WO2015139619A1 - Compound serving as rorγ modulator - Google Patents

Compound serving as rorγ modulator Download PDF

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WO2015139619A1
WO2015139619A1 PCT/CN2015/074412 CN2015074412W WO2015139619A1 WO 2015139619 A1 WO2015139619 A1 WO 2015139619A1 CN 2015074412 W CN2015074412 W CN 2015074412W WO 2015139619 A1 WO2015139619 A1 WO 2015139619A1
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group
alkyl
alkoxy
alkylamino
cyano
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French (fr)
Chinese (zh)
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薛海
赵涛
马涛
车美英
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北京韩美药品有限公司
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to a compound useful as a retinoic acid-related orphan receptor gamma (ROR ⁇ ) modulator, a pharmaceutical composition thereof, its use in pharmaceuticals, and the use thereof for preventing and/or treating mammals, especially humans A method of ROR gamma mediated disease.
  • ROR ⁇ retinoic acid-related orphan receptor gamma
  • Nuclear receptors are a class of ligand-dependent transcription factor superfamilies that are widely distributed in organisms and play a role in metabolism, development, biological rhythm, inflammation, and immune regulation.
  • Nuclear receptor ligands include thyroid hormones, steroid hormones, retinoic acid, fatty acids, sterols, etc., in addition to a class of nuclear receptors that have not yet been identified, called orphan nuclear receptors.
  • Retinoid-related orphan receptors also known as NF1R, are nuclear receptors due to their retinoic acid receptor (RAR) and retinoic acid X
  • RXR retinoid X receptor
  • the RORs subfamily mainly includes three members, ROR ⁇ , ROR ⁇ and ROR ⁇ .
  • ROR ⁇ and ROR ⁇ and their ligands (modulators) are studied more.
  • ROR ⁇ is widely expressed in various tissues and organs in the body. It can be found in brain, kidney, liver, testis, ovary, skeletal muscle, thymus, skin, lung and adipose tissue, and the expression level is the highest in brain tissue, especially cerebellum and thalamus. Recent studies have also shown that ROR ⁇ participates in human osteoblast activity by stimulating bone-promoting factors and inhibiting inflammatory responses.
  • ROR ⁇ mainly includes two subtypes, ROR ⁇ 1 and ROR ⁇ t (ROR ⁇ 2), in which ROR ⁇ 1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver; and ROR ⁇ t is only expressed in immune cells, which is unique to T cells.
  • ROR ⁇ subtype Th17 cells are a newly confirmed Th cell subset that specifically produces the cytokine IL-17. It is involved in the induction of autoimmune diseases and has a strong pro-inflammatory effect and is associated with the occurrence and development of various autoimmune diseases. Such as arthritis, multiple sclerosis and asthma.
  • ROR ⁇ is a key driver of the differentiation and regulation of Th17 cells, and it has gradually become a potential drug development target for potential autoimmune diseases.
  • ROR inverse agonists block the proliferation and growth of Th17 cells by inhibiting the function of ROR ⁇ , and inhibit the production of cytokine IL-17 to block the occurrence and development of inflammation.
  • ROR ⁇ inverse agonists
  • many papers have shown that this important physiological function of ROR ⁇ has been confirmed in experiments in which cytokine IL-17 production is inhibited in vitro and in mouse autoimmune disease models (CIA model, EAE model, etc.). Nature 2011, 472, 486-490; Nature 2011, 472, 491-496; ACS Chem. Biol. 2012, 7, 672-677; Bioorg. Med. Chem. Lett. 23 (2013) 532-536; Gastroenterology. 2009; 136(1): 257–267; Journal Exp Med.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula I (hereinafter sometimes also Known as the compound of formula I):
  • X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
  • L is selected from -C(O)-, -S(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy , haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl;
  • B is a divalent ring selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, or aryl group or heteroaryl group is optionally independently one of the following Or a plurality of groups substituted: halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula II (under Sometimes referred to herein as a compound of formula II):
  • Q is N or -CR 4 ;
  • X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl , a dialkylcarbamoyl group or an alkyl acyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • R 4 is selected from hydrogen, halogen or alkyl.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula IIa ( Sometimes referred to hereinafter as a compound of formula IIa):
  • Q is N or -CR 4 ;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present, is independently selected from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • R 4 is selected from hydrogen, halogen or alkyl.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula IIb (also sometimes referred to hereinafter as the compound of formula IIb):
  • Q is N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl ring optionally substituted independently with one or more groups: Halogen, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • n 0, 1, 2, 3 or 4;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • R 4 is selected from hydrogen, halogen or alkyl.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the formula IIc (hereinafter sometimes referred to as the compound of formula IIc):
  • Q is N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • n 0, 1, 2, 3 or 4;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • R 4 is hydrogen, halogen or alkyl.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the formula I, II, IIa, IIb, IIc or stereoisomers thereof of the invention, An isomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the formula I, II, IIa, IIb, IIc or stereoisomers thereof of the invention, An isomer or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof; one or more anti-inflammatory agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and COX- 2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunosuppressive agents and methotrexate; and pharmaceutically acceptable excipients .
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX- 2 specific cyclooxygenase inhibitors gold compounds
  • corticosteroids corticosteroids
  • tumor necrosis factor receptor antagonists include salicylates or salts, immunosuppressive agents and methotrexate
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or the use of a prodrug thereof for the preparation of a medicament for modulating ROR ⁇ activity.
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention
  • Or its prodrugs are prepared for treatment Use in the treatment or prevention of drugs for ROR gamma mediated diseases.
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or the use of a prodrug thereof for the preparation of a medicament as a ROR gamma modulator.
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or a prodrug thereof for regulating the activity of ROR ⁇ .
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or a prodrug thereof for preventing or treating a ROR ⁇ -mediated disease.
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof, of the present invention
  • a pharmaceutical composition of a compound or a prodrug thereof for regulating the activity of ROR ⁇
  • Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof, of the present invention
  • Another aspect of the invention relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa, Formula IIb of the invention A compound of the formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof.
  • Another aspect of the invention relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more Formula I of the invention A compound of Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof.
  • Another aspect of the invention relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa of the invention, A compound of Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and one or more anti-inflammatory agents.
  • C 1-4 alkyl means an alkyl group as defined below having a total of 1 to 4 carbon atoms
  • C 6-12 aryl means a aryl group as defined below having a total of 6 to 12 carbon atoms base.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • -C(O)- represents an acyl group or a carbonyl group
  • -S(O) 2 - represents a sulfonyl group
  • -S(O)- represents a sulfinyl group
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • alkyl as a group or part of another group means a straight chain consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds and attached to the rest of the molecule by a single bond. Or a branched group.
  • the alkyl group may have, for example, 1 to 18, preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methyl
  • a hexyl group, a 3-methylhexyl group, an octyl group, a decyl group, a fluorenyl group and the like are preferably a methyl group or an ethyl group.
  • haloalkyl refers to an alkyl group substituted by one or more halogen atoms, wherein alkyl is as defined above.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, dichloromethyl, bromomethyl, iodomethyl, 1,2-dichloroethyl, and the like, preferably trifluoromethyl.
  • alkoxy refers to a radical of the formula -OR a where R a is alkyl as defined above.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like, with methoxy being preferred.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogen atoms, wherein alkoxy is as defined above.
  • amino as a stand-alone group refers to a radical of the formula -NH 2 .
  • alkylamino refers to a radical of the formula -NHR a where R a is alkyl as defined above.
  • alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, and the like.
  • dialkylamino refers to a radical -NR a R b wherein R a and R b are each independently alkyl as defined above.
  • dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like, preferably dimethylamino.
  • alkylsulfonyl refers to a -S(O) 2 R a group, wherein R a is alkyl as defined above.
  • alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like, preferably a methylsulfonyl group.
  • alkylsulfonylamino refers to a radical -N(R b )S(O) 2 R a wherein R a is alkyl as defined above, R b is hydrogen or as above The alkyl group defined.
  • alkylsulfonylamino groups include, but are not limited to, methylsulfonylamino, methylsulfonyl (methyl)amino, ethylsulfonyl (methyl) amino, ethylsulfonyl (ethyl) amino, and the like.
  • aminosulfonyl refers to a radical of the formula -S(O) 2 NH 2 .
  • alkylaminosulfonyl refers to a -S(O) 2 NHR a group, wherein R a is alkyl as defined above.
  • alkylaminosulfonyl groups include, but are not limited to, methylaminosulfonyl, ethylaminosulfonyl, isopropylaminosulfonyl, t-butylaminosulfonyl and the like.
  • dialkylaminosulfonyl refers to a -S(O) 2 NR a R b group, wherein R a and R b are each an alkyl group as defined above.
  • dialkylaminosulfonyl group include, but are not limited to, dimethylaminosulfonyl group, diethylaminosulfonyl group, (meth)(ethyl)aminosulfonyl group and the like.
  • carbamoyl refers to the formula -C (O) NH 2 group.
  • alkylcarbamoyl refers to a radical of the formula -C(O)NHR a where R a is alkyl as defined above.
  • alkylcarbamoyl groups include, but are not limited to, methylcarbamoyl, ethylcarbamoyl and the like.
  • dialkylcarbamoyl refers to a radical of the formula -C(O)NR a R b wherein R a and R b are each independently alkyl as defined above.
  • dialkylcarbamoyl groups include, but are not limited to, dimethylcarbamoyl, diethylcarbamoyl, (meth)(ethyl)carbamoyl and the like, preferably dimethylcarbamoyl.
  • acylamino refers to a radical of the formula -NR a C(O)R b wherein R a is hydrogen or alkyl as defined above and R b is hydrogen or an alkane as defined above base.
  • acylamino group include, but are not limited to, formylamino group, acetylamino group, acetyl (methyl) amino group and the like.
  • alkyl acyl refers to a -C(O)R a group, wherein R a is hydrogen or alkyl as defined above.
  • alkyl acyl groups include, but are not limited to, formyl, acetyl, propionyl, isopropionyl, t-butanoyl, and the like.
  • alkyl acyloxy refers to a -OC(O)R a group, wherein R a is hydrogen or alkyl as defined above.
  • alkylacyloxy groups include, but are not limited to, formyloxy, acetyloxy, propanoyloxy, isopropionyloxy, tert-butanoyloxy and the like.
  • alkyloxycarbonyl refers to a -C(O)OR a group, wherein R a is alkyl as defined above.
  • alkyloxycarbonyl group include, but are not limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, an isopropyloxycarbonyl group, a tert-butyloxycarbonyl group and the like, preferably a methyloxycarbonyl group. Ethyloxycarbonyl.
  • cycloalkyl means a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include a fused ring system or a bridged ring system, having 3 To 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which are saturated or unsaturated and can be attached to the remainder of the molecule via a single bond via any suitable carbon atom.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, indanyl, 1,2, 3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, 6,7,8,9 -tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, indenyl, bicyclo[2.2.1]heptyl, 7, 7-Dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.
  • heterocyclyl as a group or part of another group means a stable consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system.
  • the heterocyclic group is preferably a stable 3- to 8-membered non-aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably comprising 1 to 3 stable 5- to 8-membered non-aromatic monocyclic groups selected from heteroatoms of nitrogen, oxygen and sulfur, more preferably stable to contain 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur A 5- to 6-membered non-aromatic monocyclic group.
  • the nitrogen, carbon or sulfur atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl group or a heteroaryl group, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • heterocyclic groups include, but are not limited to, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, oxazinyl, di Oxycyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline Base, octahydrofluorenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl, phthalimido and the like.
  • aryl as a group or part of another group means a system having 6 to 18 (preferably 6 to 10) carbon atoms and at least one aromatic ring.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system which can comprise a fused ring or a bridged ring system.
  • the aryl group is attached to the remainder of the molecule via a single bond via an aromatic ring atom.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-
  • a 7-group or the like is preferably a phenyl group.
  • heteroaryl as a group or part of another group means having from 1 to 15 (preferably from 1 to 10) carbon atoms and from 1 to 4 selected from nitrogen and oxygen in the ring. And a hetero atom of sulfur, and a 5- to 16-membered ring system group of at least one aromatic ring.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system, provided that the point of attachment is an aromatic ring atom .
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 a stable 5- to 10-membered aromatic monocyclic or bicyclic group to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable to contain 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur A 5- to 6-membered aromatic monocyclic or bicyclic group.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, [1,3,4]oxadiazolyl, [1,2,4]thiadiazolyl, [1,3,4]thiazide Diazolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, triazinyl, pyrimidinyl, pyridazinyl, pyridazine Base, fluorenyl, isodecyl, carbazolyl, isoxazolyl, fluorenyl, quinolyl, isoquinolinyl, diazaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, Carbazolyl, porphyrinyl, phenanthryl, phenanthroline, acriterio
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure.
  • the invention will cover various stereoisomers and mixtures thereof.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid capable of retaining the bioavailability of the free base without other side effects.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.;
  • the organic acid includes, but not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, caprylic acid, caproic acid, capric acid, eleven Carbenolic acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, azelaic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, Stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, as
  • “Pharmaceutically acceptable base addition salt” refers to a salt that is capable of retaining the biological effectiveness of the free acid without other side effects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl Amine, lysine, arginine, histidine, caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, tromethamine, hydrazine, piperazine, piperidine , N-ethyl piperidine, polyamine resin, and the like.
  • the compound of the present invention may contain a plurality of cations or anions depending on the number of charged functional groups and the valence of the cation or anion.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. They either react in a solvent or precipitate out of the solvent or crystallize out.
  • the solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may also be an organic solvent. Solvates of the compounds of the invention are also within the scope of the invention.
  • prodrug means a compound which can be hydrolyzed under physiological conditions or converted into a biologically active compound of the invention via an enzymatic reaction.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • the prodrug may not be active, but is transferred in the body.
  • the active compound of the invention is derived.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • esters of carboxyl-containing compounds e.g., compounds of the invention
  • pharmaceutically acceptable esters can be used as prodrugs of the compounds of the invention which decompose into the parent acid in the human or animal body.
  • esters include, but are not limited to, alkyl esters such as methyl, ethyl or propyl esters; alkoxymethyl esters such as methoxymethyl esters; alkanoyloxymethyl esters such as acetoxy Methyl ester; alkyl substituted carboxamide alkyl ester, such as N,N-dimethylformamidomethyl ester and N,N-diethylformamidomethyl ester (see, for example, patent documents) US5073641).
  • alkyl esters such as methyl, ethyl or propyl esters
  • alkoxymethyl esters such as methoxymethyl esters
  • alkanoyloxymethyl esters such as acetoxy Methyl ester
  • alkyl substituted carboxamide alkyl ester such as N,N-dimethylformamidomethyl ester and N,N-diethylformamidomethyl ester (see, for example, patent documents) US5073641).
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals.
  • terapéuticaally effective dose refers to an amount of a compound of the invention sufficient to effectively treat a disease in a mammal (e.g., a human) when a compound of the invention is administered to a mammal (e.g., a human).
  • the amount of a compound of the invention that constitutes a “therapeutically effective amount” will depend on the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the disease, the mode of administration, and the age of the mammal being treated. , body weight, physical condition, etc., but can be routinely determined by those skilled in the art based on their own knowledge and the content disclosed in the present application.
  • prevention includes the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • ROR ⁇ -mediated disease refers to the release or alteration of the activity level of ROR ⁇ either by ROR ⁇ itself, or by the release of a cytokine such as, but not limited to, IL-17 or IL-23. Any disease or other harmful condition that works.
  • the ROR ⁇ -mediated disease may be an autoimmune disease and/or an inflammatory disease, examples of which include, but are not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, asthma, systemic lupus erythematosus , chronic obstructive pulmonary disease, tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, irritable bowel syndrome, osteoarthritis, Kawasaki disease, bridge Ben's thyroiditis, mucosal Leishman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis in children, ankylosing spondylitis, pancreatitis, autoimmune Diabetes, autoimmune eye disease, ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromy
  • ROR ⁇ modulator refers to a molecule that interacts with the target ROR ⁇ and affects ROR ⁇ function, including but not limited to: antagonism, agonism, inverse agonism, and other similar interactions.
  • alkyl group optionally substituted with one or more halogens means that the alkyl group is unsubstituted or substituted with one or more halogens, and the description includes both substituted alkyl groups and unsubstituted alkyl groups.
  • the invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein the compound has the formula I:
  • X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
  • L is selected from -C(O)-, -S(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy , haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl;
  • B is a divalent ring selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, or aryl group or heteroaryl group is optionally independently one of the following Or a plurality of groups substituted: halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
  • R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
  • R 2 when present is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy.
  • L is selected from -C(O)-. In other embodiments, L is selected from the group consisting of -S(O)-. In other embodiments, L is selected from the group consisting of -S(O) 2- . In further preferred embodiments, L is selected from -CH 2 -.
  • A is selected from aryl or heteroaryl, preferably C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted as aryl or heteroaryl Substituted independently by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonyl Amino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl.
  • A is selected from C 6-12 aryl or 5-12 membered heteroaryl, and the C 6-12 aryl or 5-12 membered heteroaryl is optionally independent Substituted by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkyl, C 1- 8 -alkylamino, di-C 1-8 alkylamino, C 1-8 alkylsulfonyl, sulfonylamino, amido, carbamoyl, C 1-8 alkylcarbamoyl, di C 1-8 alkane A carbamoyl group or a C 1-8 alkyl acyl group.
  • A is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the C 6-10 aryl or 5-10 membered heteroaryl is optionally independent Substituted by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, C 1- 4 -alkylamino, di-C 1-4 alkylamino, carbamoyl, C 1-4 alkylcarbamoyl or di C 1-4 alkylcarbamoyl.
  • A is selected from phenyl or 5-6 membered heteroaryl, optionally substituted independently by one or more of the following Group substitution: halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy or halo C 1-4 alkyl.
  • A is selected from phenyl, which is optionally independently substituted with one or more of the following: halo, C 1-4 alkyl or halo C 1-4 alkyl.
  • B is a divalent ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, or aryl
  • the or heteroaryl group is optionally substituted independently with one or more of the following: halo, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dioxane Alkylamino, alkylsulfonyl, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amido Or an alkyl acyl group.
  • B is a divalent ring selected from the group consisting of C 6-12 aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5-
  • the 12-membered heteroaryl group is optionally substituted independently with one or more of the following groups: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, An acylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkyl acyl group.
  • X is -C(O)-. In other embodiments, X is -CH 2 C (O) -. In other embodiments, X is -CH 2 CH 2 -.
  • n is 0, 1, 2, 3 or 4. In some embodiments, m is 0, in which case R 2 is absent. In other embodiments, m is one. In still other embodiments, m is 2.
  • n is zero. In other embodiments, n is one. In still other embodiments, n is 2.
  • R 1 is selected from -C(O)R a wherein R a is selected from hydroxy, alkoxy, amino, alkylamino or dialkylamino. In other embodiments, R 1 is selected from -C(O)R a , wherein R a is selected from hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino or di C 1-4 alkane Amino group. In other embodiments, R 1 is selected from -C(O)R a wherein R a is hydroxy, alkoxy or amino. In still other embodiments, R 1 is selected from -C(O)R a , wherein R a is hydroxy.
  • R 1 is selected from -S (O) 2 R b, wherein R b is selected from alkyl, amino, alkylamino or dialkylamino. In other embodiments, R 1 is selected from -S(O) 2 R b , wherein R b is selected from C 1-4 alkyl, amino, C 1-4 alkylamino or di C 1-4 alkylamino . In yet other embodiments, R 1 is selected from -S (O) 2 R b, wherein R b is alkyl, preferably C 1-4 alkyl.
  • R 2 when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy base.
  • R 2 when present, is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C 1-4 alkyl acyloxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or halo C 1-4 alkoxy.
  • R 2 when present, is independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl Or a halogenated C 1-4 alkoxy group.
  • compounds of Formula I of the present invention is independently selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl R 2, when present. In some embodiments of compounds of Formula I of the present invention, is independently selected from halogen when R 2, when present.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula II (hereinafter sometimes referred to as the compound of formula II):
  • Q is selected from N or -CR 4 ;
  • R 3 is selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino, An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
  • Q is selected from N or -CR 4 ;
  • X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • Q is selected from N or -CR 4 ;
  • A is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6-
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein Compound has Structural Formula IIa (hereinafter sometimes referred to as the compound of Formula IIa):
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • the C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted, independently, with one or more of the following groups: halo, amino , cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • m is 0, 1, 2, 3 or 4;
  • n is 0, 1 or 2;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from hydroxy, alkoxy, amino, alkylamino Or a dialkylamin
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from phenyl or 5- a 6-membered heteroaryl group, the phenyl or 5-6 membered heteroaryl optionally being independently substituted with one or more of the following: halogen, cyano, C 1-4 alkyl, C 1-4 alkane Oxy, halo C 1-4 alkyl;
  • m is selected from 0, 1 or 2;
  • n is selected from 0 or 1;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • a is selected from hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino or di C 1-4 alkylamino;
  • R b is selected from C 1-4 alkyl, amino, C 1-4 alkane a base amino group or a di-C
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
  • A is selected from phenyl or 5- a 6-membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halo, cyano, C 1-4 alkyl or halo C 1- 4 alkyl;
  • m is 0 or 1;
  • n is 0 or 1;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from hydroxy, C 1-4 alkoxy Or an amino group;
  • R b is selected from an alkyl group; when present, R 2 is independently selected from halogen, C 1-4 alkyl or halo C 1-4 alkyl;
  • R 3 is selected from hydrogen, halogen, C 1-4 alkane a group, a C 1-4 alkoxy group
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)- or -CH 2 -;
  • A is selected from phenyl, which is optionally independently Substituted one or more of the following: halogen, C 1-4 alkyl or halo C 1-4 alkyl; m is 0 or 1; n is 0; R 1 is selected from carboxy; R 2 is independent when present Is selected from halogen, C 1-4 alkyl or halo C 1-4 alkyl; R 3 is selected from hydrogen; and R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein
  • the compound has the structural formula IIb (hereinafter sometimes referred to as the compound of formula IIb):
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from C 6-12 Aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5-12 membered heteroaryl ring optionally substituted independently with one or more of the following: halo, amino, cyano, Hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • m is 0, 1, 2, 3 or 4;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group; and
  • R b is selected from an
  • R 2 is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy ;
  • R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
  • R 4 is selected from hydrogen, halogen or alkyl.
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from phenyl or 5 a -6 membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halogen, C 1-4 alkyl, halo C 1-4 Alkyl or cyano;
  • m is 0 or 1;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from hydroxy, C 1-4 alkoxy or amino;
  • R b is selected from C 1-4 alkyl;
  • R 2 when independently present is selected from halogen or C 1-4 alkyl;
  • R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy A carbamoyl group, a C 1-4 alkylcarbamoyl group or a di C 1-4 al
  • the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein
  • the compound has the structural formula IIc (hereinafter sometimes referred to as the compound of formula IIc):
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from C 6-12 Aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5-12 membered heteroaryl optionally substituted independently with one or more of the following: halo, amino, cyano, hydroxy , carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; m is 0, 1, 2, 3 or 4 ;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from hydroxy, alkoxy, amino, alkylamino or dialkylamino;
  • R b is selected from alkyl, An amino group, an alkylamino
  • Q is selected from N or -CR 4 ;
  • L is selected from -C(O)- or -S(O) 2 -;
  • A is selected from phenyl or 5 a -6 membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halogen, C 1-4 alkyl, halo C 1-4 Alkyl or cyano;
  • m is 0 or 1;
  • R 1 is selected from -C(O)R a or -S(O) 2 R b ;
  • R a is selected from hydroxy, C 1-4 alkoxy or amino;
  • R b is selected from C 1-4 alkyl;
  • R 2 when independently present is selected from halogen or C 1-4 alkyl;
  • R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy A carbamoyl group, a C 1-4 alkylcarbamoyl group or a di C 1-4 al
  • the compounds of the invention are selected from the group consisting of
  • the compounds of Formula I, Formula II, Formula IIa, Formula IIb and Formula IIc of the present invention, or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and each asymmetric carbon atom may be in the R or S configuration. Both configurations are within the scope of the invention.
  • the compounds may exist as enantiomers, diastereomers or mixtures thereof.
  • the above compounds may be selected from the racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by chiral chromatography or fractional crystallization.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of formula I, formula II, formula IIa, formula IIb and formula IIc of the invention, or a stereoisomer, tautomer thereof or A pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.
  • compositions of the present invention can be prepared by methods well known in the pharmaceutical art.
  • a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof with sterilized distilled water to form a solution.
  • Surfactants may be added to promote the formation of a homogeneous solution or suspension.
  • Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and Practice), 20 th Edition (Philadelphia College of Pharmacy and Science, 2000).
  • routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal.
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compounds of Formula I, Formula II, Formula IIa, Formula IIb or Formula IIc of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water Emulsions, etc.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • the above carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compound can form a solution or suspension with the above carriers. The particular mode of administration and dosage form will depend on the physicochemical properties of the compound itself, as well as the severity of the disease being applied.
  • the compounds of the invention or the pharmaceutical compositions of the invention may also be used in combination or in combination with one or more anti-inflammatory agents.
  • the anti-inflammatory drugs include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunization Inhibitor and methotrexate.
  • Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof Or the use of a prodrug thereof for the preparation of a medicament for modulating ROR ⁇ activity.
  • Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof
  • a prodrug thereof or a medicament for the preparation of a medicament for preventing or treating a ROR ⁇ -mediated disease.
  • Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof Or the use of a prodrug thereof for the preparation of a medicament as a ROR gamma modulator.
  • Another aspect of the invention relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa, Formula IIb of the present invention Or a compound of the formula IIc or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof.
  • Another aspect of the invention relates to a method of preventing or treating a ROR gamma mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, the medicament
  • the composition comprises one or more compounds of Formula I, Formula II, Formula IIa, Formula IIb or Formula IIc of the present invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof Compound or its prodrug.
  • Another aspect of the invention relates to a method of preventing or treating a ROR gamma mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa of the invention, A compound of Formula IIb or Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and one or more anti-inflammatory agents.
  • the anti-inflammatory drugs include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunization Inhibitor and methotrexate.
  • the compounds herein are modulators of retinoic acid-related orphan receptor ROR, particularly modulators of RORy. These modulators can be used to treat ROR gamma mediated diseases in mammals, especially humans.
  • the ROR ⁇ -mediated disease can be one or more autoimmune and/or inflammatory diseases including, but not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, gram Ron's disease, asthma, systemic lupus erythematosus, chronic obstructive pulmonary disease, tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, stress bowel syndrome , osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucosal Leishman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis
  • compositions of this invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • a "therapeutically effective amount" of a compound of the invention consists of the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the condition, the mode of administration, and the age, weight, body of the mammal to be treated The status and other factors determine.
  • the dose for parenteral administration may be 1-200 mg/kg
  • dose for oral administration may be 1-1000 mg/kg.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • protecting groups are detailed in Greene, TW and PGMWuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), (1999), 4 th Ed., Wiley medium.
  • the protecting group can also be a polymeric resin.
  • the compounds of the invention can be prepared according to the methods shown in the following schemes:
  • X is -C(O)-;
  • A, B, R 1 , R 2 , L, m and n are as defined in Structural Formula I.
  • step 1 the synthesis of the compound of formula I wherein X is -C(O)- is based on an o-nitrofluoroaryl ring or an o-nitrofluoroheteroaryl ring B, and step 1 is basic (for example The substitution reaction is carried out under the conditions of NaH), the ring B is connected with the substituted aniline, the step 2 is used to reduce the nitro group (for example, zinc powder/ammonium chloride), and then the step 3 is prepared by using triphosgene under the catalysis of a base such as triethylamine.
  • a base such as triethylamine
  • step 4 under various conditions (such as NaH) Reaction of a substituted or unsubstituted acid halide, benzyl halide, sulfonyl halide or sulfinyl halide affords the compound of the formula I.
  • X is -CH 2 C(O)- or -CH 2 CH 2 -;
  • Z is -CH 2 - or -C(O)-;
  • A, B, R 1 , R 2 , L, m and n are as Defined in Structural Formula I.
  • step 1 is carried out under a basic (for example, NaH) substitution reaction to ring B with a substituted aniline, and the obtained aniline derivative is subjected to basic (for example, NaH) and 1,2-dibromo in step 2.
  • basic for example, NaH
  • step 3 the nitro group is reduced (for example, stannous chloride/hydrochloric acid, reflux) to form an amino group, while a ring-closing reaction is carried out in one pot to obtain a cyclic intermediate, and finally step 4 is alkaline.
  • the desired compound is obtained by reacting with various substituted or unsubstituted acid halides, benzyl halides, sulfonyl halides or sulfinyl halides under conditions of (preferably NaH).
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • the identification of the final product was performed by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
  • the compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in the step 1, 1-methyl-2-fluoro-3-nitrobenzene is used as a raw material instead of 1,2-difluoro- 3-nitrobenzene.
  • the compound of this example can be prepared by a similar procedure to that of Example 2 except that 4-fluorobenzenesulfonyl chloride is used as the starting material in place of 2,6-dichlorobenzoyl chloride.
  • the compound of this example can be prepared by a similar procedure to that of Example 1 except that 2,4-difluorobenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride.
  • the compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 2-chloro-6-fluorobenzoyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5.
  • the compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-fluorobenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride.
  • the relevant characterization data is as follows:
  • the compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-trifluoromethylbenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride.
  • the compound of this example can be prepared in a similar manner to that of the above-mentioned Example 1, except that benzyl bromide is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5.
  • the compound of this example can be prepared in a similar manner to that in the previous Example 1, except that in the step 5, 2,6-dichlorobenzyl bromide is used as a starting material instead of 2,6-dichlorobenzoyl chloride.
  • the compound of this example can be prepared in a similar manner to that of the above-mentioned Example 1, except that in step 5, 4-cyanobenzoyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride.
  • the compound of this example can be prepared in a similar manner to the previous Example 1, except that the lithium hydroxide hydrolysis (i.e., step 4) is omitted and the next step is directly carried out.
  • the compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in step 1, 4-fluoro-3-nitrobenzoic acid is used instead of 1,2-difluoro-3-nitrobenzene.
  • Ethyl 4-aminobenzoate is used in place of methyl 4-aminobenzoate, and a reaction step for converting a carboxyl group to a dimethylcarbamoyl group is added between step 1 and step 2, that is, a product of the first step reaction 4- (4'-Ethoxycarbonylphenylamino)-3-nitrobenzoic acid is dissolved in an appropriate amount of DMF, then 1 equivalent of tetramethylurea hexafluorophosphate (HATU) and 2 equivalents of diisopropyl B are added.
  • HATU tetramethylurea hexafluorophosphate
  • the compound of this example can be produced in a similar manner to that of the above-mentioned Example 1, except that in the step 1, 4-methylsulfonylaniline is used as a starting material instead of methyl 4-aminobenzoate.
  • Example 14 4-(3-(2,6-Dichlorobenzoyl)-6-methoxy-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl )benzoic acid
  • the compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 1-methoxy-3-fluoro-4-nitrobenzene is used as a raw material instead of 1,2-difluoro in the step 1. -3-nitrobenzene.
  • the compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 2-fluoro-3-nitropyridine is used as a raw material instead of 1,2-difluoro-3-nitrobenzene in the step 1. .
  • the compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that 1-fluoro-2-nitrobenzene is used as a raw material instead of 1,2-difluoro-3-nitrobenzene in the step 1. .
  • the compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in the step 1, 1-chloro-2-fluoro-3-nitrobenzene is used as a raw material instead of 1,2-difluoro-3. - Nitrobenzene.
  • the compound of this example can be prepared by a similar procedure to that of Example 1 except that methyl 4-amino-2-fluorobenzoate is used as a starting material in place of 4-amino-benzoic acid methyl ester.
  • the compound of this example can be prepared by a similar procedure to that of the above-mentioned Example 1, except that phenylacetyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5.
  • the compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-chlorophenylacetyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride.
  • Step 1 is the same as Step 1 of the preparation of the compound of Example 1, to give the intermediate 4-(2-fluoro-6-nitrophenyl) Amino)methyl benzoate (1-1)
  • the intermediate 22-4 (35 mg, 0.072 mmol) was dissolved in 5 mL of THF, 1 mL of H 2 O was added, and LiOH ⁇ H 2 O (28.8 mg, 0.72 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight.
  • the compound of this example can be prepared by a similar procedure to that of the above-mentioned Example 22 except that in the step 2, 1,2-dibromoethane is used as a starting material instead of 2-bromoacetyl chloride for the amino group substitution reaction.
  • the compound of the present invention can modulate (inhibit) the biological activity of the nuclear receptor ROR ⁇ , and the strength of this regulation (inhibition) can be evaluated by the TR-FRET screening system.
  • Nuclear receptor cofactors coactivators and cosuppressors
  • the method uses Life Technologies' LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) technique to determine the ability of a compound to modulate the interaction of RORy with its coactivator (agonism or reverse agonism).
  • Tb-labeled anti-GST antibody (Life Technologies #PV3550) was indirectly labeled by binding to the GST tag of RORy-LBD (Life Technologies #PV5887).
  • ROR ⁇ can continue to bind to fluorescein-labeled coactivators.
  • agonists bind to ROR ⁇ , they can enhance the interaction of ROR ⁇ with fluorescein-labeled coactivators.
  • Inverse agonists can inhibit ROR ⁇ by binding to ROR ⁇ .
  • Co-activation of fluorescein labeling The energy transfer can occur when the factor and the ⁇ -labeled anti-GST antibody-ROR-labeled conjugate complex are close to each other to generate a TR-FRET signal.
  • the coactivator used in the method is not limited to Fluorescein-D22 (Life Technologies #PV4386), Fluorescein-SRC1-2 (Life Technologies #PV4578), Fluorescein-SRC1-4 (Life Technologies #PV4582), and the like.
  • Complete TR-FRET Coregulator Buffer D (hereinafter referred to as complete buffer D): DTT (Life Technologies #P2325) was added to TR-FRET Coregulator Buffer D (Life Technologies #PV4420) to a final DTT concentration of 5 mM.
  • 2X Fluorescein-D22 (0.3 ⁇ M, refer to Table 1 when using other co-activator peptides) and 2X Tb-labeled anti-GST antibody (4 nM) were mixed in complete buffer D, and 10 ⁇ L/well was added to the 384-well plate (Corning 3376). )in.
  • test compound A 100X final concentration gradient of the test compound was prepared using DMSO, and then the test compound was diluted to 4X (DMSO content: 4%) using complete buffer D, and 5 ⁇ L/well was added to the above 384-well plate and mixed well. To the positive control wells, complete buffer D (no test compound) containing 4% DMSO was added at 5 ⁇ L/well.
  • 4X ROR ⁇ -LBD (8 nM) was prepared using complete buffer D, and 5 ⁇ L/well was added to the above 384-well plate and mixed well. 5 ⁇ L/well of Complete Buffer D (without ROR ⁇ -LBD) was added to the negative control wells. The 384-well plate was placed in a thermostated shaker and incubated for 4 to 5 hours at 23 ° C in the dark.
  • Fluorescence intensity was measured using Tecan M1000Pro: 1) excitation wavelength 332/20 nm, emission wavelength 490/10 nm, gain value: optimization, flash: mode 2 (100 Hz), delay time 100 ⁇ s, integration time 200 ⁇ s; 2) excitation wavelength 332/20 nm, Emission wavelength 520/20nm, gain value: optimized, flash: mode 2 (100Hz), delay time 100 ⁇ s, integration time 200 ⁇ s.
  • the logarithmic curve of the TR-FRET ratio F520/F490 - compound concentration was plotted using the program GraphPad Prism, and the EC50 value was calculated. The smaller the value, the stronger the effect of the compound on the receptor ROR ⁇ regulation (in this example, inhibition). .

Abstract

The present invention relates to a compound which can be used as a retinoid-related orphan receptor γ (RORγ) modifier, a pharmaceutical composition of said compound, the use of said compound in the manufacture of pharmaceuticals, and a method for using said compound for treatment and/or prophylaxis of a RORγ-mediated disease in a mammal (especially a human). The compound has the structural formula I.

Description

作为RORγ调节剂的化合物Compound as a RORγ modulator 技术领域Technical field
本发明涉及可用作视黄酸相关孤儿受体γ(RORγ)调节剂的化合物、其药物组合物、其在制药中的用途以及使用其预防和/或治疗哺乳动物(尤其是人)的由RORγ介导的疾病的方法。The present invention relates to a compound useful as a retinoic acid-related orphan receptor gamma (RORγ) modulator, a pharmaceutical composition thereof, its use in pharmaceuticals, and the use thereof for preventing and/or treating mammals, especially humans A method of ROR gamma mediated disease.
背景技术Background technique
核受体是一类配体依赖的转录因子超家族，其在生物体内分布广泛，在代谢、发育、生物节律、炎症和免疫调控等方面发挥作用。核受体的配体包括甲状腺激素、类固醇激素、视黄酸、脂肪酸、甾醇等，此外还有一类目前还没有确定配体的核受体，称为孤儿核受体。视黄酸相关孤儿受体(retinoid-related orphan receptors，RORs)，又称为NF1R，这类核受体由于在基因序列上与视黄酸受体(retinoic acid receptor，RAR)和视黄酸X受体(retinoid X receptor，RXR)类似而得名。RORs亚家族主要包括RORα、RORβ和RORγ等三个成员，目前对RORα和RORγ及其配体(调节剂)研究较多。RORα在体内各组织器官中广泛表达，它可以存在于脑、肾、肝、睾丸、卵巢、骨骼肌、胸腺、皮肤、肺、脂肪组织中，其中在脑组织中表达水平最高，特别是小脑和丘脑。新近研究还显示RORα通过刺激造骨促进因子，抑制炎症反应来参与人体的造骨细胞活动。RORγ主要包括RORγ1和RORγt(RORγ2)两种亚型，其中RORγ1分布于骨骼肌、胸腺、睾丸、胰腺、前列腺、心脏和肝脏等处；而RORγt仅表达于免疫细胞中，它是T细胞特有的一种RORγ亚型。Th17细胞是一种新近证实的能特异性产生细胞因子IL-17的Th细胞亚群，它参与诱导自身免疫病，具有很强的促炎症作用，并与多种自身免疫病的发生和发展有关，如关节炎、多发性硬化症及哮喘等。RORγ是Th17细胞分化和调控的一个关键驱动因子，因此逐渐成为一个新兴的有潜力的自身免疫性疾病的药物开发靶点。ROR反向激动剂(拮抗剂)通过影响RORγ的功能，调节Th17细胞的增殖和生长，抑制细胞因子IL-17的产生从而阻断炎症的发生和发展。近年来，已经有多篇论文研究显示，在体外抑制细胞因子IL-17产生的实验里及小鼠自身免疫疾病模型中(CIA模型、EAE模型等)都证实了RORγ的这一重要生理功能(Nature 2011,472,486-490；Nature 2011,472,491-496；ACS Chem.Biol.2012,7,672-677；Bioorg.Med.Chem.Lett.23(2013)532–536；Gastroenterology.2009；136(1):257–267；Journal Exp Med.2008；205(5):1063–1075；Immunol Res.2001；23(2–3):99–109；Cell 126,1121–1133,September 22,2006；WO2012158784；WO2012100732；US8389739B1；WO2013160418；WO2013092939；WO2013169704；WO2013178362；ACS Med.Chem.Lett.,2014,5(1),65–68)。Nuclear receptors are a class of ligand-dependent transcription factor superfamilies that are widely distributed in organisms and play a role in metabolism, development, biological rhythm, inflammation, and immune regulation. Nuclear receptor ligands include thyroid hormones, steroid hormones, retinoic acid, fatty acids, sterols, etc., in addition to a class of nuclear receptors that have not yet been identified, called orphan nuclear receptors. Retinoid-related orphan receptors (RORs), also known as NF1R, are nuclear receptors due to their retinoic acid receptor (RAR) and retinoic acid X The receptor (retinoid X receptor, RXR) is named after it. The RORs subfamily mainly includes three members, RORα, RORβ and RORγ. Currently, RORα and RORγ and their ligands (modulators) are studied more. RORα is widely expressed in various tissues and organs in the body. It can be found in brain, kidney, liver, testis, ovary, skeletal muscle, thymus, skin, lung and adipose tissue, and the expression level is the highest in brain tissue, especially cerebellum and thalamus. Recent studies have also shown that RORα participates in human osteoblast activity by stimulating bone-promoting factors and inhibiting inflammatory responses. RORγ mainly includes two subtypes, RORγ1 and RORγt (RORγ2), in which RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver; and RORγt is only expressed in immune cells, which is unique to T cells. A RORγ subtype. Th17 cells are a newly confirmed Th cell subset that specifically produces the cytokine IL-17. It is involved in the induction of autoimmune diseases and has a strong pro-inflammatory effect and is associated with the occurrence and development of various autoimmune diseases. Such as arthritis, multiple sclerosis and asthma. RORγ is a key driver of the differentiation and regulation of Th17 cells, and it has gradually become a potential drug development target for potential autoimmune diseases. ROR inverse agonists (antagonists) block the proliferation and growth of Th17 cells by inhibiting the function of RORγ, and inhibit the production of cytokine IL-17 to block the occurrence and development of inflammation. In recent years, many papers have shown that this important physiological function of RORγ has been confirmed in experiments in which cytokine IL-17 production is inhibited in vitro and in mouse autoimmune disease models (CIA model, EAE model, etc.). Nature 2011, 472, 486-490; Nature 2011, 472, 491-496; ACS Chem. Biol. 2012, 7, 672-677; Bioorg. Med. Chem. Lett. 23 (2013) 532-536; Gastroenterology. 2009; 136(1): 257–267; Journal Exp Med. 2008; 205(5): 1063–1075; Immunol Res. 2001; 23(2–3): 99–109; Cell 126, 1121–1133, September 22, 2006; WO2012158784; WO2012100732 US8389739B1; WO2013160418; WO2013092939; WO2013169704; WO2013178362; ACS Med. Chem. Lett., 2014, 5(1), 65-68).
鉴于RORγ在多种自身免疫疾病的发生和发展中所起的重要作用，合成一系列新的化 合物来调节RORγ的功能具有非常重要的意义，这可为自身免疫疾病的治疗奠定基础。In view of the important role played by RORγ in the occurrence and development of various autoimmune diseases, a series of newizations have been synthesized. It is very important to regulate the function of RORγ, which can lay the foundation for the treatment of autoimmune diseases.
发明内容Summary of the invention
一方面，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式I(在下文中有时也被称为式I化合物)：In one aspect, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula I (hereinafter sometimes also Known as the compound of formula I):
Figure PCTCN2015074412-appb-000001
Figure PCTCN2015074412-appb-000001
其中：among them:
X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
L选自-C(O)-、-S(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O)-, -S(O) 2 - or -CH 2 -;
A选自芳基或杂芳基，所述芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；A is selected from aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy , haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl;
B为选自以下的二价环：环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、或芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、硝基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、烷基磺酰氨基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰氨基或烷基酰基；B is a divalent ring selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, or aryl group or heteroaryl group is optionally independently one of the following Or a plurality of groups substituted: halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n是0、1或2；n is 0, 1 or 2;
R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；且R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基。R 2 when present is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy.
在一个实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式II(在下文中有时也被称为式II化合物)：In one embodiment, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula II (under Sometimes referred to herein as a compound of formula II):
Figure PCTCN2015074412-appb-000002
Figure PCTCN2015074412-appb-000002
其中：among them:
Q是N或-CR4；Q is N or -CR 4 ;
X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl , a dialkylcarbamoyl group or an alkyl acyl group;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n是0、1或2；n is 0, 1 or 2;
R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
在一个具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式IIa(在下文中有时也被称为式IIa化合物)：
Figure PCTCN2015074412-appb-000003
In a specific embodiment, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula IIa ( Sometimes referred to hereinafter as a compound of formula IIa):
Figure PCTCN2015074412-appb-000003
其中：among them:
Q是N或-CR4；Q is N or -CR 4 ;
L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n是0、1或2；n is 0, 1 or 2;
R1选自-C(O)Ra或-S(O)2Rb； R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、羟基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
在一个具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式IIb(在下文中有时也被称为式IIb化合物)：In a specific embodiment, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the structural formula IIb ( Also sometimes referred to hereinafter as the compound of formula IIb):
Figure PCTCN2015074412-appb-000004
Figure PCTCN2015074412-appb-000004
其中：among them:
Q是N或-CR4；Q is N or -CR 4 ;
L选自-C(O)-或-S(O)2-；L is selected from -C(O)- or -S(O) 2 -;
A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基环任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl ring optionally substituted independently with one or more groups: Halogen, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
在一个具体实施方案中，本发明还提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式IIc(在下文中有时也被称为式IIc化合物)： In a specific embodiment, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the formula IIc (hereinafter sometimes referred to as the compound of formula IIc):
Figure PCTCN2015074412-appb-000005
Figure PCTCN2015074412-appb-000005
其中：among them:
Q是N或-CR4；Q is N or -CR 4 ;
L选自-C(O)-或-S(O)2-；L is selected from -C(O)- or -S(O) 2 -;
A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
R4是氢、卤素或烷基。R 4 is hydrogen, halogen or alkyl.
本发明的另一方面涉及一种药物组合物，所述药物组合物包含一种或多种本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，以及药学上可接受的赋形剂。Another aspect of the invention relates to a pharmaceutical composition comprising one or more compounds of the formula I, II, IIa, IIb, IIc or stereoisomers thereof of the invention, An isomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable excipient.
本发明的另一方面涉及一种药物组合物，所述药物组合物包含一种或多种本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药；一种或多种选自以下的抗炎药：非甾体类抗炎药(NSAID)、非特异性和COX-2特异性环氧合酶抑制剂、金化合物、皮质激素类、肿瘤坏死因子受体拮抗剂、水杨酸酯或盐、免疫抑制剂和甲胺蝶呤；以及药学上可接受的赋形剂。Another aspect of the invention relates to a pharmaceutical composition comprising one or more compounds of the formula I, II, IIa, IIb, IIc or stereoisomers thereof of the invention, An isomer or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof; one or more anti-inflammatory agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and COX- 2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunosuppressive agents and methotrexate; and pharmaceutically acceptable excipients .
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药在制备用于调节RORγ活性的药物中的用途。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or the use of a prodrug thereof for the preparation of a medicament for modulating RORγ activity.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药在制备用于治 疗或预防RORγ介导的疾病的药物中的用途。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or its prodrugs are prepared for treatment Use in the treatment or prevention of drugs for ROR gamma mediated diseases.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药在制备作为RORγ调节剂的药物中的用途。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or the use of a prodrug thereof for the preparation of a medicament as a ROR gamma modulator.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药，用于调节RORγ的活性。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or a prodrug thereof for regulating the activity of RORγ.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药，用于预防或治疗RORγ介导的疾病。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the present invention Or a prodrug thereof for preventing or treating a RORγ-mediated disease.
本发明的另一方面涉及包含本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药的药物组合物，用于调节RORγ的活性。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof, of the present invention A pharmaceutical composition of a compound or a prodrug thereof for regulating the activity of RORγ.
本发明的另一方面涉及包含本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药的药物组合物，用于预防或治疗RORγ介导的疾病。Another aspect of the invention relates to a compound of Formula I, Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof, of the present invention A pharmaceutical composition of a compound or a prodrug thereof for use in preventing or treating a RORγ-mediated disease.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括给予有需要的患者治疗有效量的一种或多种本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或其溶剂化物或其前药。Another aspect of the invention relates to a method of preventing or treating a RORγ-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa, Formula IIb of the invention A compound of the formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括给予有需要的患者治疗有效量的药物组合物，该药物组合物包含一种或多种本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药。Another aspect of the invention relates to a method of preventing or treating a RORγ-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising one or more Formula I of the invention A compound of Formula II, Formula IIa, Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括对有需要的患者联合给予治疗有效量的一种或多种本发明的式I、式II、式IIa、式IIb、式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药和一种或多种抗炎药。Another aspect of the invention relates to a method of preventing or treating a RORγ-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa of the invention, A compound of Formula IIb, Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and one or more anti-inflammatory agents.
具体实施方式Detailed ways
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。Unless otherwise defined, all technical and scientific terms used herein have the same meaning meaning meaning
应理解，上述简述和下文的详述为示例性且仅用于举例说明，而不对本发明主题作任何限制。The above description and the following detailed description are exemplary and are not intended to
本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。 All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are hereby incorporated by reference in their entirety.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-4烷基是指具有总共1至4个碳原子的如下文所定义的烷基；C6-12芳基是指具有总共6至12个碳原子的如下文所定义的芳基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1-4 alkyl means an alkyl group as defined below having a total of 1 to 4 carbon atoms; C 6-12 aryl means a aryl group as defined below having a total of 6 to 12 carbon atoms base. The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically indicated.
在本申请中，-C(O)-表示酰基或羰基，-S(O)2-表示磺酰基，-S(O)-表示亚磺酰基。In the present application, -C(O)- represents an acyl group or a carbonyl group, -S(O) 2 - represents a sulfonyl group, and -S(O)- represents a sulfinyl group.
在本申请中，术语“卤素”是指氟、氯、溴或碘，优选氟或氯。In the present application, the term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
在本申请中，作为基团或是其它基团的一部分，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键且通过单键与分子的其余部分连接的直链或支链的基团。烷基可以具有例如1至18个、优选1至8个、更优选1至6个、更优选1至4个碳原子。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等，优选甲基、乙基。In the present application, the term "alkyl" as a group or part of another group means a straight chain consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds and attached to the rest of the molecule by a single bond. Or a branched group. The alkyl group may have, for example, 1 to 18, preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methyl A hexyl group, a 3-methylhexyl group, an octyl group, a decyl group, a fluorenyl group and the like are preferably a methyl group or an ethyl group.
在本申请中，术语“卤代烷基”是指被一个或多个卤素原子取代的烷基，其中烷基如上文所定义。卤代烷基的实例包括但不限于三氟甲基、三氯甲基、二氯甲基、溴甲基、碘甲基、1,2-二氯乙基等，优选三氟甲基。In the present application, the term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, wherein alkyl is as defined above. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, dichloromethyl, bromomethyl, iodomethyl, 1,2-dichloroethyl, and the like, preferably trifluoromethyl.
在本申请中，术语“烷氧基”是指式-ORa基团，其中Ra为如上文所定义的烷基。烷氧基的实例包括但不限于甲氧基、乙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等，优选甲氧基。In the present application, the term "alkoxy" refers to a radical of the formula -OR a where R a is alkyl as defined above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like, with methoxy being preferred.
在本申请中，术语“卤代烷氧基”是指被一个或多个卤素原子取代的烷氧基，其中烷氧基如上文所定义。In the present application, the term "haloalkoxy" refers to an alkoxy group substituted by one or more halogen atoms, wherein alkoxy is as defined above.
在本申请中，术语“氨基”作为独立基团时是指式-NH2基团。In the present application, the term "amino" as a stand-alone group refers to a radical of the formula -NH 2 .
在本申请中，术语“烷基氨基”是指式-NHRa基团，其中Ra为如上文所定义的烷基。烷基氨基的实例包括但不限于甲基氨基、乙基氨基、异丙基氨基等。In the present application, the term "alkylamino" refers to a radical of the formula -NHR a where R a is alkyl as defined above. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, and the like.
在本申请中，术语“二烷基氨基”是指-NRaRb基团，其中Ra和Rb分别独立地为如上文所定义的烷基。二烷基氨基的实例包括但不限于二甲基氨基、二乙基氨基、二丙基氨基、甲基乙基氨基等，优选二甲基氨基。In the present application, the term "dialkylamino" refers to a radical -NR a R b wherein R a and R b are each independently alkyl as defined above. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, dipropylamino, methylethylamino, and the like, preferably dimethylamino.
在本申请中，术语“烷基磺酰基”是指-S(O)2Ra基团，其中Ra为如上文所定义的烷基。烷基磺酰基的实例包括但不限于甲磺酰基、乙磺酰基、异丙基磺酰基等，优选甲磺酰基。In the present application, the term "alkylsulfonyl" refers to a -S(O) 2 R a group, wherein R a is alkyl as defined above. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like, preferably a methylsulfonyl group.
在本申请中，术语“烷基磺酰氨基”是指-N(Rb)S(O)2Ra基团，其中Ra为如上文所定义的烷基，Rb为氢或如上文所定义的烷基。烷基磺酰氨基的实例包括但不限于甲磺酰基氨基、甲磺酰基(甲基)氨基、乙磺酰基(甲基)氨基、乙磺酰基(乙基)氨基等。In the present application, the term "alkylsulfonylamino" refers to a radical -N(R b )S(O) 2 R a wherein R a is alkyl as defined above, R b is hydrogen or as above The alkyl group defined. Examples of alkylsulfonylamino groups include, but are not limited to, methylsulfonylamino, methylsulfonyl (methyl)amino, ethylsulfonyl (methyl) amino, ethylsulfonyl (ethyl) amino, and the like.
在本申请中，术语“氨基磺酰基”是指式-S(O)2NH2基团。 In the present application, the term "aminosulfonyl" refers to a radical of the formula -S(O) 2 NH 2 .
在本申请中，术语“烷基氨基磺酰基”是指-S(O)2NHRa基团，其中Ra为如上文所定义的烷基。烷基氨基磺酰基的实例包括但不限于甲基氨基磺酰基、乙基氨基磺酰基、异丙基氨基磺酰基、叔丁基氨基磺酰基等。In the present application, the term "alkylaminosulfonyl" refers to a -S(O) 2 NHR a group, wherein R a is alkyl as defined above. Examples of alkylaminosulfonyl groups include, but are not limited to, methylaminosulfonyl, ethylaminosulfonyl, isopropylaminosulfonyl, t-butylaminosulfonyl and the like.
在本申请中，术语“二烷基氨基磺酰基”是指-S(O)2NRaRb基团，其中Ra和Rb分别为如上文所定义的烷基。二烷基氨基磺酰基的实例包括但不限于二甲基氨基磺酰基、二乙基氨基磺酰基、(甲基)(乙基)氨基磺酰基等。In the present application, the term "dialkylaminosulfonyl" refers to a -S(O) 2 NR a R b group, wherein R a and R b are each an alkyl group as defined above. Examples of the dialkylaminosulfonyl group include, but are not limited to, dimethylaminosulfonyl group, diethylaminosulfonyl group, (meth)(ethyl)aminosulfonyl group and the like.
在本申请中，术语“氨基甲酰基”是指式-C(O)NH2基团。In the present application, the term "carbamoyl" refers to the formula -C (O) NH 2 group.
在本申请中，术语“烷基氨基甲酰基”是指式-C(O)NHRa基团，其中Ra为如上文所定义的烷基。烷基氨基甲酰基的实例包括但不限于甲基氨基甲酰基、乙基氨基甲酰基等。In the present application, the term "alkylcarbamoyl" refers to a radical of the formula -C(O)NHR a where R a is alkyl as defined above. Examples of alkylcarbamoyl groups include, but are not limited to, methylcarbamoyl, ethylcarbamoyl and the like.
在本申请中，术语“二烷基氨基甲酰基”是指式-C(O)NRaRb基团，其中Ra和Rb分别为如上文所定义的烷基。二烷基氨基甲酰基的实例包括但不限于二甲基氨基甲酰基、二乙基氨基甲酰基、(甲基)(乙基)氨基甲酰基等，优选二甲基氨基甲酰基。In the present application, the term "dialkylcarbamoyl" refers to a radical of the formula -C(O)NR a R b wherein R a and R b are each independently alkyl as defined above. Examples of dialkylcarbamoyl groups include, but are not limited to, dimethylcarbamoyl, diethylcarbamoyl, (meth)(ethyl)carbamoyl and the like, preferably dimethylcarbamoyl.
在本申请中，术语“酰氨基”是指式-NRaC(O)Rb基团，其中Ra为氢或如上文所定义的烷基，Rb为氢或如上文所定义的烷基。酰氨基的实例包括但不限于甲酰基氨基、乙酰基氨基、乙酰基(甲基)氨基等。In the present application, the term "amido" refers to a radical of the formula -NR a C(O)R b wherein R a is hydrogen or alkyl as defined above and R b is hydrogen or an alkane as defined above base. Examples of the acylamino group include, but are not limited to, formylamino group, acetylamino group, acetyl (methyl) amino group and the like.
在本申请中，术语“烷基酰基”是指-C(O)Ra基团，其中Ra为氢或如上文所定义的烷基。烷基酰基的实例包括但不限于甲酰基、乙酰基、丙酰基、异丙酰基、叔丁酰基等。In the present application, the term "alkyl acyl" refers to a -C(O)R a group, wherein R a is hydrogen or alkyl as defined above. Examples of alkyl acyl groups include, but are not limited to, formyl, acetyl, propionyl, isopropionyl, t-butanoyl, and the like.
在本申请中，术语“烷基酰基氧基”是指-OC(O)Ra基团，其中Ra为氢或如上文所定义的烷基。烷基酰基氧基的实例包括但不限于甲酰基氧基、乙酰基氧基、丙酰基氧基、异丙酰基氧基、叔丁酰基氧基等。In the present application, the term "alkyl acyloxy" refers to a -OC(O)R a group, wherein R a is hydrogen or alkyl as defined above. Examples of alkylacyloxy groups include, but are not limited to, formyloxy, acetyloxy, propanoyloxy, isopropionyloxy, tert-butanoyloxy and the like.
在本申请中，术语“烷基氧基羰基”是指-C(O)ORa基团，其中Ra为如上文所定义的烷基。烷基氧基羰基的实例包括但不限于甲基氧基羰基、乙基氧基羰基、丙基氧基羰基、异丙基氧基羰基、叔丁基氧基羰基等，优选甲基氧基羰基、乙基氧基羰基。In the present application, the term "alkyloxycarbonyl" refers to a -C(O)OR a group, wherein R a is alkyl as defined above. Examples of the alkyloxycarbonyl group include, but are not limited to, a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, an isopropyloxycarbonyl group, a tert-butyloxycarbonyl group and the like, preferably a methyloxycarbonyl group. Ethyloxycarbonyl.
在本申请中，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的一价非芳香族单环或多环烃基，其可包括稠合环体系或桥环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。 In the present application, the term "cycloalkyl" means a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include a fused ring system or a bridged ring system, having 3 To 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which are saturated or unsaturated and can be attached to the remainder of the molecule via a single bond via any suitable carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1H-indenyl, indanyl, 1,2, 3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocycloheptene-6-yl, 6,7,8,9 -tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, indenyl, bicyclo[2.2.1]heptyl, 7, 7-Dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[ 3.2.1] Octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methylene-1H-indenyl and VIII Hydrogen-2,5-methylene-cyclopentadienyl and the like.
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至12个碳原子以及1至6个选自氮、氧和硫的杂原子组成的稳定的3元至18元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的3元至8元非芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至8元非芳香性单环基团，更优选为包含1至2个选自氮、氧和硫的杂原子的稳定的5元至6元非芳香性单环基团。杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。杂环基的实例包括但不限于：吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、吗啉基、硫代吗啉基、哌嗪基、哌啶基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In the present application, the term "heterocyclyl" as a group or part of another group means a stable consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. A 3- to 18-membered non-aromatic cyclic group. Unless otherwise specifically indicated in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system. For the purposes of the present invention, the heterocyclic group is preferably a stable 3- to 8-membered non-aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably comprising 1 to 3 stable 5- to 8-membered non-aromatic monocyclic groups selected from heteroatoms of nitrogen, oxygen and sulfur, more preferably stable to contain 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur A 5- to 6-membered non-aromatic monocyclic group. The nitrogen, carbon or sulfur atom in the heterocyclic group can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond. In the heterocyclic group containing a fused ring, one or more of the rings may be an aryl group or a heteroaryl group, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. Examples of heterocyclic groups include, but are not limited to, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, oxazinyl, di Oxycyclopentyl, tetrahydroisoquinolyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline Base, octahydrofluorenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl, phthalimido and the like.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个(优选为6至10个)碳原子及至少一个芳香环的体系。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，其可以包含稠合环或桥环体系。芳基经由芳香族环原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等，优选苯基。In the present application, the term "aryl" as a group or part of another group means a system having 6 to 18 (preferably 6 to 10) carbon atoms and at least one aromatic ring. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system which can comprise a fused ring or a bridged ring system. The aryl group is attached to the remainder of the molecule via a single bond via an aromatic ring atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one- A 7-group or the like is preferably a phenyl group.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个(优选为1至10个)碳原子和1至4个选自氮、氧及硫的杂原子，以及至少一个芳香环的5元至16元环体系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，其可包括稠合环体系或桥环体系，条件是连接点为芳香族环原子。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性单环或双环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性单环或双环基团，更优选为包含1至2个选自氮、氧和硫的杂原子的稳定的5元至6元芳香性单环或双环基团。杂芳基的实例包括但不限于噻吩基、呋喃基、吡咯基、[1,3,4]噁二唑基、[1,2,4]噻二唑基、[1,3,4]噻二唑基、咪唑基、苯并咪唑基、吡唑基、苯并吡唑基、三唑基、四唑基、吡啶基、吡嗪基、三嗪基、嘧啶基、哒嗪基、吲嗪基、吲哚基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、噻唑基、异噻唑基、苯并噻唑基、苯并噻吩基、噁唑基、异噁唑基、噁二唑基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、 邻二氮杂菲基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基等，优选吡咯基、吡唑基、咪唑基、噻吩基、呋喃基、三唑基、四唑基、噁唑基、异噁唑基、嘧啶基、哒嗪基等，更优选吡啶基。In the present application, the term "heteroaryl" as a group or part of another group means having from 1 to 15 (preferably from 1 to 10) carbon atoms and from 1 to 4 selected from nitrogen and oxygen in the ring. And a hetero atom of sulfur, and a 5- to 16-membered ring system group of at least one aromatic ring. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system, provided that the point of attachment is an aromatic ring atom . The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 a stable 5- to 10-membered aromatic monocyclic or bicyclic group to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable to contain 1 to 2 heteroatoms selected from nitrogen, oxygen and sulfur A 5- to 6-membered aromatic monocyclic or bicyclic group. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, [1,3,4]oxadiazolyl, [1,2,4]thiadiazolyl, [1,3,4]thiazide Diazolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzopyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, triazinyl, pyrimidinyl, pyridazinyl, pyridazine Base, fluorenyl, isodecyl, carbazolyl, isoxazolyl, fluorenyl, quinolyl, isoquinolinyl, diazaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, Carbazolyl, porphyrinyl, phenanthryl, phenanthroline, acridinyl, phenazinyl, thiazolyl, isothiazolyl, benzothiazolyl, benzothienyl, oxazolyl, isoxazolyl , oxadiazolyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, mesoindolyl, O-diazepine, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthylpyridyl, etc., preferably pyrrolyl, pyrazolyl, imidazole A pyridyl group, a thienyl group, a furyl group, a triazolyl group, a tetrazolyl group, an oxazolyl group, an isoxazolyl group, a pyrimidinyl group, a pyridazinyl group or the like is more preferred.
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。"Stereoisomer" refers to a compound composed of the same atoms bonded by the same bond but having a different three-dimensional structure. The invention will cover various stereoisomers and mixtures thereof.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的、与无机酸或有机酸所形成的盐。所述无机酸包括但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等；所述有机酸包括但不限于甲酸、乙酸、三氟乙酸、丙酸、辛酸、己酸、癸酸、十一碳烯酸、乙醇酸、葡糖酸、乳酸、草酸、癸二酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、硬脂酸、油酸、肉桂酸、月桂酸、苹果酸、谷氨酸、焦谷氨酸、天冬氨酸、苯甲酸、甲磺酸、对甲苯磺酸、海藻酸、抗环血酸、水杨酸、4-氨基水杨酸、萘二磺酸等。"Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid capable of retaining the bioavailability of the free base without other side effects. The inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; the organic acid includes, but not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, caprylic acid, caproic acid, capric acid, eleven Carbenolic acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, azelaic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, Stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, Salicylic acid, 4-aminosalicylic acid, naphthalene disulfonic acid, and the like.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的盐。这些盐是通过将无机碱或有机碱添加至游离酸而制备的。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐和镁盐。衍生自有机碱的盐包括但不限于以下碱的盐：伯胺、仲胺及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。"Pharmaceutically acceptable base addition salt" refers to a salt that is capable of retaining the biological effectiveness of the free acid without other side effects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of the following bases: primary, secondary and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl Amine, lysine, arginine, histidine, caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, tromethamine, hydrazine, piperazine, piperidine , N-ethyl piperidine, polyamine resin, and the like.
根据带电荷官能团的数目和阳离子或阴离子的化合价，本发明化合物可以含有多个阳离子或阴离子。The compound of the present invention may contain a plurality of cations or anions depending on the number of charged functional groups and the valence of the cation or anion.
通常，结晶化作用会产生本发明化合物的溶剂化物。在本申请中，“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。它们或者在溶剂中反应或者从溶剂中沉淀析出或者结晶出来。溶剂可以是水，该情况下的溶剂化物是水合物。或者，溶剂也可以是有机溶剂。本发明化合物的溶剂化物也属于本发明范围之内。Generally, crystallization will result in a solvate of the compound of the invention. As used herein, "solvate" refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. They either react in a solvent or precipitate out of the solvent or crystallize out. The solvent may be water, and the solvate in this case is a hydrate. Alternatively, the solvent may also be an organic solvent. Solvates of the compounds of the invention are also within the scope of the invention.
在本申请中，术语“前药”表示可在生理学条件下被水解或经由酶反应而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。但被给予有需要的个体时，前药可以不具有活性，但在体内被转 化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。对于前药的评述可以参见以下文献：Kevin Beaumont,et al.,Current Drug Metabolism,4(6),461-485,2003；Peter Ettmayer,et al.,Journal of Medicinal Chemistry,47(10),2393-2404,2004；Stella V.J.,Expert Opinion on Therapeutic Patents,14(3),277-280,2004；Jarkko Rautio,et al.,Nature Review Drug Discovery,7(3),255-270,2008。In the present application, the term "prodrug" means a compound which can be hydrolyzed under physiological conditions or converted into a biologically active compound of the invention via an enzymatic reaction. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention. However, when given to an individual in need, the prodrug may not be active, but is transferred in the body. The active compound of the invention is derived. Prodrugs are typically rapidly converted in vivo to produce the parent compound of the invention, for example by hydrolysis in blood. Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms. A review of prodrugs can be found in Kevin Beaumont, et al., Current Drug Metabolism, 4(6), 461-485, 2003; Peter Ettmayer, et al., Journal of Medicinal Chemistry, 47(10), 2393. -2404, 2004; Stella VJ, Expert Opinion on Therapeutic Patents, 14(3), 277-280, 2004; Jarkko Rautio, et al., Nature Review Drug Discovery, 7(3), 255-270, 2008.
本领域技术人员所熟知的是，含羧基的化合物(例如本发明化合物)的酯，例如药学上可接受的酯，可以作为本发明化合物的前药，其在人体或动物体内可分解成为母体酸。药学可接受的酯包括但不限于烷基酯，例如甲酯，乙酯或丙酯等；烷氧基甲基酯，例如甲氧基甲基酯；烷酰氧基甲基酯，例如乙酰氧基甲基酯；烷基取代的甲酰胺基烷基酯，例如N,N-二甲基甲酰胺基甲基酯和N,N-二乙基甲酰胺基甲基酯等(例如参见专利文献US5073641)。It is well known to those skilled in the art that esters of carboxyl-containing compounds (e.g., compounds of the invention), such as pharmaceutically acceptable esters, can be used as prodrugs of the compounds of the invention which decompose into the parent acid in the human or animal body. . Pharmaceutically acceptable esters include, but are not limited to, alkyl esters such as methyl, ethyl or propyl esters; alkoxymethyl esters such as methoxymethyl esters; alkanoyloxymethyl esters such as acetoxy Methyl ester; alkyl substituted carboxamide alkyl ester, such as N,N-dimethylformamidomethyl ester and N,N-diethylformamidomethyl ester (see, for example, patent documents) US5073641).
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的赋形剂。In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable excipient.
在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂等。In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals. Sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, and the like.
在本申请中，“治疗有效剂量”是指当将本发明化合物给予哺乳动物(例如人)时，足以有效地治疗该哺乳动物(例如人)的疾病的本发明化合物的量。构成“治疗有效剂量”的本发明化合物的量取决于所用的具体化合物、要治疗的具体病症、病症的起因、药物的靶点、疾病的严重程度、给药方式以及待治疗的哺乳动物的年龄、体重、身体状况等，但可常规地由本领域技术人员根据其自身的知识及本申请公开的内容而决定。In the present application, "therapeutically effective dose" refers to an amount of a compound of the invention sufficient to effectively treat a disease in a mammal (e.g., a human) when a compound of the invention is administered to a mammal (e.g., a human). The amount of a compound of the invention that constitutes a "therapeutically effective amount" will depend on the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the disease, the mode of administration, and the age of the mammal being treated. , body weight, physical condition, etc., but can be routinely determined by those skilled in the art based on their own knowledge and the content disclosed in the present application.
本文所用术语“预防”包括使病患减少疾病或病症的发生或恶化的可能性。The term "prevention" as used herein includes the possibility of reducing the occurrence or progression of a disease or condition by a patient.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：The term "treatment" and other similar synonyms as used herein includes the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, ie, curbing its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or
(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.
本文中使用的术语“疾病”与“病症”可以互换使用或可能不同。The terms "disease" and "condition" as used herein are used interchangeably or may vary.
在本申请中，术语“RORγ介导的疾病”是指其中RORγ或者通过RORγ本身的产生或改变活性水平，或者通过引起一种细胞因子例如(但不限于)IL-17或IL-23的释放 而起作用的任何疾病或其它有害的情况。RORγ介导的疾病可以是自体免疫性疾病和/或炎性疾病，其实例包括但不限于类风湿性关节炎、多发性硬化症、银屑病、克罗恩病、哮喘、系统性红斑狼疮、慢性阻塞性肺病、组织移植物排斥反应和移植器官的排斥反应、硬皮病、紫癜、自身免疫溶血性和血小板减少性症状、应激性肠综合症、骨关节炎、川崎氏病、桥本氏甲状腺炎、粘膜利斯曼病、支气管炎、过敏性鼻炎、特应性皮炎、囊性纤维化、肺代谢排斥反应、儿童类风湿关节炎、强直性脊柱炎、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、sjorgen氏综合症、视神经炎、糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合症、银屑病性关节炎、葛瑞夫氏病或巩膜炎。In the present application, the term "RORγ-mediated disease" refers to the release or alteration of the activity level of RORγ either by RORγ itself, or by the release of a cytokine such as, but not limited to, IL-17 or IL-23. Any disease or other harmful condition that works. The RORγ-mediated disease may be an autoimmune disease and/or an inflammatory disease, examples of which include, but are not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, asthma, systemic lupus erythematosus , chronic obstructive pulmonary disease, tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, irritable bowel syndrome, osteoarthritis, Kawasaki disease, bridge Ben's thyroiditis, mucosal Leishman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis in children, ankylosing spondylitis, pancreatitis, autoimmune Diabetes, autoimmune eye disease, ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriatic arthritis, griff Disease or scleritis.
在本申请中，“RORγ调节剂”是指与靶点RORγ有相互作用并影响RORγ功能的分子，这种相互作用包括但不限于：拮抗、激动、反向激动及其它的类似的相互作用。In the present application, "RORγ modulator" refers to a molecule that interacts with the target RORγ and affects RORγ function, including but not limited to: antagonism, agonism, inverse agonism, and other similar interactions.
在本申请中，“任选”、“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被一个或多个卤素取代的烷基”表示烷基未被取代或被一个或多个卤素取代，且该描述同时包括被取代的烷基与未被取代的烷基。In the present application, "optional", "optional" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition. . For example, "alkyl group optionally substituted with one or more halogens" means that the alkyl group is unsubstituted or substituted with one or more halogens, and the description includes both substituted alkyl groups and unsubstituted alkyl groups.
一方面，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或者其溶剂化物或前药，其中所述化合物具有结构式I：In one aspect, the invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or prodrug thereof, wherein the compound has the formula I:
Figure PCTCN2015074412-appb-000006
Figure PCTCN2015074412-appb-000006
其中：among them:
X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
L选自-C(O)-、-S(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O)-, -S(O) 2 - or -CH 2 -;
A选自芳基或杂芳基，所述芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；A is selected from aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy , haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl;
B为选自以下的二价环：环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、或芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、硝基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、烷基磺酰氨基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰氨基或烷基酰基；B is a divalent ring selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, or aryl group or heteroaryl group is optionally independently one of the following Or a plurality of groups substituted: halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
n是0、1或2； n is 0, 1 or 2;
R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
Rb选自烷基、氨基、烷基氨基或二烷基氨基；且R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基。R 2 when present is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy.
在本发明的式I化合物的一些实施方式中，L选自-C(O)-。在另一些实施方式中，L选自-S(O)-。在另一些实施方式中，L选自-S(O)2-。在又一些优选实施方式中，L选自-CH2-。In some embodiments of the compounds of Formula I of the invention, L is selected from -C(O)-. In other embodiments, L is selected from the group consisting of -S(O)-. In other embodiments, L is selected from the group consisting of -S(O) 2- . In further preferred embodiments, L is selected from -CH 2 -.
在本发明的式I化合物的一些实施方式中，A选自芳基或杂芳基，优选为C6-12芳基或5-12元杂芳基，所述芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基。In some embodiments of the compounds of Formula I of the present invention, A is selected from aryl or heteroaryl, preferably C 6-12 aryl or 5-12 membered heteroaryl, optionally substituted as aryl or heteroaryl Substituted independently by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonyl Amino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl.
在本发明的式I化合物的一些实施方式中，A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、C1-8烷基、C1-8烷氧基、卤代C1-8烷基、C1-8烷基氨基、二C1-8烷基氨基、C1-8烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、C1-8烷基氨基甲酰基、二C1-8烷基氨基甲酰基或C1-8烷基酰基。In some embodiments of the compounds of Formula I of the present invention, A is selected from C 6-12 aryl or 5-12 membered heteroaryl, and the C 6-12 aryl or 5-12 membered heteroaryl is optionally independent Substituted by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkyl, C 1- 8 -alkylamino, di-C 1-8 alkylamino, C 1-8 alkylsulfonyl, sulfonylamino, amido, carbamoyl, C 1-8 alkylcarbamoyl, di C 1-8 alkane A carbamoyl group or a C 1-8 alkyl acyl group.
在本发明的式I化合物的一些实施方式中，A选自C6-10芳基或5-10元杂芳基，所述C6-10芳基或5-10元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、C1-4烷基氨基、二C1-4烷基氨基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基。In some embodiments of the compounds of Formula I of the present invention, A is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the C 6-10 aryl or 5-10 membered heteroaryl is optionally independent Substituted by one or more of the following groups: halogen, amino, cyano, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, C 1- 4 -alkylamino, di-C 1-4 alkylamino, carbamoyl, C 1-4 alkylcarbamoyl or di C 1-4 alkylcarbamoyl.
在本发明的式I化合物的一些实施方式中，A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氰基、C1-4烷基、C1-4烷氧基或卤代C1-4烷基。In some embodiments of the compounds of Formula I of the present invention, A is selected from phenyl or 5-6 membered heteroaryl, optionally substituted independently by one or more of the following Group substitution: halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy or halo C 1-4 alkyl.
在本发明的式I化合物的一些实施方式中，A选自苯基，所述苯基任选独立地被以下的一个或多个基团取代：卤素、C1-4烷基或卤代C1-4烷基。In some embodiments of the compounds of Formula I of the present invention, A is selected from phenyl, which is optionally independently substituted with one or more of the following: halo, C 1-4 alkyl or halo C 1-4 alkyl.
在本发明的式I化合物的一些实施方式中，B为选自以下的二价环：环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、或芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、硝基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、烷基磺酰氨基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰氨基或烷基酰基。In some embodiments of the compounds of Formula I of the invention, B is a divalent ring selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, said cycloalkyl, heterocyclyl, or aryl The or heteroaryl group is optionally substituted independently with one or more of the following: halo, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dioxane Alkylamino, alkylsulfonyl, alkylsulfonylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, amido Or an alkyl acyl group.
在本发明的式I化合物的一些优选实施方式中，B为选自以下的二价环：C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个 基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基。In some preferred embodiments of the compounds of formula I of the present invention, B is a divalent ring selected from the group consisting of C 6-12 aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5- The 12-membered heteroaryl group is optionally substituted independently with one or more of the following groups: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, An acylamino group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkyl acyl group.
在本发明的式I化合物的一些实施方式中，X为-C(O)-。在另一些实施方式中，X为-CH2C(O)-。在另一些实施方式中，X为-CH2CH2-。In some embodiments of the compounds of Formula I of the invention, X is -C(O)-. In other embodiments, X is -CH 2 C (O) -. In other embodiments, X is -CH 2 CH 2 -.
在本发明的式I化合物的一些实施方式中，m为0、1、2、3或4。在一些实施方式中，m为0，此时R2不存在。在另一些实施方式中，m为1。在又一些实施方式中，m为2。In some embodiments of the compounds of Formula I of the invention, m is 0, 1, 2, 3 or 4. In some embodiments, m is 0, in which case R 2 is absent. In other embodiments, m is one. In still other embodiments, m is 2.
在本发明的式I化合物的一些实施方式中，n为0。在另一些实施方式中，n为1。在又一些实施方式中，n为2。In some embodiments of the compounds of Formula I of the invention, n is zero. In other embodiments, n is one. In still other embodiments, n is 2.
在本发明的式I化合物的一些实施方式中，R1选自-C(O)Ra，其中Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基。在另一些实施方式中，R1选自-C(O)Ra，其中Ra选自羟基、C1-4烷氧基、氨基、C1-4烷基氨基或二C1-4烷基氨基。在另一些实施方案中，R1选自-C(O)Ra，其中Ra为羟基、烷氧基或氨基。在又一些实施方案中，R1选自-C(O)Ra，其中Ra为羟基。In some embodiments of the compounds of Formula I of the present invention, R 1 is selected from -C(O)R a wherein R a is selected from hydroxy, alkoxy, amino, alkylamino or dialkylamino. In other embodiments, R 1 is selected from -C(O)R a , wherein R a is selected from hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino or di C 1-4 alkane Amino group. In other embodiments, R 1 is selected from -C(O)R a wherein R a is hydroxy, alkoxy or amino. In still other embodiments, R 1 is selected from -C(O)R a , wherein R a is hydroxy.
在本发明的式I化合物的一些实施方式中，R1选自-S(O)2Rb，其中Rb选自烷基、氨基、烷基氨基或二烷基氨基。在另一些实施方案中，R1选自-S(O)2Rb，其中Rb选自C1-4烷基、氨基、C1-4烷基氨基或二C1-4烷基氨基。在又一些实施方案中，R1选自-S(O)2Rb，其中Rb为烷基，优选为C1-4烷基。In some embodiments of compounds of formula I of the invention, R 1 is selected from -S (O) 2 R b, wherein R b is selected from alkyl, amino, alkylamino or dialkylamino. In other embodiments, R 1 is selected from -S(O) 2 R b , wherein R b is selected from C 1-4 alkyl, amino, C 1-4 alkylamino or di C 1-4 alkylamino . In yet other embodiments, R 1 is selected from -S (O) 2 R b, wherein R b is alkyl, preferably C 1-4 alkyl.
在本发明的式I化合物的一些实施方式中，R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基。In some embodiments of the compounds of Formula I of the present invention, R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy base.
在本发明的式I化合物的一些实施方式中，R2当存在时独立地选自卤素、氰基、硝基、羟基、C1-4烷基酰基氧基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或卤代C1-4烷氧基。In some embodiments of the compounds of Formula I of the invention, R 2 , when present, is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, C 1-4 alkyl acyloxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or halo C 1-4 alkoxy.
在本发明的式I化合物的一些实施方式中，R2当存在时独立地选自卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或卤代C1-4烷氧基。In some embodiments of the compounds of Formula I of the present invention, R 2 , when present, is independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl Or a halogenated C 1-4 alkoxy group.
在本发明的式I化合物的一些实施方式中，R2当存在时独立地选自卤素、C1-4烷基或卤代C1-4烷基。在本发明的式I化合物的一些实施方式中，R2当存在时独立地选自卤素。In some embodiments of compounds of Formula I of the present invention, is independently selected from halogen, C 1-4 alkyl or halogenated C 1-4 alkyl R 2, when present. In some embodiments of compounds of Formula I of the present invention, is independently selected from halogen when R 2, when present.
在本发明的式I化合物中，上述A、B、L、X、R1、R2、m和n可以以任意适当的方式进行组合，例如但不限于组合成下文所述的式II化合物、式IIa化合物、式IIb化合物、式IIc化合物，所有这些组合均涵盖在本发明范围内。In the compounds of formula I of the present invention, the above A, B, L, X, R 1 , R 2 , m and n may be combined in any suitable manner, such as, but not limited to, in combination with a compound of formula II as described below, Compounds of formula IIa, compounds of formula IIb, compounds of formula IIc, all such combinations are embraced within the scope of the invention.
在一些具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有结构式II(在下文有时被称为式II化合物)： In some embodiments, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula II (hereinafter sometimes referred to as the compound of formula II):
Figure PCTCN2015074412-appb-000007
Figure PCTCN2015074412-appb-000007
其中：among them:
Q选自N或-CR4；Q is selected from N or -CR 4 ;
R3选自氢、卤素、氨基、氰基、羟基、羧基、硝基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、烷基磺酰氨基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰氨基或烷基酰基；且R 3 is selected from the group consisting of hydrogen, halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino, An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
X、L、A、m、n、R1和R2均如上面对式I化合物中所定义。X, L, A, m, n, R 1 and R 2 are all as defined above in the compound of formula I.
在本发明的式II化合物的一些实施方案中，在式II中，Q选自N或-CR4；X选自-C(O)-、-CH2C(O)-或-CH2CH2-；L选自-C(O)-、-S(O)2-或-CH2-；A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；m是0、1、2、3或4；n是0、1或2；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；Rb选自烷基、氨基、烷基氨基或二烷基氨基；R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R4选自氢、卤素或烷基。In some embodiments of a compound of Formula II of the present invention, in Formula II, Q is selected from N or -CR 4 ; X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -; L is selected from -C(O)-, -S(O) 2 - or -CH 2 -; A is selected from C 6-12 aryl or 5-12 membered heteroaryl, said C 6-12 The aryl or 5-12 membered heteroaryl is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, Dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group; R b is selected from alkyl, amino, alkylamino or dialkylamino; when present, R 2 is, independently, selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy; R 3 is selected from hydrogen, halo, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino Amino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl group; and R 4 is selected from hydrogen, halo or alkyl.
在本发明的式II化合物的一些实施方案中，在式II中，Q选自N或-CR4；A选自C6-10芳基或5-10元杂芳基，所述C6-10芳基或5-10元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、C1-4烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；n是0、1或2；m是0、1或2；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、C1-4烷氧基、氨基、C1-4烷基氨基或二C1-4烷基氨基；Rb选自C1-4烷基、氨基、C1-4烷基氨基或二C1-4烷基氨基；R2当存在时独立地选自卤素、氰基、羟基、烷基、烷氧基、卤代烷基或卤代烷氧基；R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R4选自氢、卤素或烷基。In some embodiments of a compound of Formula II of the present invention, in Formula II, Q is selected from N or -CR 4 ; A is selected from C 6-10 aryl or 5-10 membered heteroaryl, said C 6- The 10 aryl or 5-10 membered heteroaryl is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, C 1-4 alkyl, alkoxy, haloalkyl , alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; n is 0, 1 or 2; m is 0, 1 or 2; R 1 is selected from -C ( O) R a, or -S (O) 2 R b; R a is selected from hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino or di C 1-4 alkylamino group; R b is selected from From C 1-4 alkyl, amino, C 1-4 alkylamino or di C 1-4 alkylamino; R 2 when present is independently selected from halo, cyano, hydroxy, alkyl, alkoxy, Haloalkyl or haloalkoxy; R 3 is selected from hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or An alkylcarbamoyl group; and R 4 is selected from hydrogen, halogen or alkyl.
在式II化合物的一些具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有 结构式IIa(在下文有时被称为式IIa化合物)：In some embodiments of the compound of Formula II, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein Compound has Structural Formula IIa (hereinafter sometimes referred to as the compound of Formula IIa):
Figure PCTCN2015074412-appb-000008
Figure PCTCN2015074412-appb-000008
其中Q、L、A、R1、R2、R3、m和n均如式II中所定义。Wherein Q, L, A, R 1 , R 2 , R 3 , m and n are as defined in formula II.
在式IIa化合物的一些优选实施方案中，在式IIa中，Q选自N或-CR4；L选自-C(O)-、-S(O)2-或-CH2-；A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；m是0、1、2、3或4；n是0、1或2；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；Rb选自烷基、氨基、烷基氨基或二烷基氨基；R2当存在时独立地选自卤素、氰基、羟基、烷基、烷氧基、卤代烷基或卤代烷氧基；R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R4选自氢、卤素或烷基。In some preferred embodiments of the compound of Formula IIa, in Formula IIa, Q is selected from N or -CR 4 ; L is selected from -C(O)-, -S(O) 2 - or -CH 2 -; From a C 6-12 aryl or a 5-12 membered heteroaryl, the C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted, independently, with one or more of the following groups: halo, amino , cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from hydroxy, alkoxy, amino, alkylamino Or a dialkylamino group; R b is selected from alkyl, amino, alkylamino or dialkylamino; R 2 when present is independently selected from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl or Haloalkoxy; R 3 is selected from hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylamino Formyl; and R 4 is selected from hydrogen, halogen or alkyl.
在式IIa化合物的一些实施方案中，Q选自N或-CR4；L选自-C(O)-、-S(O)2-或-CH2-；A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基；m选自0、1或2；n选自0或1；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、C1-4烷氧基、氨基、C1-4烷基氨基或二C1-4烷基氨基；Rb选自C1-4烷基、氨基、C1-4烷基氨基或二C1-4烷基氨基；R2当存在时独立地选自卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或卤代C1-4烷氧基；R3选自氢、卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；且R4选自氢、卤素或C1-4烷基。In some embodiments of a compound of Formula IIa, Q is selected from N or -CR 4 ; L is selected from -C(O)-, -S(O) 2 - or -CH 2 -; A is selected from phenyl or 5- a 6-membered heteroaryl group, the phenyl or 5-6 membered heteroaryl optionally being independently substituted with one or more of the following: halogen, cyano, C 1-4 alkyl, C 1-4 alkane Oxy, halo C 1-4 alkyl; m is selected from 0, 1 or 2; n is selected from 0 or 1; R 1 is selected from -C(O)R a or -S(O) 2 R b ; a is selected from hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino or di C 1-4 alkylamino; R b is selected from C 1-4 alkyl, amino, C 1-4 alkane a base amino group or a di-C 1-4 alkylamino group; when present, R 2 is independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or Halogen C 1-4 alkoxy; R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, carbamoyl, C 1-4 alkylcarbamoyl or diC 1-4 alkylcarbamoyl; and R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
在式IIa化合物的一些实施方案中，Q选自N或-CR4；L选自-C(O)-、-S(O)2-或-CH2-；A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氰基、C1-4烷基或卤代C1-4烷基；m是0或1；n是0或1；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、C1-4烷氧基或氨基；Rb选自烷基；R2当存在时独立地选自卤素、C1-4烷基或卤代C1-4烷基；R3选自氢、卤素、C1-4烷基、C1-4烷氧基或二C1-4烷基氨基甲酰基；且R4选自氢、卤素或C1-4烷基。In some embodiments of a compound of Formula IIa, Q is selected from N or -CR 4 ; L is selected from -C(O)-, -S(O) 2 - or -CH 2 -; A is selected from phenyl or 5- a 6-membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halo, cyano, C 1-4 alkyl or halo C 1- 4 alkyl; m is 0 or 1; n is 0 or 1; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from hydroxy, C 1-4 alkoxy Or an amino group; R b is selected from an alkyl group; when present, R 2 is independently selected from halogen, C 1-4 alkyl or halo C 1-4 alkyl; R 3 is selected from hydrogen, halogen, C 1-4 alkane a group, a C 1-4 alkoxy group or a di C 1-4 alkylcarbamoyl group; and R 4 is selected from the group consisting of hydrogen, halogen or C 1-4 alkyl.
在式IIa化合物的又一些实施方案中，Q选自N或-CR4；L选自-C(O)-或-CH2-；A选自苯基，所述苯基任选独立地被以下的一个或多个基团取代：卤素、C1-4烷基或卤代C1-4烷基；m是0或1；n是0；R1选自羧基；R2当存在时独立地选自卤素、C1-4 烷基或卤代C1-4烷基；R3选自氢；且R4选自氢、卤素或C1-4烷基。In still other embodiments of the compound of Formula IIa, Q is selected from N or -CR 4 ; L is selected from -C(O)- or -CH 2 -; A is selected from phenyl, which is optionally independently Substituted one or more of the following: halogen, C 1-4 alkyl or halo C 1-4 alkyl; m is 0 or 1; n is 0; R 1 is selected from carboxy; R 2 is independent when present Is selected from halogen, C 1-4 alkyl or halo C 1-4 alkyl; R 3 is selected from hydrogen; and R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
在式II化合物的一些具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有结构式IIb(在下文有时被称为式IIb化合物)：In some embodiments of the compound of Formula II, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein The compound has the structural formula IIb (hereinafter sometimes referred to as the compound of formula IIb):
Figure PCTCN2015074412-appb-000009
Figure PCTCN2015074412-appb-000009
其中Q、L、A、R1、R2、R3和m均如式II中所定义。Wherein Q, L, A, R 1 , R 2 , R 3 and m are as defined in formula II.
在式IIb化合物的一些具体实施方案中，在式IIb中，Q选自N或-CR4；L选自-C(O)-或-S(O)2-；A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基环任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；m是0、1、2、3或4；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；Rb选自烷基、氨基、烷基氨基或二烷基氨基；R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R4选自氢、卤素或烷基。In some embodiments of the compound of Formula IIb, in Formula IIb, Q is selected from N or -CR 4 ; L is selected from -C(O)- or -S(O) 2 -; A is selected from C 6-12 Aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5-12 membered heteroaryl ring optionally substituted independently with one or more of the following: halo, amino, cyano, Hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; m is 0, 1, 2, 3 or 4; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group; and R b is selected from an alkyl group. , an amino group, an alkylamino group or a dialkylamino group; when present, R 2 is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy ; R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; And R 4 is selected from hydrogen, halogen or alkyl.
在式IIb化合物的一些具体实施方案中，在式IIb中，Q选自N或-CR4；L选自-C(O)-或-S(O)2-；A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基环任选独立地被以下的一个或多个基团取代：卤素、C1-4烷基、卤代C1-4烷基或氰基；m是0或1；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、C1-4烷氧基或氨基；Rb选自C1-4烷基；R2当存在时独立地选自卤素或C1-4烷基；R3选自氢、卤素、C1-4烷基、C1-4烷氧基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；且R4选自氢、卤素或C1-4烷基。In some specific embodiments of the compound of Formula IIb, in Formula IIb, Q is selected from N or -CR 4 ; L is selected from -C(O)- or -S(O) 2 -; A is selected from phenyl or 5 a -6 membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halogen, C 1-4 alkyl, halo C 1-4 Alkyl or cyano; m is 0 or 1; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from hydroxy, C 1-4 alkoxy or amino; R b is selected from C 1-4 alkyl; R 2 when independently present is selected from halogen or C 1-4 alkyl; R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy A carbamoyl group, a C 1-4 alkylcarbamoyl group or a di C 1-4 alkylcarbamoyl group; and R 4 is selected from the group consisting of hydrogen, halogen or C 1-4 alkyl.
在式II化合物的一些具体实施方案中，本发明提供了一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有结构式IIc(在下文有时被称为式IIc化合物)：In some embodiments of the compound of Formula II, the present invention provides a compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein The compound has the structural formula IIc (hereinafter sometimes referred to as the compound of formula IIc):
Figure PCTCN2015074412-appb-000010
Figure PCTCN2015074412-appb-000010
其中Q、L、A、R1、R2、R3和m均如式II中所定义。Wherein Q, L, A, R 1 , R 2 , R 3 and m are as defined in formula II.
在式IIc化合物的一些具体实施方案中，在式IIc中，Q选自N或-CR4；L选自-C(O)-或-S(O)2-；A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；m是0、1、2、3或4；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；Rb选自烷基、氨基、烷基氨基或二烷基氨基；R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R4是氢、卤素或烷基。In some specific embodiments of the compound of Formula IIc, in Formula IIc, Q is selected from N or -CR 4 ; L is selected from -C(O)- or -S(O) 2 -; A is selected from C 6-12 Aryl or 5-12 membered heteroaryl, said C 6-12 aryl or 5-12 membered heteroaryl optionally substituted independently with one or more of the following: halo, amino, cyano, hydroxy , carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; m is 0, 1, 2, 3 or 4 ; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from hydroxy, alkoxy, amino, alkylamino or dialkylamino; R b is selected from alkyl, An amino group, an alkylamino group or a dialkylamino group; when present, R 2 is independently selected from halogen, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy; R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl; R 4 is hydrogen, halogen or alkyl.
在式IIc化合物的一些具体实施方案中，在式IIc中，Q选自N或-CR4；L选自-C(O)-或-S(O)2-；A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基环任选独立地被以下的一个或多个基团取代：卤素、C1-4烷基、卤代C1-4烷基或氰基；m是0或1；R1选自-C(O)Ra或-S(O)2Rb；Ra选自羟基、C1-4烷氧基或氨基；Rb选自C1-4烷基；R2当存在时独立地选自卤素或C1-4烷基；R3选自氢、卤素、C1-4烷基、C1-4烷氧基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；且R4选自氢、卤素或C1-4烷基。In some specific embodiments of the compound of Formula IIc, in Formula IIc, Q is selected from N or -CR 4 ; L is selected from -C(O)- or -S(O) 2 -; A is selected from phenyl or 5 a -6 membered heteroaryl group, which is optionally substituted independently with one or more of the following groups: halogen, C 1-4 alkyl, halo C 1-4 Alkyl or cyano; m is 0 or 1; R 1 is selected from -C(O)R a or -S(O) 2 R b ; R a is selected from hydroxy, C 1-4 alkoxy or amino; R b is selected from C 1-4 alkyl; R 2 when independently present is selected from halogen or C 1-4 alkyl; R 3 is selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy A carbamoyl group, a C 1-4 alkylcarbamoyl group or a di C 1-4 alkylcarbamoyl group; and R 4 is selected from the group consisting of hydrogen, halogen or C 1-4 alkyl.
在一些实施方案中，本发明的化合物选自：In some embodiments, the compounds of the invention are selected from the group consisting of
Figure PCTCN2015074412-appb-000011
Figure PCTCN2015074412-appb-000011
Figure PCTCN2015074412-appb-000012
Figure PCTCN2015074412-appb-000012
本发明的式I、式II、式IIa、式IIb和式IIc化合物或其药学上可接受的盐可能含一个或多个手性碳原子，每个不对称碳原子可以是R或S构型，两种构型都在本发明范围之内。因此，化合物可以作为对映异构体、非对映异构体或它们的混合物存在。上述化合物可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术拆分，例如通过手性色谱法或者分段结晶法。The compounds of Formula I, Formula II, Formula IIa, Formula IIb and Formula IIc of the present invention, or a pharmaceutically acceptable salt thereof, may contain one or more chiral carbon atoms, and each asymmetric carbon atom may be in the R or S configuration. Both configurations are within the scope of the invention. Thus, the compounds may exist as enantiomers, diastereomers or mixtures thereof. The above compounds may be selected from the racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by chiral chromatography or fractional crystallization.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法解析外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu. Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH Ed.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography. See, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3: 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH Ed., Longman Scientific and Technical Ltd., Essex, 1991, 809- 816; Heller, Acc. Chem. Res. 1990, 23, 128.
本发明的另一方面涉及药物组合物，其包含一种或多种本发明的式I、式II、式IIa、式IIb和式IIc化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，以及药学上可接受的赋形剂。Another aspect of the invention relates to a pharmaceutical composition comprising one or more compounds of formula I, formula II, formula IIa, formula IIb and formula IIc of the invention, or a stereoisomer, tautomer thereof or A pharmaceutically acceptable salt or a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable excipient.
本发明的药物组合物可以被配制为固态、半固态、液态或气态制剂，如片剂、胶囊、粉剂、颗粒剂、膏剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶。The pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and Aerosol.
本发明的药物组合物可以通过制药领域中公知的方法制备。例如，旨在注射给药的药物组合物可以通过将本发明的化合物或其药学上可接受的盐或前药与灭菌的蒸馏水组合来制备，从而形成溶液剂。可添加表面活性剂以促进形成均匀溶液或混悬液。制备药物组合物的实际方法为本领域技术人员所已知，例如可参见The Science and Practice of Pharmacy(制药科学与实践)，20th Edition(Philadelphia College of Pharmacy and Science,2000)。The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof with sterilized distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Actual methods of preparing pharmaceutical compositions are known to those skilled in the art, for example see The Science and Practice of Pharmacy (Pharmaceutical Science and Practice), 20 th Edition (Philadelphia College of Pharmacy and Science, 2000).
本发明的药物组合物的给药途径包括但不限于口服、局部、经皮、肌肉、静脉、吸入、肠胃外、舌下、直肠、阴道及鼻内。例如，适合口服给药的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本发明的式I、式II、式IIa、式IIb或式IIc化合物可以是固体粉末或颗粒；水性或非水性液体中的溶液或混悬液；油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其它辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括但不限于水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。具体的给药方式和剂型取决于化合物本身的理化性质以及所应用疾病的严重程度等。本领域技术人员能够根据上述因素并结合其自身具有的知识来确定具体的给药途径。例如可参见：李俊，《临床药理学》，人民卫生出版社，2008.06；丁玉峰，论临床剂型因素与合理用药，医药导报，26(5)，2007；Howard C.Ansel,Loyd V.Allen,Jr.,Nicholas G.Popovich著，江志强主译，《药物剂型与给药体系》，中国医药科技出版社，2003.05。Routes of administration of the pharmaceutical compositions of the invention include, but are not limited to, oral, topical, transdermal, intramuscular, intravenous, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like. The compounds of Formula I, Formula II, Formula IIa, Formula IIb or Formula IIc of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water Emulsions, etc. The above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods. The above carriers need to be compatible with the active compound or other excipients. For solid formulations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include, but are not limited to, water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compound can form a solution or suspension with the above carriers. The particular mode of administration and dosage form will depend on the physicochemical properties of the compound itself, as well as the severity of the disease being applied. Those skilled in the art will be able to determine the specific route of administration based on the above factors in combination with their own knowledge. For example, see: Li Jun, "Clinical Pharmacology", People's Health Publishing House, 2008.06; Ding Yufeng, on clinical dosage forms and rational use of drugs, Medical Herald, 26 (5), 2007; Howard C. Ansel, Loyd V. Allen, Jr., Nicholas G. Popovich, Jiang Zhiqiang, “Pharmaceutical Formulation and Drug Delivery System”, China Medical Science and Technology Press, 2003.05.
本发明的化合物或者本发明的药物组合物还可以与一种或多种抗炎药联合或组合使用。所述抗炎药包括但不限于：NSAID、非特异性和COX-2特异性环氧合酶抑制剂、金化合物、皮质激素类、肿瘤坏死因子受体拮抗剂、水杨酸酯或盐、免疫抑制剂和甲胺蝶呤。The compounds of the invention or the pharmaceutical compositions of the invention may also be used in combination or in combination with one or more anti-inflammatory agents. The anti-inflammatory drugs include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunization Inhibitor and methotrexate.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药在制备用于调节RORγ活性的药物中的用途。 Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof Or the use of a prodrug thereof for the preparation of a medicament for modulating RORγ activity.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药在制备用于预防或治疗RORγ介导的疾病的药物中的用途。Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof Use of a prodrug thereof or a medicament for the preparation of a medicament for preventing or treating a RORγ-mediated disease.
本发明的另一方面涉及本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药在制备作为RORγ调节剂的药物中的用途。Another aspect of the invention relates to a compound of formula I, formula II, formula IIa, formula IIb or formula IIc of the invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof Or the use of a prodrug thereof for the preparation of a medicament as a ROR gamma modulator.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括给予有需要的患者治疗有效剂量的一种或多种本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药。Another aspect of the invention relates to a method of preventing or treating a RORγ-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa, Formula IIb of the present invention Or a compound of the formula IIc or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括给予有需要的患者治疗有效剂量的药物组合物，给予有需要的患者治疗有效剂量的药物组合物，该药物组合物包含一种或多种本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药。Another aspect of the invention relates to a method of preventing or treating a ROR gamma mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition, the medicament The composition comprises one or more compounds of Formula I, Formula II, Formula IIa, Formula IIb or Formula IIc of the present invention, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvent thereof Compound or its prodrug.
本发明的另一方面涉及一种预防或治疗RORγ介导的疾病的方法，其包括对有需要的患者联合给予治疗有效剂量的一种或多种本发明的式I、式II、式IIa、式IIb或式IIc化合物或其立体异构体、互变异构体、或其药学上可接受的盐或者其溶剂化物或其前药和一种或多种抗炎药。所述抗炎药包括但不限于：NSAID、非特异性和COX-2特异性环氧合酶抑制剂、金化合物、皮质激素类、肿瘤坏死因子受体拮抗剂、水杨酸酯或盐、免疫抑制剂和甲胺蝶呤。Another aspect of the invention relates to a method of preventing or treating a ROR gamma mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of one or more of Formula I, Formula II, Formula IIa of the invention, A compound of Formula IIb or Formula IIc, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and one or more anti-inflammatory agents. The anti-inflammatory drugs include, but are not limited to, NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunization Inhibitor and methotrexate.
本文的化合物是视黄酸相关孤儿受体ROR的调节剂，特别是RORγ的调节剂。这些调节剂可以用于治疗哺乳动物(尤其是人)的由RORγ介导的疾病。在一些实施方案中，RORγ介导的疾病可以是一种或多种自体免疫和/或炎性疾病，所述疾病包括但不限于类风湿性关节炎、多发性硬化症、银屑病、克罗恩病、哮喘、系统性红斑狼疮、慢性阻塞性肺病、组织移植物排斥反应和移植器官的排斥反应、硬皮病、紫癜、自身免疫溶血性和血小板减少性症状、应激性肠综合症、骨关节炎、川崎氏病、桥本氏甲状腺炎、粘膜利斯曼病、支气管炎、过敏性鼻炎、特应性皮炎、囊性纤维化、肺代谢排斥反应、儿童类风湿关节炎、强直性脊柱炎、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、sjorgen氏综合症、视神经炎、糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合症、银屑病性关节炎、葛瑞夫氏病或巩膜炎。The compounds herein are modulators of retinoic acid-related orphan receptor ROR, particularly modulators of RORy. These modulators can be used to treat ROR gamma mediated diseases in mammals, especially humans. In some embodiments, the RORγ-mediated disease can be one or more autoimmune and/or inflammatory diseases including, but not limited to, rheumatoid arthritis, multiple sclerosis, psoriasis, gram Ron's disease, asthma, systemic lupus erythematosus, chronic obstructive pulmonary disease, tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, stress bowel syndrome , osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucosal Leishman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis in children, rigidity Spondylitis, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barre syndrome , psoriatic arthritis, Graves' disease or scleritis.
本发明的药物组合物以符合医学实践规范的方式配制，定量和给药。本发明化合物的“治疗有效剂量”由所用的具体化合物、要治疗的具体病症、病症的起因、药物的靶点、疾病的严重程度、给药方式以及待治疗的哺乳动物的年龄、体重、身体状况等因素决定。通常，经胃肠道外给药的剂量可以是1-200mg/kg，口服给药的剂量可以是1-1000mg/kg。The pharmaceutical compositions of this invention are formulated, quantified, and administered in a manner consistent with medical practice. A "therapeutically effective amount" of a compound of the invention consists of the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the condition, the mode of administration, and the age, weight, body of the mammal to be treated The status and other factors determine. Generally, the dose for parenteral administration may be 1-200 mg/kg, and the dose for oral administration may be 1-1000 mg/kg.
本文中所提供的有效剂量的范围并非意图限制本发明的范围，而是代表优选的剂 量范围。但是，最优选的剂量可针对具体个体而进行调整，这是本领域技术人员所了解且可决定的(例如参阅Berkow等人编著，Merck手册，第16版，Merck公司，Rahway,N.J.,1992)。The range of effective dosages provided herein is not intended to limit the scope of the invention, but rather to represent preferred agents The range of quantities. However, the most preferred dosages can be adjusted for a particular individual, as will be appreciated and determined by those skilled in the art (see, for example, Berkow et al., Merck Handbook, 16th Ed., Merck Corporation, Rahway, NJ, 1992). .
本发明化合物的制备Preparation of the compounds of the invention
以下反应方案示例性地说明本发明的式I化合物的制备方法。The following reaction schemes exemplify the preparation of the compounds of formula I of the present invention.
本领域技术人员应当理解，在以下描述中，只有当取代基的组合可以得到稳定的化合物时，这类取代基的组合才是允许的。It will be understood by those skilled in the art that in the following description, combinations of such substituents are permissible only if a combination of substituents results in a stable compound.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、脒基、胍基、巯基及羧基基团。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, a fluorenyl group, a fluorenyl group, and a carboxyl group. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein.
保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organic Synthesis(有机合成中的保护基),(1999),4thEd.,Wiley中。保护基还可为聚合物树脂。Use of protecting groups are detailed in Greene, TW and PGMWuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), (1999), 4 th Ed., Wiley medium. The protecting group can also be a polymeric resin.
本发明的化合物可按照下列反应路线所示的方法进行制备：The compounds of the invention can be prepared according to the methods shown in the following schemes:
方案1：plan 1:
Figure PCTCN2015074412-appb-000013
Figure PCTCN2015074412-appb-000013
其中，X是-C(O)-；A、B、R1、R2、L、m和n如结构式I中所定义。Wherein X is -C(O)-; A, B, R 1 , R 2 , L, m and n are as defined in Structural Formula I.
根据方案1，其中X是-C(O)-的式I化合物的合成是以邻硝基氟代芳环或邻硝基氟代杂芳环B为起始原料，步骤1在碱性(例如NaH)条件下进行取代反应将环B与取代的苯胺相连，步骤2将硝基还原(例如锌粉/氯化铵)，然后步骤3在碱(例如三乙胺)催化下利用三光气制备得到并环中间体，最后步骤4在碱性(例如NaH)条件下同各种 取代或非取代的酰卤、苄基卤、磺酰卤或亚磺酰卤反应得到目标式I化合物。According to Scheme 1, the synthesis of the compound of formula I wherein X is -C(O)- is based on an o-nitrofluoroaryl ring or an o-nitrofluoroheteroaryl ring B, and step 1 is basic (for example The substitution reaction is carried out under the conditions of NaH), the ring B is connected with the substituted aniline, the step 2 is used to reduce the nitro group (for example, zinc powder/ammonium chloride), and then the step 3 is prepared by using triphosgene under the catalysis of a base such as triethylamine. Hexacyclic intermediates, and finally step 4 under various conditions (such as NaH) Reaction of a substituted or unsubstituted acid halide, benzyl halide, sulfonyl halide or sulfinyl halide affords the compound of the formula I.
方案2：Scenario 2:
Figure PCTCN2015074412-appb-000014
Figure PCTCN2015074412-appb-000014
其中，X是-CH2C(O)-或-CH2CH2-；Z是-CH2-或-C(O)-；A、B、R1、R2、L、m和n如结构式I中所定义。Wherein X is -CH 2 C(O)- or -CH 2 CH 2 -; Z is -CH 2 - or -C(O)-; A, B, R 1 , R 2 , L, m and n are as Defined in Structural Formula I.
根据方案2，其中X是-CH2C(O)-或-CH2CH2-的式I化合物的合成同样是以邻硝基氟代芳环或邻硝基氟代杂芳环B为起始原料，步骤1在碱性(例如NaH)条件下进行取代反应将环B与取代的苯胺相连，得到的苯胺衍生物在步骤2中碱性(例如NaH)条件下与1,2-二溴乙烷或与溴乙酰氯反应，然后步骤3中将硝基还原(例如氯化亚锡/盐酸，回流)成氨基，同时一锅发生关环反应得到并环中间体，最后步骤4在碱性(优选NaH)条件下同各种取代或非取代的酰卤、苄基卤、磺酰卤或亚磺酰卤反应得到目标化合物。According to Scheme 2, the synthesis of a compound of formula I wherein X is -CH 2 C(O)- or -CH 2 CH 2 - is likewise based on an o-nitrofluoroaryl ring or an o-nitrofluoroheteroaryl ring B. Starting from the starting material, step 1 is carried out under a basic (for example, NaH) substitution reaction to ring B with a substituted aniline, and the obtained aniline derivative is subjected to basic (for example, NaH) and 1,2-dibromo in step 2. Ethane or react with bromoacetyl chloride, then in step 3, the nitro group is reduced (for example, stannous chloride/hydrochloric acid, reflux) to form an amino group, while a ring-closing reaction is carried out in one pot to obtain a cyclic intermediate, and finally step 4 is alkaline. The desired compound is obtained by reacting with various substituted or unsubstituted acid halides, benzyl halides, sulfonyl halides or sulfinyl halides under conditions of (preferably NaH).
上述通用的合成路线仅代表大多数实施例的一般方法，对带有特殊取代基的化合物，可以在某步反应中进行本领域普通技术人员所知的变动。例如对于具有酯基团的化合物，可以在反应中加入酯水解的步骤。The above general synthetic routes represent only the general methods of most of the examples, and for compounds having a particular substituent, variations known to those skilled in the art can be made in a certain step of the reaction. For example, for a compound having an ester group, a step of ester hydrolysis can be added to the reaction.
实施例Example
下面的实施例举例说明在本发明范围内的化合物的制备和生物活性评价。The following examples illustrate the preparation and biological activity evaluation of compounds within the scope of the present invention.
提供下面的这些实施例以使本领域的技术人员能够更清楚地理解并且能够实践本发明。它们不应当被认为是限制本发明的范围，而仅仅是举例说明性的和代表性的。The following examples are provided to enable those skilled in the art to understand and practice the invention. They should not be considered as limiting the scope of the invention, but are merely illustrative and representative.
本发明中实验所使用的起始原料或购买自试剂供应商或经由本领域公知的方法由已知原料制备。除非另有说明，本文的实施例应用下述条件：The starting materials used in the experiments of the present invention are either purchased from a reagent supplier or prepared from known starting materials by methods well known in the art. The examples herein apply the following conditions unless otherwise stated:
温度的单位是摄氏度(℃)；室温的定义是18-25℃；The unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
有机溶剂使用无水硫酸镁或无水硫酸钠干燥；使用旋转蒸发仪在减压升温条件下旋干(例如：15mmHg，30℃)； Drying the organic solvent with anhydrous magnesium sulfate or anhydrous sodium sulfate; using a rotary evaporator to spin dry under reduced pressure (for example: 15 mmHg, 30 ° C);
柱层析分离时使用200-300目硅胶作为载体，TLC表示薄层色谱法；Column chromatography separation using 200-300 mesh silica gel as a carrier, TLC means thin layer chromatography;
通常情况下，反应的进度通过TLC或LC-MS监测；Normally, the progress of the reaction is monitored by TLC or LC-MS;
最终产品的鉴定由核磁共振(Bruker AVANCE 300，300MHz)和LC-MS(Bruker esquine 6000，Agilent 1200series)完成。The identification of the final product was performed by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
实施例1：4-(3-(2,6-二氯苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 1: 4-(3-(2,6-Dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Formic acid
Figure PCTCN2015074412-appb-000015
Figure PCTCN2015074412-appb-000015
制备实施例1化合物的具体步骤如下：The specific steps for preparing the compound of Example 1 are as follows:
(1)4-(2-氟-6-硝基-苯基氨基)苯甲酸甲酯(1-1)的制备：(1) Preparation of methyl 4-(2-fluoro-6-nitro-phenylamino)benzoate (1-1):
Figure PCTCN2015074412-appb-000016
Figure PCTCN2015074412-appb-000016
将4-氨基苯甲酸甲酯(302mg，2mmol)溶解在四氢呋喃(THF)(20mL)和二甲基甲酰胺(DMF)(4mL)中，室温下，缓慢加入氢化钠(NaH)(60％，120mg，3mmol)，搅拌10min，然后再加入1,2-二氟-3-硝基苯(318mg，2mmol)搅拌5小时，加水(10mL)淬灭，用乙酸乙酯(50mL)萃取，有机相经无水硫酸钠干燥，减压浓缩，将浓缩物经硅胶柱层析(洗脱剂：正己烷:乙酸乙酯＝50:1)分离纯化，得到4-(2-氟-6-硝基苯基氨基)苯甲酸甲酯1-1(300mg)，为黄色固体。收率52％。MS+H+＝291。Methyl 4-aminobenzoate (302 mg, 2 mmol) was dissolved in tetrahydrofuran (THF) (20 mL) and dimethylformamide (DMF) (4 mL). 120 mg, 3 mmol), stirred for 10 min, then EtOAc (EtOAc (EtOAc) The organic layer was dried over anhydrous sodium sulfate (MgSO4) Methyl phenylamino)benzoate 1-1 (300 mg) as a yellow solid. The yield was 52%. MS+H + =291.
(2)4-(2-氨基-6-氟-苯基氨基)苯甲酸甲酯(1-2)的制备：(2) Preparation of methyl 4-(2-amino-6-fluoro-phenylamino)benzoate (1-2):
Figure PCTCN2015074412-appb-000017
Figure PCTCN2015074412-appb-000017
将4-(2-氟-6-硝基-苯基氨基)苯甲酸甲酯(290mg，1mmol)溶解在四氢呋喃(20mL)和水(2mL)中，室温下加入锌粉(390mg，6mmol)和氯化铵(321mg，6mmol)，搅拌2小时。停止反应，反应混合物过滤；将滤液中的水相分离出，有机相经无水硫酸钠干燥，过滤，减压浓缩得到4-(2-氨基-6-氟苯胺基)苯甲酸甲酯1-2(260mg)，为无色油状物，得到的产物无需进一步纯化即可用于下一步反应。MS+H+＝261.1。Methyl 4-(2-fluoro-6-nitro-phenylamino)benzoate (290 mg, 1 mmol) was dissolved in tetrahydrofuran (20 mL) and water (2 mL). Ammonium chloride (321 mg, 6 mmol) was stirred for 2 hours. The reaction was stopped and the reaction mixture was filtered; the aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. 2 (260 mg) as a colourless oil. MS+H + = 261.1.
(3)4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸甲酯(1-3)的制备 (3) Preparation of methyl 4-(4-fluoro-1,2-dihydro-2-one-benzo[d]imidazol-3-yl)benzoate (1-3)
Figure PCTCN2015074412-appb-000018
Figure PCTCN2015074412-appb-000018
将4-(2-氨基-6-氟-苯基氨基)苯甲酸甲酯(260mg，1mmol)溶解在二氯甲烷(DCM)(20mL)中，加入三乙胺(606mg，6mmol)。冷却至-78℃，加入三光气(297mg，1mmol)，缓慢升温到室温。加入水(10mL)淬灭，乙酸乙酯萃取(20mL×3)，有机相经无水硫酸钠干燥，过滤，减压浓缩，将浓缩物经硅胶柱层析(正己烷:乙酸乙酯＝1:1)分离纯化，得到4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸甲酯1-3(250mg)，为灰白色固体。MS+H+＝287.2。Methyl 4-(2-amino-6-fluoro-phenylamino)benzoate (260 mg, 1 mmol) was dissolved in dichloromethane (EtOAc) (EtOAc) Cool to -78 ° C, add triphosgene (297 mg, 1 mmol) and slowly warm to room temperature. After adding water (10 mL), EtOAc (EtOAc)EtOAc. :1) Isolation and purification to give 4-(4-fluoro-1,2-dihydro-2-one-benzo[d]imidazol-3-yl)benzoate methyl ester 1-3 (250 mg) as a white solid. . MS+H + = 287.2.
(4)4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸(1-4)的制备(4) Preparation of 4-(4-fluoro-1,2-dihydro-2-one-benzo[d]imidazol-3-yl)benzoic acid (1-4)
Figure PCTCN2015074412-appb-000019
Figure PCTCN2015074412-appb-000019
把LiOH(188mg，7.86mmol)溶解在10mL水中，加入4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸甲酯(250mg，0.87mmol)溶解在20mL甲醇中的溶液。室温搅拌3小时。减压蒸除甲醇，加入20mL水，水相用乙酸乙酯洗三次(20mL×3)，加盐酸酸化到pH＝5，析出固体，过滤，干燥，得到4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸1-4(230mg)，为白色固体，收率97％。MS+H+＝273.2。LiOH (188 mg, 7.86 mmol) was dissolved in 10 mL of water, and methyl 4-(4-fluoro-1,2-dihydro-2-one-benzo[d]imidazol-3-yl)benzoate (250 mg, 0.87 mmol) solution dissolved in 20 mL of methanol. Stir at room temperature for 3 hours. The methanol was evaporated under reduced pressure, 20 mL of water was added, and the aqueous phase was washed three times with ethyl acetate (20 mL×3), acidified with hydrochloric acid to pH=5, and solids were separated, filtered and dried to give 4-(4-fluoro-1,2 -Dihydro-2-one-benzo[d]imidazol-3-yl)benzoic acid 1-4 (230 mg) as a white solid. MS+H + = 273.2.
(5)4-(3-(2,6-二氯苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸(化合物1)的制备(5) 4-(3-(2,6-Dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid Preparation of (Compound 1)
Figure PCTCN2015074412-appb-000020
Figure PCTCN2015074412-appb-000020
将4-(4-氟-1,2-二氢-2-酮-苯并[d]咪唑-3-基)苯甲酸(27mg，0.1mmol)溶解在DMF(2mL)中，室温下加入氢化钠(60％，12mg，0.3mmol)，搅拌5min，然后加入2,6-二氯苯甲酰氯(31mg，0.15mmol)，搅拌10min，用水(5mL)淬灭，加盐酸酸化至pH＝5，乙酸乙酯萃取(10mL×3)，有机相经无水硫酸钠干燥后，过滤，滤液浓缩，浓缩物经硅胶柱层析(洗脱剂：正己烷：乙酸乙酯＝1:1)分离纯化得到10mg目标化合物，为白色固体，收率22％。数据表征如下：MS+Na+＝467.4；1H-NMR(CDCl3，300MHz)δ:ppm 8.29 (d,J＝8.1Hz,1H),8.20(d,J＝8.7Hz,2H),7.56(dd,J1＝8.7Hz,J2＝2.7Hz,1H),7.40～7.25(m,4H)，7.13-7.06(m,2H)。4-(4-Fluoro-1,2-dihydro-2-one-benzo[d]imidazol-3-yl)benzoic acid (27 mg, 0.1 mmol) was dissolved in DMF (2 mL). Sodium (60%, 12 mg, 0.3 mmol), stirred for 5 min, then added 2,6-dichlorobenzoyl chloride (31 mg, 0.15 mmol), stirred for 10 min, quenched with water (5 mL) and acidified to pH=5 with hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The purified product was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1:1) 10 mg of the title compound was obtained as a white solid, yield 22%. The data were characterized as follows: MS + Na + = 467.4; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.29 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.7 Hz, 2H), 7.56 ( Dd, J 1 = 8.7 Hz, J 2 = 2.7 Hz, 1H), 7.40 to 7.25 (m, 4H), 7.13 - 7.06 (m, 2H).
实施例2：4-(3-(2,6-二氯苯甲酰基)-7-甲基-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 2: 4-(3-(2,6-Dichlorobenzoyl)-7-methyl-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl) benzoic acid
Figure PCTCN2015074412-appb-000021
Figure PCTCN2015074412-appb-000021
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用1-甲基-2-氟-3-硝基苯为原料代替1,2-二氟-3-硝基苯。相关表征数据如下：MS+H+＝441.7；1H-NMR(CDCl3，300MHz)δ:ppm 8.36(d,J＝8.1Hz,1H),8.22(d,J＝8.4Hz,2H),7.51(d,J1＝8.4Hz,1H),7.37～7.19(m,4H)，7.06(d,J＝8.1Hz,1H),1.87(s,3H)。The compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in the step 1, 1-methyl-2-fluoro-3-nitrobenzene is used as a raw material instead of 1,2-difluoro- 3-nitrobenzene. The relevant characterization data is as follows: MS + H + = 441.7; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.36 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.51 (d, J 1 = 8.4 Hz, 1H), 7.37 to 7.19 (m, 4H), 7.06 (d, J = 8.1 Hz, 1H), 1.87 (s, 3H).
实施例3：4-(3-(4-氟苯磺酰基)-7-甲基-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 3: 4-(3-(4-Fluorophenylsulfonyl)-7-methyl-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000022
Figure PCTCN2015074412-appb-000022
本实施例化合物可以按照与前述实施例2类似的步骤方法进行制备，不同之处在于步骤5中使用4-氟苯磺酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+H+＝427.5；1H-NMR(CD3OD，300MHz)δ:ppm 8.22～8.18(m,2H),8.11(d,J＝8.4Hz,2H),7.90(d,J＝8.1Hz,1H),7.41～7.36(m,4H)，7.18～7.13(m,1H),7.01(m,1H),1.78(s,3H)。The compound of this example can be prepared by a similar procedure to that of Example 2 except that 4-fluorobenzenesulfonyl chloride is used as the starting material in place of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + H + = 427.5; 1 H-NMR (CD 3 OD, 300 MHz) δ: ppm 8.22 - 8.18 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.90 (d , J = 8.1 Hz, 1H), 7.41 to 7.36 (m, 4H), 7.18 to 7.13 (m, 1H), 7.01 (m, 1H), 1.78 (s, 3H).
实施例4：4-(3-(2,4-二氟苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 4: 4-(3-(2,4-Difluorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Formic acid
Figure PCTCN2015074412-appb-000023
Figure PCTCN2015074412-appb-000023
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用2,4-二氟苯甲酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+H+＝413.9；1H-NMR(CDCl3，300MHz)δ:ppm 8.21(d,J＝8.7Hz,2H),8.03(d,J＝ 8.1Hz,1H),7.71～7.63(m,1H),7.56(dd,J1＝8.7Hz,J2＝2.7Hz,2H),7.05～6.21(m,1H)，7.09～6.84(m,3H)。The compound of this example can be prepared by a similar procedure to that of Example 1 except that 2,4-difluorobenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + H + = 413.9; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.21 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.1 Hz, 1H), 7.71 ～7.63 (m, 1H), 7.56 (dd, J 1 = 8.7 Hz, J 2 = 2.7 Hz, 2H), 7.05 to 6.21 (m, 1H), 7.09 to 6.84 (m, 3H).
实施例5：4-(3-(2-氯-6-氟苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 5: 4-(3-(2-Chloro-6-fluorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl) benzoic acid
Figure PCTCN2015074412-appb-000024
Figure PCTCN2015074412-appb-000024
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用2-氯-6-氟苯甲酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+Na+＝451.5；1H-NMR(CDCl3，300MHz)δ:ppm 8.20(d,J＝8.1Hz,1H),8.14(d,J＝8.7Hz,2H),7.51(dd,J1＝8.7Hz,J2＝2.7Hz,1H),7.24～7.17(m,4H)，7.05-6.99(m,2H)。The compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 2-chloro-6-fluorobenzoyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5. The relevant characterization data is as follows: MS + Na + = 451.5; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.20 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 8.7 Hz, 2H), 7.51 (dd, J 1 = 8.7 Hz, J 2 = 2.7 Hz, 1H), 7.24 to 7.17 (m, 4H), 7.05-6.99 (m, 2H).
实施例6：4-(3-(4-氟苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 6: 4-(3-(4-Fluorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000025
Figure PCTCN2015074412-appb-000025
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用4-氟苯甲酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：The compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-fluorobenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows:
1H-NMR(DMSO-d6，300MHz)δ:ppm 8.08(d,J＝8.7Hz,2H),8.03～7.99(m,2H),7.76(d,J＝7.2Hz,1H),7.68(dd,J1＝8.7Hz,J2＝2.1Hz,2H),7.38～7.18(m,4H)。 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 8.08 (d, J = 8.7 Hz, 2H), 8.03 - 7.99 (m, 2H), 7.76 (d, J = 7.2 Hz, 1H), 7.68 ( Dd, J 1 = 8.7 Hz, J 2 = 2.1 Hz, 2H), 7.38 to 7.18 (m, 4H).
实施例7：4-(3-(4-三氟甲基苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 7: 4-(3-(4-Trifluoromethylbenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Formic acid
Figure PCTCN2015074412-appb-000026
Figure PCTCN2015074412-appb-000026
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用4-三氟甲基苯甲酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+Na+＝467.2；1H-NMR(DMSO-d6，300MHz)δ:ppm 13.2(brs,1H),8.08～8.05(m,4H),7.90～7.86(m,3H),7.67(dd,J1＝8.7Hz,J2＝2.1Hz,2H),7.32～7.19(m,2H)。 The compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-trifluoromethylbenzoyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + Na + = 467.2; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 13.2 (brs, 1H), 8.08 to 8.05 (m, 4H), 7.90 to 7.86 (m, 3H) ), 7.67 (dd, J 1 = 8.7 Hz, J 2 = 2.1 Hz, 2H), 7.32 to 7.19 (m, 2H).
实施例8：4-(3-苄基-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 8: 4-(3-Benzyl-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000027
Figure PCTCN2015074412-appb-000027
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用苄基溴为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+H+＝363.2；1H-NMR(CDCl3，300MHz)δ:ppm 8.24(d,J＝8.7Hz,2H),7.65(dd,J1＝8.7Hz,J2＝2.7Hz,2H),7.41～7.30(m,5H),7.07～7.00(m,1H),6.86(d,J＝8.4Hz,1H),6.79(d,J＝8.1Hz,1H),5.14(s,2H)。The compound of this example can be prepared in a similar manner to that of the above-mentioned Example 1, except that benzyl bromide is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5. The relevant characterization data is as follows: MS + H + = 363.2; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.24 (d, J = 8.7 Hz, 2H), 7.65 (dd, J 1 = 8.7 Hz, J 2 = 2.7 Hz, 2H), 7.41 to 7.30 (m, 5H), 7.07 to 7.00 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 5.14 ( s, 2H).
实施例9：4-(3-(2,6-二氯苄基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 9: 4-(3-(2,6-Dichlorobenzyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000028
Figure PCTCN2015074412-appb-000028
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用2,6-二氯苄基溴为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+H+＝433.3；1H-NMR(CDCl3，300MHz)δ:ppm 8.22(d,J＝6.9Hz,2H),7.64～7.59(m,2H),7.38(d,J＝7.5Hz,2H),7.27～7.24(m,1H),7.00～6.93(m,1H),6.84～6.78(m,1H),6.67(d,J＝7.8Hz,1H),5.45(s,2H)。The compound of this example can be prepared in a similar manner to that in the previous Example 1, except that in the step 5, 2,6-dichlorobenzyl bromide is used as a starting material instead of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + H + = 433.3; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.22 (d, J = 6.9 Hz, 2H), 7.64 - 7.59 (m, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.27 to 7.24 (m, 1H), 7.00 to 6.93 (m, 1H), 6.84 to 6.78 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H), 5.45 (s) , 2H).
实施例10：4-(3-(4-氰基苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 10: 4-(3-(4-Cyanobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000029
Figure PCTCN2015074412-appb-000029
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用4-氰基苯甲酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+Na+＝425.1；1H-NMR(CDCl3，300MHz)δ:ppm 8.24(d,J＝8.7Hz,2H),7.98(d,J＝8.1Hz,1H),7.78～7.69(dd,J1＝8.4Hz,J2＝24.3Hz,4H),7.59(dd,J1＝2.7Hz,J2＝8.7Hz,2H),7.13(m,1H)。The compound of this example can be prepared in a similar manner to that of the above-mentioned Example 1, except that in step 5, 4-cyanobenzoyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + Na + = 425.1; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.24 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 8.1 Hz, 1H), 7.78 ～7.69 (dd, J 1 = 8.4 Hz, J 2 = 24.3 Hz, 4H), 7.59 (dd, J 1 = 2.7 Hz, J 2 = 8.7 Hz, 2H), 7.13 (m, 1H).
实施例11：4-(3-(2,6-二氯苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯 甲酸甲酯Example 11: 4-(3-(2,6-Dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Methyl formate
Figure PCTCN2015074412-appb-000030
Figure PCTCN2015074412-appb-000030
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于省略氢氧化锂水解(即步骤4)直接进行下步反应。相关表征数据如下：MS+Na+＝481.7；1H-NMR(CDCl3，300MHz)δ:ppm 8.28(d,J＝8.1Hz,1H),8.13(d,J＝8.4Hz,2H),8.02(s,1H),7.53～7.50(m,2H),7.39～7.23(m,3H)，7.11～7.04(m,1H),3.93(s,3H)。The compound of this example can be prepared in a similar manner to the previous Example 1, except that the lithium hydroxide hydrolysis (i.e., step 4) is omitted and the next step is directly carried out. The relevant characterization data is as follows: MS + Na + = 481.7; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.28 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 7.53 to 7.50 (m, 2H), 7.39 to 7.23 (m, 3H), 7.11 to 7.04 (m, 1H), 3.93 (s, 3H).
实施例12：4-(3-(2,6-二氯苯甲酰基)-5-二甲基氨基甲酰基-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸乙酯Example 12: 4-(3-(2,6-Dichlorobenzoyl)-5-dimethylcarbamoyl-2-one-2,3-dihydro-1H-benzo[d]imidazole- Ethyl 1-benzoate
Figure PCTCN2015074412-appb-000031
Figure PCTCN2015074412-appb-000031
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用4-氟-3-硝基苯甲酸代替1,2-二氟-3-硝基苯以及使用4-氨基苯甲酸乙酯代替4-氨基苯甲酸甲酯，且在步骤1和步骤2之间加入将羧基转换为二甲基氨基甲酰基的反应步骤，即将第一步反应的产物4-(4’-乙氧羰基苯基氨基)-3-硝基苯甲酸溶解在适量的DMF中，然后加入1当量的四甲基脲六氟磷酸酯(HATU)和2当量的二异丙基乙胺(DIEA)，室温搅拌15分钟后加入2当量的二甲胺/四氢呋喃溶液，搅拌过夜后，硅胶柱层析(洗脱剂：正己烷：乙酸乙酯＝1:1)分离纯化。相关表征数据如下：MS+H+＝527.8。The compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in step 1, 4-fluoro-3-nitrobenzoic acid is used instead of 1,2-difluoro-3-nitrobenzene. Ethyl 4-aminobenzoate is used in place of methyl 4-aminobenzoate, and a reaction step for converting a carboxyl group to a dimethylcarbamoyl group is added between step 1 and step 2, that is, a product of the first step reaction 4- (4'-Ethoxycarbonylphenylamino)-3-nitrobenzoic acid is dissolved in an appropriate amount of DMF, then 1 equivalent of tetramethylurea hexafluorophosphate (HATU) and 2 equivalents of diisopropyl B are added. The amine (DIEA) was stirred at room temperature for 15 minutes, and then a solution of dimethylamine/tetrahydrofuran was added, and the mixture was stirred and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1:1). The relevant characterization data is as follows: MS + H + = 527.8.
实施例13：1-(2,6-二氯苯甲酰基)-4-氟-3-(4-甲基磺酰基苯基)-1H-苯并[d]咪唑-2(3H)-酮Example 13: 1-(2,6-Dichlorobenzoyl)-4-fluoro-3-(4-methylsulfonylphenyl)-1H-benzo[d]imidazole-2(3H)-one
Figure PCTCN2015074412-appb-000032
Figure PCTCN2015074412-appb-000032
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在 于步骤1中使用4-甲基磺酰基苯胺为原料代替4-氨基苯甲酸甲酯。相关表征数据如下：MS+H+＝479.7；1H-NMR(CDCl3，300MHz)δ:ppm 8.30(d,J＝8.1Hz,1H),8.04(d,J＝8.7Hz,2H),7.66(dd,J1＝8.7Hz,J2＝2.7Hz,2H),7.40～7.27(m,4H),7.39～7.23(m,3H)，7.15～7.08(m,1H),3.06(s,3H)。The compound of this example can be produced in a similar manner to that of the above-mentioned Example 1, except that in the step 1, 4-methylsulfonylaniline is used as a starting material instead of methyl 4-aminobenzoate. The relevant characterization data is as follows: MS + H + = 479.7; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.30 (d, J = 8.1 Hz, 1H), 8.04 (d, J = 8.7 Hz, 2H), 7.66 (dd, J 1 =8.7 Hz, J 2 =2.7 Hz, 2H), 7.40 to 7.27 (m, 4H), 7.39 to 7.23 (m, 3H), 7.15 to 7.08 (m, 1H), 3.06 (s, 3H) ).
实施例14：4-(3-(2,6-二氯苯甲酰基)-6-甲氧基-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 14: 4-(3-(2,6-Dichlorobenzoyl)-6-methoxy-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl )benzoic acid
Figure PCTCN2015074412-appb-000033
Figure PCTCN2015074412-appb-000033
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用1-甲氧基-3-氟-4-硝基苯为原料代替1,2-二氟-3-硝基苯。相关表征数据如下：MS+H+＝459.2；1H-NMR(DMSO-d6，300MHz)δ:ppm 8.20(d,J＝9Hz,1H),8.13(d,J＝8.7Hz,2H),7.69(d,J＝8.4Hz,2H),7.61～7.52(m,3H),6.94(dd,J1＝8.7Hz,J2＝2.4Hz,1H),6.70(d,J＝2.4Hz,1H),3.80(s,3H)。The compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 1-methoxy-3-fluoro-4-nitrobenzene is used as a raw material instead of 1,2-difluoro in the step 1. -3-nitrobenzene. The relevant characterization data is as follows: MS + H + = 459.2; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 8.20 (d, J = 9 Hz, 1H), 8.13 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.61 to 7.52 (m, 3H), 6.94 (dd, J 1 = 8.7 Hz, J 2 = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H) ), 3.80 (s, 3H).
实施例15：4-(1-(2,6-二氯苯甲酰基)-2-酮-1H-咪唑[4,5-b]并吡啶-3(2H)-基)苯甲酸Example 15: 4-(1-(2,6-Dichlorobenzoyl)-2-one-1H-imidazo[4,5-b]pyridin-3(2H)-yl)benzoic acid
Figure PCTCN2015074412-appb-000034
Figure PCTCN2015074412-appb-000034
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用2-氟-3-硝基吡啶为原料代替1,2-二氟-3-硝基苯。相关表征数据如下：MS+H+＝428.1；1H-NMR(DMSO-d6，300MHz)δ:ppm 13.090(brs,1H),8.527-8.498(dd,1H,J1＝7.8Hz,J2＝0.9Hz),8.281-8.260(dd,1H,J1＝5.1Hz,J2＝1.2Hz),8.130-7.947(m,3H),7.786-7.757(d,2H,J＝8.7Hz),7.651-7.545(m,3H),7.426-7.382(m,1H)。The compound of this example can be prepared by a similar method to that of the above-mentioned Example 1, except that 2-fluoro-3-nitropyridine is used as a raw material instead of 1,2-difluoro-3-nitrobenzene in the step 1. . The relevant characterization data is as follows: MS + H + = 428.1; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 13.090 (brs, 1H), 8.527-8.498 (dd, 1H, J 1 = 7.8 Hz, J 2 = 0.9 Hz), 8.281-8.260 (dd, 1H, J 1 = 5.1 Hz, J 2 = 1.2 Hz), 8.130-7.947 (m, 3H), 7.786-7.757 (d, 2H, J = 8.7 Hz), 7.651 -7.545 (m, 3H), 7.426-7.382 (m, 1 H).
实施例16：4-(3-(2,6-二氯苯甲酰基)-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 16: 4-(3-(2,6-Dichlorobenzoyl)-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000035
Figure PCTCN2015074412-appb-000035
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在 于步骤1中使用1-氟-2-硝基苯为原料代替1,2-二氟-3-硝基苯。相关表征数据如下：MS+H+＝401.2；1H-NMR(DMSO-d6，300MHz)δ:ppm 13.20(s,1H),8.28-8.31(m,1H),8.12(d,J＝8.4Hz,2H),7.69(d,J＝8.7Hz,2H),7.52-7.63(m,3H),7.36-7.39(m,2H),7.19-7.22(m,1H)。The compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that 1-fluoro-2-nitrobenzene is used as a raw material instead of 1,2-difluoro-3-nitrobenzene in the step 1. . The relevant characterization data is as follows: MS + H + = 401.2; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 13.20 (s, 1H), 8.28-8.31 (m, 1H), 8.12 (d, J = 8.4) Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.52-7.63 (m, 3H), 7.36-7.39 (m, 2H), 7.19-7.22 (m, 1H).
实施例17：4-(7-氯-3-(2,6-二氯苯甲酰基)-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 17: 4-(7-Chloro-3-(2,6-dichlorobenzoyl)-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Formic acid
Figure PCTCN2015074412-appb-000036
Figure PCTCN2015074412-appb-000036
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用1-氯-2-氟-3-硝基苯为原料代替1,2-二氟-3-硝基苯。相关表征数据如下：MS+H+＝459.1；1H-NMR(DMSO-d6，300MHz)δ:ppm 13.185(brs,1H),8.314-8.289(d,1H,J＝7.5Hz),8.054-8.026(d,2H,J＝8.4Hz),7.656-7.539(m,5H),7.421-7.351(m,2H)The compound of this example can be prepared in a similar manner to the above-mentioned Example 1, except that in the step 1, 1-chloro-2-fluoro-3-nitrobenzene is used as a raw material instead of 1,2-difluoro-3. - Nitrobenzene. The relevant characterization data is as follows: MS + H + = 459.1; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 13.185 (brs, 1H), 8.314-8.289 (d, 1H, J = 7.5 Hz), 8.054- 8.026 (d, 2H, J = 8.4 Hz), 7.656-7.539 (m, 5H), 7.421-7.351 (m, 2H)
实施例18：4-(3-(2,6-二氯苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)-2-氟苯甲酸Example 18: 4-(3-(2,6-Dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)- 2-fluorobenzoic acid
Figure PCTCN2015074412-appb-000037
Figure PCTCN2015074412-appb-000037
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤1中使用4-氨基-2-氟苯甲酸甲酯为原料代替4-氨基-苯甲酸甲酯。相关表征数据如下：MS+H+＝463.2；1H-NMR(CDCl3，300MHz)δ:ppm 8.30(d,J＝8.1Hz,1H),8.12(dd,J1＝8.7Hz,J2＝7.8Hz,1H),7.39～7.29(m,6H),7.12(ddd,J1＝8.7Hz,J2＝7.8Hz,J3＝0.9Hz,1H)。The compound of this example can be prepared by a similar procedure to that of Example 1 except that methyl 4-amino-2-fluorobenzoate is used as a starting material in place of 4-amino-benzoic acid methyl ester. The relevant characterization data is as follows: MS + H + = 463.2; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.30 (d, J = 8.1 Hz, 1H), 8.12 (dd, J 1 = 8.7 Hz, J 2 = 7.8 Hz, 1H), 7.39 to 7.29 (m, 6H), 7.12 (ddd, J 1 = 8.7 Hz, J 2 = 7.8 Hz, J 3 = 0.9 Hz, 1H).
实施例19：4-(3-苯乙酰基-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 19: 4-(3-Phenylacetyl-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000038
Figure PCTCN2015074412-appb-000038
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用苯乙酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下： MS+Na+＝413.2；1H-NMR(DMSO-d6，300MHz)δ:ppm 7.39～7.29(m,2H),8.01(d,J＝7.5Hz,1H),7.70(dd,J1＝8.4Hz,J2＝2.1Hz,2H),7.38～7.14(m,7H),4.50(s,2H)。The compound of this example can be prepared by a similar procedure to that of the above-mentioned Example 1, except that phenylacetyl chloride is used as a starting material instead of 2,6-dichlorobenzoyl chloride in the step 5. The relevant characterization data is as follows: MS + Na + = 413.2; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 7.39 to 7.29 (m, 2H), 8.01 (d, J = 7.5 Hz, 1H), 7.70 ( Dd, J 1 = 8.4 Hz, J 2 = 2.1 Hz, 2H), 7.38 to 7.14 (m, 7H), 4.50 (s, 2H).
实施例20：4-(3-(4-氯苯乙酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酸Example 20: 4-(3-(4-Chlorophenylacetyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzoic acid
Figure PCTCN2015074412-appb-000039
Figure PCTCN2015074412-appb-000039
本实施例化合物可以按照与前述实施例1类似的步骤方法进行制备，不同之处在于步骤5中使用4-氯苯乙酰氯为原料代替2,6-二氯苯甲酰氯。相关表征数据如下：MS+Na+＝447.3；1H-NMR(DMSO-d6，300MHz)δ:ppm 8.12(d,J＝8.7Hz,2H),7.99(d,J＝7.2Hz,1H),7.69(dd,J1＝8.7Hz,J2＝2.1Hz,2H),7.41～7.14(m,6H),4.50(s,2H)。The compound of this example can be prepared by a similar procedure to that of Example 1 except that 4-chlorophenylacetyl chloride is used as a starting material in place of 2,6-dichlorobenzoyl chloride. The relevant characterization data is as follows: MS + Na + = 447.3; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 8.12 (d, J = 8.7 Hz, 2H), 7.99 (d, J = 7.2 Hz, 1H) , 7.69 (dd, J 1 = 8.7 Hz, J 2 = 2.1 Hz, 2H), 7.41 to 7.14 (m, 6H), 4.50 (s, 2H).
实施例21：4-(3-(2,6-二氯苯甲酰基)-7-氟-2-酮-2,3-二氢-1H-苯并[d]咪唑-1-基)苯甲酰胺Example 21: 4-(3-(2,6-Dichlorobenzoyl)-7-fluoro-2-one-2,3-dihydro-1H-benzo[d]imidazol-1-yl)benzene Formamide
Figure PCTCN2015074412-appb-000040
Figure PCTCN2015074412-appb-000040
称取20mg化合物1(获自实施例1)置于50mL圆底瓶中，加入5mL二氯亚砜，搅拌加热回流至化合物1全溶，30分钟后，蒸除溶剂，然后将残留物溶解在10mL二氯甲烷中，室温下缓慢滴入0.5N的氨气/二氧六环溶液5mL，搅拌10分钟，然后加入10mL水洗，有机相用无水硫酸镁干燥，过滤，浓缩后用薄层硅胶(GF-254)板(正己烷：乙酸乙酯＝1：1)分离纯化，得17mg标题化合物，为白色粉末，收率：87％。相关表征数据如下：MS+H+＝444.0；1H-NMR(CDCl3,300MHz)δ:ppm 8.29(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.53(dd,J1＝8.7Hz,J2＝2.4Hz,2H),7.40～7.25(m,4H),7.11～7.07(m,1H)。Weigh 20 mg of Compound 1 (obtained from Example 1) in a 50 mL round bottom flask, add 5 mL of thionyl chloride, and heat to reflux until the compound 1 is completely dissolved. After 30 minutes, the solvent is distilled off, and then the residue is dissolved. In 10 mL of dichloromethane, 5 mL of 0.5 N ammonia/dioxane solution was slowly added dropwise at room temperature, stirred for 10 minutes, then 10 mL of water was added, and the organic phase was dried over anhydrous magnesium sulfate. The (GF-254) plate (n-hexane: ethyl acetate = 1:1) was isolated and purified to give 17 mg of the title compound as white powder. The relevant characterization data is as follows: MS + H + = 444.0; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm 8.29 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.53 (dd, J 1 = 8.7 Hz, J 2 = 2.4 Hz, 2H), 7.40 to 7.25 (m, 4H), 7.11 to 7.07 (m, 1H).
实施例22：4-(4-(2,6-二氯苯甲酰基)-8-氟-2-酮-3,4-二氢喹喔啉-1(2H)-基)苯甲酸Example 22: 4-(4-(2,6-Dichlorobenzoyl)-8-fluoro-2-one-3,4-dihydroquinoxaline-1(2H)-yl)benzoic acid
Figure PCTCN2015074412-appb-000041
Figure PCTCN2015074412-appb-000041
制备实施例22化合物的具体步骤如下：The specific steps for preparing the compound of Example 22 are as follows:
(1)步骤1与制备实施例1化合物的步骤1相同，得到中间体4-(2-氟-6-硝基苯基 氨基)苯甲酸甲酯(1-1)(1) Step 1 is the same as Step 1 of the preparation of the compound of Example 1, to give the intermediate 4-(2-fluoro-6-nitrophenyl) Amino)methyl benzoate (1-1)
(2)4-(2-溴-N-(2-氟-6-硝基苯)基-乙酰氨基)苯甲酸乙酯(22-2)的制备(2) Preparation of ethyl 4-(2-bromo-N-(2-fluoro-6-nitrophenyl)-acetamido)benzoate (22-2)
Figure PCTCN2015074412-appb-000042
Figure PCTCN2015074412-appb-000042
将中间体1-1(152mg，0.5mmol)溶于3mL DMF，室温下加入NaH(60％，60mg，1.5mmol)，室温搅拌0.5h后，加入2-溴代乙酰氯(118mg，0.75mmol)，室温搅拌2h，TLC检测1-1完全消失后，淬灭反应，反应液倒入30mL水中，乙酸乙酯(30mL×3)萃取。合并后的有机相经饱和碳酸氢钠和饱和食盐水依次洗涤，无水硫酸钠干燥，过滤，浓缩，薄层硅胶(GF-254)板分离(正己烷:乙酸乙酯＝3:1)得128mg淡黄色固体为22-2，收率60.4％。Intermediate 1-1 (152 mg, 0.5 mmol) was dissolved in 3 mL of DMF, NaH (60%, 60 mg, 1.5 mmol) was added at room temperature, stirred at room temperature for 0.5 h, then 2-bromoacetyl chloride (118 mg, 0.75 mmol) After stirring at room temperature for 2 h, after TLC detection 1-1 completely disappeared, the reaction was quenched, and the reaction mixture was poured into 30 mL of water, and ethyl acetate (30 mL×3) was extracted. The combined organic phase was washed with saturated aqueous sodium hydrogen sulfate and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. 128 mg of pale yellow solid was 22-2, yield 60.4%.
(3)4-(8-氟-2-酮-3,4-二氢喹喔啉-1(2H)-基)苯甲酸乙酯(22-3)的制备(3) Preparation of ethyl 4-(8-fluoro-2-one-3,4-dihydroquinoxaline-1(2H)-yl)benzoate (22-3)
Figure PCTCN2015074412-appb-000043
Figure PCTCN2015074412-appb-000043
中间体22-2(106mg，0.25mmol)溶于5mL乙醇中，室温加入氯化亚锡(237mg，1.25mmol)，加热回流3.5h，TLC检测22-2完全消失后，浓缩蒸干反应液，所得残渣加入30mL乙酸乙酯中，搅拌混匀，然后用饱和碳酸氢钠、饱和食盐水依次洗涤上述混合物，分液后有机相经无水硫酸钠干燥，过滤，滤液浓缩后用薄层层析板分离(正己烷:乙酸乙酯＝1:1)得46mg淡黄色固体为22-3，收率58.6％。Intermediate 22-2 (106 mg, 0.25 mmol) was dissolved in 5 mL of ethanol. Stannous chloride (237 mg, 1.25 mmol) was added at room temperature, and the mixture was heated to reflux for 3.5 hr. The obtained residue was added to 30 mL of ethyl acetate, and the mixture was stirred and mixed, and then the mixture was washed successively with saturated sodium hydrogen carbonate and brine, and then the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The plate was separated (n-hexane: ethyl acetate = 1:1) to afford 46 mg of pale yellow solid (yield: 58.
(4)4-(4-(2,6-二氯苯甲酰基)-8-氟-2-酮-3,4-二氢喹喔啉-1(2H)-基)苯甲酸乙酯(22-4)的制备(4) 4-(4-(2,6-Dichlorobenzoyl)-8-fluoro-2-one-3,4-dihydroquinoxaline-1(2H)-yl)benzoic acid ethyl ester ( Preparation of 22-4)
Figure PCTCN2015074412-appb-000044
Figure PCTCN2015074412-appb-000044
将中间体22-3(31.4mg，0.1mmol)溶于3mL DMF，室温加入NaH(60％，12mg，0.3mmol)，室温搅拌0.5h后，加入酰氯(41.9mg，0.2mmol)，室温搅拌2h，TLC检测22-3完全消失后，淬灭反应，反应液倒入10mL水中，乙酸乙酯(10mL×3)萃取。合并有机相，用饱和碳酸氢钠、饱和食盐水依次洗涤，无水硫酸钠干燥有机相，过滤， 浓缩滤液，经薄层层析板分离纯化(正己烷:乙酸乙酯＝5:1)得35mg淡黄色固体为22-4，收率72％。The intermediate 22-3 (31.4 mg, 0.1 mmol) was dissolved in 3 mL of DMF, then NaH (60%, 12 mg, 0.3 mmol) was stirred at room temperature for 0.5 h, then acid chloride (41.9 mg, 0.2 mmol). After the TLC test 22-3 completely disappeared, the reaction was quenched, and the reaction solution was poured into 10 mL of water and extracted with ethyl acetate (10 mL×3). The organic phase was combined, washed with saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate The filtrate was concentrated and purified (yield: n-hexane: ethyl acetate = 5:1) to afford 35 mg of pale yellow solid.
(5)4-(4-(2,6-二氯苯甲酰基)-8-氟-2-酮-3,4-二氢喹喔啉-1(2H)-基)苯甲酸(22)的制备(5) 4-(4-(2,6-Dichlorobenzoyl)-8-fluoro-2-one-3,4-dihydroquinoxaline-1(2H)-yl)benzoic acid (22) Preparation
将中间体22-4(35mg，0.072mmol)溶于5mL THF，加入1mL H2O，室温下加入LiOH·H2O(28.8mg，0.72mmol)，反应液室温搅拌过夜，TLC检测22-4完全消失后，加入3mL H2O，加入1mL 1N盐酸水溶液，搅拌5min，乙酸乙酯(5mL×3)萃取，合并有机相，经饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩滤液，经薄层层析板分离(正己烷:乙酸乙酯＝3:1)得16mg淡黄色固体22，收率48.5％。相关表征数据如下：MS+H+＝463.2；1H-NMR(DMSO-d6，300MHz)δ:ppm13.248(brs,1H),8.119-8.091(d,2H,J＝8.4Hz),7.806-7.778(m,2H),7.635-7.539(m,4H),7.365-7.126(m,2H),5.500(s,2H)。The intermediate 22-4 (35 mg, 0.072 mmol) was dissolved in 5 mL of THF, 1 mL of H 2 O was added, and LiOH·H 2 O (28.8 mg, 0.72 mmol) was added at room temperature, and the reaction mixture was stirred at room temperature overnight. After completely disappearing, 3 mL of H 2 O was added, and 1 mL of 1N aqueous hydrochloric acid was added, and the mixture was stirred for 5 min, ethyl acetate (5 mL×3), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Separation by a thin layer chromatography (n-hexane: ethyl acetate = 3:1) afforded 16 mg of pale yellow solid. The relevant characterization data is as follows: MS + H + = 463.2; 1 H-NMR (DMSO-d 6 , 300 MHz) δ: ppm 13.248 (brs, 1H), 8.119-8.091 (d, 2H, J = 8.4 Hz), 7.806 -7.778 (m, 2H), 7.635-7.539 (m, 4H), 7.635-7.126 (m, 2H), 5.500 (s, 2H).
实施例23：4-(4-(2,6-二氯苯甲酰基)-8-氟-3,4-二氢喹喔啉-1(2H)-基)苯甲酸Example 23: 4-(4-(2,6-Dichlorobenzoyl)-8-fluoro-3,4-dihydroquinoxaline-1(2H)-yl)benzoic acid
Figure PCTCN2015074412-appb-000045
Figure PCTCN2015074412-appb-000045
本实施例化合物可以按照与前述实施例22类似的步骤方法进行制备，不同之处在于步骤2中使用1,2-二溴乙烷为原料代替2-溴代乙酰氯进行氨基的取代反应。相关表征数据如下：MS+H+＝445.2；1H-NMR(CDCl3，300MHz)δ:ppm,4.10(t,J＝5.7Hz,2H),4.30(t,J＝5.7Hz,2H),6.61-6.70(m,1H),6.97(d,J＝8.4Hz,2H),7.25-7.35(m,5H),7.97(d,J＝8.4Hz,2H)。The compound of this example can be prepared by a similar procedure to that of the above-mentioned Example 22 except that in the step 2, 1,2-dibromoethane is used as a starting material instead of 2-bromoacetyl chloride for the amino group substitution reaction. The relevant characterization data is as follows: MS + H + = 445.2; 1 H-NMR (CDCl 3 , 300 MHz) δ: ppm, 4.10 (t, J = 5.7 Hz, 2H), 4.30 (t, J = 5.7 Hz, 2H), 6.61-6.70 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H), 7.25-7.35 (m, 5H), 7.97 (d, J = 8.4 Hz, 2H).
体外生物活性筛选In vitro biological activity screening
本发明的化合物可以调节(抑制)核受体RORγ的生物活性，此调节(抑制)作用的强弱能通过TR-FRET筛选体系来评价。核受体辅因子(共激活因子和共抑制因子)通过与核受体的相互作用可以调节目的基因的转录。如果配体(受试化合物)影响了核受体和辅因子的相互作用，那么这种配体(受试化合物)就可以调节相应基因的转录。The compound of the present invention can modulate (inhibit) the biological activity of the nuclear receptor RORγ, and the strength of this regulation (inhibition) can be evaluated by the TR-FRET screening system. Nuclear receptor cofactors (coactivators and cosuppressors) regulate the transcription of the gene of interest through interaction with nuclear receptors. If the ligand (test compound) affects the interaction between the nuclear receptor and the cofactor, the ligand (test compound) can modulate the transcription of the corresponding gene.
本方法采用Life Technologies公司的LanthaScreen TR-FRET(时间分辨荧光能量共振转移)技术测定化合物对RORγ与其共激活因子相互作用的调节能力(激动或反向激动)。铽(Tb)标记的抗GST抗体(Life Technologies#PV3550)通过结合在RORγ-LBD(Life Technologies#PV5887)的GST标签上而对RORγ-LBD进行非直接标记。没有配体存在时RORγ可以与荧光素标记的共激活因子持续结合，激动剂与RORγ结合后可以增强RORγ与荧光素标记的共激活因子的相互作用；反向激动剂与RORγ结合后可以抑制RORγ与荧光素标记的共激活因子的相互作用。荧光素标记的共激活 因子与铽标记的抗GST抗体-ROR标记的共激复合物相互接近到一定距离即可发生能量转移，产生TR-FRET信号。本方法使用的共激活因子不限于Fluorescein-D22(Life Technologies#PV4386)、Fluorescein-SRC1-2(Life Technologies#PV4578)、Fluorescein-SRC1-4(Life Technologies#PV4582)等。The method uses Life Technologies' LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) technique to determine the ability of a compound to modulate the interaction of RORy with its coactivator (agonism or reverse agonism). Tb-labeled anti-GST antibody (Life Technologies #PV3550) was indirectly labeled by binding to the GST tag of RORy-LBD (Life Technologies #PV5887). In the absence of ligand, RORγ can continue to bind to fluorescein-labeled coactivators. When agonists bind to RORγ, they can enhance the interaction of RORγ with fluorescein-labeled coactivators. Inverse agonists can inhibit RORγ by binding to RORγ. Interaction with fluorescein-labeled coactivators. Co-activation of fluorescein labeling The energy transfer can occur when the factor and the 铽-labeled anti-GST antibody-ROR-labeled conjugate complex are close to each other to generate a TR-FRET signal. The coactivator used in the method is not limited to Fluorescein-D22 (Life Technologies #PV4386), Fluorescein-SRC1-2 (Life Technologies #PV4578), Fluorescein-SRC1-4 (Life Technologies #PV4582), and the like.
(1)本方法反应体系的终浓度和反应条件如下表：(表1)(1) The final concentration and reaction conditions of the reaction system of the present method are as follows: (Table 1)
Figure PCTCN2015074412-appb-000046
Figure PCTCN2015074412-appb-000046
(2)实验方法(2) Experimental method
配制Complete TR-FRET Coregulator Buffer D(以下简称完全缓冲液D)：向TR-FRET Coregulator Buffer D(Life Technologies#PV4420)加入DTT(Life Technologies#P2325)至DTT终浓度为5mM。Complete TR-FRET Coregulator Buffer D (hereinafter referred to as complete buffer D): DTT (Life Technologies #P2325) was added to TR-FRET Coregulator Buffer D (Life Technologies #PV4420) to a final DTT concentration of 5 mM.
使用完全缓冲液D配制2X Fluorescein-D22(0.3μM，使用其它共激活肽时参照表1)和2X Tb标记的抗GST抗体(4nM)的混合溶液，10μL/孔加入到384-孔板(Corning3376)中。2X Fluorescein-D22 (0.3 μM, refer to Table 1 when using other co-activator peptides) and 2X Tb-labeled anti-GST antibody (4 nM) were mixed in complete buffer D, and 10 μL/well was added to the 384-well plate (Corning 3376). )in.
使用DMSO配制100X终浓度梯度稀释的待测化合物，然后使用完全缓冲液D将待测化合物稀释至4X(DMSO含量为4％)，5μL/孔加入到上述384-孔板中，混合均匀。阳性对照孔中以5μL/孔加入含有4％DMSO的完全缓冲液D(无待测化合物)。A 100X final concentration gradient of the test compound was prepared using DMSO, and then the test compound was diluted to 4X (DMSO content: 4%) using complete buffer D, and 5 μL/well was added to the above 384-well plate and mixed well. To the positive control wells, complete buffer D (no test compound) containing 4% DMSO was added at 5 μL/well.
使用完全缓冲液D配制4X RORγ-LBD(8nM)，5μL/孔加入到上述384-孔板中，混合均匀。阴性对照孔中加入5μL/孔完全缓冲液D(无RORγ-LBD)。将384-孔板置于恒温振荡器中，于23℃避光孵育4～5小时。4X RORγ-LBD (8 nM) was prepared using complete buffer D, and 5 μL/well was added to the above 384-well plate and mixed well. 5 μL/well of Complete Buffer D (without RORγ-LBD) was added to the negative control wells. The 384-well plate was placed in a thermostated shaker and incubated for 4 to 5 hours at 23 ° C in the dark.
使用Tecan M1000Pro测定荧光强度：1)激发波长332/20nm，发射波长490/10nm，增益值：优化，闪光：模式2(100Hz)，延迟时间100μs，整合时间200μs；2)激发波长332/20nm，发射波长520/20nm，增益值：优化，闪光：模式2(100Hz)，延迟时间100μs，整合时间200μs。Fluorescence intensity was measured using Tecan M1000Pro: 1) excitation wavelength 332/20 nm, emission wavelength 490/10 nm, gain value: optimization, flash: mode 2 (100 Hz), delay time 100 μs, integration time 200 μs; 2) excitation wavelength 332/20 nm, Emission wavelength 520/20nm, gain value: optimized, flash: mode 2 (100Hz), delay time 100μs, integration time 200μs.
(3)数据分析(3) Data analysis
使用程序GraphPad Prism绘制TR-FRET比值F520/F490–化合物浓度的对数曲线，并计算出EC50值，此数值越小说明化合物对受体RORγ调节(在本实施例中为抑制)作用的越强。The logarithmic curve of the TR-FRET ratio F520/F490 - compound concentration was plotted using the program GraphPad Prism, and the EC50 value was calculated. The smaller the value, the stronger the effect of the compound on the receptor RORγ regulation (in this example, inhibition). .
部分实施例化合物对RORγ作用的EC50值见下表：(表2) The EC50 values of the effects of some of the compounds on RORγ are shown in the following table: (Table 2)
Figure PCTCN2015074412-appb-000047
Figure PCTCN2015074412-appb-000047
已经通过举例说明和实施例的方式详细描述了上述发明，以用于阐述和理解的目的。对于本领域技术人员显而易见的是，可以在后附的权利要求的范围内进行改变和改进。因此，应该理解上述说明是举例说明性的而不是限制性的。因此，本发明的范围不应该参考上述说明书而确定，而应该参考下列后附的权利要求以及由权利要求授权的等价物的全部范围而确定。 The above invention has been described in detail by way of illustration and example of the embodiments of the invention. It will be apparent to those skilled in the art that changes and modifications may be made within the scope of the appended claims. Therefore, the above description is to be considered as illustrative and not restrictive. The scope of the invention should, therefore, be construed in the claims

Claims (15)

  1. 一种化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，所述化合物具有结构式I：A compound, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, which has the formula I:
    Figure PCTCN2015074412-appb-100001
    Figure PCTCN2015074412-appb-100001
    其中：among them:
    X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
    L选自-C(O)-、-S(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O)-, -S(O) 2 - or -CH 2 -;
    A选自芳基或杂芳基，所述芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；A is selected from aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, amino, cyano, hydroxy, carboxy, alkyl, alkoxy , haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkyl acyl;
    B为选自以下的二价环：环烷基、杂环基、芳基或杂芳基，所述环烷基、杂环基、或芳基或杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、硝基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、烷基磺酰氨基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基、酰氨基或烷基酰基；B is a divalent ring selected from a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, and the cycloalkyl group, heterocyclic group, or aryl group or heteroaryl group is optionally independently one of the following Or a plurality of groups substituted: halogen, amino, cyano, hydroxy, carboxy, nitro, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, alkylsulfonylamino An aminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group, an acylamino group or an alkyl acyl group;
    m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n是0、1或2；n is 0, 1 or 2;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
    Rb选自烷基、氨基、烷基氨基或二烷基氨基；且R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
    R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基。R 2 when present is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy.
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有结构式II：The compound according to claim 1 or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula II:
    Figure PCTCN2015074412-appb-100002
    Figure PCTCN2015074412-appb-100002
    其中：among them:
    Q选自N或-CR4； Q is selected from N or -CR 4 ;
    X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
    L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
    A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、烷基磺酰基、磺酰氨基、酰氨基、氨基甲酰基、烷基氨基甲酰基、二烷基氨基甲酰基或烷基酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, alkylsulfonyl, sulfonylamino, amido, carbamoyl, alkylcarbamoyl , a dialkylcarbamoyl group or an alkyl acyl group;
    m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n是0、1或2；n is 0, 1 or 2;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
    Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
    R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
    R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
  3. 根据权利要求2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中，在式II中：The compound according to claim 2, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein, in Formula II:
    Q是N或-CR4；Q is N or -CR 4 ;
    X选自-C(O)-、-CH2C(O)-或-CH2CH2-；X is selected from -C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
    L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
    A选自C6-10芳基或5-10元杂芳基，所述C6-10芳基或5-10元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、C1-4烷基氨基、二C1-4烷基氨基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；A is selected from C 6-10 aryl or 5-10 membered heteroaryl, C 6-10 aryl or a 5-10 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, C 1-4 alkylamino, di C 1-4 alkylamino , carbamoyl, C 1-4 alkylcarbamoyl or di C 1-4 alkylcarbamoyl;
    m是0或1；m is 0 or 1;
    n是0、1或2；n is 0, 1 or 2;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、C1-4烷氧基、氨基、C1-4烷基氨基或二C1-4烷基氨基；R a is selected from a hydroxyl group, a C 1-4 alkoxy group, an amino group, a C 1-4 alkylamino group or a di C 1-4 alkylamino group;
    Rb选自C1-4烷基、氨基、C1-4烷基氨基或二C1-4烷基氨基；R b is selected from C 1-4 alkyl, amino, C 1-4 alkylamino or di C 1-4 alkylamino;
    R2当存在时独立地选自卤素、氰基、羟基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或卤代C1-4烷氧基；R 2 , when present, is independently selected from halo, cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or halo C 1-4 alkoxy;
    R3选自氢、卤素、氰基、羧基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、C1-4烷基氨基、二C1-4烷基氨基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；且 R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, C 1-4 alkylamino, di C 1-4 An alkylamino group, a carbamoyl group, a C 1-4 alkylcarbamoyl group or a di C 1-4 alkylcarbamoyl group;
    R4选自氢、卤素或C1-4烷基。R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
  4. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物具有结构式IIa：The compound according to claim 1 or 2, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula IIa:
    Figure PCTCN2015074412-appb-100003
    Figure PCTCN2015074412-appb-100003
    其中：among them:
    Q选自N或-CR4；Q is selected from N or -CR 4 ;
    L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
    A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    n是0、1或2；n is 0, 1 or 2;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
    Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
    R2当存在时独立地选自卤素、氰基、羟基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, hydroxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
    R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
  5. 根据权利要求4所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中，在式IIa中：The compound according to claim 4, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein, in Formula IIa:
    Q是N或-CR4；Q is N or -CR 4 ;
    L选自-C(O)-、-S(O)2-或-CH2-；L is selected from -C(O)-, -S(O) 2 - or -CH 2 -;
    A选自苯基或5-6元杂芳基，所述苯基或5-6元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基；A is selected from phenyl or 5-6 membered heteroaryl, which is optionally substituted independently with one or more of the following groups: halogen, cyano, C 1-4 An alkyl group, a C 1-4 alkoxy group, a halogenated C 1-4 alkyl group;
    m是0、1或2；m is 0, 1 or 2;
    n是0或1；n is 0 or 1;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、C1-4烷氧基、氨基、C1-4烷基氨基或二C1-4烷基氨基；R a is selected from a hydroxyl group, a C 1-4 alkoxy group, an amino group, a C 1-4 alkylamino group or a di C 1-4 alkylamino group;
    Rb选自C1-4烷基、氨基、C1-4烷基氨基或二C1-4烷基氨基； R b is selected from C 1-4 alkyl, amino, C 1-4 alkylamino or di C 1-4 alkylamino;
    R2当存在时独立地选自卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基或卤代C1-4烷氧基；R 2 , when present, is independently selected from halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl or halo C 1-4 alkoxy;
    R3选自氢、卤素、氰基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、氨基甲酰基、C1-4烷基氨基甲酰基或二C1-4烷基氨基甲酰基；且R 3 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, carbamoyl, C 1-4 alkylcarbamoyl or C 1-4 alkylcarbamoyl;
    R4选自氢、卤素或C1-4烷基。R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
  6. 根据权利要求4所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中，在式IIa中：The compound according to claim 4, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein, in Formula IIa:
    Q选自N或-CR4；Q is selected from N or -CR 4 ;
    L选自-C(O)-或-CH2-；L is selected from -C(O)- or -CH 2 -;
    A为苯基，所述苯基任选独立地被以下的一个或多个基团取代：卤素、C1-4烷基或卤代C1-4烷基；A is phenyl, which is optionally independently substituted with one or more of the following: halo, C 1-4 alkyl or halo C 1-4 alkyl;
    m是0或1；m is 0 or 1;
    n是0；n is 0;
    R1为-COOH；R 1 is -COOH;
    R2当存在时独立地选自卤素、C1-4烷基或卤代C1-4烷基；R 2 , when present, is independently selected from halo, C 1-4 alkyl or halo C 1-4 alkyl;
    R3选自氢；且R 3 is selected from hydrogen;
    R4选自氢、卤素或C1-4烷基。R 4 is selected from hydrogen, halogen or C 1-4 alkyl.
  7. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中，所述化合物具有结构式IIb：The compound according to claim 1 or 2, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula IIb:
    Figure PCTCN2015074412-appb-100004
    Figure PCTCN2015074412-appb-100004
    其中：among them:
    Q是N或-CR4；Q is N or -CR 4 ;
    L选自-C(O)-或-S(O)2-；L is selected from -C(O)- or -S(O) 2 -;
    A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基环任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl ring optionally substituted independently with one or more groups: Halogen, amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
    Rb选自烷基、氨基、烷基氨基或二烷基氨基； R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
    R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
    R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    R4选自氢、卤素或烷基。R 4 is selected from hydrogen, halogen or alkyl.
  8. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中，所述化合物具有结构式IIc：The compound according to claim 1 or 2, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound has the formula IIc:
    Figure PCTCN2015074412-appb-100005
    Figure PCTCN2015074412-appb-100005
    其中：among them:
    Q是N或-CR4；Q is N or -CR 4 ;
    L选自-C(O)-或-S(O)2-；L is selected from -C(O)- or -S(O) 2 -;
    A选自C6-12芳基或5-12元杂芳基，所述C6-12芳基或5-12元杂芳基任选独立地被以下的一个或多个基团取代：卤素、氨基、氰基、羟基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；A is selected from C 6-12 aryl or 5-12 membered heteroaryl, C 6-12 aryl or a 5-12 membered heteroaryl group optionally independently substituted with one or more of the following radicals: halogen , amino, cyano, hydroxy, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    m是0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    R1选自-C(O)Ra或-S(O)2Rb；R 1 is selected from -C(O)R a or -S(O) 2 R b ;
    Ra选自羟基、烷氧基、氨基、烷基氨基或二烷基氨基；R a is selected from a hydroxyl group, an alkoxy group, an amino group, an alkylamino group or a dialkylamino group;
    Rb选自烷基、氨基、烷基氨基或二烷基氨基；R b is selected from an alkyl group, an amino group, an alkylamino group or a dialkylamino group;
    R2当存在时独立地选自卤素、氰基、硝基、羟基、烷基酰基氧基、烷基、烷氧基、卤代烷基或卤代烷氧基；R 2 , when present, is independently selected from halo, cyano, nitro, hydroxy, alkyl acyloxy, alkyl, alkoxy, haloalkyl or haloalkoxy;
    R3选自氢、卤素、氰基、羧基、烷基、烷氧基、卤代烷基、烷基氨基、二烷基氨基、氨基甲酰基、烷基氨基甲酰基或二烷基氨基甲酰基；且R 3 is selected from the group consisting of hydrogen, halogen, cyano, carboxy, alkyl, alkoxy, haloalkyl, alkylamino, dialkylamino, carbamoyl, alkylcarbamoyl or dialkylcarbamoyl;
    R4是氢、卤素或烷基。R 4 is hydrogen, halogen or alkyl.
  9. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，其中所述化合物选自：The compound according to claim 1 or 2, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2015074412-appb-100006
    Figure PCTCN2015074412-appb-100006
    Figure PCTCN2015074412-appb-100007
    Figure PCTCN2015074412-appb-100007
  10. 一种药物组合物，包含权利要求1-9中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药，以及药学上可接受的赋形 剂。A pharmaceutical composition comprising the compound of any one of claims 1-9, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, and Pharmaceutically acceptable form Agent.
  11. 根据权利要求10所述的药物组合物，还包含一种或多种选自以下的抗炎药：非甾体类抗炎药、非特异性和COX-2特异性环氧合酶抑制剂、金化合物、皮质激素类、肿瘤坏死因子受体拮抗剂、水杨酸酯或盐、免疫抑制剂和甲胺蝶呤。The pharmaceutical composition according to claim 10, further comprising one or more anti-inflammatory agents selected from the group consisting of non-steroidal anti-inflammatory drugs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold Compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunosuppressive agents and methotrexate.
  12. 根据权利要求1至9中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药在制备预防或治疗RORγ介导的疾病的药物中的用途。The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for the preparation of a preventive or therapeutic RORγ-mediated The use of the disease in medicine.
  13. 根据权利要求1至9中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或者其溶剂化物或其前药在制备作为RORγ调节剂的药物中的用途。The compound according to any one of claims 1 to 9, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof or a prodrug thereof, for preparing a drug as a RORγ modulator Use in.
  14. 一种预防或治疗RORγ介导的疾病的方法，包含给予有需要的患者治疗有效量的一种或多种根据权利要求1-9中任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂化物或其前药或根据权利要求10或11所述的药物组合物。A method of preventing or treating a disease mediated by a ROR gamma comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds according to any one of claims 1 to 9 or a stereoisomer thereof, An isomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a pharmaceutical composition according to claim 10 or 11.
  15. 根据权利要求12所述的用途或者根据权利要求14所述的方法，其中所述RORγ介导的疾病选自：类风湿性关节炎、多发性硬化症、银屑病、克罗恩病、哮喘、系统性红斑狼疮、慢性阻塞性肺病、组织移植物排斥反应和移植器官的排斥反应、硬皮病、紫癜、自身免疫溶血性和血小板减少性症状、应激性肠综合症、骨关节炎、川崎氏病、桥本氏甲状腺炎、粘膜利斯曼病、支气管炎、过敏性鼻炎、特应性皮炎、囊性纤维化、肺代谢排斥反应、儿童类风湿关节炎、强直性脊柱炎、胰腺炎、自身免疫性糖尿病、自身免疫性眼病、溃疡性结肠炎、sjorgen氏综合症、视神经炎、糖尿病、视神经脊髓炎、重症肌无力、葡萄膜炎、格林-巴利综合症、银屑病性关节炎、葛瑞夫氏病或巩膜炎。 The use according to claim 12 or the method according to claim 14, wherein the RORγ-mediated disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, asthma , systemic lupus erythematosus, chronic obstructive pulmonary disease, tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, stress bowel syndrome, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucosal Lissman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis in children, ankylosing spondylitis, pancreas Inflammation, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia gravis, uveitis, Guillain-Barré syndrome, psoriasis Arthritis, Graves' disease or scleritis.
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