WO2015139619A1 - Composé servant de modulateur rorγ - Google Patents

Composé servant de modulateur rorγ 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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alkyl
alkoxy
alkylamino
cyano
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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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    • C07D235/24—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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    • C07D241/44—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). .

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Abstract

La présente invention concerne un composé qui peut être utilisé en tant que modificateur du récepteur γ (RORγ) orphelin associé aux rétinoïdes, une composition pharmaceutique dudit composé, l'utilisation dudit composé dans la fabrication de produits pharmaceutiques, ainsi qu'un procédé pour utiliser ledit composé dans le traitement et/ou la prophylaxie d'une maladie à médiation par RORγ chez un mammifère (notamment un être humain) Le composé présente la formule structurelle (I).
PCT/CN2015/074412 2014-03-18 2015-03-17 Composé servant de modulateur rorγ WO2015139619A1 (fr)

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WO2016110821A1 (fr) * 2015-01-08 2016-07-14 Advinus Therapeutics Limited Composés bicycliques, compositions et applications médicinales de ceux-ci
WO2020054788A1 (fr) * 2018-09-13 2020-03-19 キッセイ薬品工業株式会社 Composé d'imidazopyridinone
CN112574191A (zh) * 2019-09-29 2021-03-30 南京圣和药业股份有限公司 异噁唑杂环类化合物及其应用
CN114230523A (zh) * 2016-01-29 2022-03-25 生命医药有限责任公司 作为ROR-γ的调节剂的苯并咪唑衍生物
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CN109111418B (zh) * 2017-06-23 2022-10-11 江苏柯菲平医药股份有限公司 一类2，3-二氢-1H-茚-4-磺酰胺RORγ调节剂及其用途

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CN114230523A (zh) * 2016-01-29 2022-03-25 生命医药有限责任公司 作为ROR-γ的调节剂的苯并咪唑衍生物
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