipofectamine 2000 (Invitrogen) protocol (50 ng full-length hPPAR ⁇ , 100 ng PPAR ⁇ , 5 ng Renilla luciferase plasmid). ). After 24 h, the transfected cells were treated with 1 ⁇ M of compounds 1 to 39, respectively, of which 1 ⁇ M rosiglitazone was used as a positive control and DMSO was used as a negative control. After 24 h of intervention, the luciferase activity was determined according to the Reporter luciferase assay kits (Promega) protocol, and 3 independent test wells were set for each group.
  • TR-FRET method tests the binding ability of a compound to PPAR ⁇ :
  • the diluted compound (1 to 39, rosiglitazone) was again diluted to 2 ⁇ M with TR-FRETbuffer.
  • TR-FRET buffer as a solvent to prepare Fluormone TM Pan-PPAR Green solution ( 20nM).
  • 3T3-L1 preadipocytes were purchased from ATCC and cultured in 10% FBS DMEM containing penicillin-streptomycin double antibody in a 37 ° C, 5% CO 2 incubator. Inoculated on the culture plate, the induction solution was added 2 days after confluence (10% FBS DMEM containing 0.5 mmol/L IBMX (3-isobutyl-1-methylxanthine), 1 ⁇ mol/L DEX (dexamethasone), 850 nmol/L insulin). After 72h, it was replaced with 10% FBS high glucose DMEM containing 850nmol/L insulin, which was changed every 2d.
  • the compound synthesized by the present invention has weak activation ability to PPAR ⁇ , and the antidiabetic drug rosiglitazone is used as a positive control (specified as 100%), indicating that the compound synthesized by the present invention activates PPAR ⁇ value of only 0.3 at a concentration of 10 ⁇ M. %-27%, suggesting that the side effects of the compounds of the invention are small.
  • the compound synthesized by the present invention has strong binding ability to PPAR ⁇ , and the anti-diabetic drug rosiglitazone is used as a positive control (specified as 1), indicating that the compound synthesized by the present invention has a binding strength to PPAR ⁇ at a concentration of 1 ⁇ M of 0.2. Between 1.3 and 1, this suggests that the compounds of the invention have excellent hypoglycemic activity.
  • the compound synthesized by the present invention has weak ability to differentiate into adipocytes.
  • the anti-diabetic drug rosiglitazone was used as a positive control (test value was 85.2), indicating that the compound of the present invention has a fat cell differentiation rate far lower than that of rosiglitazone at a concentration of 10 ⁇ M, which is only between 1 and 5.77.
  • the data for most compounds is ⁇ 30.
  • N-benzyl-5/6-formylaminopurine-2-carboxylic acid derivative synthesized by the present invention exerts a biological function as a novel PPAR ⁇ selective modulator.
  • rosiglitazone which is an antidiabetic drug, it has a low ability to induce adipocyte differentiation, thereby reducing or even eliminating some related side effects such as obesity and weight gain.
  • mice Male, weighing 200-220 g, were randomly divided into two groups, 4/3 each, intragastric or intravenous administration of compound 29 gavage group with 5% DMSO / 5% Tween 80 / 90% saline Formulated, the intravenous group was prepared with 10% DMSO/10% Tween 80/80% physiological saline. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • Administration by intragastric administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration;
  • Intravenous administration 5 min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h;
  • venous blood was taken from the posterior venous plexus of the rat eye, placed in an EDTA-2K anticoagulant tube, centrifuged at 11,000 rpm for 5 min, plasma was separated, and frozen in a refrigerator at -20 °C.

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Abstract

本发明公开了一种N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途，具体地，本发明公开了一种式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐。本发明化合物用于治疗和/或预防受PPARγ激动剂调节的疾病，因此，具有广泛的应用前景。

Description

N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途 技术领域
本发明属于药物化学领域，具体地，设计N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物及其用途。
背景技术
近年来，随着我国社会发展，糖尿病的发病率在不断增高。2008年中华医学会糖尿病学分会(CDS)组织的糖尿病流行病学调查结果显示，在我国20岁以上的人群中，年龄标化的患病率已达9.7％，成人患病总人数已达到9240万。据世界卫生组织统计，至2012年全球糖尿病患病总人数已达到3.47亿，而我国已成为世界上糖尿病患病人数最多的国家。非胰岛素依赖的II型糖尿病(T2DM)患者在我国患病人群中占据90％以上。糖尿病已成为危害我国人民健康的高发病。
目前临床上过氧化物酶体增殖物激活受体伽马(PPARγ)完全激动剂噻唑烷二酮(TZD)类口服降糖药物(文迪雅和艾可托)给II型糖尿病治疗带来了重大突破。TZDs是PPARγ的完全激动剂，虽然TZDs激活PPARγ的能力与其调控胰岛素增敏性(即抗糖尿病效应)相吻合，但长期服用TZDs产生很多潜在副作用，如肥胖、体重增加、浮肿、心脏肿大以及引发心衰等。这些副作用也被认为主要是与TZDs完全激活PPARγ相关联。因此发展疗效好、低毒副作用的口服降糖药物已经成为医疗界迫切的需要，同时也是当今学术界和制药工业界的研究热点。
本发明的化合物作用靶点为TZD类药物作用靶点的PPARγ。考虑到作为PPARγ的完全激动剂的TZD类药物强效激活PPARγ能力伴随而来的一些相关副作用，近年来人们将研究力量转向了发展选择性的PPARγ调控剂，希望找到一类潜在的选择性调控剂，既能够保留它的胰岛素增敏性，又能降低PPARγ完全激动剂导致的副作用。
发明内容
本发明的目的在于提供一种既能够保留它的胰岛素增敏性，又能降低PPARγ完全激动剂导致的副作用的PPARγ选择性调控剂。
本发明第一方面提供了一种式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，
Figure PCTCN2016103810-appb-000001
式中，
各R0各自独立地选自下组：
Figure PCTCN2016103810-appb-000002
卤素、取代或未取代的C1-C8烷基、取代或未取代的C2-C8链烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C8 环烷基、-OH、-NO2、-CN；其中，所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
并且至少一个R0为
Figure PCTCN2016103810-appb-000003
n为1-4的正整数；
R1选自下组：取代或未取代的C1-C10烷基；取代或未取代的C3-C10环烷基；Z-Y-和R5(R6)N-；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基；
R5和R6各自独立地为氢、取代或未取代的C1-C10烷基、取代或未取代的C1-C10烷基-羰基、取代或未取代的C1-C10烷氧基-羰基、或取代或未取代的C5-C20芳基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基；
Z选自下组：取代或未取代的C5-C20芳基、取代或未取代的C3-C20杂芳基、和取代或未取代的5-20元杂环基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
Y为无、取代或未取代的C1-C10亚烷基，其中取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、和C2-C4链烯基；
R2选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C3-C8环烷基、-NO2、-CN、-OH、取代或未取代的C1-C6烷基-羰基、或取代或未取代的C1-C6烷氧基羰基；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基；
R3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C20芳基、R9-C(O)-、氰基、甲酰胺、和四氮唑；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基。
每个R4各自独立地选自下组：卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20的芳基、-NO2、-CN、-OH、R9-C(O)-、R10(R11)N-、或C5-C20芳基-C(O)-N(R10)R11-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基。
R9选自下组：羟基、巯基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基和R10(R11)N-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基。
R10和R11各自独立地为氢、C1-C10烷基或C1-C10卤代烷基；以及
m为0-5的整数。
在另一优选例中，m为1-5的整数。
在另一优选例中，n为1-2的正整数。
在另一优选例中，所述杂芳基为4-10元，较佳地，5-7元，且含有1-3个选自N、O、S的杂原子。
在另一优选例中，1或2个R0为
Figure PCTCN2016103810-appb-000004
在另一优选例中，所述的化合物具有式Ic或Id结构：
Figure PCTCN2016103810-appb-000005
式中，R0为
Figure PCTCN2016103810-appb-000006
R1、R2、R3、R4、和m的定义如上所述，
R7和R8各自独立地选自下组：H、卤素、取代或未取代的C1-C8烷基、取代或未取代的C2-C8链烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C8环烷基、-OH、-NO2、-CN；其中，所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基。
在另一优选例中，Z-Y-基团选自下组：取代或未取代的(5-20元杂环基)-(C1-C10亚烷基)-、取代或未取代的C5-C20芳基、取代或未取代的(C5-C20芳基)-(C1-C10亚烷基)-、取代或未取代的(5-20元杂芳基)-(C1-C10亚烷基)-。
在另一优选例中，所述的卤素包括F、Cl、Br或I。
在另一优选例中，所述的卤素包括F、Cl、或Br。
在另一优选例中，所述化合物具有式I-1的结构：
Figure PCTCN2016103810-appb-000007
式I-1中，R1、R2、R3、R4的定义如上所述。
在另一优选例中，所述化合物具有式Ia和式Ib的结构：
Figure PCTCN2016103810-appb-000008
式Ia和式Ib中，R1、R2、R3、R4的定义如上所述。
在另一优选例中，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、S和O中的杂原子的5-10元杂环基C1-C6亚烷基、取代或未取代的C5-C10芳基、取代或未取代的C5-C10芳基C1-C6亚烷基、取代或未取代的含有1-3个选自N、S和O中的杂原子的5-10元杂芳基、或R5(R6)N-，其中，R2和R3各自独立地为氢、C1-C6烷基、C1-C6烷基-羰基、C1-C6烷氧基-羰基、C5-C10芳基；和/或
R2选自下组：H、卤素、C1-C6烷基、C1-C6烷氧基、C2-C6链烯基、C3-C8环烷基、CF3、-NO2、-CN、羟基、C1-C6烷基-羰基或C1-C6烷氧基羰基；和/或
R3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、 取代或未取代的C5-C20的芳基、C1-C6烷氧基-C(O)-、羧基、氰基、甲酰胺、四氮唑；和/或
R4选自下组：H、卤素、C1-C6烷基、C1-C6烷氧基、C2-C6链烯基、C3-C8环烷基、CF3、-NO2、-CN、羟基、羧基、酯基、氨基或取代氨基、C1-C6烷基-羰基或C1-C6烷氧基-羰基、C3-C10环烷基或C5-C10的芳基、C3-C10环烷基或C5-C10的芳基甲酰基；
其中，m为1或2，和n为1。
在另一优选例中，R1选自下组：苄基、苯基、吡啶-4-基甲基、吡啶-4-基乙基、1-苯乙基、甲氧基羰基苄基、或羧基苄基；和/或
R2选自下组：H、或卤素；和/或
R3选自下组：羧基、氰基、甲酰胺、四氮唑、甲酯基；和/或
R4选自下组：H、卤素、甲基、甲氧基、环丙基、CF3、-NO2、-CN、羟基、羧基、酯基、氨基或取代氨基、乙酰基、苯基或取代苯基；
其中，m为1或2，n为1。
在另一优选例中，R1、R2、R3、R4为实施例中各具体化合物相对应的具体基团。
在另一优选例中，所述式I化合物的前药为酯类化合物。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2016103810-appb-000009
Figure PCTCN2016103810-appb-000010
Figure PCTCN2016103810-appb-000011
Figure PCTCN2016103810-appb-000012
在另一优选例中，所述化合物选自下组：
Figure PCTCN2016103810-appb-000013
本发明第二方面提供了一种式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐的用途，用于制备药物或制剂，所述药物或 制剂用于(i)制备PPARγ选择性调控剂；和/或(ii)治疗和/或预防受PPARγ激动剂调节的疾病。
在另一优选例中，所述疾病选自下组：糖尿病、非胰岛素依赖型糖尿病、升高的血压、提高的脂质、胆固醇水平的代谢综合症、或其组合。
在另一优选例中，所述药物或制剂还具有选自下组的一个或多个特性：
(a)对PPARγ弱激活能力；
(b)对PPARγ强结合能力；
(c)弱的前脂肪细胞3T3-L1向脂肪细胞转化的能力。
在另一优选例中，所述“弱激活能力”指测试组测量值M1与对照组参比值M0之比(M1/M0)＜0.75，较佳地＜0.6，更佳地＜0.5，更佳地＜0.4，最佳地＜0.3，其中，所述对照组的化合物为罗格列酮。
在另一优选例中，所述“强结合能力”指测试组测量值C1与对照组参比值C0之比(C1/C0)＞0.9，较佳地＞1，更佳地＞1.15，更佳地＞1.25，最佳地＞1.35，其中，所述对照组的化合物为罗格列酮。
在另一优选例中，所述“弱的前脂肪细胞3T3-L1向脂肪细胞转化的能力”指测试组测量值T1与对照组参比值T0之比(T1/T0)＜0.5，较佳地＜0.25，更佳地＜0.1，更佳地＜0.06,其中，所述对照组的化合物为罗格列酮。
本发明第三方面提供了一种药物组合物，包括：
(i)本发明第一方面所述的式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐；和
(ii)药学上可接受的载体。
在另一优选例中，所述的药物组合物含有治疗有效量或安全有效量的式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐。
在另一优选例中，所述药物组合物中，含有0.0001-99wt％(较佳地0.01-90wt％，更佳地，0.1-80wt％)的组分(i)，以药物组合物的总重量计。
在另一优选例中，所述的药物组合物用于制备PPARγ选择性调控剂。
在另一优选例中，所述的药物组合物用于治疗和/或预防受PPARγ激动剂调节的疾病(例如，糖尿病、非胰岛素依赖型糖尿病、升高的血压、提高的脂质和胆固醇水平的代谢综合症)。
本发明第四方面提供了一种化合物的制备方法，所述方法包括步骤：
(i)在惰性溶剂中，在碱的作用下，化合物I1-2与式V所示的取代苄溴进行反应，形成化合物I1-3；
Figure PCTCN2016103810-appb-000014
上述各式中，R1、R2、R3、R4如本发明第一方面中所定义。
在另一优选例中，当R2＝卤素并且R3为R9-C(O)-且R9为取代或未取代的C1-C6烷氧基时，所述方法还包括步骤：
(ii-A)在惰性溶剂中，在碱的作用下，将化合物I1-3进行水解反应，形成式I-1化合物；
Figure PCTCN2016103810-appb-000015
其中，
R1、R4如本发明第一方面中所定义；并且
在式I1-3中，R3为R9-C(O)-且R9为取代或未取代的C1-C6烷氧基；
在式I1-1中，R3为R9-C(O)-且R9为羟基。
在另一优选例中，当R2＝H时，所述方法还包括步骤：
(ii-B)在惰性溶剂中，在卤化试剂作用下，将化合物I1-3进行卤代反应，形成化合物I1-4；
Figure PCTCN2016103810-appb-000016
R1、R3、R4如本发明第一方面中所定义；并且
在式I1-3中，R2为H；
在式I1-4中，R2为卤素。
在另一优选例中，所述方法还包括步骤：
(ii-C)对化合物I1-4进行水解反应，从而形成式I-1化合物；
Figure PCTCN2016103810-appb-000017
其中，R1、R4如本发明第一方面中所定义，R2为卤素；并且
在式I1-4中，R3为R9-C(O)-且R9为取代或未取代的C1-C6烷氧基；
在式I1-1中，R3为R9-C(O)-且R9为羟基。
在另一优选例中，在步骤(i)中，所述惰性溶剂选自下组：DMF、二氯甲烷，四氢呋喃或其组合。
在另一优选例中，在步骤(i)中，所述碱选自下组：碳酸钠、氢化钠、氢氧化钠、叔丁醇钠、氢氧化锂、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙胺、DBU、DMAP、吗啉、吡啶、或其组合。
在另一优选例中，在步骤(i)中，所述反应温度为0-100℃，较佳地，0-60℃，更佳地，10-40℃。
在另一优选例中，在步骤(i)中，所述反应时间为2-24h，较佳地，4-12h，更佳地，5-8h。
在另一优选例中，在步骤(ii-A)中，所述惰性溶剂选自下组：水、甲醇、THF、乙醇或其组合。
在另一优选例中，在步骤(ii-A)中，所述碱选自下组：碳酸钠、氢化钠、氢氧化钠、叔丁醇钠、氢氧化锂、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙胺、DBU、DMAP、吗啉、吡啶、或其组合。
在另一优选例中，在步骤(ii-A)中，所述反应温度为0-100℃，较佳地，0-60℃，更佳地，10-40℃。
在另一优选例中，在步骤(ii-A)中，所述反应时间为2-24h，较佳地，4-12h，更佳地，5-8h。
在另一优选例中，在步骤(ii-B)中，所述惰性溶剂选自下组：DCM、DMF、或其组合。
在另一优选例中，在步骤(ii-B)中，所述卤化试剂选自下组：NBS、NCS、NIS、1-氟-2,6-二氯吡啶三氟甲磺酸盐、1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸盐)、或其组合。
在另一优选例中，在步骤(ii-B)中，所述反应温度为0-100℃，较佳地，0-60℃，更佳地，10-40℃。
在另一优选例中，在步骤(ii-B)中，所述反应时间为2-24h，较佳地，4-12h，更佳地，5-8h。
在另一优选例中，在步骤(ii-C)中，所述惰性溶剂选自下组：水、甲醇、THF、乙醇或其组合。
在另一优选例中，在步骤(ii-C)中，所述碱选自下组：碳酸钠、氢化钠、氢氧化钠、叔丁醇钠、氢氧化锂、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙胺、DBU、DMAP、吗啉、吡啶、或其组合。
在另一优选例中，在步骤(ii-C)中，所述反应温度为0-100℃，较佳地，0-60℃，更佳地，10-40℃。
在另一优选例中，在步骤(ii-C)中，所述反应时间为2-24h，较佳地，4-12h，更佳地，5-8h。
在另一优选例中，所述化合物I1-2由如下方法制备：
在惰性溶剂中，在碱的作用下，在酰胺缩合剂的作用下，将化合物I1-1与式VI所示的取代苄胺进行反应，从而得到化合物I1-2；
Figure PCTCN2016103810-appb-000018
上述各式中，R2、R3的定义如本发明第一方面所述；
在式VI和式I1-2中，R1为Z-Y-，且为取代或未取代的(C5-C20芳基)-(C1-C10亚烷基)-。
在另一优选例中，所述惰性溶剂选自下组：DCM、DMF、乙腈、或其组合。
在另一优选例中，所述碱选自下组：碳酸钠、氢化钠、氢氧化钠、叔丁醇钠、氢氧化锂、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙胺、DBU、DMAP、吗啉、吡啶、或其组合。
在另一优选例中，所述酰胺缩合剂选自下组：HATU、HBTU、HCTU、PyBop、Bop、TBTU、TSTU、TNTU、EDCI、DCC、或其组合。
在另一优选例中，所述反应温度为0-100℃，较佳地，0-60℃，更佳地，10-40℃。
在另一优选例中，所述反应时间为2-24h，较佳地，4-12h，更佳地，5-8h。
本发明第五方面提供了一种体外对PPARγ进行处理的方法，包括步骤：
(a)将式I化合物与所述的PPARγ进行接触，从而使得所述式I化合物结合 于PPARγ。
在另一优选例中，所述式I化合物对PPARγ产生弱激活作用。
在另一优选例中，在步骤(a)中，所述的PPARγ位于活的表达PPARγ的细胞(如哺乳动物细胞)上。
在另一优选例中，所述方法为非治疗非诊断性的。
本发明第六方面提供了一种用于治疗和/或预防受PPARγ激动剂调节的疾病的方法，所述方法包括：
向所需对象施用本发明第一方面所述的式I化合物或本发明第三方面所述的药物组合物。
在另一优选例中，所述疾病选自下组：糖尿病、非胰岛素依赖型糖尿病、升高的血压、提高的脂质和胆固醇水平的代谢综合症、或其组合。
在另一优选例中，所述对象包括人。
在另一优选例中，所述对象包括非人哺乳动物。
在另一优选例中，所述非人哺乳动物包括啮齿动物，如小鼠、大鼠。
在另一优选例中，施用剂量为10-10000mg/kg/天，较佳地，500-10000mg/kg/天，更佳地，1000-10000mg/kg/天。
在另一优选例中，施用频率为1-5次/天，较佳地，1-2次/天。
在另一优选例中，施用包括一个或多个周期，各周期为2-30天，较佳地，3-7天。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，合成了一系列的N-苄基-5/6-甲酰氨基吲哚-2-羧酸衍生物，所述的化合物既能够保留它的胰岛素增敏性，又能降低PPARγ完全激动剂导致的副作用，因此能够被作PPARγ选择调控剂。在此基础上，本发明人完成了本发明。
基团定义
如本文所用，术语“取代或未取代的”指所述基团可以是未取代的，或者所述基团中的H被一个或多个(如1-10个，较佳地1-5个，更佳地1-3个，最佳地1-2个)取代基所取代。
如本文所用，所述的“取代”或“取代的”指所述基团具有一个或多个(较佳地1-6个，更佳地1-3个)选自下组的取代基：卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基。
如本文所用，术语“C1-C10烷基”是指具有1-10个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团；“C1-C3烷基”是指具有1-3个碳原子的直链或支链烷基，例如甲基、乙基、正丙基、异丙基、或类似基团。
如本文所用，术语“C3-C10环烷基”指具有3-10个碳原子的环状烷基，例如环丙基、环丁基、环戊基、环己基、环庚基、或类似基团。
如本文所用，术语“C1-C10亚烷基”指具有1-10个碳原子的二价烃基，例如，亚甲基、亚乙基、亚丙基、亚丁基、或类似基团。
如本文所用，术语“C2-C8链烯基”指具有2-8个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用，术语“C2-C8链炔基”是指具有2-8个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、或类似基团。
如本文所用，术语“C1-C10烷基-羰基”指具有“-CO-(C1-C10烷基)”结构的基团，例如甲基酰基、乙基酰基、丙基酰基、异丙基酰基、丁基酰基、异丁基酰基、仲丁基酰基、叔丁基酰基、或类似基团。
如本文所用，术语“C1-C10烷氧基-羰基”指具有(C1-C10烷基)-O-CO-结构的基团，例如CH3-O-CO-、C2H5-O-CO-、C3H8-O-CO-、(CH3)2CH-O-CO-、nC4H9-O-CO-、tC4H9-O-CO-、或类似基团。
如本文所用，术语“C5-C20芳基”指5至20个(较佳5-14个)碳原子的单价芳香族碳环基团，它具有单环(如苯基)或稠环(如萘基或蒽基)，如果连接点在芳香碳原上，稠环可能是非芳香性的(如2-苯并噁唑酮，2H-1,4-苯并噁嗪-3(4H)-酮-7-基等)。优选的芳基包括苯基和萘基。该术语包括取代或未取代的形式，其中取代基的定义如上。
如本文所用，术语“C3-C20杂芳基”指具有3至20个碳原子和1至4个(优选1-3个)选自氧、氮和硫的杂原子的芳香基团，这样的杂芳基可以是单环的(如吡啶基或呋喃基)或稠环(如吲嗪基(indolizinyl)或苯并噻吩基)，其中，所述稠环可以是非芳香性的和/或含有一个杂原子，只要连接点是通过芳香性杂芳基的原子。优选地杂芳基包括吡啶基、吡咯基、吲哚基、噻吩基和呋喃基。该术语包括取代或未取代的杂芳基。
如本文所用，术语“C5-C20杂环基”指饱和的、部分饱和的或不饱和的基团(但不是芳香性的)，具有单环或稠环(包括桥环体系和螺环体系，具有5至20个碳原子和1至4个选自氮、硫或氧的杂原子，在稠环体系中，一个或多个环可以是环烷基、芳基或杂芳基，只要连接点通过非芳香性环。该术语包括取代或未取代的杂环基。
如本文所用，术语“卤素”是指氟、氯、溴、或碘，优选氟、氯和溴。
如本文所用，术语“卤代的”指被相同或不同的一个或多个上述卤原子取代的基团，可以部分卤代或全部卤代，例如三氟甲基、五氟乙基、七氟异丙基、或类似基团。
如本文所用，术语“C1-C3卤代烷基”是指氢被1个或1个以上的卤素取代的具有1-3个碳原子的直链或支链烷基，例如，卤代甲基、卤代乙基、卤代丙基、卤代异丙基、或类似基团。
本发明的化合物可以含有一个或多个不对称中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物 和纯或部分纯的化合物包括在本发明的范围之内。本发明包括化合物的所有异构形式。
本文中，术语“室温”指4-40℃，优选为20-25℃。
本发明化合物
如本文所用，“本发明化合物”、“式I化合物”、“N-苄基-5/6-甲酰氨基吲哚-2-羧酸类衍生物”可互换使用，指通式I(或式I-1)化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐。
典型地，本发明提供通式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐。
Figure PCTCN2016103810-appb-000019
式中，
各R0各自独立地选自下组：
Figure PCTCN2016103810-appb-000020
卤素、取代或未取代的C1-C8烷基、取代或未取代的C2-C8链烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C8环烷基、-OH、-NO2、-CN；其中，所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
并且至少一个R0为
Figure PCTCN2016103810-appb-000021
n为1-4的正整数；
R1选自下组：取代或未取代的C1-C10烷基；取代或未取代的C3-C10环烷基；Z-Y-和R5(R6)N-；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基；
R5和R6各自独立地为氢、取代或未取代的C1-C10烷基、取代或未取代的C1-C10烷基-羰基、取代或未取代的C1-C10烷氧基-羰基、或取代或未取代的C5-C20芳基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基；
Z选自下组：取代或未取代的C5-C20芳基、取代或未取代的C3-C20杂芳基、和取代或未取代的5-20元杂环基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
Y为无、取代或未取代的C1-10亚烷基，其中取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、和C2-C4链烯基；
R2选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C3-C8环烷基、-NO2、-CN、-OH、取代或未取代的C1-C6烷基-羰基、或取代或未取代的C1-C6烷氧基羰基；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基；
R3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C20芳基、R9-C(O)-、氰基、甲酰胺、和四氮唑；其中取代指 具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基。
每个R4各自独立地选自下组：卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C2-C6炔基、取代或未取代的C3-C8环烷基、取代或未取代的C5-C20的芳基、-NO2、-CN、-OH、R9-C(O)-、R10(R11)N-、或C5-C20芳基-C(O)-N(R10)R11-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基。
R9选自下组：羟基、巯基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基和R10(R11)N-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基。
R10和R11各自独立地为氢、C1-C10烷基或C1-C10卤代烷基；以及
m为0-5的整数。
在另一优选例中，m为1-5的整数。
在另一优选例中，n为1-2的正整数。
在另一优选例中，1或2个R0为
Figure PCTCN2016103810-appb-000022
在另一优选例中，所述通式I化合物为：
Figure PCTCN2016103810-appb-000023
式I-1中，R1、R2、R3、R4的定义如上所述。
在本发明所述的化合物有立体异构体存在的情况下，本发明包括化合物的所有立体异构体。
在本发明所述的化合物有互变异构体存在的情况下，本发明包括化合物的所有互变异构体。
本发明还包括所述化合物中的任何一个或多个氢原子被其稳定同位素氘取代而产生的氘代化合物。
本发明化合物的制备方法
本发明通式(I)所示化合物可通过如本文所述的方法制得，然而制备方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面及实施例的表述。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度0～100℃(较佳地，0-60℃，更佳地10～40℃)下进行。反应时间通常为2～24h，较佳地为4～12h。
反应中所用的碱包括(但并不限于)：氢化钠、氢氧化钠、叔丁醇钠、氢氧化钠、氢氧化锂、碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、二异丙基乙 胺、DBU、DMAP、吗啉、或吡啶。
反应中所用的酰胺缩合剂包括(但不限于)：HATU、HBTU、HCTU、PyBop、Bop、TBTU、TSTU、TNTU、EDCI、或DCC。
反应中所用的卤化试剂包括(但并不限于)：NBS、NCS、NIS、1-氟-2,6-二氯吡啶三氟甲磺酸盐、或1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸盐)。
较佳地，本发明式I化合物可以通过以下方案及实施例中所述的示例性方法以及本领域技术人员所用的相关公开文献操作完成。
典型地，本发明的式I-1化合物的制备方法可包括(但不限于)如下流程。
方案I
Figure PCTCN2016103810-appb-000024
制备式I-1化合物
步骤1：在碱(如二异丙基乙胺，DMAP，三乙胺)的存在下，在酰胺缩合剂(如HATU，HBTU，HCTU)的作用下，在惰性溶剂(如DCM，DMF)中，化合物I1-1与取代苄胺在一定温度(如0-60℃)下进行缩合反应，从而得到化合物I1-2。
步骤2：在碱(如碳酸钠，氢化钠)的作用下，在惰性溶剂(如DMF)中，化合物I1-2与化合物取代苄溴在一定温度(如0-60℃)下反应，从而得到化合物I1-3。
步骤3：在卤化试剂(如NBS，NCS)作用下，在惰性溶剂(如DCM，DMF)中，化合物I1-3在一定温度(如0-60℃)下发生卤代反应，从而得到化合物I1-4。
步骤4：在碱(如氢氧化钠，氢氧化锂，氢氧化钾)的作用下，在惰性溶剂(如水，甲醇，THF)中，化合物I1-4在一定温度(如0-100℃)下进行水解反应，从而得到化合物I-1。
方案I中，在步骤1、2、3中(即在化合物式I1-1、I1-2、I1-3中)，R2为H，在步骤4中(即在化合物式I1-4、式I-1中)，R2为卤素；在化合物I1-1、I1-2、I1-3、I1-4中，R3为R9-C(O)-且R9为取代或未取代的C1-C6烷氧基；在化合物式I-1中，R3为R9-C(O)-且R9为羟基；R1、R4的定义如说明书中所述。
药物组合物
本发明还提供了一种药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的通式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐。
本发明所述的“活性成分”和药物组合物可用作PPARγ选择性调控剂。在另一优选例中，用于制备治疗和/或预防受PPARγ激动剂调节的疾病的药物。在另一优选例中，所述疾病选自下组：糖尿病、非胰岛素依赖型糖尿病、升高的血压、提高的脂质和胆固醇水平的代谢综合症、或其组合。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
本发明优选实施例的化合物可以作为单独活性药剂给药，也可以与一个或多个其它用于治疗糖尿病的试剂组合使用。本发明优选实施例的化合物与已知的治疗剂组合使用也是有效的，目前已知的化合物和其它治疗糖尿病的治疗剂的组合在优选实施例范围之内。基于药物的特殊性质和所涉及的疾病，本领域普通技术人员能够辨别有效的药剂组合。这种治疗糖尿病的治疗剂包括(但不限于)如下：文迪亚、艾可托等。优选实施例的化合物与治疗糖尿病的治疗剂同时施用时也有效。
通常，优选实施例的化合物将以治疗有效量、通过具有类似作用的药剂的任意一种可接受的模式施用。优选实施例的化合物(即活性成分)的实际用量根据多个因素确定，如待治疗疾病的严重程度、患者的年龄和相对健康程度、被使用化合物的效力、施用的路径和形式，以及其他因素。该药物可一天施用多次，优选地，每天一次或两次。所有这些因素都在主治医生的考虑范围内。
在本发明中，治疗有效剂量通常可以是对患者一次性施用或分次施用的每日总剂量，例如，每日约0.001至约1000毫克/公斤体重，优选地，每日约1.0至约30毫克/千克体重。单位剂量组合物(Dosage unit composition)可包含其剂量因数以形成每日剂量。剂型的选择取决于各种因素，例如给药模式和药物物质的生物利用度。通常，优选实施例的化合物可作为药物组合物通过以下任意一种路线给药：口服、全身给药(如透皮、鼻内或通过栓剂)、或肠外给药(如肌内、静脉内或皮下)。优选的给药方式为口服，可根据苦的程度调节方便的日剂量。组合物可采取的形式为片剂、丸剂、胶囊、半固体、粉剂、缓释制剂、溶液、悬浮液、酏剂、气雾剂或任何其他适当的组合物。另一种优选的施用优选实施例化合物的方式为吸入。这是一种将治疗剂直接运送给呼吸道的有效方法(参见，如美国专利号5,607,915)。
合适的药学上可接受的载体或赋形剂包括：如处理剂和药物运送改性剂和促进剂，诸如磷酸钙、硬脂酸镁、滑石、单糖、二糖、淀粉、明胶、纤维素、 甲基纤维素钠、羧甲基纤维素、葡萄糖、羟丙基-B-环糊精、聚乙烯吡咯烷酮、低熔点蜡、离子交换树脂等，及其任意两种或多种的组合。液体和半固体的赋形剂可以选自甘油、丙二醇、水、乙醇和各种油，包括石油、动物油、植物油或合成来源，如花生油、豆油、矿物油、芝麻油等。优选的液体载体，特别是用于可注射溶液的载体，包括水、盐水、葡萄糖水性溶液和乙二醇。其它适宜的药学上可接受的赋形剂在《雷明顿药物科学》(Remington’s Pharmaceutical Sciences),Mack Pub.Co.,新泽西(1991)有描述，通过引用纳入本文。
如本文所用，术语“药学上可接受的盐”是指通式I化合物的非毒性酸或碱土金属盐。这些盐可在最终分离和纯化通式I化合物时原位制得、或分别将合适的有机或无机酸或碱与碱性或酸性官能团反应制得。代表性的盐包括，但不限于：乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡萄糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘基磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、硫氰酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一烷酸盐。此外，含氮的碱性基团可被如下试剂季铵盐化：烷基卤化物，如甲基、乙基、丙基、丁基的氯化物、溴化物和碘化物；二烷基硫酸盐，如二甲基、二乙基、二丁基和二戊基硫酸酯；长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物；芳烷基卤化物如苄基和苯乙基溴化物等。由此得到水溶性或油溶性或可分散产品。可被用于形成药学上可接受的酸加成盐的酸的例子包括如盐酸、硫酸、磷酸的无机酸，和如草酸、马来酸、甲磺酸、琥珀酸、柠檬酸的有机酸。碱加成盐可在最终分离和纯化通式I的化合物时原位制得、或使羧酸部分分别与合适的碱(如药学上可接受的金属阳离子的氢氧化物，碳酸盐或碳酸氢盐)或氨、或有机伯、仲或叔胺反应制得。药学上可接受的盐包括，但不限于，基于碱金属和碱土金属的阳离子，如钠、锂、钾、钙、镁、铝的盐等，以及无毒的铵、季铵和胺阳离子，包括，但不限于：铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。其它代表性的用于形成碱加成盐的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
如本文所用，术语“药学上可接受的前药”是指那些优选实施例的化合物的前药，在体内迅速转化为上述通式所示的母体化合物的化合物，例如在血液中水解。在“T.Higuchi和V.Stella，作为新型运送系统的前药(Pro-drugs as Novel Delivery Systems)，A.C.S.15Symposium Series的14卷”和“Edward B.Roche编，药物设计中的生物可逆载体(Bioreversible Carriers in Drug Design)，美国药学协会和Pergamon出版社，1987年”中提供了完整的讨论，这两者都引入本文作为参考。
本发明化合物的用途
本发明还提供了所述的式I化合物的用途。
在本发明的一个优选例中，所述式I化合物用于制备PPARγ选择性调控剂；所述的PPARγ选择性调控剂包括：有效量的的式I化合物或其药学上可接受的 盐。
在本发明的一个优选例中，所述式I化合物用于制备治疗和/或预防受PPARγ激动剂调节的疾病的药物组合物。
在一个优选例中，所述疾病包括(但不限于)：糖尿病、非胰岛素依赖型糖尿病、升高的血压、提高的脂质和胆固醇水平的代谢综合症。
在一个优选例中，所述式I化合物具有选自下组的一个或多个特性：
(a)对PPARγ弱激活能力；
(b)对PPARγ强结合能力；
(c)弱的前脂肪细胞3T3-L1向脂肪细胞转化的能力。
在另一优选例中，所述“弱激活能力”指测试组测量值M1与对照组参比值M0之比(M1/M0)＜0.75，较佳地＜0.6，更佳地＜0.5，更佳地＜0.4，最佳地＜0.3。
在另一优选例中，所述“强结合能力”指测试组测量值C1与对照组参比值C0之比(C1/C0)＞0.9，较佳地＞1，更佳地＞1.15，更佳地＞1.25，最佳地＞1.35。
在另一优选例中，所述“弱的前脂肪细胞3T3-L1向脂肪细胞转化的能力”指测试组测量值T1与对照组参比值T0之比(T1/T0)＜0.5，较佳地＜0.25，更佳地＜0.1，更佳地＜0.06。
本发明的主要优点包括：
(1)提供一种结构新颖的通式I化合物；
(2)本发明的化合物可以作为高效的PPARγ选择调控剂；
(3)合成方法温和，操作简单易行，收率较高，易于衍生化，适合工业放大量生产；
(4)既能够保留它的胰岛素增敏性，又能降低PPARγ完全激动剂导致的副作用。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
制备实施例
所用仪器及主要实验材料如下：
4-肼基苯甲酸盐酸盐、丙酮酸甲酯、苄溴、苄胺、4-甲氨基吡啶、苯胺等所涉及化学试剂购于sigma公司。石油醚、乙酸乙酯等溶剂购于上海国药集团，所有溶剂均为分析纯。BrukerAM-400型和Varian Mercury plus-400型核磁共振仪，及200-300目柱层析硅胶(青岛海洋化工厂)，HSGF254TLC板(烟台市化工研究院)。
实施例1 5-(苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(1)的制备
Figure PCTCN2016103810-appb-000025
向反应瓶中加入5-羧基吲哚-2-甲酸甲酯(2.0mmol)、Pybop(1H-苯并三唑-1-基氧三吡咯烷基鏻六氟磷酸盐，2.4mmol)、苄胺(2.2mmol)、二异丙基乙胺(3.0mmol)和DMF(N,N-二甲基甲酰胺)(10mL)，室温搅拌4h，TLC检测反应完全。向反应瓶中加入水(50ml)，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得5-(苄胺甲酰基)-1H-吲哚-2-羧酸甲酯41(500mg，产率83％)。
Figure PCTCN2016103810-appb-000026
向反应瓶中加入5-(苄胺甲酰基)-1H-吲哚-2-羧酸甲酯(0.2mmol)、NaH(0.22mmol)和DMF(N,N-二甲基甲酰胺)(2mL)，冰浴下搅拌30min后加入3-氟-4-氯苄溴(0.22mmol)，室温搅拌，TLC检测反应完全。乙酸乙酯萃取，水和饱和NaCl分别洗涤，干燥浓缩得粗产品，硅胶柱层析得5-(苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(1)(75mg，产率83％)。
1H NMR(400MHz,DMSO)δ:9.01(t,J＝5.9Hz,1H),8.35(s,1H),7.88(d,J＝8.8Hz,1H),7.67(d,J＝8.8Hz,1H),7.48(dd,J＝14.7,6.6Hz,2H),7.36–7.17(m,5H),7.11(d,J＝9.0Hz,1H),6.78(d,J＝8.5Hz,1H),5.88(s,2H),4.49(d,J＝5.9Hz,2H),3.83(s,3H).
实施例2 5-(苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(2)的制备
Figure PCTCN2016103810-appb-000027
向所得5-(苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(0.10mmol) 中加入4mol/L的NaOH溶液(8mL)，回流搅拌，TLC检测反应完全。向反应瓶中加入1mol/L盐酸溶液调pH为酸性，乙酸乙酯萃取3次，合并有机相、饱和NaCl洗有机相，无水硫酸钠干燥，旋干得粗产品。再经硅胶柱层析得水解产物5-(苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(2)(40mg)，产率92％。
1H NMR(400MHz,DMSO)δ:9.05(s,1H),8.29(s,1H),7.80(d,J＝8.5Hz,1H),7.55(d,J＝8.8Hz,1H),7.45(t,J＝8.1Hz,1H),7.41–7.18(m,6H),7.12(d,J＝9.4Hz,1H),6.84(d,J＝8.4Hz,1H),5.96(s,2H),4.47(d,J＝5.9Hz,2H).
实施例3 N5-苄基-1-(4-氯-3-氟苄基)-1H-吲哚-2,5-二甲酰胺(3)的制备
Figure PCTCN2016103810-appb-000028
向反应瓶中加入2(0.05mmol)、Pybop(0.06mmol)、氯化铵(0.10mmol)、二异丙基乙胺(0.20mmol)和DMF(1mL)，室温搅拌4h，TLC检测反应完全。向反应瓶中加入水(50ml)，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得3(20mg，产率91％)。
1H NMR(400MHz,DMSO)δ:8.97(t,J＝6.0Hz,1H),8.27(d,J＝1.1Hz,1H),8.14(s,1H),7.80(dd,J＝8.8,1.6Hz,1H),7.58(d,J＝8.8Hz,1H),7.53–7.41(m,2H),7.37–7.19(m,6H),7.10(dd,J＝10.3,1.7Hz,1H),6.85(dd,J＝8.3,1.4Hz,1H),5.91(s,2H),4.49(d,J＝5.9Hz,2H).
实施例4 N5-苄基-1-(4-氯-3-氟苄基)-N2-甲基-1H-吲哚-2,5-二甲酰胺(4)的制备
Figure PCTCN2016103810-appb-000029
用甲胺盐酸盐代替氯化铵按照制备3的方法制备4(产率85％)。
1H NMR(400MHz,DMSO)δ:9.09(t,J＝6.0Hz,1H),8.79(d,J＝4.6Hz,1H),8.30(s,1H),7.81(dd,J＝8.8,1.4Hz,1H),7.56(d,J＝8.8Hz,1H),7.46(t,J＝8.1Hz,1H),7.42–7.17(m,6H),7.11(dd,J＝10.4,1.6Hz,1H),6.85(d,J＝7.2Hz,1H),5.89(s,2H),4.48(d,J＝5.9Hz,2H),2.74(t,J＝8.8Hz,3H).
实施例5 N5-苄基-1-(4-氯-3-氟苄基)-N2,N2-二甲基-1H-吲哚-2,5-二甲酰胺(5)的制备
Figure PCTCN2016103810-appb-000030
用二甲胺盐酸盐代替氯化铵按照制备3的方法制备5(产率80％)。
1H NMR(400MHz,DMSO)δ:9.07(t,J＝5.9Hz,1H),8.27(s,1H),7.79(d,J＝8.6Hz,1H),7.59–7.42(m,2H),7.38–7.10(m,6H),6.91–6.88(m,2H),5.52(s,2H),4.48(d,J＝5.9Hz,2H),2.99(s,6H).
实施例6 5-(苄胺甲酰基)-3-氯-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(6)的制备
Figure PCTCN2016103810-appb-000031
将1(0.1mmol)溶于DMF(1ml)，冰水浴下加入NCS(N-氯代丁二酰亚胺，0.1mmol)，升至室温搅拌至原料转化完全，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得3(34mg，产率70％)。
1H NMR(400MHz,CDCl3)δ:8.20(d,J＝1.2Hz,1H),7.92(dd,J＝8.8,1.7Hz,1H),7.42–7.30(m,7H),6.80(dd,J＝15.1,5.3Hz,2H),6.55(s,1H),5.78(s,2H),4.71(d,J＝5.6Hz,2H),3.96(s,3H).
实施例7 5-(苄胺甲酰基)-3-氯-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(7)的制备
Figure PCTCN2016103810-appb-000032
以6为原料按照制备2的方法制备7(产率94％)。
1H NMR(400MHz,DMSO)δ:9.17(t,J＝5.9Hz,1H),8.33(s,1H),8.00–7.93(m,1H),7.73(d,J＝8.9Hz,1H),7.50(dd,J＝15.7,7.7Hz,1H),7.39–7.21(m,5H),7.14(t,J＝17.8Hz,1H),6.80(d,J＝8.2Hz,1H),5.88(s,2H),4.52(d,J＝5.8Hz,2H).
实施例8 N5-苄基-3-氯-1-(4-氯-3-氟苄基)-1H-吲哚-2,5-二甲酰胺(8)的制备
Figure PCTCN2016103810-appb-000033
以7为原料按照制备3的方法制备8(产率74％)。
1H NMR(400MHz,DMSO)δ:9.13(t,J＝5.9Hz,1H),8.26(d,J＝1.0Hz,1H),8.09(d,J＝4.7Hz,2H),7.90(dd,J＝8.8,1.5Hz,1H),7.69(d,J＝8.8Hz,1H),7.51(t,J＝8.1Hz,1H),7.37–7.22(m,5H),7.17(dd,J＝10.3,1.6Hz,1H),6.96(dd,J＝8.3,1.1Hz,1H),5.70(s,2H),4.52(d,J＝5.9Hz,2H).
实施例9 5-(苄胺甲酰基)-3-氟-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(9)的制备
Figure PCTCN2016103810-appb-000034
将1(0.1mmol)溶于DCM(1ml)，冰水浴下加入2,6-二氯-1-氟吡啶三氟甲磺酸盐(0.15mmol)，升至室温搅拌至原料转化完全，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得9(22mg，产率47％)。
1H NMR(400MHz,DMSO)δ:9.12(t,J＝5.9Hz,1H),8.36(t,J＝2.8Hz,1H),7.95(dd,J＝9.0,1.6Hz,1H),7.73(d,J＝9.0Hz,1H),7.47(t,J＝8.1Hz,1H),7.34–7.21(m,6H),7.13(dd,J＝10.3,1.9Hz,1H),6.80(d,J＝8.3Hz,1H),5.80(s,2H),4.49(d,J＝5.9Hz,2H),3.85(s,3H).
实施例10 5-(苄胺甲酰基)-3-氟-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(10)的制备
Figure PCTCN2016103810-appb-000035
以9为原料按照制备2的方法制备10(产率91％)。
1H NMR(400MHz,DMSO)δ:9.10(t,J＝5.9Hz,1H),8.34(d,J＝0.8Hz,1H),7.92(dd,J＝9.0,1.5Hz,1H),7.69(d,J＝9.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.36–7.19(m,5H),7.12(dd,J＝10.3,1.6Hz,1H),6.78(dd,J＝8.2,1.2Hz,1H),5.82(s,2H),4.49(d,J＝5.8Hz,2H).
实施例11 N5-苄基-3-氟-1-(4-氯-3-氟苄基)-1H-吲哚-2,5-二甲酰胺(11)的制备
Figure PCTCN2016103810-appb-000036
以10为原料按照制备3的方法制备11(产率81％)。
1H NMR(400MHz,DMSO)δ:9.08(t,J＝6.0Hz,1H),8.31(d,J＝1.1Hz,1H),7.92–7.65(m,4H),7.48(t,J＝8.1Hz,1H),7.34–7.20(m,5H),7.13(dd,J＝10.3,1.9Hz,1H),6.89(dd,J＝8.3,1.4Hz,1H),5.79(s,2H),4.51(d,J＝5.9Hz,2H).
实施例12 5-(3-氟苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(12)的制备
Figure PCTCN2016103810-appb-000037
向反应瓶中加入5-羧基吲哚-2-甲酸甲酯(2.0mmol)、Pybop(1H-苯并三唑-1-基氧三吡咯烷基鏻六氟磷酸盐，2.4mmol)、3-氟苄胺(2.2mmol)、二异丙基乙胺(3.0mmol)和DMF(N,N-二甲基甲酰胺)(10mL)，室温搅拌4h，TLC检测反应完全。向反应瓶中加入水(50ml)，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得5-(3-氟苄胺甲酰基)-1H-吲哚-2-羧酸甲酯42(480mg，产率77％)。
1H NMR(400MHz,DMSO)δ:12.19(s,1H),8.98(t,J＝5.7Hz,1H),8.31(s,1H),7.83(dd,J＝8.7,1.4Hz,1H),7.50(s,1H),7.39(dd,J＝8.0,6.4Hz,1H),7.36–7.28(m,2H),7.23–7.13(m,2H),4.54(d,J＝5.7Hz,2H),3.90(s,3H).
Figure PCTCN2016103810-appb-000038
向反应瓶中加入5-(3-氟苄胺甲酰基)-1H-吲哚-2-羧酸甲酯(0.1mmol)、NaH(0.2mmol)和DMF(N,N-二甲基甲酰胺)(2mL)，冰浴下搅拌30min后加入3-氟-4-氯苄溴(0.11mmol)，室温搅拌，TLC检测反应完全。乙酸乙酯萃取，水和饱和NaCl分别洗涤，干燥浓缩得粗产品，硅胶柱层析得5-(3-氟苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸甲酯(43)(38mg，产率83％)。
1H NMR(400MHz,CDCl3)δ:8.24(d,J＝1.2Hz,1H),7.82(dd,J＝8.8,1.6Hz,1H),7.59–7.42(m,1H),7.44–7.24(m,4H),7.17(d,J＝7.6Hz,1H),7.10(d,J＝9.6Hz,1H),7.01(td,J＝8.5,2.4Hz,1H),6.79(t,J＝9.6Hz,2H),6.53(s,1H),5.83(s,2H),4.70(d,J＝5.7Hz,2H),3.94(d,J＝21.3Hz,3H).
Figure PCTCN2016103810-appb-000039
以4为原料按照制备A2的方法制备A12(产率85％)。1H NMR(400MHz,DMSO)δ:8.97(t,J＝5.9Hz,1H),8.24(s,1H),7.76(dd,J＝8.9,1.4Hz,1H),7.55(d,J＝8.9Hz,1H),7.43–7.35(m,2H),7.26(dd,J＝14.1,7.8Hz,1H),7.14–6.90(m,4H),6.68(d,J＝8.3Hz,1H),5.80(s,2H),4.40(d,J＝5.9Hz,2H).
实施例13 5-(2-氟苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(13)的制备
Figure PCTCN2016103810-appb-000040
以2-氟苄胺代替3-氟苄胺照制备12的方法制备13(产率41％)。1H NMR(400MHz,DMSO)δ:9.00(t,J＝5.8Hz,1H),8.35(s,1H),7.87(dd,J＝8.9,1.4Hz,1H),7.66(d,J＝8.9Hz,1H),7.48(dd,J＝13.4,5.2Hz,2H),7.39(t,J＝7.5Hz,1H),7.33–7.28(m,1H),7.21–7.11(m,3H),6.79(d,J＝8.4Hz,1H),5.91(s,2H),4.54(d,J＝5.7Hz,2H).
实施例14 5-(4-氟苄胺甲酰基)-1-(4-氯-3-氟苄基)-1H-吲哚-2-羧酸(14)的制备
Figure PCTCN2016103810-appb-000041
以4-氟苄胺代替3-氟苄胺照制备12的方法制备13(产率45％)。1H NMR(400MHz,MeOD)δ:8.29(s,1H),7.84(d,J＝8.7Hz,1H),7.51(d,J＝12.7Hz,2H),7.45–7.30(m,3H),7.06(t,J＝8.3Hz,2H),6.92(d,J＝10.1Hz,1H),6.84(d,J＝8.3Hz,1H),5.90(s,2H),4.59(s,2H).
实施例15 5-(苄胺甲酰基)-1-(3-氯-4-氟苄基)-1H-吲哚-2-羧酸(15)的制备
Figure PCTCN2016103810-appb-000042
向反应瓶中加入5-(3-氟苄胺甲酰基)-1H-吲哚-2-羧酸甲酯(0.1mmol)、NaH(0.2mmol)和DMF(N,N-二甲基甲酰胺)(2mL)，冰浴下搅拌30min后加入3-氯-4-氟苄溴(0.11mmol)，室温搅拌，TLC检测反应完全。乙酸乙酯萃取，水和饱和NaCl分别洗涤，干燥浓缩得粗产品，硅胶柱层析得5-(苄胺甲酰基)-1-(3-氯-4-氟苄基)-1H-吲哚-2-羧酸甲酯(45)(39mg，产率86％)。
1H NMR(400MHz,CDCl3)δ:8.22(s,1H),7.85(t,J＝20.9Hz,1H),7.52–7.31(m,7H),7.17–6.99(m,2H),6.96–6.87(m,1H),6.54(s,1H),5.80(s,2H),4.70(d,J＝5.2Hz,2H),3.91(s,3H).
以45为原料按照制备2的方法制备15(产率88％)。1H NMR(400MHz,MeOD)δ:8.30(s,1H),7.86(s,1H),7.68–6.91(m,10H),5.89(s,2H),4.63(s,2H).
实施例16 5-(苄胺甲酰基)-1-(3,4-二氯苄基)-1H-吲哚-2-羧酸(16)的制备
Figure PCTCN2016103810-appb-000043
以3,4-二氯苄溴代替3-氯-4-氟苄溴按照制备15的方法制备16(产率61％)。1H NMR(400MHz,MeOD)δ:8.29(s,1H),7.85(d,J＝8.0Hz,1H),7.58–7.18(m,8H),6.96(d,J＝7.9Hz,1H),5.90(s,2H),4.62(s,2H).
实施例17 5-(苄胺甲酰基)-1-(3,4-二氟苄基)-1H-吲哚-2-羧酸(17)的制备
Figure PCTCN2016103810-appb-000044
以3,4-二氟苄溴代替3-氯-4-氟苄溴按照制备15的方法制备17(产率54％)。1H NMR(400MHz,MeOD)δ:8.24(d,J＝1.2Hz,1H),7.79(dd,J＝8.8,1.7Hz,1H),7.48(d,J＝8.9Hz,1H),7.43(s,1H),7.37–7.27(m,4H),7.20(t,J＝7.1Hz,1H),7.09(m,1H),6.93(m,1H),6.88–6.74(m,1H),5.85(s,2H),4.57(s,2H).
实施例18 5-(苄胺甲酰基)-1-(2,5-二氟苄基)-1H-吲哚-2-羧酸(18)的制备
Figure PCTCN2016103810-appb-000045
以2,5-二氟苄溴代替3-氯-4-氟苄溴按照制备15的方法制备17(产率66％)。1H NMR(400MHz,MeOD)δ:8.30(d,J＝1.2Hz,1H),7.85(dd,J＝8.8,1.6Hz,1H),7.55–7.46(m,2H),7.42–7.29(m,4H),7.25(t,J＝7.2Hz,1H),7.14(m,1H),6.97(m,1H),6.23(m,1H),5.95(s,2H),4.62(s,2H).
实施例19 5-(苄胺甲酰基)-1-(2,5-二氟苄基)-1H-吲哚-2-羧酸(19)的制备
Figure PCTCN2016103810-appb-000046
以3-氟-4-溴苄溴代替3-氯-4-氟苄溴按照制备15的方法制备19(产率45％)。1H NMR(400MHz,MeOD)δ:8.29(d,J＝1.5Hz,1H),7.84(dd,J＝8.8,1.7Hz,1H),7.54–7.45(m,3H),7.35(m,4H),7.25(m,1H),6.89(dd,J＝9.7,1.9Hz,1H),6.77(dd,J＝8.3,1.5Hz,1H),5.88(s,2H),4.61(s,2H).
实施例20 5-(苄胺甲酰基)-1-(2-氟苄基)-1H-吲哚-2-羧酸(20)的制备
Figure PCTCN2016103810-appb-000047
以2-氟苄溴代替3-氯-4-氟苄溴按照制备15的方法制备20(产率49％)。1H NMR(400MHz,MeOD)δ:8.30(s,1H),7.83(d,J＝7.5Hz,1H),7.56–7.07(m,9H),6.96(t,J＝7.4Hz,1H),6.56(t,J＝7.3Hz,1H),6.00(s,2H),4.62(s,2H).
实施例21 5-(苄胺甲酰基)-1-(3-氟苄基)-1H-吲哚-2-羧酸(21)的制备
Figure PCTCN2016103810-appb-000048
以3-氟苄溴代替3-氯-4-氟苄溴按照制备15的方法制备21(产率48％)。1H NMR(400MHz,MeOD)δ:8.28(d,J＝1.2Hz,1H),7.82(dd,J＝8.9,1.6Hz,1H),7.49(d,J＝6.9Hz,2H),7.42–7.20(m,6H),6.93(m,1H),6.85(d,J＝7.7Hz,1H),6.75(d,J＝9.9Hz,1H),5.92(s,2H),4.61(s,2H).
实施例22 5-(苄胺甲酰基)-1-(4-氟苄基)-1H-吲哚-2-羧酸(22)的制备
Figure PCTCN2016103810-appb-000049
以4-氟苄溴代替3-氯-4-氟苄溴按照制备15的方法制备22(产率48％)。1H NMR(400MHz,MeOD)δ:8.27(s,1H),7.81(s,1H),7.61–6.83(m,10H),5.88(s,2H),4.60(s,2H).
实施例23 5-(苄胺甲酰基)-1-(4-乙烯基苄基)-1H-吲哚-2-羧酸(23)的制备
Figure PCTCN2016103810-appb-000050
以4-乙烯基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备23(产率51％)。1H NMR(400MHz,MeOD)δ:8.22(d,J＝1.3Hz,1H),7.73(dd,J＝8.8,1.7Hz,1H),7.43–7.19(m,9H),7.00(d,J＝8.2Hz,2H),6.63(dd,J＝17.6,11.0Hz,1H),5.93(s,2H),5.67(dd,J＝17.6,0.8Hz,1H),5.13(dd,J＝10.9,0.8Hz,1H),4.59(s,2H).
实施例24 5-(苄胺甲酰基)-1-(4-异丙基苄基)-1H-吲哚-2-羧酸(24)的制备
Figure PCTCN2016103810-appb-000051
以4-异丙基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备24(产率71％)。1H NMR(400MHz,MeOD)δ:8.20(d,J＝1.2Hz,1H),7.71(dd,J＝8.8,1.6Hz,1H),7.49–7.19(m,7H),7.05(m,4H),5.96(s,2H),4.61(s,2H),2.87–2.72(m,1H),1.18(d,J＝6.9Hz,6H).
实施例25 5-(苄胺甲酰基)-1-(2，4-二甲基苄基)-1H-吲哚-2-羧酸(25)的制备
Figure PCTCN2016103810-appb-000052
以2，4-二甲基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备25(产率62％)。1H NMR(400MHz,DMSO)δ:8.89(s,1H),8.23(s,1H),7.69(d,J＝8.7Hz,1H),7.38–7.27(m,2H),7.26–7.17(m,4H),7.13(m,1H),6.90(s,1H),6.60(d,J＝7.8Hz,1H),5.79–5.68(m,3H),4.40(d,J＝5.5Hz,2H),2.26(s,3H),2.07(s,3H).
实施例26 5-(苄胺甲酰基)-1-(4-三氟甲氧基苄基)-1H-吲哚-2-羧酸(26)的制备
Figure PCTCN2016103810-appb-000053
以4-三氟甲氧基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备26(产率68 ％)。1H NMR(400MHz,MeOD)δ:8.28(d,J＝1.3Hz,1H),7.82(dd,J＝8.8,1.8Hz,1H),7.53–7.45(m,2H),7.35(m,4H),7.25(t,J＝7.2Hz,1H),7.19–7.11(m,4H),5.94(s,2H),4.61(s,2H).
实施例27 5-(苄胺甲酰基)-1-(4-三氟甲基苄基)-1H-吲哚-2-羧酸(27)的制备
Figure PCTCN2016103810-appb-000054
以4-三氟甲基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备27(产率64％)。1H NMR(400MHz,MeOD)δ:8.27(d,J＝1.4Hz,1H),7.81(dd,J＝8.9,1.6Hz,1H),7.49(m,4H),7.33(m,4H),7.26–7.13(m,3H),5.99(s,2H),4.60(s,2H).
实施例28 5-(苄胺甲酰基)-1-(3,4-二甲氧基苄基)-1H-吲哚-2-羧酸(28)的制备
Figure PCTCN2016103810-appb-000055
以3,4-二甲氧基苄溴代替3-氯-4-氟苄溴按照制备15的方法制备28(产率77％)。1H NMR(400MHz,MeOD)δ:8.26(d,J＝1.3Hz,1H),7.81(dd,J＝8.9,1.6Hz,1H),7.53(d,J＝8.9Hz,1H),7.45(s,1H),7.42–7.27(m,4H),7.23(t,J＝7.2Hz,1H),6.78(m,2H),6.56(dd,J＝8.3,1.8Hz,1H),5.81(d,J＝8.1Hz,2H),4.60(s,2H),3.74(s,3H),3.69(s,3H).
实施例29 5-{1-(4-氟苯基)乙胺甲酰基}-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(29)的制备
Figure PCTCN2016103810-appb-000056
以1-(4-氟苯基)乙胺代替3-氟苄胺按照制备12的方法制备29(产率48％)。1H NMR(400MHz,DMSO)δ:8.59(d,J＝7.8Hz,1H),8.12(s,1H),7.60(d,J＝8.8Hz,1H), 7.40(d,J＝8.7Hz,1H),7.35–7.24(m,3H),7.12(s,1H),6.98(t,J＝8.8Hz,3H),6.69(d,J＝8.2Hz,1H),5.82(s,2H),1.32(d,J＝7.0Hz,3H).
实施例30 5-{(S)-1-(4-氟苯基)乙胺甲酰基}-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(30)的制备
Figure PCTCN2016103810-appb-000057
以(S)-1-(4-氟苯基)乙胺代替3-氟苄胺按照制备12的方法制备30(产率43％)。1H NMR(400MHz,DMSO)δ:8.59(d,J＝7.8Hz,1H),8.12(s,1H),7.60(d,J＝8.8Hz,1H),7.40(d,J＝8.7Hz,1H),7.35–7.24(m,3H),7.12(s,1H),6.98(t,J＝8.8Hz,3H),6.69(d,J＝8.2Hz,1H),5.82(s,2H),1.32(d,J＝7.0Hz,3H).
实施例31 5-{(R)-1-(4-氟苯基)乙胺甲酰基}-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(31)的制备
Figure PCTCN2016103810-appb-000058
以(R)-1-(4-氟苯基)乙胺代替3-氟苄胺按照制备12的方法制备31(产率44％)。1H NMR(400MHz,DMSO)δ:8.59(d,J＝7.8Hz,1H),8.12(s,1H),7.60(d,J＝8.8Hz,1H),7.40(d,J＝8.7Hz,1H),7.35–7.24(m,3H),7.12(s,1H),6.98(t,J＝8.8Hz,3H),6.69(d,J＝8.2Hz,1H),5.82(s,2H),1.32(d,J＝7.0Hz,3H).
实施例32 5-(吡啶-2-甲胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(32)的制备
Figure PCTCN2016103810-appb-000059
以2-胺甲基吡啶代替3-氟苄胺按照制备12的方法制备32(产率32％)。1H NMR(400MHz,DMSO)δ:9.11(t,J＝5.8Hz,1H),8.51(d,J＝4.2Hz,1H),8.36(s,1H),7.87(d,J＝7.7Hz,1H),7.74(d,J＝6.0Hz,1H),7.64(d,J＝8.9Hz,1H),7.49(t,J＝8.1Hz,1H),7.40(s,1H),7.33(d,J＝7.9Hz,1H),7.28–7.22(m,1H),7.14(d,J＝10.3Hz,1H),6.81(d,J＝8.1Hz,1H),5.94(s,2H),4.58(d,J＝5.7Hz,2H).
实施例33 5-(吡啶-3-甲胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(33) 的制备
Figure PCTCN2016103810-appb-000060
以3-胺甲基吡啶代替3-氟苄胺按照制备12的方法制备33(产率36％)。1H NMR(400MHz,DMSO)δ:9.11(t,J＝5.9Hz,1H),8.57(s,1H),8.46(d,J＝3.5Hz,1H),8.35(s,1H),7.87(dd,J＝8.9,1.5Hz,1H),7.72(dd,J＝17.4,8.4Hz,2H),7.50(dd,J＝15.5,7.4Hz,2H),7.36(dd,J＝7.7,4.6Hz,1H),7.15–7.09(m,1H),6.79(d,J＝8.3Hz,1H),5.89(s,2H),4.52(d,J＝5.8Hz,2H),3.84(s,3H).
实施例34 5-(吡啶-4-甲胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(34)的制备
Figure PCTCN2016103810-appb-000061
以4-胺甲基吡啶代替3-氟苄胺按照制备12的方法制备34(产率36％)。1H NMR(400MHz,DMSO)δ:9.28(t,J＝5.9Hz,1H),8.67(d,J＝5.8Hz,2H),8.40(d,J＝7.4Hz,1H),7.90(dd,J＝8.8,1.4Hz,1H),7.66(dd,J＝17.2,7.4Hz,3H),7.56–7.44(m,2H),7.13(dd,J＝10.3,1.6Hz,1H),6.80(d,J＝8.3Hz,1H),5.92(s,2H),4.64(d,J＝5.7Hz,2H).
实施例35 5-(噻吩-3-甲胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(35)的制备
Figure PCTCN2016103810-appb-000062
以2-胺甲基噻吩代替3-氟苄胺按照制备12的方法制备35(产率44％)。1H NMR(400MHz,DMSO)δ:9.12(t,J＝5.8Hz,1H),8.32(s,1H),7.88–7.79(m,1H),7.65(d,J＝8.9Hz,1H),7.55–7.45(m,2H),7.41–7.37(m,1H),7.13(d,J＝10.2Hz,1H),7.07–6.95(m,2H),6.78(d,J＝8.3Hz,1H),5.91(s,2H),4.65(d,J＝5.8Hz,2H).
实施例36 5-(呋喃-3-甲胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(36)的制备
Figure PCTCN2016103810-appb-000063
以2-胺甲基呋喃代替3-氟苄胺按照制备12的方法制备36(产率41％)。1H NMR(400MHz,MeOD)δ:8.26(d,J＝1.2Hz,1H),7.82(dd,J＝8.9,1.6Hz,1H),7.49–7.38(m,3H),7.32(t,J＝7.9Hz,1H),6.94–6.80(m,2H),6.38–6.30(m,2H),5.88(s,2H),4.59(s,2H).
实施例37 2-氰基-1-(3-氟-4-氯苄基)-1H-吲哚-5-甲酰苄胺(37)的制备
Figure PCTCN2016103810-appb-000064
向反应瓶中加入2-氰基-1H-吲哚-5-羧酸甲酯(0.5mmol)、NaH(0.55mmol)和DMF(N,N-二甲基甲酰胺)(5mL)，冰浴下搅拌30min后加入3-氟-4-氯苄溴(0.55mmol)，室温搅拌，TLC检测反应完全。乙酸乙酯萃取，水和饱和NaCl分别洗涤，干燥浓缩得粗产品，硅胶柱层析得化合物46(161mg，产率94％)。1H NMR(400MHz,DMSO)δ:8.44(s,1H),7.98(d,J＝8.9Hz,1H),7.83(d,J＝8.9Hz,1H),7.74(s,1H),7.57(t,J＝8.0Hz,1H),7.28(d,J＝10.1Hz,1H),6.90(d,J＝7.8Hz,1H),5.69(s,2H),3.87(s,3H).
向所得化合物46(0.40mmol)中加入4mol/L的LiOH溶液(10mL)，回流搅拌，TLC检测反应完全。向反应瓶中加入1mol/L盐酸溶液调pH为酸性，乙酸乙酯萃取3次，合并有机相、饱和NaCl洗有机相，无水硫酸钠干燥，旋干得产品47(130mg)，产率99％。1H NMR(400MHz,DMSO)δ:12.88(brs,1H),8.41(s,1H),7.97(d,J＝8.8Hz,1H),7.80(d,J＝8.9Hz,1H),7.73(s,1H),7.57(t,J＝8.0Hz,1H),7.28(d,J＝10.0Hz,1H),6.90(d,J＝8.2Hz,1H),5.68(s,2H).
向反应瓶中加入化合物47(2.0mmol)、Pybop(1H-苯并三唑-1-基氧三吡咯烷基鏻六氟磷酸盐，2.4mmol)、苄胺(2.2mmol)、二异丙基乙胺(3.0mmol)和 DMF(N,N-二甲基甲酰胺)(10mL)，室温搅拌4h，TLC检测反应完全。向反应瓶中加入水(50ml)，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得产物37(63mg，收率76％)。1H NMR(400MHz,DMSO)δ:9.09(t,J＝5.9Hz,1H),8.35(s,1H),7.96(dd,J＝8.9,1.3Hz,1H),7.80(d,J＝8.9Hz,1H),7.71(s,1H),7.57(t,J＝8.0Hz,1H),7.32(t,J＝6.5Hz,4H),7.29–7.19(m,2H),6.90(d,J＝8.3Hz,1H),5.68(s,2H),4.51(d,J＝5.9Hz,2H).
实施例38 5-(苄胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-(1H四氮唑)(38)的制备
Figure PCTCN2016103810-appb-000065
将化合物37(1.0mmol)溶于DMF(2mL)，分别加入氯化铵(16.4mg,0.31mmol)和叠氮化钠(16.4mg,0.31mmol)，120℃下搅拌反应，TLC检测反应完全。反应冷却至室温，向反应瓶中加入水(50ml)，乙酸乙酯萃取，饱和NaCl洗涤，无水硫酸钠干燥，浓缩得粗产品，硅胶柱层析得产物38(33mg，收率72％)。
1H NMR(400MHz,DMSO)δ:9.00(s,1H),8.35(s,1H),7.83(d,J＝8.5Hz,1H),7.65(d,J＝8.7Hz,1H),7.52–7.41(m,2H),7.32(s,4H),7.22(s,1H),7.11(d,J＝9.8Hz,1H),6.78(d,J＝8.1Hz,1H),6.05(s,2H),4.50(d,J＝5.3Hz,2H).
实施例39 6-(1-(4-氟苯基)乙胺甲酰基)-1-(3-氟-4-氯苄基)-1H-吲哚-2-羧酸(39)的制备
Figure PCTCN2016103810-appb-000066
以6-羧基吲哚-2-甲酸甲酯代替5-羧基吲哚-2-甲酸甲酯按照制备29的方法制备39(产率28％)。1H NMR(400MHz,DMSO)δ8.77(d,J＝7.7Hz,1H),8.07(s,1H),7.72(m,2H),7.57–7.37(m,3H),7.26(s,1H),7.13(dd,J＝14.6,6.5Hz,3H),6.80(d,J＝7.9Hz,1H),5.97(m,2H),5.25–5.11(m,1H),1.49(d,J＝6.8Hz,3H).
实施例40 化合物对PPARγ激活能力评估(荧光素酶活性测定法)：
Cos-7细胞购自ATCC，培养于10％FBS无抗生素DMEM，37℃，5％CO2孵育箱中。待细胞进入对数生长期接种于24孔板中，细胞融合约70％时，按照lipofectamine 2000(Invitrogen)操作说明进行质粒共转染(50ng全长hPPARγ，100ng PPARγ，5ng海肾荧光素酶质粒)。24h后转染细胞分别用1μM化合物1至39干预，其中1μM罗格列酮做阳性对照，DMSO做阴性对照。干预24h后按 Reporter luciferase assay kits(Promega)操作说明测定荧光素酶活性，每组设定3个独立测试孔。
实验结果见表1。
表1
DMSO 0％
罗格列酮 100％
1 26.303
2 41.499
3 47.782
4 23.153
5 24.487
6 NT
7 32.091
8 55.141
9 NT
10 24.681
11 48.269
12 24.783
13 18.318
14 17.740
15 39.033
16 20.380
17 56.754
18 52.509
19 43.989
20 41.045
21 58.241
22 44.882
23 41.361
24 48.948
25 73.012
26 61.136
27 51.661
28 20.380
29 52.118
30 45.327
31 5.901
32 40.560
33 29.366
34 NT
35 54.883
36 57.921
37 13.941
38 4.871
39 NT
注：“NT”为未测试
TR-FRET方法测试化合物与PPARγ结合能力步骤：
1.将化合物1至39用DMSO稀释到1mM。DMSO做阴性对照，罗格列酮阳性对照。
2.将稀释好的化合物(1至39,罗格列酮)用TR-FRETbuffer再次稀释到2μM。
3.以TR-FRET buffer为溶剂准备FluormoneTMPan-PPAR Green solution(20nM)。
4.以TR-FRET buffer为溶剂准备20nM Tb anti-GST antibody和4μM PPARγ-LBD protein。
5.将20μl步骤2溶液,10μl步骤3溶液和10μl步骤4溶液混合在384孔板中，震荡6小时。
6.在酶标仪上读数。
实验结果见表2。
表2
DMSO 0 0
罗格列酮 0.170 100％
1 0.091 53.5％
2 0.320 188％
3 0.111 65.3％
4 0.166 97.6％
5 0.342 201％
6 NT NT
7 0.041 24.1％
8 0.046 27.1％
9 NT NT
10 0.040 23.5％
11 0.059 34.7％
12 0.203 119％
13 0.213 125％
14 0.203 119％
15 0.194 114％
16 0.197 116％
17 0.198 116％
18 0.197 116％
19 0.197 116％
20 0.214 126％
21 0.233 137％
22 0.219 129％
23 0.217 128％
24 0.209 123％
25 0.199 117％
26 0.195 115％
27 0.196 115％
28 0.308 181％
29 0.096 56.4％
30 0.095 55.9％
31 0.306 180％
32 0.307 181％
33 0.323 190％
34 NT NT
35 0.104 61.2％
36 0.140 82.4％
37 0.386 227％
38 0.112 65.9％
39 NT NT
注：“NT”为未测试
表3
Figure PCTCN2016103810-appb-000067
Figure PCTCN2016103810-appb-000068
化合物致脂肪分化能力测试及Real-time PCR测定
3T3-L1前脂肪细胞购自ATCC，培养于含青霉素-链霉素双抗的10％FBS DMEM，37℃，5％CO2孵育箱中。接种于培养板，汇合后2d加入诱导液(10％FBS DMEM含0.5mmol/L IBMX(3-异丁基-1-甲基黄嘌呤),1μmol/L DEX(地塞米松),850nmol/L胰岛素)。72h后换成10％FBS高糖DMEM含850nmol/L胰岛素，每2d换一次。1μM罗格列酮为阳性对照，DMSO为阴性对照，样品组为1μM 1至39。诱导开始第8d进行油红O染色及DAPI染色，显微镜(OLYMPUS)拍照，计算脂肪细胞分化率。
实验结果见表4。
表4
DMSO 0％
罗格列酮 100％
1 23.08
2 34.90
3 39.74
4 19.55
5 16.06
6 NT
7 32.13
8 16.65
9 NT
10 31.02
11 13.47
12 36.58
13 48.71
14 50.79
15 28.84
16 37.91
17 52.20
18 43.64
19 50.29
20 43.14
21 41.65
22 47.71
23 42.14
24 41.56
25 41.40
26 52.20
27 59.77
28 5.65
29 27.06
30 38.74
31 2.66
32 15.21
33 2.41
34 NT
35 21.01
36 14.82
37 17.14
38 1.00
39 NT
注：“NT”为未测试
上述结果显示：
(1)本发明合成的化合物具有对PPARγ弱的激活能力，以抗糖尿病药物罗格列酮为阳性对照(规定为100％)，表明本发明合成的化合物在10μM浓度下激活PPARγ值仅为0.3％－27％，这提示本发明化合物的副作用很小。
(2)本发明合成的化合物与PPARγ具有强的结合力，以抗糖尿病药物罗格列酮为阳性对照(规定为1)，表明本发明合成的化合物在1μM浓度下与PPARγ结合力值在0.2至1.3之间，这提示本发明化合物具有优良的降糖活性。
(3)本发明合成的化合物具有微弱的致脂肪细胞分化能力。以抗糖尿病药物罗格列酮为阳性对照(测试值为85.2)，表明本发明合成的化合物在10μM浓度下脂肪细胞分化率远低于罗格列酮，仅为1－59.77之间，其中绝大多数化合物的数据＜30。
由此得出如下结论：本发明合成的N-苄基-5/6-甲酰氨基吲哚-2-甲酸类衍生物作为新型PPARγ选择性调控剂而发挥生物学功能。与以抗糖尿病药物的罗格列酮相比，具有低的诱导脂肪细胞分化能力，从而降低或甚至消除了一些相关的副作用，例如：肥胖、体重增加。
实施例41 化合物29的初步药物代谢测试
给药方案：
SD大鼠7只，雄性，体重200-220g，随机分成2组，每组4/3只，灌胃或静脉给予化合物29灌胃组以5％DMSO/5％吐温80/90％生理盐水配制，静脉组以10％DMSO/10％吐温80/80％生理盐水配制。试验前禁食12h，自由饮水。给药后2h统一进食。
采血时间点及样品处理：
灌胃给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
静脉给药：给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；
在以上设定时间点经大鼠眼球后静脉丛取静脉血0.3ml，置EDTA-2K抗凝管中，11000rpm离心5min，分离血浆，于–20℃冰箱中冷冻。
表1  大鼠灌胃20mg/kg化合物29后的药动学参数
Figure PCTCN2016103810-appb-000069
表2  大鼠静脉注射5mg/kg化合物29后的药动学参数
Figure PCTCN2016103810-appb-000070
结果如表1和表2所示。上述结果显示，静脉注射给药后，化合物29在大鼠体内清除率较低，CL为0.354L/h/kg，稳态分布容积Vss为0.335L/kg；暴露量(AUC0-t)为28330ng·h/mL。灌胃给药后化合物29在大鼠体内血浆达峰时间Tmax为0.438h，暴露量(AUC0-t)为13096ng·h/mL，剂量标准化后，绝对生物利用度为23.1％。化合物29理化性质较好，适合口服给药，具有很好的成药性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，
    Figure PCTCN2016103810-appb-100001
    式中，
    各R0各自独立地选自下组：
    Figure PCTCN2016103810-appb-100002
    卤素、取代或未取代的C1-C8烷基、取代或未取代的C2-C8链烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C8环烷基、-OH、-NO2、-CN；其中，所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
    并且至少一个R0为
    Figure PCTCN2016103810-appb-100003
    n为1-4的正整数；
    R1选自下组：取代或未取代的C1-C10烷基；取代或未取代的C3-C10环烷基；Z-Y-和R5(R6)N-；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基；
    R5和R6各自独立地为氢、取代或未取代的C1-C10烷基、取代或未取代的C1-C10烷基-羰基、取代或未取代的C1-C10烷氧基-羰基、或取代或未取代的C5-C20芳基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基；
    Z选自下组：取代或未取代的C5-C20芳基、取代或未取代的C3-C20杂芳基、和取代或未取代的5-20元杂环基；其中所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基；
    Y为无、取代或未取代的C1-C10亚烷基，其中取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、和C2-C4链烯基；
    R2选自下组：H、卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C3-C8环烷基、-NO2、-CN、-OH、取代或未取代的C1-C6烷基-羰基、或取代或未取代的C1-C6烷氧基羰基；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基；
    R3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C20芳基、R9-C(O)-、氰基、甲酰胺、和四氮唑；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基；
    每个R4各自独立地选自下组：卤素、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C2-C6链烯基、取代或未取代的C2-C6炔基、 取代或未取代的C3-C8环烷基、取代或未取代的C5-C20的芳基、-NO2、-CN、-OH、R9-C(O)-、R10(R11)N-、或C5-C20芳基-C(O)-N(R10)R11-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、羧基、-OH、－NH2、和苯基；
    R9选自下组：羟基、巯基、取代或未取代的C1-C6烷基、取代或未取代的C1-C6烷氧基和R10(R11)N-；其中取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C2-C4链烯基、和苯基；
    R10和R11各自独立地为氢、C1-C10烷基或C1-C10卤代烷基；以及
    m为0-5的整数。
  2. 如权利要求1所述的式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，其特征在于，所述的化合物具有式Ic或Id结构：
    Figure PCTCN2016103810-appb-100004
    式中，R0为
    Figure PCTCN2016103810-appb-100005
    R1、R2、R3、R4、和m的定义如权利要求1所述，
    R7和R8各自独立地选自下组：H、卤素、取代或未取代的C1-C8烷基、取代或未取代的C2-C8链烯基、取代或未取代的C2-C8炔基、取代或未取代的C3-C8环烷基、-OH、-NO2、-CN；其中，所述的取代为具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、和苯基。
  3. 如权利要求1所述的式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，其特征在于，Z-Y-基团选自下组：取代或未取代的(5-20元杂环基)-(C1-C10亚烷基)-、取代或未取代的C5-C20芳基、取代或未取代的(C5-C20芳基)-(C1-C10亚烷基)-、取代或未取代的(5-20元杂芳基)-(C1-C10亚烷基)-。
  4. 如权利要求1所述的式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，其特征在于，所述化合物具有式I-1的结构：
    Figure PCTCN2016103810-appb-100006
    式I-1中，R1、R2、R3、R4的定义如权利要求1所述。
  5. 如权利要求4所述的式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，其特征在于，R1选自下组：取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的含有1-3个选自N、S和O中的杂原子的5-10元杂环基C1-C6亚烷基、取代或未取代的C5-C10芳基、取代或未取代的C5-C10芳基C1-C6亚烷基、取代或未取代的含有1-3个选自N、S和O中的杂原子的5-10元杂芳基、或R5(R6)N-，其中，R2和R3各自独立地为氢、C1-C6烷基、C1-C6烷基-羰基、C1-C6烷氧基-羰基、C5-C10芳基；和/或
    R2选自下组：H、卤素、C1-C6烷基、C1-C6烷氧基、C2-C6链烯基、C3-C8环烷基、CF3、-NO2、-CN、羟基、C1-C6烷基-羰基或C1-C6烷氧基羰基；和/或
    R3选自下组：取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C5-C20的芳基、C1-C6烷氧基-C(O)-、羧基、氰基、甲酰胺、四氮唑；和/或
    R4选自下组：H、卤素、C1-C6烷基、C1-C6烷氧基、C2-C6链烯基、C3-C8环烷基、CF3、-NO2、-CN、羟基、羧基、酯基、氨基或取代氨基、C1-C6烷基-羰基或C1-C6烷氧基-羰基、C3-C10环烷基或C5-C10的芳基、C3-C10环烷基或C5-C10的芳基甲酰基；
    其中，m为1或2，和n为1。
  6. 如权利要求1所述的式I化合物、其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐，其特征在于，所述化合物选自下组：
    Figure PCTCN2016103810-appb-100007
    Figure PCTCN2016103810-appb-100008
    Figure PCTCN2016103810-appb-100009
    Figure PCTCN2016103810-appb-100010
  7. 一种式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐的用途，其特征在于，用于制备药物或制剂，所述药物或制剂用于(i)制备PPARγ选择性调控剂；和/或(ii)治疗和/或预防受PPARγ激动剂调节的疾病。
  8. 一种药物组合物，其特征在于，包括：
    (i)权利要求1所述的式I化合物，其光学异构体、水合物、溶剂化物、其前药或其药学上可接受的盐；和
    (ii)药学上可接受的载体。
  9. 一种化合物的制备方法，其特征在于，所述方法包括步骤：
    (i)在惰性溶剂中，在碱的作用下，化合物I1-2与式V所示的取代苄溴进行反应，形成化合物I1-3；
    Figure PCTCN2016103810-appb-100011
    上述各式中，R1、R2、R3、R4如权利要求1中所定义。
  10. 一种体外对PPARγ进行处理的方法，包括步骤：
    (a)将式I化合物与所述的PPARγ进行接触，从而使得所述式I化合物结合于PPARγ。
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