WO2018171602A1 - Composé d'urée utilisé en tant qu'inhibiteur double de l'ido et du tdo - Google Patents

Composé d'urée utilisé en tant qu'inhibiteur double de l'ido et du tdo Download PDF

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Publication number
WO2018171602A1
WO2018171602A1 PCT/CN2018/079718 CN2018079718W WO2018171602A1 WO 2018171602 A1 WO2018171602 A1 WO 2018171602A1 CN 2018079718 W CN2018079718 W CN 2018079718W WO 2018171602 A1 WO2018171602 A1 WO 2018171602A1
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ring
group
alkyl
compound
pharmaceutically acceptable
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PCT/CN2018/079718
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English (en)
Chinese (zh)
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王大可
张英利
王树龙
闵汪洋
陈坤成
刘志华
刘希杰
胡远东
赵娜
彭勇
罗鸿
田心
张喜全
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
北京赛林泰医药技术有限公司
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Priority to CN201880015782.2A priority Critical patent/CN110382500B/zh
Publication of WO2018171602A1 publication Critical patent/WO2018171602A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicine, relates to urea compounds of dual inhibitors of IDO and TDO, a preparation method thereof, a pharmaceutical composition containing the same, and the activity thereof in regulating IDO and TDO and treating diseases and disorders mediated by them the use of.
  • IDO Indoleamine 2,3-dioxygenase
  • TDO tryptophan 2,3-oxygenase
  • IDO inhibitors may be an effective treatment for these diseases.
  • IDO inhibitors are mainly classified into the following categories: 1) competitive inhibitors such as tryptophan derivatives 1-MT; 2) non-competitive inhibitors such as phenylimidazole; 3) anti-competitive Inhibitors such as alkaloids exiguamine A; 4) inhibitors through other mechanisms of action.
  • TDO is expressed in a variety of tumor cells, resulting in increased survival and migration of tumor cells and inhibition of the immune system's ability to respond to tumor cells.
  • the effect of TDO on tumor cells and immunosuppression has made it a new anti-tumor drug target. Therefore, screening new IDO/TDO inhibitors and studying their in vivo activities, pharmacokinetics, therapeutic effects and adverse reactions are still a field worth exploring.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,
  • Ring A is absent or ring A is a benzene ring or contains 1, 2 or 3 5-6 membered heteroaryl rings selected from N, O or S atoms;
  • Ring B is a five-membered aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, specifically,
  • Y and V are N, Z and W are CH, and X is C;
  • X is N, Z, V and W are CH, and Y is C;
  • Y is N, Z, V and W are CH, and X is C;
  • Viii) Z is NH, V and W are CH, and X and Y are C;
  • V is NH, Z and W are CH, and X and Y are C;
  • x) W is NH, V and Z are CH, and X and Y are C;
  • V and W are N or NH, Z is CH, and X and Y are C;
  • V and Z are N or NH, W is CH, and X and Y are C;
  • Xiii) Z and W are N or NH, V is CH, and X and Y are C;
  • Y and W are N, V and Z are CH, and X is C;
  • X and W are N, V and Z are CH, and Y is C;
  • X and Z are N or NH, V and W are CH, and Y is C;
  • Y and Z are N, V and W are CH, and X is C;
  • Xix) Z, V and W are N or NH, X and Y are C;
  • Xxi) Y, Z and W are N, V is CH, X is C; or
  • P is C(R 6 ) or N
  • Q is O or S
  • D is selected from NH, O, S or CH 2 ;
  • E is selected from NH, O or CH 2 ;
  • L is selected from the group consisting of a single bond, S, SO, SO 2 , CO, C(O)O, S(O)O or S(O) 2 O;
  • Each R 1 is independently selected from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 2 is selected from C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R 3 ;
  • R 3 is selected from the group consisting of halogen, cyano, nitro, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C 3-6 cycloalkyl CH 2 -, C 3-6 heterocycloalkyl CH 2 -, containing 1, 2 or 3 5-6 membered heteroaryl CH 2 -, -OR 4 , -SR 4 , -N(R 4 ) 2 , -C(O)OR 4 , -C(O)N from N, O or S atoms R 4 ) 2 , -C(O)R 4 , -S(O)R 4 , -S(O)OR 4 , -S(O)N(R 4 ) 2 , -S(O) 2 R 4 , -S(O) 2 OR 4 ,
  • Each R 4 is independently selected from H, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;
  • R 5 is selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 6 is selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C 1-3 alkyl;
  • n 0, 1, or 2.
  • ring A is absent or ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine.
  • ring A is absent or ring A is a benzene ring or a pyridine ring.
  • ring A is absent or ring A is
  • each R 1 is independently selected from halo, halo C 1-3 alkyl or C 1-6 alkyl.
  • each R 1 is independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.
  • each R 1 is independently selected from fluoro, chloro or trifluoromethyl.
  • m is 0 or 1.
  • ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) Y, Z, V and W are N, X Is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, X is C; v) X, Z and V are N, W Is CH, Y is C.
  • D is selected from NH, O or CH 2 ;
  • E is selected from NH, O or CH 2 .
  • -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC(O)NH-, -NHC(O) CH 2 - or -CH 2 C(O)NH-.
  • One embodiment of the compounds of the invention of formula I, L is selected from a single bond or SO 2.
  • R 2 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl or contains 1, 2 or 3 selected from N, O or S atoms 5-6 membered heteroaryl group, which may optionally be substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the loss of one hydrogen atom at any position.
  • R 2 is selected from cyclohexyl, which loses a hydrogen atom at any position.
  • Phenyl, pyridyl or pyrimidyl group which may optionally be substituted with one or more substituents independently selected from R 3 group.
  • R 2 is selected from Which may be optionally substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from
  • R 3 is selected from the group consisting of halogen, cyano, nitro, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, containing 1 , 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C 3-6 heterocycloalkyl CH 2 -, -OR 4 , -SR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 or -P(O)(OR 4 ) 2 , wherein C 1-6 alkyl, C 3-6 heterocycloalkyl, containing 1, 2 or 3 are selected from The 5-6 membered heteroaryl or C
  • R 3 is selected from the group consisting of fluorine, chlorine, bromine, cyano, nitro, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl , trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR 4 , -SR 4 , -S(O) 2 R 4 ,- S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 , -P(O)(OR 4 ) 2 , methyl, ethyl, propyl, iso
  • R 3 is selected from fluoro, chloro, bromo, cyano, nitro, trifluoromethyl, -OR 4, -SR 4, -S (O) 2 R 4, - S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 , -P(O)(OR 4 ) 2 , methyl, loss of one hydrogen atom at any position Tetrazolyl or Where the methyl group, at any position, loses a hydrogen atom Tetrazolyl or Optionally substituted with one or more groups independently selected from R 5 .
  • R 3 is selected from fluoro, chloro, bromo, cyano, nitro, trifluoromethyl, -OCF 3, -SCH 3, -S (O) 2 CH 3, - S(O) 2 NH 2 , -C(O)OCH 3 , -COOH, -C(O)NHCH 3 , -C(O)NH 2 , -NHS(O) 2 NH 2 , -P(O) ( CH 3 ) 2 , -P(O)(OCH 2 CH 3 ) 2 , -C(OH)(CF 3 ) 2 ,
  • each R4 is independently selected from H, halo C1-3 alkyl or C1-6 alkyl.
  • each R 4 is independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl , tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • each R 4 is independently selected from H, trifluoromethyl, methyl or ethyl.
  • R 5 is selected from the group consisting of hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl Base, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl.
  • R 5 is selected from hydroxy or trifluoromethyl.
  • R 6 is selected from H or halogen.
  • R 6 is selected from H or chloro.
  • the invention provides a compound of Formula II, or a pharmaceutically acceptable salt thereof,
  • Ring A is a benzene ring or a 5-6 membered heteroaryl ring containing 1, 2 or 3 atoms selected from N, O or S atoms;
  • Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular,
  • Y and V are N, Z and W are CH, and X is C;
  • X is N, Z, V and W are CH, and Y is C;
  • Y is N, Z, V and W are CH, and X is C;
  • Viii) Z is NH, V and W are CH, and X and Y are C;
  • V is NH, Z and W are CH, and X and Y are C;
  • x) W is NH, V and Z are CH, and X and Y are C;
  • V and W are N or NH, Z is CH, and X and Y are C;
  • V and Z are N or NH, W is CH, and X and Y are C;
  • Xiii) Z and W are N or NH, V is CH, and X and Y are C;
  • Y and W are N, V and Z are CH, and X is C;
  • X and W are N, V and Z are CH, and Y is C;
  • X and Z are N or NH, V and W are CH, and Y is C;
  • Y and Z are N, V and W are CH, and X is C;
  • Xix) Z, V and W are N or NH, X and Y are C;
  • Xxi) Y, Z and W are N, V is CH, X is C; or
  • P is C(R 6 ) or N
  • Q is O or S
  • L is selected from the group consisting of a single bond, S, SO, SO 2 , CO, C(O)O, S(O)O or S(O) 2 O;
  • Each R 1 is independently selected from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 2 is selected from C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R 3 ;
  • R 3 is selected from the group consisting of halogen, cyano, nitro, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C 3-6 cycloalkyl CH 2 -, C 3-6 heterocycloalkyl CH 2 -, containing 1, 2 or 3 5-6 membered heteroaryl CH 2 -, -OR 4 , -SR 4 , -N(R 4 ) 2 , -C(O)OR 4 , -C(O)N from N, O or S atoms R 4 ) 2 , -C(O)R 4 , -S(O)R 4 , -S(O)OR 4 , -S(O)N(R 4 ) 2 , -S(O) 2 R 4 , -S(O) 2 OR 4 ,
  • Each R 4 is independently selected from H, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;
  • R 5 is selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 6 is selected from H, halogen, amino, cyano, hydroxy, -COOH or halogenated C 1-3 alkyl;
  • n 0, 1, or 2.
  • Ring A is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a thiazole ring, Isothiazole ring, oxazole ring, isoxazole ring, tetrazole ring or triazine ring.
  • Ring A is a phenyl ring or a pyridine ring.
  • ring A is absent or ring A is
  • each R 1 is independently selected from halo, halo C 1-3 alkyl or C 1-6 alkyl.
  • each R 1 is independently selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.
  • each R 1 is independently selected from fluoro, chloro or trifluoromethyl.
  • m is 0 or 1.
  • ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) Y, Z, V and W are N, X Is C; iii) X and V are N, Z and W are CH, Y is C; iv) Y, Z and V are N, W is CH, X is C; v) X, Z and V are N, W Is CH, Y is C.
  • L is selected from a single bond or SO 2.
  • R 2 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl or contains 1, 2 or 3 selected from N, O or S atoms. 5-6 membered heteroaryl group, which may optionally be substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a hydrogen atom is lost at any position.
  • R 2 is selected from cyclohexyl, which loses a hydrogen atom at any position.
  • Phenyl, pyridyl or pyrimidyl group which may optionally be substituted with one or more substituents independently selected from R 3 group.
  • R 2 is selected from Which may be optionally substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from
  • R 3 is selected from the group consisting of halogen, cyano, nitro, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 heterocycloalkyl, containing 1 , 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C 3-6 heterocycloalkyl CH 2 -, -OR 4 , -SR 4 , -S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 or -P(O)(OR 4 ) 2 , wherein C 1-6 alkyl, C 3-6 heterocycloalkyl, containing 1, 2 or 3 are selected from The 5-6 membered heteroaryl or C
  • R 3 is selected from fluoro, chloro, bromo, cyano, nitro, fluoromethyl, difluoromethyl, trifluoromethyl group, a fluoroethyl, difluoro ethyl , trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, -OR 4 , -SR 4 , -S(O) 2 R 4 ,- S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 , -P(O)(OR 4 ) 2 , methyl, ethyl, propyl, isopropyl
  • R 3 is selected from fluoro, chloro, bromo, cyano, nitro, trifluoromethyl, -OR 4, -SR 4, -S (O) 2 R 4, - S(O) 2 N(R 4 ) 2 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -N(R 4 )S(O) 2 N(R 4 ) 2 , -P(O)(R 4 ) 2 , -P(O)(OR 4 ) 2 , methyl, loss of one hydrogen atom at any position Tetrazolyl or Where the methyl group, at any position, loses a hydrogen atom Tetrazolyl or Optionally substituted with one or more groups independently selected from R 5 .
  • R 3 is selected from fluoro, chloro, bromo, cyano, nitro, trifluoromethyl, -OCF 3, -SCH 3, -S (O) 2 CH 3, - S(O) 2 NH 2 , -C(O)OCH 3 , -COOH, -C(O)NHCH 3 , -C(O)NH 2 , -NHS(O) 2 NH 2 , -P(O) ( CH 3 ) 2 , -P(O)(OCH 2 CH 3 ) 2 , -C(OH)(CF 3 ) 2 ,
  • each R 4 is independently selected from H, halo C 1-3 alkyl or C 1-6 alkyl.
  • each R 4 is independently selected from the group consisting of H, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl , tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
  • each R 4 is independently selected from H, trifluoromethyl, methyl or ethyl.
  • R 5 is selected from the group consisting of hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl Base, pentafluoroethyl, monochloromethyl, dichloromethyl or trichloromethyl.
  • R 5 is selected from hydroxy or trifluoromethyl.
  • R 6 is selected from H or halogen.
  • R 6 is selected from H or chloro.
  • the present invention provides a compound of Formula II-1, or a pharmaceutically acceptable salt thereof,
  • the invention provides a compound of Formula II-2, or a pharmaceutically acceptable salt thereof,
  • the present invention provides a compound of Formula II-3, or a pharmaceutically acceptable salt thereof,
  • the invention provides a compound of Formula II-4, or a pharmaceutically acceptable salt thereof,
  • the invention provides a compound of Formula II-5, or a pharmaceutically acceptable salt thereof,
  • the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof,
  • Ring B is an aromatic ring in which one, two, three or four of W, V, X, Y and Z are selected from N or NH, and others are selected from C or CH, in particular,
  • Y and V are N, Z and W are CH, and X is C;
  • X is N, Z, V and W are CH, and Y is C;
  • Y is N, Z, V and W are CH, and X is C;
  • Viii) Z is NH, V and W are CH, and X and Y are C;
  • V is NH, Z and W are CH, and X and Y are C;
  • x) W is NH, V and Z are CH, and X and Y are C;
  • V and W are N or NH, Z is CH, and X and Y are C;
  • V and Z are N or NH, W is CH, and X and Y are C;
  • Xiii) Z and W are N or NH, V is CH, and X and Y are C;
  • Y and W are N, V and Z are CH, and X is C;
  • X and W are N, V and Z are CH, and Y is C;
  • X and Z are N or NH, V and W are CH, and Y is C;
  • Y and Z are N, V and W are CH, and X is C;
  • Xix) Z, V and W are N or NH, X and Y are C;
  • Xxi) Y, Z and W are N, V is CH, X is C; or
  • Q is O or S
  • D is selected from NH, O, S or CH 2 ;
  • E is selected from NH, O, or CH 2 ;
  • L is selected from the group consisting of a single bond, S, SO, SO 2 , CO, C(O)O, S(O)O or S(O) 2 O;
  • Each R 1 is independently selected from halogen, amino, hydroxy, cyano, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • R 2 is selected from C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, 6-12 membered aryl or 5-12 membered heteroaryl containing 1, 2 or 3 selected from N, O or S atoms. a group, which may be optionally substituted with one or more groups independently selected from R 3 ;
  • R 3 is selected from the group consisting of halogen, cyano, nitro, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, containing 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, C 3-6 cycloalkyl CH 2 -, C 3-6 heterocycloalkyl CH 2 -, containing 1, 2 or 3 5-6 membered heteroaryl CH 2 -, -OR 4 , -SR 4 , -N(R 4 ) 2 , -C(O)OR 4 , -C(O)N from N, O or S atoms R 4 ) 2 , -C(O)R 4 , -S(O)R 4 , -S(O)OR 4 , -S(O)N(R 4 ) 2 , -S(O) 2 R 4 , -S(O) 2 OR 4 ,
  • Each R 4 is independently selected from H, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, phenyl or contains 1, 2 Or 3 5-6 membered heteroaryl selected from N, O or S atoms;
  • R 5 is selected from the group consisting of halogen, amino, cyano, hydroxy, -COOH, halo C 1-3 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl or C 3-6 heterocycloalkyl;
  • n 0, 1, or 2.
  • each R 1 is independently selected from halo, halo C 1-3 alkyl or C 1-6 alkyl.
  • each R 1 is independently selected from fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, monochloromethyl, dichloromethyl or tri Chloromethyl.
  • each R 1 is independently selected from chloro or trifluoromethyl.
  • m is 0 or 1.
  • ring B is an aromatic ring wherein i) Y and V are N, Z and W are CH, X is C; ii) X and V are N, Z and W are CH , Y is C.
  • D is selected from NH, O or CH 2; E is selected from NH, O or CH 2.
  • -DC(Q)-E- is selected from the group consisting of -NHC(O)NH-, -NHC(S)NH-, -OC(O)NH-, -NHC(O) CH 2 - or -CH 2 C(O)NH-.
  • L is selected from the group consisting of a single bond.
  • R 2 is selected from phenyl or contains 1, 2 or 3 5-6 membered heteroaryl selected from N, O or S atoms, which may optionally be one or A plurality of groups independently selected from R 3 are substituted.
  • R 2 is selected from the group consisting of phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl , isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, triazinyl, which may be optionally substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from phenyl, pyridyl or pyrimidyl group, which may optionally be substituted with one or more substituents independently selected from R 3 group.
  • R 2 is selected from Which may be optionally substituted with one or more groups independently selected R 3 groups.
  • R 2 is selected from
  • R 3 is selected from halogen or halogenated C 1-3 alkyl.
  • R 3 is selected from fluoro, chloro, bromo or trifluoromethyl.
  • the invention provides a compound of formula III-1, or a pharmaceutically acceptable salt thereof,
  • the invention provides a compound of formula III-2, or a pharmaceutically acceptable salt thereof,
  • the present invention preferably comprises the following compound or a pharmaceutically acceptable salt thereof,
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, of the invention.
  • the pharmaceutical compositions of the present invention further comprise one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical compositions of the invention may further comprise one or more additional therapeutic agents.
  • the invention relates to a method of treating a mammalian immunosuppressive disorder mediated by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-oxygenase (TDO), including
  • IDO indoleamine 2,3-dioxygenase
  • TDO tryptophan 2,3-oxygenase
  • a mammal preferably a human in need of such treatment, is administered a therapeutically effective amount of a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the invention relates to a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prophylaxis or treatment of guanamine 2,3-dual addition
  • Uses of oxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) mediated drugs for immunosuppressive diseases for the prophylaxis or treatment of guanamine 2,3-dual addition
  • IDO oxygenase
  • TDO tryptophan 2,3-oxygenase
  • the present invention relates to a compound of formula I, a compound of formula II, and a compound of formula III, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prophylaxis or treatment of guanamine 2,3-dual plus Use of oxygenase (IDO) and tryptophan 2,3-oxygenase (TDO) mediated immunosuppressive diseases.
  • IDO oxygenase
  • TDO tryptophan 2,3-oxygenase
  • the immunosuppressive disease is associated with an infectious disease or cancer.
  • the immunosuppressive disease may be selected from, but not limited to, pneumonia, malignancy, measles, hepatitis, kidney disease or arthritis.
  • the infectious disease is selected from the group consisting of influenza, hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), poliovirus , herpes zoster virus, human immunodeficiency virus (HIV), Epstein-Barr virus (EBV) or Coxsackie virus.
  • the cancer is selected from the group consisting of colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, renal cancer, head or neck cancer, lymphoma, leukemia or melanoma.
  • references to “one embodiment” or “an embodiment” or “in another embodiment” or “in some embodiments” throughout the specification are meant to include in the at least one embodiment The specific reference elements, structures or features described.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a reaction including a “catalyst” includes a catalyst, or two or more catalysts.
  • the term “or” is generally used in its meaning including “and/or” unless it is specifically defined otherwise.
  • an ethyl group “optionally” means ethyl substituted with halo may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn means having mn carbon atoms in this moiety.
  • C 3-10 cycloalkyl means that the cycloalkyl group has 3 to 10 carbon atoms.
  • the "C 0-6 alkylene group” means that the alkylene group has 0 to 6 carbon atoms, and when the alkylene group has 0 carbon atoms, the group is a bond. It is easy to understand that when a hetero atom is contained, mn represents the sum of the number of carbon atoms and hetero atoms.
  • C 1-10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 One carbon atom, nine carbon atoms or ten carbon atoms.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive Toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, as a pharmaceutically acceptable salt of a compound of the formula I, formula II and formula III, for example, a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, or a salt formed with a basic or acidic amino acid.
  • metal salts include, but are not limited to, salts of alkali metals such as sodium salts, potassium salts, and the like; salts of alkaline earth metals such as calcium salts, magnesium salts, barium salts, and the like; aluminum salts and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting a compound of the free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds of formula I, formula II and formula III of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • the compounds of formula I of the present invention may exist in polymorph or amorphous form.
  • the compounds of the formula I, formula II and formula III of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of formula I, formula II and formula III of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are also included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide purity The desired enantiomer.
  • a molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group)
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then known to those skilled in the art.
  • the diastereomeric resolution is carried out by fractional crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of Formula I, Formula II, and Formula III of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). All isotopic compositions of the compounds of Formula I, Formula II, and Formula III of the present invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • pharmaceutical composition refers to a mixture of one or more compounds of the invention or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.
  • halo or halogen, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl; for example, the term “halo C 1-3 alkyl” is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoro. Ethyl and 3-bromopropyl and the like. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • hydroxy refers to -OH.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • amino refers to -NH 2 , -NH(alkyl) and -N(alkyl) 2 , and specific examples of the amino group include, but are not limited to, -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , - N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )C 2 H 5 and the like.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, ⁇ , ⁇ , etc.
  • the specific alkyl group includes all isomeric forms thereof, for example, the propyl group includes -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , for example, butyl includes -CH 2 CH 2 CH 2 CH 3 ,- CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 .
  • C 1-8 alkyl refers to an alkyl group having from 1 to 8 carbon atoms.
  • C1-6 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 carbon atoms.
  • C 1-3 alkyl refers to an alkyl group having from 1 to 3 carbon atoms.
  • the "alkyl”, “C 1-8 alkyl”, “C 1-6 alkyl”, “C 1-4 alkyl” or “C 1-3 alkyl” may be unsubstituted or one Or a plurality of substituents selected from a hydroxyl group, a halogen or an amino group.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, such as a C3-20 cycloalkyl group, preferably a C3-6 cycloalkyl group, such as a cyclopropyl group, Cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the cycloalkyl group may be unsubstituted or substituted, and the substituent includes, but is not limited to, an alkyl group, an alkyloxy group, a cyano group, a carboxyl group, an aryl group, a heteroaryl group, an amino group, a halogen, a sulfonyl group. , sulfinyl group, phosphoryl group, hydroxyl group and the like.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5-7 membered ring” means 5-7 atoms arranged around. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenyl, pyridine, and piperidinyl; in another aspect, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bicyclic or spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 7 membered ring containing from 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, cyclohexylethane, cycloalkylethane, non-limiting examples of 4-membered heterocycloalkyl including, but not limited to, azetidinyl, acetophenan
  • Examples of a cyclic group, a thibutyl group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • Examples of the group, imidazolidinyl group, tetrahydropyrazolyl group, pyrrolinyl group, dihydrofuranyl group, dihydrothienyl group, 6-membered heterocycloalkyl group include, but are not limited to
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially a 5 to 8 membered ring, or a plurality of fused rings containing from 6 to 14, especially from 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, fluorenyl, isodecyl and the like.
  • compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the daily dose is from 0.01 to 200 mg/kg body weight, preferably from 0.01 to 20 mg/kg body weight, more preferably from 0.01 to 10 mg/ Kg body weight, either alone or in divided doses.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the compound of the formula 1 is reacted with triphosgene in dichloromethane to give the compound of the formula 2; the compound of the formula 2 is reacted with R 2 -L-NH 2 in pyridine to give the compound of the formula 3.
  • the compound of the formula 1 is reacted with thiophosgene in dichloromethane to give the compound of the formula 4; the compound of the formula 4 is reacted with R 2 -L-NH 2 in pyridine to give the compound of the formula 5.
  • the temperature is Celsius.
  • the reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing Belling Technology Co., Ltd., and these reagents can be used directly without further purification unless otherwise stated.
  • the following reactions are carried out in an anhydrous solvent, under a positive pressure of nitrogen or argon or using a drying tube; a reaction vessel is provided with a rubber septum to add substrate and reagents via a syringe; glassware is dried and/or Heat and dry.
  • the column chromatography was performed using 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; the thin layer chromatography was used to separate the thin layer chromatography silica gel prefabricated panels (HSGF254) produced by Yantai Chemical Industry Research Institute; the measurement of MS was performed by Thermo LCQ.
  • ESI Fleet type liquid chromatography-mass spectrometer.
  • Nuclear magnetic data ( 1 H-NMR) was run at 400 MHz using a Varian apparatus unless otherwise stated.
  • the solvent used for the nuclear magnetic data is CDCl 3 , CD 3 OD, D 2 O, DMSO-d 6 , etc., based on tetramethylsilane (0.00 ppm) or based on residual solvent (CDCl 3 : 7.26 ppm; CD 3 OD : 3.31 ppm; D 2 O: 4.79 ppm; DMSO-d 6 : 2.50 ppm).
  • NBS stands for N-bromosuccinimide
  • m-CPBA stands for m-chloroperoxybenzoic acid
  • NCS stands for N-chlorosuccinimide
  • DPPA stands for azidophosphate Diphenyl ester
  • Boc- represents t-butoxycarbonyl
  • room temperature represents 20-30 °C.
  • the compound of the formula 2 was added portionwise to a solution of R 2 -L-NH 2 (0.5 eq.) in pyridine and stirred at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was poured into water, and ethyl acetate was evaporated.
  • the compound of the formula 4 was added portionwise to a solution of R 2 -L-NH 2 (1.0 eq.) in pyridine and stirred at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate.
  • Triphenylphosphine 49.8 g was added to a solution of 1-azidomethyl-3-chloroisoquinoline (35.6 g) in tetrahydrofuran (300 mL) and water (30 mL). The reaction mixture was poured into water (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjj (27.7g).
  • Step 7 Synthesis of N-(imidazo[5,1-a]isoquinolin-5-yl)-1,1-benzophenone imide
  • N-(imidazo[5,1-a]isoquinolin-5-yl)-1,1-benzophenone imine (15.0 g) was dissolved in tetrahydrofuran (200 mL), and hydrochloric acid was added to the obtained solution. (30 mL, 2N), stirred at room temperature for 2 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc m. 1-a] Isoquinoline-5-amine (6.3 g).
  • Step 3 Synthesis of tetrazolo[5,1-a]isoquinoline-5-amine
  • 5-Fluoro-2,3-dihydro-1H-inden-1-one (8.0 g) was dissolved in diethyl ether (150 mL), cooled to 0 ° C, dry hydrogen chloride was passed to the solution for 3 hours, then slowly drip Isoamyl nitrite (12.5 g) was added, and after completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours, solid was formed, filtered, and the filter cake was washed with diethyl ether. The filter cake was dried to give 5-fluoro-2-mercapto-2,3 -Dihydro-1H-inden-1-one (7.0 g).
  • Steps 3, 4, 5, 6, 7, 8, and 9 refer to steps 1, 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.
  • step 1 in the synthesis of intermediate 3 5-fluoro-2,3-dihydro-1H-inden-1-one was substituted for 5-fluoro-2,3-dihydro-1H-inden-1-one.
  • Steps 2, 3, 4, 5, 6, 7, 8, and 9 refer to steps 2, 3, 4, 5, 6, 7, 8, and 9 in the synthesis of Intermediate 3, respectively.
  • 3-Chloro-1-methylisoquinoline (8.3 g) was slowly added to concentrated sulfuric acid (100 mL) at 0 ° C, then potassium nitrate (5.7 g) was added portionwise, and the mixture was stirred at 0 ° C for 1 hour. Pour the reaction solution into crushed ice, adjust the pH to 9 with ammonia water, filter, wash the filter cake with water, and dry the filter cake in vacuo to obtain 3-chloro-1-methyl-5-nitroisoquinoline (6.2 g).
  • 3-Chloro-1-methyl-5-nitroisoquinoline (6.0 g) was dissolved in a mixed solvent of methanol and water (1:1, 200 mL), ammonium chloride (14.4 g) was added and heated to 60 After the solution became clear, the reduced iron powder (15.1 g) was added, and the mixture was stirred at 60 ° C for 30 minutes, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove methanol and extracted with ethyl acetate (150 mL ⁇ 2). The mixture was washed with brine, dried over anhydrous sodium sulfate -aminoisoquinoline (3.9 g).
  • Steps 4, 5, 6, 7, 8, and 9 refer to steps 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.
  • 3-Bromo-2-indolylquinoline (0.4 g) was added to formic acid (25 mL), and then stirred at room temperature overnight, and the mixture was poured into water and extracted with ethyl acetate (100 mL ⁇ 2). The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated.
  • Zoxao[4,3-a]quinoline (0.32 g).
  • Steps 1, 2, 3, 4, 5, and 6 refer to steps 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.
  • Steps 4, 5, 6, 7, 8, 9, and 10 refer to steps 1, 2, 3, 4, 5, 6, and 7 in the synthesis of Intermediate 1, respectively.
  • N-chlorosuccinimide (2.7 g) was slowly added to a solution of 1-methylisoquinolin-3-amine (3.2 g) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 1 hour, then cold water was added. The reaction was quenched (5 ml), EtOAcjjjjjjj -Methylisoquinolin-3-amine (3.5 g).
  • Step 4 Synthesis of 2-(1-(azidomethyl)-4-chloroisoquinolin-3-yl)isoindole-1,3-dione
  • Step 1 Synthesis of 2-methylquinoline-3-carboxylic acid ethyl ester
  • Step 3 Synthesis of tert-butyl (2-methylquinolin-3-yl)carbamate
  • Step 4 Synthesis of tert-butyl imidazo[1,5-a]quinolin-4-ylcarbamate
  • Step 2 Synthesis of ethyl 6-(tert-butoxycarbonylamino)-4-chloropicolinate
  • Step 3 Synthesis of (4-chloro-6-(hydroxymethyl)pyridin-2-yl)carbamic acid tert-butyl ester
  • Step 4 Synthesis of (4-chloro-6-(chloromethyl)pyridin-2-yl)carbamic acid tert-butyl ester
  • Step 5 Synthesis of (4-chloro-6-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-2-yl)carbamic acid tert-butyl ester
  • Step 6 Synthesis of (6-(aminomethyl)-4-chloropyridin-2-yl)carbamic acid tert-butyl ester
  • Steps 7 and 8 refer to steps 5 and 6 in the synthesis of Intermediate 1, respectively.
  • Step 5 (5-Chloro-2-((1,3-dioxoisoindolin-2-yl)methyl)pyridin-3-yl)-tert-butoxyamide
  • Steps 7 and 8 refer to steps 5 and 6 in the synthesis of Intermediate 1, respectively.
  • Step 3 Synthesis of (2-cyano-5-(trifluoromethyl)pyridin-3-yl)carbamic acid tert-butyl ester
  • Step 4 Synthesis of tert-butyl (2-(aminomethyl)-5-(trifluoromethyl)pyridin-3-yl)carbamate
  • Steps 5 and 6 refer to steps 5 and 6 in the synthesis of Intermediate 1.
  • Steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 are referred to the synthesis steps 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 of Intermediate 3, respectively, to give the title compound.
  • Test Example 1 Biological activity assay
  • PCR amplification of IDO RNA derived from HeLa cells
  • TDO RNA derived from U87MG cells
  • amplification of the amplified PCR product and then pET28a plasmid and IDO (TDO) gel recovery product
  • the restriction endonuclease of NotI and EcoRI was digested (37 ° C, digested for 2 h), and the T4 rapid ligase ligation product was added to E. coli DH5 ⁇ .
  • Competent cells were placed on ice for 30 min, heat shocked at 42 °C for 90 s, shaken in LB medium and plated, picked up monoclonal overnight shakes, extracted plasmid and identified by enzyme digestion, and then sent After sequencing, positive clones, ie His-IDO/pET28a and His-TDO/pET28a plasmids were successfully constructed.
  • IPTG was induced at 30 ° C for 3.5 h, and after induction, the cells were collected by centrifugation at 6000 rpm for 45 min.
  • the collected cells were resuspended with lysate (40 mM Tris-HCl, pH 8.0; 110 mM NaCl; 2.2 mM KCl; 10% glycerol; 0.5% Tween-20; 20 mM imidazole; 1 mM DTT).
  • Ultrasonic lysis power 30%, cleavage on ice for 15 min
  • the lysed broth was centrifuged at 12000 rpm, 4 ° C for 60 min, and the resulting supernatant was filtered through a 0.22 ⁇ M filter to prepare a sample for use.
  • the nickel column was equilibrated with lysate for 5 column volumes, and the prepared supernatant sample was applied to a nickel column.
  • the eluent 40 mM Tris-HCl, pH 8.0; 110 mM NaCl; 2.2
  • the protein was eluted with a gradient of mM KCl; 10% glycerol; 20-250 mM imidazole.
  • the eluted protein solution was dialyzed overnight at 4 ° C, concentrated after dialysis, and stored at -80 ° C until use.
  • the enzymatic activity detection platform of IDO and TDO was established by light absorption method.
  • Compounds were diluted 10 times with 100% DMSO starting from 10 mM (5 concentrations in total), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer.
  • the mixture was mixed in a liquid (50 mM K 2 HPO 4 -KH 2 PO 4 phosphate buffer, pH 6.5) and used as a 4* compound.
  • 2*IDO enzyme was prepared using reaction buffer at a final concentration of 75 nM (total TDO enzyme concentration of 300 nM), 4* substrate (L-(+)-Absorbate with a final concentration of 20 ⁇ M, respectively, purchased from Alfa Aesar, Cat. No.
  • the 384-well plate was placed in an incubator for 13 minutes at 23 ° C (TDO reaction for 120 minutes), then 4 ⁇ L of 6 M TCA was added to each well for 30 min at 55 ° C, centrifuged at 2500 rpm for 10 min, and 40 ⁇ L of supernatant was taken per well.
  • 2% 4-dimethylaminobenzaldehyde available from TCI, Cat. No. D495, dissolved in glacial acetic acid
  • the absorbance 480 nM light absorption
  • mice Male Sprague-Dawley rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into groups of 3, and the test sample suspension (5 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.3 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4 ° C, 4000 rpm for 5 min, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.
  • Example 51 40 52 Dose (mg/kg) 5 5 5 T 1/2 (hr) 3.28 4.31 3.56 T max (hr) 0.25 0.58 0.33 C max (ng/mL) 721 243 507 AUC 0-inf (hr*ng/mL) 1520 1018 2180

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Abstract

L'invention concerne un composé d'urée ayant une double activité inhibitrice contre IDO et TDO et représenté par la formule, ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation et une composition pharmaceutique de celui-ci, ainsi qu'une utilisation dudit composé dans le traitement d'une maladie immunosuppressive induite par IDO ou TDO.
PCT/CN2018/079718 2017-03-21 2018-03-21 Composé d'urée utilisé en tant qu'inhibiteur double de l'ido et du tdo WO2018171602A1 (fr)

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WO2021005222A1 (fr) 2019-07-11 2021-01-14 Idorsia Pharmaceuticals Ltd Inhibiteurs de l'indoléamine 2,3-dioxygénase et/ou de la tryptophane 2,3-dioxygénase
WO2022178437A1 (fr) * 2021-02-22 2022-08-25 Regents Of The University Of Minnesota Immunomodulateurs et conjugués immunomodulateurs
WO2023102800A1 (fr) * 2021-12-09 2023-06-15 Theravance Biopharma R&D Ip, Llc Synthèse de 5, 7-dichloro-1, 6-naphtyridine
JP7577819B2 (ja) 2022-11-15 2024-11-05 イーライ リリー アンド カンパニー Ａｈｒアゴニスト
WO2024193464A1 (fr) * 2023-03-17 2024-09-26 西藏海思科制药有限公司 Dérivé tricyclique contenant de l'azote et son utilisation en médecine

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