WO2016119641A1 - N-苯甲酸基取代的苯并吡咯啉-2-酮类衍生物及其用途 - Google Patents

N-苯甲酸基取代的苯并吡咯啉-2-酮类衍生物及其用途 Download PDF

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WO2016119641A1
WO2016119641A1 PCT/CN2016/071778 CN2016071778W WO2016119641A1 WO 2016119641 A1 WO2016119641 A1 WO 2016119641A1 CN 2016071778 W CN2016071778 W CN 2016071778W WO 2016119641 A1 WO2016119641 A1 WO 2016119641A1
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group
alkyl
alkoxy
compound
halogen
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PCT/CN2016/071778
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English (en)
French (fr)
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薛海
赵涛
马涛
车美英
金孟燮
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北京韩美药品有限公司
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Priority to US15/541,137 priority Critical patent/US10322108B2/en
Priority to KR1020177024048A priority patent/KR102004721B1/ko
Priority to EP16742703.8A priority patent/EP3252038B1/en
Priority to JP2017540241A priority patent/JP6449470B2/ja
Publication of WO2016119641A1 publication Critical patent/WO2016119641A1/zh

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Definitions

  • the present application relates to compounds useful as retinoic acid-related orphan receptor gamma (ROR ⁇ ) modulators, pharmaceutical compositions thereof, their use in pharmaceuticals, and the use thereof for the treatment and/or prevention of ROR ⁇ in mammals, especially humans.
  • 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 RORs
  • NF1R Retinoid-related orphan receptors
  • RAR retinoic acid receptor
  • RXR The retinoid X receptor (RXR) is named after it.
  • 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 multiple sclerosis, psoriasis, arthritis and asthma.
  • ROR ⁇ is a key driver of TH17 cell differentiation and regulation, 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 ROR ⁇ , and inhibit the production of cytokine IL-17 to block the occurrence and development of inflammation.
  • cytokine IL-17 production is inhibited in vitro and in mouse autoimmune disease models (CIA model, EAE model, etc.).
  • the present application provides a series of compounds useful as retinoic acid-related orphan receptor gamma (ROR ⁇ ) modulators, pharmaceutical compositions thereof, pharmaceutical uses thereof, and use thereof for the treatment and/or prevention of ROR ⁇ in mammals, especially humans A method of mediated disease.
  • ROR ⁇ retinoic acid-related orphan receptor gamma
  • One aspect of the present application provides a compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof, which has the structural formula (I):
  • A is a 5- or 6-membered aryl or heteroaryl group
  • R 6 is selected from one or more of the group consisting of alkyl, cycloalkyl, alkoxy, aryl, halogen, trifluoromethyl, amino, cyano, hydroxy, carboxy, haloalkyl, haloalkoxy, alkane Alkylamino, dialkylamino, alkylsulfonyl, aminosulfonyl, sulfonylamino, amido, carbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
  • B is an aryl or heteroaryl group
  • Q is aryl or heteroaryl, which is optionally substituted, independently, with one or more of the following: halo, trifluoromethyl, alkyl, cycloalkyl, alkoxy, a hydroxy, amino, cyano, nitro, carbonyl, aryl, heteroaryl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylsulfonyl or alkylcarbonyl group, An alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, a heteroaryl group may be optionally substituted with one or more halogens;
  • the (C 1-4 )alkyl group, (C 1-4 ) alkoxy group may be optionally substituted with one or more halogens;
  • n 0, 1, 2, 3 or 4;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • A is a 5- or 6-membered aryl or heteroaryl group
  • R 6 is selected from one or more of the group consisting of alkyl, cycloalkyl, alkoxy, aryl, halogen, trifluoromethyl, amino, cyano, carboxy, haloalkyl, haloalkoxy, alkylamino , a dialkylamino group, an alkylsulfonyl group, an aminosulfonyl group, a sulfonylamino group, an acylamino group, a carbonyl group, an alkylaminocarbonyl group or a dialkylaminocarbonyl group;
  • B is an aryl or heteroaryl group
  • the (C 1-4 )alkyl group, (C 1-4 ) alkoxy group may be optionally substituted with one or more halogens;
  • R 3 , R 4 , R 5 may be independently selected from H, halogen, trifluoromethyl, alkyl, cycloalkyl, alkoxy, hydroxy, amino, cyano, aryl, heteroaryl, alkyl An amino group, a dialkylamino group, an alkylsulfonyl group or an alkylcarbonyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • A is a phenyl group, a pyridyl group, a thienyl group, a furyl group or a pyrimidinyl group;
  • R 6 is selected from one or more of the group consisting of alkyl, cycloalkyl, alkoxy, aryl, halogen, trifluoromethyl, amino, cyano, carboxy, haloalkyl, haloalkoxy, alkylamino , a dialkylamino group, an alkylsulfonyl group, an aminosulfonyl group, a sulfonylamino group, an acylamino group, a carbonyl group, an alkylaminocarbonyl group or a dialkylaminocarbonyl group;
  • the (C 1-4 )alkyl group, (C 1-4 ) alkoxy group may be optionally substituted with one or more halogens;
  • R 3 , R 4 , R 5 may be independently selected from H, halogen, trifluoromethyl, alkyl, cycloalkyl, alkoxy, hydroxy, amino, cyano, aryl, heteroaryl, alkyl An amino group, a dialkylamino group, an alkylsulfonyl group or an alkylcarbonyl group;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • R 3 , R 4 , R 5 may be independently selected from H, halogen, trifluoromethyl, alkyl, cycloalkyl, alkoxy, hydroxy, amino, cyano, aryl, heteroaryl, alkyl An amino group, a dialkylamino group, an alkylsulfonyl group or an alkylcarbonyl group;
  • R 6 is selected from one or more of the group consisting of alkyl, cycloalkyl, alkoxy, aryl, halogen, trifluoromethyl, amino, cyano, carboxy, haloalkyl, haloalkoxy, alkylamino , a dialkylamino group, an alkylsulfonyl group, an aminosulfonyl group, a sulfonylamino group, an acylamino group, a carbonyl group, an alkylaminocarbonyl group or a dialkylaminocarbonyl group;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • m is 0 or 1, and when m is 1, R 2 is a hydroxyl group;
  • R 6 is C 1-4 alkyl, cycloalkyl, alkoxy
  • the compound of the present application is represented by (Id):
  • R 6 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3-4 )cycloalkyl or C 5-10 Aryl;
  • R 3 and R 4 are independently selected independently from halogen (for example, chloro), trifluoromethyl, (C 1-4 )alkyl, (C 1-4 )alkoxy or (C 3 -4 )cycloalkyl ( For example, cyclopropane).
  • the (C 1-4 )alkyl group, (C 1-4 ) alkoxy group may be optionally substituted by one or more halogen atoms
  • R 6 is selected from the group consisting of hydrogen, halogen, trifluoromethyl a group, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3-4 )cycloalkyl or C 5-10 aryl
  • R 3 is selected from halogen
  • R 4 is independently and independently It is selected from the group consisting of halogen, trifluoromethyl, (C 1-4 )alkyl, (C 1-4 ) alkoxy or (C 3-4 )cycloalkyl.
  • R 2 is hydrogen, hydroxy or halogen;
  • R 6 is fluoro, methyl, trifluoromethyl or methoxy;
  • R 3 is selected from halogen (for example chlorine); and
  • R 4 arbitrarily independently selected from halogen (e.g. chlorine), trifluoromethyl, (C 1-4) alkyl, (C 1-4) alkoxy, (C 3-4) cycloalkyl (e.g. cyclopropyl ).
  • R 2 is hydroxy; R 6 is fluoro, methyl or methoxy; R 3 is selected from halogen (eg, chloro); and R 4 is independently selected from halogen (eg, Chloro), trifluoromethyl, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3-4 )cycloalkyl (eg cyclopropyl).
  • R 2 is hydroxy; R 6 is methyl; R 3 is chloro; and R 4 is cyclopropyl, trifluoromethyl or chloro.
  • Another aspect of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the present application, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or a prodrug thereof, and a pharmaceutically acceptable excipient.
  • a further aspect of the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the present application, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate or a prodrug thereof; and one or more anti-inflammatory agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and specific cyclooxygenase-2 inhibitors, gold compounds, cortex Hormone, tumor necrosis factor receptor antagonist, salicylate or salt, immunosuppressant and methotrexate; and pharmaceutically acceptable excipients.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Another aspect of the present application relates to a compound of the present application, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof for use in modulating ROR ⁇ activity (for example, inhibiting ROR ⁇ activity) Or for the prevention or treatment of ROR ⁇ -mediated diseases.
  • Another aspect of the present application relates to a compound of the present application, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for use in the preparation of a modulator of ROR ⁇ activity (for example, inhibition) Use in drugs of ROR ⁇ activity).
  • Another aspect of the present application relates to a compound of the present application, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, as a ROR ⁇ modulator (for example, ROR ⁇ activity) Inhibitors) use in medicines.
  • a ROR ⁇ modulator for example, ROR ⁇ activity
  • Inhibitors use in medicines.
  • a further aspect of the present application relates to a compound of the present application, or a stereoisomer, tautomer thereof, or pharmaceutically acceptable thereof An acceptable salt or solvate thereof or a prodrug thereof for use in modulating RORy activity (e.g., inhibiting RORy activity).
  • Another aspect of the present application relates to a compound of the present application, or a stereoisomer, tautomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, for use in the prevention or treatment of ROR ⁇ -mediated The disease.
  • Another aspect of the present application relates to a method of modulating ROR ⁇ comprising the compounds of the present application or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof or solvates thereof or The drug is in contact with ROR ⁇ .
  • Another aspect of the present application relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a compound of the present application, or a stereoisomer, tautomer thereof, or A pharmaceutically acceptable salt thereof or a solvate thereof or a prodrug thereof, or a pharmaceutical composition of the present application.
  • Another aspect of the present application relates to a method of preventing or treating a ROR ⁇ -mediated disease comprising administering a prophylactically or therapeutically effective amount of a compound of the present application, or a stereoisomer or tautomer thereof, to a patient in need 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 agent includes, but is not limited to, one or more anti-inflammatory drugs selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs), non-specific and specific cyclooxygenase-2 inhibitors, gold compounds, Corticosteroids, tumor necrosis factor receptor antagonists, salicylates or salts, immunosuppressive agents and methotrexate.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • non-specific and specific cyclooxygenase-2 inhibitors gold compounds
  • Corticosteroids corticosteroids
  • tumor necrosis factor receptor antagonists include salicylates or salts, immunosuppressive agents and methotrexate.
  • the ROR ⁇ -mediated disease described herein can be an autoimmune disease and/or an inflammatory disease.
  • the prophylactic or therapeutic ROR gamma mediated disease is selected from the group consisting of: multiple sclerosis, rheumatoid arthritis, 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, Hashimoto's thyroiditis, Mucosal Leishmaniasis, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, pulmonary metabolic rejection, rheumatoid arthritis in children, ankylosing spondylitis, pancreatitis, autoimmune diabetes, autoimmune Eye disease, ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromyelitis
  • Figure 1 is a graph showing the in vivo activity of a compound of the present application against a vehicle control in a rat anti-arthritic CIA model.
  • C 1-8 alkyl means an alkyl group as defined below having a total of 1 to 8 carbon atoms
  • C 3-8 cycloalkyl means a group having a total of 3 to 8 carbon atoms as defined below Cycloalkyl
  • C 5-10 aryl means an aryl group as defined below having a total of 5 to 10 carbon atoms (or ring atoms).
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • “member” means the number of ring atoms of the group
  • 5-membered aryl means that the number of ring atoms of the aryl group is 5.
  • 5-tetrazole is Express HOC(CF 3 ) 2 is an indication -OH represents a hydroxyl group
  • -NH 2 represents an amino group
  • -CN represents a cyano group
  • -NO 2 represents a nitro group.
  • R a and R are as herein A defined alkyl group (such as a C 1-6 alkyl group).
  • acylamino group include, but are not limited to, formylamino, formylaminomethyl, N-acetylamino, N-methyl-N'-acetylamino, and the like.
  • phosphate group means -
  • phosphate group means R a and R b each represent an alkyl group, as defined below.
  • halogen means fluoro, chloro, bromo or iodo, such as fluoro or chloro.
  • alkyl group as a group or part of another group (ie, a separate alkyl group or other The group-bonded alkyl group), the term "alkyl group” means a straight or branched chain group consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds and attached to the remainder of the molecule by a single bond.
  • the alkyl group may have, for example, 1 to 18, 1 to 8, 1 to 6, and 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.
  • 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.
  • 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.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogen atoms, wherein alkoxy is as defined above.
  • alkylthio refers to a radical of the formula -SR a where R a is alkyl as defined above.
  • alkylthio groups include, but are not limited to, methylthio, ethylthio, isopropylthio, and the like.
  • 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.
  • alkylcarbonyl refers to a -COR a group wherein R a is alkyl as defined above.
  • alkylaminocarbonyl refers to -CONHR a or -CONR a R b , wherein R a and R b are alkyl as defined herein (eg, C 1-6 alkyl).
  • alkenyl as a part of a group or other group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14, 2 to 10, 2 a linear or branched hydrocarbon chain group of up to 8 carbon atoms and attached to the remainder of the molecule by a single bond, including but not limited to vinyl, propenyl, allyl, but-1-enyl, butyl- 2-Alkenyl, pent-1-enyl, pent-2-enyl, pentane-1,4-dienyl and the like.
  • alkynyl as a group or part of another group means consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example 2 a linear or branched hydrocarbon chain group of up to 14, 2 to 10, 2 to 8 carbon atoms and attached to the remainder of the molecule by a single bond.
  • Alkyne Examples of the group include, but are not limited to, ethynyl, prop-1-ynyl, pent-1-en-4-ynyl, and the like.
  • the term "carbocyclyl” as a group or part of another group means a non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include a fused ring system. a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, having from 3 to 8 carbon atoms, from 3 to 7 carbon atoms, and which is saturated or unsaturated and It is attached to the remainder of the molecule via a single bond via any suitable carbon atom.
  • a carbocyclic group may be saturated (which may be referred to as a cycloalkyl group) or unsaturated (which may be referred to as a cycloalkenyl group).
  • the carbon atom in the cycloalkyl group can be optionally oxidized.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo [2.2.1] heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl
  • heterocyclyl as a group or part of another group means a 3 member composed of 2 to 12 carbon atoms and 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur. Up to 18-membered non-aromatic cyclic groups. Heterocyclyl groups can be saturated or unsaturated. 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.
  • the heterocyclic group is preferably a 5- to 12-membered non-aromatic monocyclic or bicyclic group containing from 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, more preferably containing 1 to a 5- to 8-membered non-aromatic monocyclic group selected from the group consisting of nitrogen, oxygen and sulfur hetero atoms, more preferably 5 to 6 yuan containing 1 to 2 hetero atoms selected from nitrogen, oxygen and sulfur Non-aromatic monocyclic groups.
  • 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 A group, an octahydroindenyl group, an octahydroisodecyl group, a pyrrolidinyl group, a pyrazolidinyl group, a phthalimido group or the like is preferably a tetrahydropyranyl group, a piperidinyl
  • aryl as a group or part of another group means a system having 6 to 18 (eg 6 to 10, 5 to 10) carbon atoms and at least one aromatic ring.
  • the aryl group can be monocyclic, bicyclic, tricyclic or more.
  • a ring system of the ring which may comprise a fused ring or a bridged ring system.
  • the fused ring fused to the aryl group may be a carbocyclic group, a heterocyclic group, an aryl group or a heteroaryl group as defined herein.
  • 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 (eg 1 to 10) carbon atoms and from 1 to 4 selected from nitrogen, oxygen and a hetero atom of sulfur, and a group of a 5- to 16-membered ring system 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 5- to 12-membered aromatic monocyclic or bicyclic group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 3 a 5- to 8-membered aromatic monocyclic or bicyclic group selected from hetero atoms of nitrogen, oxygen and sulfur, more preferably 5 to 6 yuan containing 1 to 2 hetero atoms selected from nitrogen, oxygen and sulfur Aromatic monocyclic or bicyclic groups.
  • 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. This application 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 present application are also intended to be encompassed within the scope of the present application.
  • pharmaceutically acceptable salt refers to a salt which retains the biological effectiveness of the free acid or free base of the compound of the present application and which has no adverse effects biologically or otherwise.
  • a pharmaceutically acceptable salt refers to a form in which a base group or an acidic group in a parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of base groups such as amine (amino) groups.
  • salts of the present application can be synthesized from the parent compound, suitable salts include the Remingtong's Pharmaceutical Scicences, 17 th ed ., Mack Publishing Company, Easton, Pa., 1985, p.1418 , and Journal of Pharmaceutical Science, 66, 2 (1977). Unless otherwise specified, the salt in the present application may be an acid salt formed from an organic acid/inorganic acid, and a basic salt formed from an organic base/inorganic base.
  • the acidic functional group of the compound of the formula is pyridine or imidazole (but not limited to pyridine or imidazole)
  • the acidic functional group is a carboxylic acid (but not limited to a carboxylic acid)
  • a zwitterion internal salt
  • the inner salt Also included in the salt in this application.
  • the compounds of the present application 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 the compound of the present application 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 present application are also within the scope of this application.
  • prodrug means a compound which can be hydrolyzed under physiological conditions or converted to a biologically active compound of the application by an enzymatic reaction.
  • prodrug refers to a pharmaceutically acceptable metabolic precursor of a compound of the present application.
  • the prodrug when administered to an individual in need, the prodrug may be inactive, but is converted in vivo to the active compound applied.
  • Prodrugs are typically rapidly converted in vivo to produce the parent compound of the present application, for example by hydrolysis in blood.
  • Prodrug compounds generally provide the advantage of solubility, tissue compatibility or sustained release in mammalian organisms.
  • an ester of a carboxyl-containing compound e.g., a compound of the present application
  • a pharmaceutically acceptable ester can be a prodrug of a compound of the present invention which decomposes into the parent acid in the human or animal body.
  • pharmaceutical composition refers to a formulation of a compound of the present application and a medium generally accepted in the art for delivering 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.
  • prophylactically or therapeutically effective amount means the amount of the compound of the present application when the compound of the present application is In mammals (e.g., humans), the amount is sufficient to effectively prevent or treat a disease in a mammal, such as a human.
  • the amount of a compound of the present application which constitutes a “prophylactically or 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 mammal to be treated The age, weight, physical condition, and the like, but can be conventionally determined by those skilled in the art based on their own knowledge and the content disclosed in the present application.
  • prevention includes reducing the likelihood of developing or worsening a disease or condition.
  • treatment includes the following meanings:
  • ROR ⁇ -mediated disease refers to a level in which ROR ⁇ is produced or altered by ROR ⁇ itself, or by causing another mononuclear factor such as, but not limited to, IL-17 or IL-23. The release of any disease or other harmful condition that works.
  • ROR ⁇ modulator refers to a molecule that interacts with a target ROR ⁇ and affects ROR ⁇ function, including but not limited to: antagonism, agonism, inverse agonism, and other similar interactions. .
  • the compounds of the present application may contain one or more chiral carbon atoms, and each asymmetric carbon atom may be in the R or S configuration, both configurations being within the scope of the present application.
  • 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 present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of the formula I, stereoisomers, tautomers, solvates or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof Acceptable excipients.
  • compositions of the present application 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 application 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 application 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).
  • dosage forms suitable for oral administration include capsules, tablets, granules, and syrups and the like.
  • the compounds of formula I of the present application 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 and the like.
  • the above dosage forms can be prepared from the active compound with one or more carriers or excipients via conventional pharmaceutical methods.
  • 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 present application or the pharmaceutical compositions of the present application 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 specific cyclooxygenase-2 (COX-2) inhibitors, gold compounds, corticosteroids, tumor necrosis factor receptor antagonists, salicylates Or salt, immunosuppressant and methotrexate.
  • compositions of the present application are formulated, quantified, and administered in a manner consistent with medical practice.
  • a "prophylactically or therapeutically effective amount" of a compound of the present application is determined by the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the dose for parenteral administration can be 1-200 mg/kg, mouth
  • the dose to be administered 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 can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. Use of protecting groups are detailed in Greene, TW and PGMWuts, Protective Groups in Organi Synthesis (Protective Groups in Organic Synthesis), (1999), 4 th Ed., Wiley medium.
  • the protecting group can also be a polymeric resin.
  • R is a 6-membered aromatic or aromatic heterocyclic ring; m is 0, 1, 2, 3 or 4, preferably 0 or 1; X is I, Br, Cl, preferably I or Br; Expressed.
  • a metal catalyst copper or palladium catalyst, preferably iodide
  • the base means sodium hydroxide, lithium hydroxide or potassium hydroxide
  • the solvent means methanol, ethanol, tetrahydrofuran or the like
  • R is a C 1-4 hydrocarbon group, and the other groups are as defined above.
  • R includes a C 1-6 alkyl group or a cycloalkyl group, an aryl group, and a heteroaryl group.
  • R 3 includes a C 1-6 alkyl group or a cycloalkyl group, an aryl group, a heteroaryl group, preferably a cyclopropyl group.
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • the organic solvent is dried over anhydrous magnesium sulfate or anhydrous sodium sulfate; the solvent is distilled off to dryness (for example: 15 mmHg, 30 ° C) using a rotary evaporator under reduced pressure;
  • 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).
  • Step 1 Synthesis of methyl 4-(4-methylindolino-2-one)-iodosalicylate (1-2)
  • Example 2 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 3b in Table 1 is used instead of the starting material 3a in Step 1, to obtain (trans)-4-( 3-(2-Chloro-6-cyclopropyl-benzylidene)-4-methylindol-2-one-1-yl)-benzoic acid (2A)
  • Example 3 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1a in Table 1 is used instead of the starting material 1a in Step 2 to obtain (trans)-4-( 3-(2-Chloro-6-methoxy-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 4 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1b in Table 1 is used instead of the starting material 1a in the step 2 to obtain (trans)-4-( 3-(2,6-Dichloro-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 5 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the raw material 3b in Table 1 is used instead of the raw material 3a in the step 1, and the use of the raw material 3a in the step 2 is used. Substrate 1b is substituted for starting material 1a to give (trans)-4-(3-(2,6-dichlorobenzylidene)-4-methylindol-2-one-1-yl)-benzoic acid
  • Example 6 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1c in Table 1 is used instead of the starting material 1a in Step 2 to obtain (trans)-4-( 3-(2chloro-6-(trifluoromethyl)-benzylidene)-4-methylindol-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 7 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1a in Table 1 is used instead of the starting material 1a in Step 2 to obtain (trans)-4-( 3-(2chloro-6-bromo-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 8 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2d in Table 1 is used instead of the starting material 2a in the step 1, to obtain (reverse)-4. -(3-(2chloro-6-bromo-benzylidene)-4-methoxyindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 9 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the step 2, the raw material 1g in Table 1 is used instead of the starting material 1a to obtain (trans)-4-( 3-(2chloro-6-fluoro-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 10 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1a in Table 1 is used instead of the starting material 1a in Step 2 to obtain (trans)-4-( 3-(2chloro-6-methyl-benzylidene)-4-methylindol-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 11 The preparation of the compound of the present Example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2d in Table 1 is used instead of the starting material 2a in Step 1, and the starting material is used in Step 2. Substituting 1b for starting material 1a to give (trans)-4-(3-(2,6-dichloro-benzylidene)-4-methoxyindoline-2-one-1-yl)-2-hydroxyl benzoic acid
  • Example 12 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2e in Table 1 is used instead of the starting material 2a in the step 1, to obtain (reverse)-4. -(3-(2chloro-6-cyclopropyl-benzylidene)-4-cyclopropylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 13 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2f in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. Obtaining (trans)-4-(3-(2chloro-6-cyclopropyl-benzylidene)-4-phenylindolin-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 14 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2c in Table 1 is used instead of the starting material 2a in the step 1, to obtain 4-(3- (2chloro-6-cyclopropyl-benzylidene)-4-chloro-indololin-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 15 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. In the second step, the starting material 1b is used instead of the starting material 1a to obtain (trans)-4-(3-(2,6-dichloro-benzylidene)-4-fluoro-indololin-2-one-1-yl. )-benzoic acid (15A)
  • Example 16 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. Obtaining (trans)-4-(3-(2-chloro-6-cyclopropyl-benzylidene)-4-fluoro-indololin-2-one-1-yl)-benzoic acid (16A)
  • Example 17 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. In the second step, 1 g of the starting material was used instead of the starting material 1a to obtain (trans)-4-(3-(2-chloro-6-fluoro-benzylidene)-4-fluoro-indololin-2-one-1- Benzoic acid (17A)
  • Example 18 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. In step 2, starting material 1d is used instead of starting material 1a to give (trans)-4-(3-(2,6-difluoro-benzylidene)-4-fluoro-indololin-2-one-1-yl )-benzoic acid (18A)
  • Example 19 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. In step 2, starting material 1c is used instead of starting material 1a to give (trans)-4-(3-(2-chloro-6-trifluoromethyl-benzylidene)-4-fluoro-carboline-2-one. -1-yl)-benzoic acid (19A)
  • Example 20 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a.
  • starting material 1i is used instead of starting material 1a to give (trans)-4-(3-(2-chloro-6-n-propyl-benzylidene)-4-fluoro-oxalin-2-one- 1-yl)-benzoic acid (20A)
  • Example 21 The preparation of the compound of the present Example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2b in Table 1 is used instead of the starting material 2a in Step 1, to obtain (reverse)-4. -(3-(2-chloro-6-cyclopropyl-benzylidene)-4-fluoro-indolino-2-one-1-yl)-2-hydroxy-benzoic acid (21A)
  • Example 22 Preparation of the compound of the present example can be carried out in accordance with the similar steps of the above Preparation Example 1. The difference is that in the first step, the starting material 2b in Table 1 is used instead of the starting material 2a, and in the second step, the starting material 1b is used instead of the starting material 1a to obtain (trans)-4-(3-(2,6-dichloro). -benzylidene)-4-fluoro-oxalin-2-one-1-yl)-2-hydroxy-benzoic acid (22A)
  • Example 23 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that in the first step, the starting material 2c in Table 1 is used instead of the starting material 2a, and the starting material 3b is used instead of the starting material 3a. In the second step, the starting material 1b is used instead of the starting material 1a to obtain (trans)-4-(3-(2,6-dichloro-benzylidene)-4-chloro-indololin-2-one-1-yl. )-benzoic acid
  • Example 24 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 3c in Table 1 is used instead of the starting material 3a in Step 1, to obtain (trans)-4-( 3-(2-Chloro-6-cyclopropyl-benzylidene)-4-methylindolino-2-one-1-yl)-2-chloro-benzoic acid
  • Example 25 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 3d in Table 1 is used instead of the starting material 3a in Step 1, to obtain (trans)-4-( 3-(2-Chloro-6-cyclopropyl-benzylidene)-4-methylindol-2-one-1-yl)-2-fluoro-benzoic acid
  • Example 26 The preparation of the compound of the present Example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2g in Table 1 is used instead of the starting material 2a in Step 1, to obtain (reverse)-4. -(3-(2chloro-6-bromo-benzylidene)-4-trifluoromethylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 27 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2h in Table 1 is used instead of the starting material 2a in Step 1, to obtain (reverse)-4. -(3-(2chloro-6-bromo-benzylidene)-indololin-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 29 Preparation of the compound of the present example can be carried out in accordance with the similar steps of the above Preparation Example 1. The difference is that in step 2, the starting material 1h in Table 1 is used instead of the starting material 1a, and in step 3, 3b is used instead of 3a to obtain (trans)-4-(3-(2chloro-6-methyl-). Benzamethylene)-4-methylindolino-2-one-1-yl)-benzoic acid
  • Example 30 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 2d in Table 1 is used instead of the starting material 2a in Step 1, and 3b is used in Step 3. Instead of 3a, (trans)-4-(3-(2chloro-6-methyl-benzylidene)-4-methoxyindoline-2-one-1-yl)-benzoic acid is obtained.
  • Example 31 The preparation of the compound of the present example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1b in Table 1 is used instead of the starting material 1a in Step 2, and 3b is used in Step 3. Instead of 3a, (trans)-4-(3-(2,6-dichloro-benzylidene)-4-methoxyindoline-2-one-1-yl)-benzoic acid is obtained.
  • Example 32 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1f in Table 1 is used instead of the starting material 1a in Step 2, and 3b is used in Step 3. Instead of 3a, (trans)-4-(3-(2chloro-6-methoxy-benzylidene)-4-methylindol-2-one-1-yl)-benzoic acid is obtained.
  • Example 33 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that 3e is used instead of 3a in the step 3 to obtain (trans)-4-(3-(2-chloro) -6-methoxy-benzylidene)-4-methylindolino-2-one-1-yl)-2-aminobenzoic acid
  • Example 34 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1j in Table 1 is used instead of the starting material 1a in Step 2, and 3b is used in Step 3. Instead of 3a, (trans)-4-(3-(2chloro-6-cyclobutyl-benzylidene)-4-methylindol-2-one-1-yl)-benzoic acid is obtained.
  • Example 35 The preparation of the compound of this example can be carried out in the same manner as in the above-mentioned Preparation Example 1, except that the starting material 1j in Table 1 is used instead of the starting material 1a in Step 2 to obtain (reverse)-4. -(3-(2chloro-6-cyclobutyl-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 36 The preparation of the compound of this example can be carried out in a similar manner to that of the above-mentioned Preparation Example 1, except that the starting material 1k in Table 1 is used instead of the starting material 1a in the step 2 to obtain (reverse)-4. -(3-(2chloro-6-isopropyl-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • Example 37 The preparation of the compound of this example can be carried out in a similar manner to that of the above Preparation Example 1, except that in the step 2, starting material 1a in Table 1 is used instead of the starting material 1a to obtain (reverse)-4. -(3-(2chloro-6-ethyl-benzylidene)-4-methylindolino-2-one-1-yl)-2-hydroxybenzoic acid
  • the compound of the present application can modulate (inhibit) the biological activity of the nuclear receptor ROR ⁇ , and the strength of this regulation (inhibition) can be evaluated by a TR-FRET (Time-Resolved Fluorescence Energy Resonance Transfer) 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.
  • 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 (agonistic or reverse agonistic).
  • 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 ⁇ .
  • the fluorescein-labeled coactivator and the europium-labeled anti-GST antibody-ROR ⁇ -LBD complex are close to each other to a certain distance to generate energy transfer, resulting in a TR-FRET signal.
  • the coactivator used in the method is not limited to D22 (Life Technologies #PV4386) or 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 2 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).
  • 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 of 4%) 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 containing 4% DMSO (no test compound) was added to the positive control wells.
  • 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 (no 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 [manufacturer: Tecan]: 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 520/20 nm, gain value: optimization, flash: mode 2 (100 Hz), 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 IC 50 value was calculated. The smaller the value, the stronger the effect of the compound on the receptor ROR ⁇ regulation (inhibition).
  • 96 plates (37 ° C, 2-6 hours) were coated with 5 ⁇ g/mL mouse CD3 antibody (purchased from BD) for use.
  • C57 mouse lymph node initial CD4-positive T cells were isolated using CD4+ T cell isolation kit II (purchased from MACS) and seeded in coated 96-well plates at 5 ⁇ 10 5 cells/well/100 ⁇ L.
  • the sample to be tested was diluted with RMPI-1640 medium (Gibco, 22440) and allowed to be 4 times the final concentration (starting at 1 ⁇ M, 10-fold dilution, setting 6 drug concentrations).
  • the diluted sample to be tested was added to the test well of the seeded cells at 50 ⁇ L per well, and the positive control and the negative control well were added to 50 ⁇ L of RMPI-1640 medium, respectively.
  • 50 ⁇ L of 4 times final concentration of stimulant mixture (20 ug/mL mouse CD28 antibody (purchased from BD); 40 ug/mL mouse IL-4 antibody (purchased from BD) was added to each well of the experimental well and the positive control well; 40 ug/mL mouse IFN ⁇ antibody (purchased from BD); 4 ng/mL mouse TGF- ⁇ 1 (purchased from R&D); 200 ng/mL mouse IL-6 (purchased from R&D); 20 ng/mL mouse IL-23 ( Purchased from R&D)), negative control wells were spiked with 50 [mu]L of RMPI-1640 medium.
  • the well-prepared 96-well plates were incubated at 37 ° C in a 5% CO 2 incubator for 66 hours, after which 50 uL of PMA (purchased from Sigma, working concentration 50 ng/mL) and Ionomycin (purchased from Sigma, working concentration 1 ug/) were added to each well. The mixture was incubated at 37 ° C for 6 hours. After the completion of the culture, the cell culture supernatant was taken, and the IL-17A content in the supernatant was measured using a mouse IL-17A ELISA kit (purchased from Daktronics), and the inhibition rate and IC50 were calculated. Refer to the kit instructions for specific operations (see below):
  • Washing the plate Deduct the liquid in the well, add 1 ⁇ washing buffer to 300 ⁇ L/well; leave the liquid in the well after staying for 1 minute. Repeat 4 times, each time on the filter paper.
  • Color development 100 ⁇ L/well was added to TMB, and incubation was carried out at 37 ° C for 5-30 minutes in the dark, and the termination reaction was judged according to the depth of the color in the well (dark blue). Usually 10-20 minutes of color development can achieve good results.
  • Test animals Female Wistar rats, weighing only 180-220 g.
  • the test drug (the compound of Example 1 of the present invention and the compound of Example 2A of Example 2) was administered to the rats by oral gavage on the 12th day after the initial immunization, and administered twice a day. After the administration, the degree of joint disease of the extremities of the rats was observed and recorded, and recorded every 2 days.
  • Scoring criteria Systemic lesions were evaluated according to a 5-point scale, and the score of the arthritis index was calculated based on the cumulative score of the lesions of the limbs of the limbs. The criteria were as follows: 0 points, no redness; 1 point, ankle or patella joint swelling; 2 points, ankle to patella joint swelling; 3 points, ankle to patella joint swelling; 4 points, including ankle joint All feet and joints are swollen.

Abstract

公开了一种化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，其可用于预防或治疗RORγ介导的疾病。所述化合物具有结构式(I)

Description

N-苯甲酸基取代的苯并吡咯啉-2-酮类衍生物及其用途 技术领域
本申请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治疗和/或预防哺乳动物(尤其是人)中RORγ介导的疾病的方法。
背景技术
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-relatedorphan 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，如多发性硬化症、银屑病、关节炎及哮喘等。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；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；Bioorg.Med.Chem.2014(22)，692–702；J Immunol 2014(192)，2564-2575；Immunity 2014(40),477–489)。
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。
发明内容
本申请提供了一系列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、其制药用途以及使用其治疗和/或预防哺乳动物(尤其是人)中RORγ介导的疾病的方法。
本申请的一个方面提供了一种化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物如具有结构式(I)：
Figure PCTCN2016071778-appb-000001
其中：
A是5元或6元的芳基或杂芳基；
R6选自一个或多个以下基团：烷基、环烷基、烷氧基、芳基、卤素、三氟甲基、氨基、氰基、羟基、羧基、卤代烷基、卤代烷氧基、烷基氨基、二烷基氨基、烷基磺酰基、氨基磺酰基、磺酰氨基、酰氨基、羰基、烷基氨基羰基或二烷基氨基羰基；
B是芳基或杂芳基；
Q是芳基或杂芳基，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、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、硝基、羰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基氨基羰基、二烷基氨基羰基、烷基磺酰基或烷基羰基，所述烷基、环烷基、烷氧基、芳基、杂芳基可以任选地被1个或多个卤素取代；
R1是任选独立地选自-C(＝O)OH、烷基-OC(＝O)-、酰氨基、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基、 烷基磺酰基；
R2是氢、羟基、卤素、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-3)烷基C(＝O)O-、,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
m是0,1,2,3或4；
所述杂环基或杂芳基具有一个或多个选自N、O和S的杂原子。
根据一些实施方式，本申请的一些化合物具有结构式(Ia)：
Figure PCTCN2016071778-appb-000002
其中：
A是5元或6元的芳基或杂芳基；
R6选自一个或多个以下基团：烷基、环烷基、烷氧基、芳基、卤素、三氟甲基、氨基、氰基、羧基、卤代烷基、卤代烷氧基、烷基氨基、二烷基氨基、烷基磺酰基、氨基磺酰基、磺酰氨基、酰氨基、羰基、烷基氨基羰基或二烷基氨基羰基；
B是芳基或杂芳基；
R1是任选独立地选自-C(＝O)OH、烷基-OC(＝O)-、酰氨基、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基、烷基磺酰基；
R2是氢、羟基、卤素、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-3)烷基C(＝O)O-、,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
R3，R4，R5可以任意独立地选自H,卤素、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基磺酰基或烷基羰基；
m是0,1,2,3或4；
n是0,1,2或3；
所述杂环基或杂芳基具有一个或多个选自N、O和S的杂原子。
根据一些实施方式，本申请的一些化合物具有结构式(Ⅰb)：
Figure PCTCN2016071778-appb-000003
其中：
A是苯基、吡啶基、噻吩基、呋喃基或嘧啶基；
R6选自一个或多个以下基团：烷基、环烷基、烷氧基、芳基、卤素、三氟甲基、氨基、氰基、羧基、卤代烷基、卤代烷氧基、烷基氨基、二烷基氨基、烷基磺酰基、氨基磺酰基、磺酰氨基、酰氨基、羰基、烷基氨基羰基或二烷基氨基羰基；
R1是任选独立地选自-C(＝O)OH、烷基-OC(＝O)-、酰氨基、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基、烷基磺酰基；
R2是氢、羟基、卤素、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-3)烷基C(＝O)O-、,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
R3，R4，R5可以任意独立地选自H,卤素、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基磺酰基或烷基羰基；
m是0,1,2,3或4；
n是0,1,2或3；
所述杂环基或杂芳基具有一个或多个选自N、O和S的杂原子。
根据一些实施方式，本申请的一些化合物具有结构式(Ⅰc)：
Figure PCTCN2016071778-appb-000004
其中:
R1是任选独立地选自-C(＝O)OH、烷基-OC(＝O)-、酰氨基(例如-C(＝O)NH2、-C(＝O)NHR、-C(＝O)NRRa，其中R和Ra都选自C1-6烷基)、5-四氮唑、HOC(CF3)2、 磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基、烷基磺酰基；
R2是氢、羟基、卤素、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-4)烷基C(＝O)O-(例如(Cl-3)烷基C(＝O)O-)、,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
R3，R4，R5可以任意独立地选自H,卤素、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基磺酰基或烷基羰基；
R6选自一个或多个以下基团：烷基、环烷基、烷氧基、芳基、卤素、三氟甲基、氨基、氰基、羧基、卤代烷基、卤代烷氧基、烷基氨基、二烷基氨基、烷基磺酰基、氨基磺酰基、磺酰氨基、酰氨基、羰基、烷基氨基羰基或二烷基氨基羰基；
所述杂环基或杂芳基具有一个或多个选自N、O和S的杂原子。
根据一些实施方式，式(Ⅰ)和(Ⅰa)、(Ⅰb)、(Ⅰc)中，m是0或1，当m是1时，R2是羟基；
根据一些实施方式，式(Ⅰ)和(Ⅰa)、(Ⅰb)、(Ⅰc)，R1是-C(＝O)OH；
根据一些实施方式，式(Ⅰ)和(Ⅰa)、(Ⅰb)、(Ⅰc)中，R6是C1-4烷基、环烷基、烷氧基；
根据一些实施方式，本申请的所述化合物由(Id)表示：
Figure PCTCN2016071778-appb-000005
其中，
R2任意选自氢、羟基、卤素、氨基、(C1-4)烷基、(C1-4)烷氧基或(Cl-4)烷基C(＝O)O-(例如(Cl-3)烷基C(＝O)O-),所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素原子取代；
R6选自以下基团：氢、卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基或C5-10芳基；
R3和R4任意独立地选自卤素(例如氯)、三氟甲基、(C1-4)烷基、(C1-4)烷氧基或(C3 -4)环烷基(例如环丙烷基)。
根据进一步的实施方式，式(Id)中，R2任意选自氢、羟基、卤素、氨基、(C1-4)烷 氧基或(Cl-4)烷基C(＝O)O-,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素原子取代；R6选自以下基团：氢、卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基或C5-10芳基；R3选自卤素；且R4任意独立地选自卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基或(C3-4)环烷基。
根据进一步的实施方式，式(Id)中，R2是氢、羟基或卤素；R6是氟、甲基、三氟甲基或甲氧基；R3选自卤素(例如氯)；且R4任意独立地选自卤素(例如氯)、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基(例如环丙烷基)。
根据进一步的实施方式，式(Id)中，R2是羟基；R6是氟、甲基或甲氧基；R3选自卤素(例如氯)；且R4任意独立地选自卤素(例如氯)、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基(例如环丙烷基)。
根据进一步的实施方式，式(Id)中，R2是羟基；R6是甲基；R3是氯；且R4是环丙基、三氟甲基或氯。
本申请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申请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，以及药学上可接受的赋形剂。
本申请的又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申请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；以及一种或多种选自以下的抗炎药：非甾体类抗炎药(NSAID)、非特异性和特异性环氧合酶-2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；和药学上可接受的赋形剂。
本申请的另一方面涉及本申请的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，用于调节RORγ活性(例如抑制RORγ活性)，或用于预防或治疗RORγ介导的疾病。
本申请的另一方面涉及本申请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用于调节RORγ活性(例如抑制RORγ活性)的药物中的用途。
本申请的另一方面涉及本申请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(例如RORγ活性抑制剂)的药物中的用途。
本申请的又一方面涉及本申请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，其用于调节RORγ活性(例如抑制RORγ活性)。
本申请的另一方面涉及本申请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，其用于预防或治疗RORγ介导的疾病。
本申请的另一方面涉及一种调节RORγ的方法，其包括将本申请的化合物或它们的立体异构体、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与RORγ接触。
本申请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预防或治疗有效量的本申请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，或本申请的药物组合物。本申请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给予预防或治疗有效剂量的本申请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，以及一种或多种抗炎药。所述抗炎药包括但不限于选自以下的一种或多种抗炎药：非甾体类抗炎药(NSAID)、非特异性和特异性环氧合酶-2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。
根据一些实施方式，本申请所述的RORγ介导的疾病可以是自体免疫性疾病和/或炎性疾病。
根据一些实施方式，所述预防或治疗的RORγ介导的疾病选自：多发性硬化症、类风湿性关节炎、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。
附图说明
图1为本申请的化合物与溶媒对照在大鼠抗关节炎CIA模型的体内活性。
发明详述
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。
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，而不对本申请主题作任何限制。
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。
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或环原子总数。例如，C1-8烷基是指具有总共1至8个碳原子的如下文所定义的烷基；C3-8环烷基是指具有总共3至8个碳原子的如下文所定义的环烷基；C5-10芳基是指具有总共5至10个碳原子(或环原子)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。下文“元”是指基团的环原子数，如“5元芳基”意指芳基的环原子数目为5个。
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。
在本申请中，
Figure PCTCN2016071778-appb-000006
表示
Figure PCTCN2016071778-appb-000007
或
Figure PCTCN2016071778-appb-000008
优选
Figure PCTCN2016071778-appb-000009
在本申请中，C(＝O)表示酰基或羰基，C(＝O)OH表示羧基，S(＝O)2表示磺酰基，S(＝O)表示亚磺酰基,5-四氮唑是表示
Figure PCTCN2016071778-appb-000010
HOC(CF3)2是表示示
Figure PCTCN2016071778-appb-000011
-OH表示羟基，-NH2表示氨基、-CN表示氰基，-NO2表示硝基。
在本申请中，术语“烷基磺酰基”是指RaS(＝O)2；Ra代表烷基，定义如下。
在本申请中，术语“酰氨基”是指-C(＝O)NH2或RC(＝O)NH-、RC(＝O)N(Ra)-，其中Ra和R为如本文所定义的烷基(如C1-6烷基)。酰氨基的实例包括但不限于甲酰氨基、甲酰氨甲基、N-乙酰基氨基、N-甲基-N’-乙酰基氨基等。
在本申请中，术语“磺酰氨基”是指RaS(＝O)2NH-或RaS(＝O)2NRb-，其中Ra和Rb为如本文所定义的烷基(如C1-6烷基)。
在本申请中，术语“氨基磺酰基”是指-S(＝O)2NH2、-S(＝O)2NHRa、-S(＝O)2NRaRb，其中Ra和Rb为如本文所定义的烷基(如C1-6烷基)。
在本申请中，术语“磷酸基”是指-
Figure PCTCN2016071778-appb-000012
术语“磷酸酯基”是指
Figure PCTCN2016071778-appb-000013
Ra和Rb分别代表烷基，定义如下。
在本申请中，术语“卤素”是指氟、氯、溴或碘，例如氟或氯。
在本申请中，作为基团或是其它基团的一部分的烷基(即，单独的烷基或与其它 基团连接的烷基)，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、1至8个、1至6个、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。
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。
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。
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。
在本申请中，术语“烷硫基”是指式-SRa基团，其中Ra为如上文所定义的烷基。烷硫基的实例包括但不限于甲硫基、乙硫基、异丙硫基等。
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氨基、乙氨基、异丙氨基等。
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氨基、二乙氨基、二丙氨基、甲基乙基氨基等。
在本申请中，术语“烷基羰基”是指-CORa基团，其中Ra为如上文所定义的烷基。
在本申请中，术语“烷基氨基羰基”是指-CONHRa或-CONRaRb，其中Ra和Rb为如本文所定义的烷基(如C1-6烷基)。
在本申请中，作为基团或其他基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个、2至10个、2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，包括但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-2-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或其他基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个、2至10个、2至8个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。炔 基的实例包括但不限于乙炔基、丙-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“碳环基”意指仅由碳原子和氢原子组成的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，具有3至8个碳原子，3-7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。除非本说明书中另外特别指明，碳环基可以是饱和的(可称为环烷基)或不饱和的(可称为环烯基)。环烷基中的碳原子可以任选地被氧化。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、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。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3元至18元非芳香族环状基团。杂环基可以是饱和的或不饱和的。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。就本申请的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的5元至12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，优选四氢吡喃基、哌啶基、吗啉基。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(例如6至10个，5至10个)碳原子及至少一个芳香环的体系。就本申请而言，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。与芳基稠合的稠合环可以是本申请所定义的碳环基、杂环基、芳基或杂芳基。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。
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(例如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元环体系的基团。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。就本申请的目的而言，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5元至8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。
“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。本申请将涵盖各种立体异构体及其混合物。
“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。本申请的化合物的所有互变异构形式也将包含在本申请的范围内。
本文所用术语“药学可接受的盐”是指保留了本申请化合物的游离酸或游离碱的生物效力，并且在生物学或其它方面上没有不良作用的盐。药学可接受的盐是指把母体化合物中的碱基基团或酸性基团转换成盐的形式。药学可接受的盐包括，但不仅限于，碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学可接受的盐可以由母体化合物合成，合适的盐列举在Remingtong’s Pharmaceutical Scicences,17th ed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66, 2(1977)中。除特别指示外，本申请中的盐可以是有机酸/无机酸形成的酸式盐，以及用有机碱/无机碱形成的碱式盐。另外，当通式化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑)，酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐)，内盐也包括在本申请中的盐内。
根据带电荷官能团的数目和阳离子或阴离子的化合价，本申请化合物可以含有多个阳离子或阴离子。
通常，结晶化作用会产生本申请化合物的溶剂化物。在本申请中，“溶剂化物”是指包含一个或多个本申请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。本申请化合物的溶剂化物也属于本申请范围之内。
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申请的生物活性化合物的化合物。因此，术语“前药”是指本申请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申请的活性化合物。前药通常在体内迅速转化，而产生本申请的母体化合物，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。本领域技术人员所熟知的是，含羧基的化合物(例如本申请化合物)的酯，例如药学上可接受的酯，可以作为本申请化合物的前药，其在人体或动物体内可分解成为母体酸。
在本申请中，“药物组合物”是指本申请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。
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。
在本申请中，“预防或治疗有效量”是指本申请化合物的量，当本申请化合物被基 于哺乳动物(例如人)时，该量足以有效地预防或治疗哺乳动物(例如人)的疾病。构成“预防或治疗有效量”的本申请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。
本文所用术语“预防”包括减少使疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”包括以下含义：
(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；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文中使用的术语“疾病”与“病症”可以互换使用或可能不同。
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，或者通过引起另一种单核因子例如(但不限于)IL-17或IL-23的释放而起作用的任何疾病或其他有害的情况。
在本申请中，术语“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、反向激动及其他的类似的相互作用。
本申请的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，两种构型都在本申请范围之内。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。
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。
本申请的另一方面涉及药物组合物，其包含一种或多种本申请的式Ⅰ化合物、其立体异构体、互变异构体、溶剂化物或其药学上可接受的盐，以及药学上可接受的赋形剂。
本申请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。
本申请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申请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)。
本申请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申请的式I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是混悬液；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他辅料兼容。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。
本申请的化合物或者本申请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、非特异性和特异性环氧合酶-2(COX-2)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。
本申请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。本申请化合物的“预防或治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及给药方式等因素决定。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。
本文中所提供的有效剂量的范围并非意图限制本申请的范围，而是代表优选的剂量范围。但是，最优选的剂量可针对个别个体而进行调整，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)。
具体实施方式
本申请的化合物的制备
本申请中实施例化合物可以按照以下几种方案制备得到。但是以下反应方案仅示例性地说明本申请化合物的制备方法。
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。
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、巯基及羧酸。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。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。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis(有机合成中的保护基),(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
方案1：
Figure PCTCN2016071778-appb-000014
其中，R是有取代基的6元芳环或芳杂环；m是0，1，2，3或4，优选0或1；X是I、Br、Cl，优选I或Br；其它如前文所表述。
通式Ⅰ的本申请化合物中，其合成是(见方案1)以取代或非取代的芳(杂)环并吡咯-2-酮为起始原料，首先在碱性(碳酸钾或碳酸铯、三乙胺、二异丙基乙基胺、氢化钠等)以及金属催化剂(铜或钯催化剂，优选碘化亚酮)条件下，与式中所示的卤代芳烃或卤代烃(卤素优选碘或溴)反应，得到N-取代的芳(杂)环并吡咯-2-酮中间体，然后在碱性(哌 啶、三乙胺、醇钠等，优选哌啶)反应条件下与取代的芳(杂)醛发生缩合反应生成目标化合物。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的一般从业人员所知的变动。例如实施例1的合成中，在最后应当有一步酯水解得到羧基的反应(步骤3)。
Figure PCTCN2016071778-appb-000015
这里碱是指氢氧化钠、氢氧化锂或氢氧化钾等，溶剂是指甲醇、乙醇、四氢呋喃等，R是C1-4的烃基，其他基团的定义同上文。
上述方案1中所用到起始原料1上有取代基时，烷基、芳基或杂芳基等可以通过铃木反应引入(路线A)：
Figure PCTCN2016071778-appb-000016
这里R包括C1-6烷基或环烷基、芳基、杂芳基。
上述方案1中所用到醛R-CHO是取代的苯甲醛时，烷基、芳基或杂芳基等取代基可以通过铃木反应引入(路线B)：
Figure PCTCN2016071778-appb-000017
这里R3包括C1-6烷基或环烷基、芳基、杂芳基，优选环丙基。
上述方案1中所用到起始原料1上有取代基是CF3时(2m)，可以借鉴文献(Tetrahedron Letters,43(50),9175-9178,2002；Synthesis,(1),51-53,1993)的方法，利用下述路线(路线C)合成得到：
Figure PCTCN2016071778-appb-000018
表1：方案1中各步骤所用原料及其来源
Figure PCTCN2016071778-appb-000019
Figure PCTCN2016071778-appb-000020
下面的实施例举例说明在本申请范围内的化合物的制备和生物活性评价。提供下面的这些实施例和制备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申请。它们不应当被解释为限制本申请的范围，而仅仅是其举例说明性的和代表性的。
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：
温度的单位是摄氏度(℃)；室温的定义是18-25℃；
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蒸除溶剂至干(例如：15mmHg，30℃)；
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；
通常情况下，反应的进度通过TLC或LC-MS监测；
最终产品的鉴定由核磁共振(Bruker AVANCE 300，300MHz)和LC-MS(Bruker esquine6000，Agilent 1200series)完成。
实施例1：(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000021
合成化合物实施例1以(1-1)为起始原料，详细路线如下图：
Figure PCTCN2016071778-appb-000022
(1)步骤1：4-(4-甲基吲哚啉-2-酮)-碘水杨酸甲酯(1-2)的合成
Figure PCTCN2016071778-appb-000023
4-甲基-2-吲哚酮(147毫克,1毫摩尔)，4-碘水杨酸甲酯(306毫克,1.1毫摩尔)，溶解于2毫升二氧六环中，然后加入碘化亚铜(38毫克,0.2毫摩尔)，1，10-邻菲罗啉(54毫克,0.3毫摩尔)，碳酸钾(415毫克,3毫摩尔)。微波加热125℃，反应120分钟。冷却到室温，20毫升乙酸乙酯稀释，过滤，减压蒸除溶剂。残余物柱层析分离(硅胶200～300目，洗脱剂：正己烷/乙酸乙酯＝4/1)得到4-(4-甲基吲哚啉-2-酮)-碘水杨酸甲酯70毫克，黄色固体，收率23.5％。
(2)步骤2：4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸甲酯(1-3)的合成
Figure PCTCN2016071778-appb-000024
4-(4-甲基-2-吲哚酮)-碘水杨酸甲酯(2，70毫克,0.24毫摩尔)，2-氯-6-环丙基苯甲醛(85毫克,0.48毫摩尔)，哌啶(22毫克,0.24毫摩尔)，溶解在甲醇(5毫升)中，氮气保护，加热回流两小时。冷却至室温，减压蒸除溶剂，柱层析(硅胶200～300目，洗脱剂：正己烷/乙酸乙酯＝4/1)得到4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸甲酯88毫克，收率80％.
(3)步骤3：4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸(实施例1)的合成
Figure PCTCN2016071778-appb-000025
4-(3-(2-氯-6-环丙基苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸甲酯(1-3，88毫克,0.19毫摩尔)溶解在四氢呋喃(10毫升)中，室温下，加入氢氧化锂(40毫克)的水溶液(1毫升)。室温搅拌过夜。减压蒸除溶剂，残余物溶于水，1摩尔/升的盐酸调节使体系的pH值为5，乙酸乙酯萃取，减压浓缩，利用prep-HPLC制备液相色谱纯化，得到45毫克实施例1，淡黄色粉末，收率：53％。
相关表征数据如下：ESI-MS:[M+H]+＝446.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.91(d,J＝9.0Hz,1H)，7.87(s,1H),7.22-7.31(m,3H),6.95-7.03(m,4H),6.81(d,J＝7.8Hz,1H),2.64(s,3H),1.89-1.99(m,1H),0.84-0.87(m,2H),0.64-0.70(m,2H)。
实施例2：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中原料3b替代原料3a，得到(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸(2A)
Figure PCTCN2016071778-appb-000026
相关表征数据如下：ESI-MS:[M+H]+＝430.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.03(d,2H,J＝8.7Hz),7.84(s,1H),7.50(d,2H,J＝8.7Hz),7.22(m,3H),6.96(q,2H,J＝7.8Hz),6.73(d,1H,J＝7.8Hz),2.60(s,3H),1.87(m,1H),0.81(m,2H),0.62(m,2H)。
和(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸(2B)
Figure PCTCN2016071778-appb-000027
相关表征数据如下：ESI-MS:[M+H]+＝430.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.03(d,2H,J＝8.7Hz),7.84(s,1H),7.50(d,2H,J＝8.7Hz),7.22(m,3H),6.96(q,2H,J＝7.8Hz),6.73(d,1H,J＝7.8Hz),2.60(s,3H),1.87(m,1H),0.81(m,2H),0.62(m,2H)。
实施例3：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1f替代原料1a，得到(反)-4-(3-(2-氯-6-甲氧基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000028
相关表征数据如下：ESI-MS:[M+H]+＝436.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.92(dd,J＝7.5Hz,J＝1.2Hz,1H)，7.59(s,1H),7.35(t,J＝8.1Hz,1H),7.24(t,J＝7.8Hz,1H),6.96-7.11(m,5H),6.80(d,J＝8.1Hz,1H)3.77(s,3H),2.59(s,3H)。
实施例4：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000029
相关表征数据如下：ESI-MS:[M+H]+＝440.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.91(d,1H,J＝8.1Hz),7.70(s,1H),7.52(d,2H,J＝7.8Hz),7.36-7.42(m,1H),7.27(t,1H,J＝7.8Hz),7.03(d,1H,J＝7.8Hz),6.93-6.97(m,2H),6.81(d,1H,J＝8.1Hz),2.61(s,3H)。
实施例5：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中原料3b替代原料3a，在步骤2中使用表1中原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000030
相关表征数据如下：ESI-MS:[M+H]+＝424.1
1H-NMR(300MHz,CDCl3)δ:ppm 8.19(d,J＝8.4Hz,2H),7.57(s,1H),7.55(d,J＝8.1Hz,2H),7.36(d,J＝7.8Hz,2H),7.21(t,2H),6.98(d,J＝7.8Hz,1H),6.83(d,J＝7.8Hz,1H),2.69(s,3H)。
实施例6：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1c替代原料1a，得到(反)-4-(3-(2氯-6-(三氟甲基)-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000031
相关表征数据如下：ESI-MS:[M+H]+＝474.2
1H-NMR(300MHz,CD3OD-d4)δ:ppm 7.95(d,1H,J＝8.1Hz),7.69(m,3H),7.46(m,1H),7.21(m,1H),7.00(m,1H),6.86(s,1H),6.77(d,1H,J＝7.8Hz),2.59(s,3H)。
实施例7：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1e替代原料1a，得到(反)-4-(3-(2氯-6-溴-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000032
相关表征数据如下：ESI-MS:[M+H]+＝486.1
1H-NMR(300MHz,CDCl3)δ:ppm 7.98(d,1H,J＝8.4Hz),7.58(d,2H,J＝5.4Hz),7.45(d,1H,J＝8.1Hz),7.14-7.25(m,3H),7.00-7.08(m,2H),6.93(d,1H,J＝8.1Hz),2.72(s,3H)。
实施例8：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2d替代原料2a，得到(反)-4-(3-(2氯-6-溴-苯亚甲基)-4-甲氧基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000033
相关表征数据如下：ESI-MS:[M+H]+＝462.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.06(s,1H)，7.91(d,J＝9.3Hz,1H),7.21-7.36(m,3H),6.89-6.98(m,4H),6.60(d,J＝7.8Hz,1H),4.02(s,3H),1.85-1.94(m,1H),0.85-0.88(m,2H),0.58-0.75(m,2H)。
实施例9：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1g替代原料1a，得到(反)-4-(3-(2氯-6-氟-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000034
相关表征数据如下：ESI-MS:[M+H]+＝424.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.55(s,1H)，7.15-7.33(m,4H),7.03-7.06(m,1H), 6.94(d,J＝7.8Hz,1H),6.80-6.84(m,2H),6.72(d,J＝7.8Hz,1H),2.60(s,3H)。
实施例10：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中原料1h替代原料1a，得到(反)-4-(3-(2氯-6-甲基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000035
相关表征数据如下：ESI-MS:[M+H]+＝420.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.89(d,1H,J＝8.1Hz),7.77(s,1H),7.22-7.34(m,4H),6.94-7.03(m,3H),6.79(d,1H,J＝7.8Hz),2.63(s,3H),2.28(s,3H).
实施例11：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2d替代原料2a，在步骤2中使用原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-甲氧基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000036
相关表征数据如下：ESI-MS:[M+H]+＝456.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.85-7.80(m,1H),7.55-7.30(m,5H),6.91-6.78(m,3H),6.57-6.54(m,1H),5.97-5.95(m,1H),4.01(s,3H).
实施例12：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2e替代原料2a，得到(反)-4-(3-(2氯-6-环丙基-苯亚甲基)-4-环丙基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
相关表征数据如下：ESI-MS:[M+H]+＝472.2
1H-NMR(300MHz,CD3OD-d4)δ:ppm 8.35(s,1H),7.98(d,1H,J＝9.0Hz),7.24(m,3H),6.91-7.07(m,4H),6.81(d,1H,J＝7.8Hz),2.22(m,1H),1.98(m,1H),1.13(m,2H),0.88(m,4H),0.72(m,1H),0.63(m,1H).
实施例13：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2f替代原料2a，原料3b替代原料3a，得到(反)-4-(3-(2氯-6-环丙基-苯亚甲基)-4-苯基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000038
相关表征数据如下：ESI-MS:[M+H]+＝492.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.18-8.08(m,2H),7.78-7.14(m,10H),7.02-6.87(m,4H),1.54-1.50(m,1H),1.29-1.17(m,2H),0.85-0.75(m,2H).
实施例14：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2c替代原料2a，得到4-(3-(2氯-6-环丙基-苯亚甲基)-4-氯-吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000039
相关表征数据如下：ESI-MS:[M+H]+＝466.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.46-7.94(m,1H),7.79-7.76(m,1H),7.35-7.19(m,4H),7.10-6.79(m,2H),6.76-6.60(m,2H),1.71-1.69(m,1H),1.29-1.23(m,2H), 0.88-0.83(m,2H)。
实施例15：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，在步骤2中使用原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(15A)
Figure PCTCN2016071778-appb-000040
相关表征数据如下：ESI-MS:[M+H]+＝427.8
1H-NMR(CDCl3)δ:ppm 8.21(d,J＝8.4Hz,2H),7.78(d,J＝1.5Hz,1H),7.57(d,J＝8.7Hz,2H),7.39～7.35(m,2H),7.31～7.20(m,2H),6.93～6.87(m,1H),6.78(d,J＝7.8Hz,1H)。
和(顺)-4-(3-(2，6-二氯-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(15B)
Figure PCTCN2016071778-appb-000041
相关表征数据如下：ESI-MS:[M+H]+＝427.8
1H-NMR(CDCl3)δ:ppm 8.30(d,J＝8.4Hz,2H),7.90(s,1H),7.65(d,J＝8.7Hz,2H),7.42～7.38(m,2H),7.32～7.29(m,1H),7.25～7.19(m,1H),7.75～6.65(m,2H)。
实施例16：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，得到(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(16A)
Figure PCTCN2016071778-appb-000042
相关表征数据如下：ESI-MS:[M+H]+＝433.9
1H-NMR(300MHz,CDCl3)δ:ppm 8.20(d,2H,J＝8.7Hz),8.04(s,1H),7.56(d,2H,J＝8.4Hz),7.27(m,2H),7.19(m,1H),6.90(m,2H),6.79(d,1H,J＝7.8Hz),1.92(m,1H),0.88(m,3H),0.61(m,1H)。
和(顺)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(16B)
Figure PCTCN2016071778-appb-000043
相关表征数据如下：ESI-MS:[M+H]+＝433.9
1H-NMR(300MHz,CDCl3)δ:ppm 8.20(d,2H,J＝8.7Hz),8.04(s,1H),7.56(d,2H,J＝8.4Hz),7.27(m,2H),7.20(d,1H,J＝8.1Hz),6.90(m,2H),6.89(d,1H,J＝7.8Hz),1.92(m,1H),0.83(m,3H),0.59(m,1H)。
实施例17：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，在步骤2中使用原料1g替代原料1a，得到(反)-4-(3-(2-氯-6-氟-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(17A)
Figure PCTCN2016071778-appb-000044
相关表征数据如下：ESI-MS:[M+H]+＝411.9
1H-NMR(300MHz,CDCl3)δ:ppm 8.30(d,2H,J＝8.4Hz),7.88(s,1H),7.62(d,2H,J＝8.7Hz),7.21-7.37(m,3H),7.09(t,1H,J＝8.7Hz),6.73(d,2H,J＝8.1Hz)；和
(顺)-4-(3-(2-氯-6-氟-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(17B)
Figure PCTCN2016071778-appb-000045
相关表征数据如下：ESI-MS:[M+H]+＝411.9
1H-NMR(300MHz,CDCl3)δ:ppm 8.22(d,2H,J＝8.4Hz),7.76(s,1H),7.56(d,2H,J＝8.4Hz),7.22-7.31(m,3H),7.05(t,1H,J＝8.7Hz),6.88(t,1H,J＝9.0Hz),6.75(d,1H,J＝7.8Hz)。
实施例18：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，在步骤2中使用原料1d替代原料1a，得到(反)-4-(3-(2，6-二氟-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(18A)
Figure PCTCN2016071778-appb-000046
相关表征数据如下：ESI-MS:[M+H]+＝396.1
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.15-8.08(m,2H),7.68-7.66(m,2H),7.60-7.39(m,3H),7.27-6.87(m,3H),6.78-6.73(m,1H)。
和(顺)-4-(3-(2，6-二氟-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(18B)
Figure PCTCN2016071778-appb-000047
相关表征数据如下：ESI-MS:[M+H]+＝396.1
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.15-8.08(m,2H),7.69-7.57(m,4H),7.41-6.88(m,4H),6.78-6.73(m,1H)。
实施例19：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，在步骤2中使用原料1c替代原料1a，得到(反)-4-(3-(2-氯-6-三氟甲基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(19A)
Figure PCTCN2016071778-appb-000048
相关表征数据如下：ESI-MS:[M+H]+＝462.1
1H-NMR(300MHz,DMSO-d6)δ:ppm 13.11(brs,1H),8.16-8.13(d,2H),7.90-7.79(m,3H),7.64-7.58(t,1H),7.55-7.52(d,1H),7.45-7.40(m,1H),7.13-7.07(t,1H),6.83-6.80(d,1H)；和
(顺)-4-(3-(2-氯-6-三氟甲基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(19B)
Figure PCTCN2016071778-appb-000049
相关表征数据如下：ESI-MS:[M+H]+＝462.1
1H-NMR(300MHz,DMSO-d6)δ:ppm 13.14(brs,1H),8.15-8.13(d,2H),7.93-7.84(m,3H),7.72-7.65(m,3H),7.40-7.33(m,1H),6.83-6.73(m,2H)。
实施例20：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，原料3b替代原料3a，在步骤2中使用原料1i替代原料1a，得到(反)-4-(3-(2-氯-6-正丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(20A)
Figure PCTCN2016071778-appb-000050
相关表征数据如下：ESI-MS:[M+H]+＝436.2
1H-NMR(CDCl3)δ:ppm 8.31(d,J＝8.4Hz,2H),8.02(s,1H),7.67(d,J＝8.7Hz,2H),7.32～7.27(m,2H),7.23～7.15(m,2H),6.74(d,J＝7.8Hz,1H),6.68～6.62(m,1H),2.60(t,2H),1.58(m,2H),0.89(t,3H)；和
(顺)-4-(3-(2-氯-6-正丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-苯甲酸(20B)
Figure PCTCN2016071778-appb-000051
相关表征数据如下：ESI-MS:[M+H]+＝436.2
1H-NMR(CDCl3)δ:ppm 8.20(d,J＝8.4Hz,2H),7.94(s,1H),7.56(d,J＝9.0Hz,2H),7.30～7.27(m,2H),7.25～7.17(m,2H),6.93～6.88(m,1H),6.79(d,J＝7.8Hz,1H),2.63(t,2H),1.60(m,2H),0.91(t,3H)。
实施例21：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，得到(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-2-羟基-苯甲酸(21A)
Figure PCTCN2016071778-appb-000052
相关表征数据如下：ESI-MS:[M+H]+＝450.2
1H-NMR(300MHz,CD3OD-d4)δ:ppm 8.02(m,2H),7.35(m,1H),7.24(m,3H),6.95(m,3H),6.82(d,1H,J＝8.1Hz),1.92(m,1H),0.91(m,2H),0.74(m,1H),0.65(m,1H)；和
(顺)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-2-羟基-苯甲酸(21B)
Figure PCTCN2016071778-appb-000053
相关表征数据如下：ESI-MS:[M+H]+＝450.2
1H-NMR(300MHz,CD3OD-d4)δ:ppm 8.04(d,1H,J＝8.4Hz),8.02(s,1H),7.27(m,3H),7.01-7.19(m,3H),6.93(m,1H),6.76(d,1H,J＝7.8Hz),6.69(s,1H),1.83(m,1H),0.90(m,2H),0.67(m,2H)。
实施例22：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进 行,不同之处在于在步骤1中使用表1中起始原料2b替代原料2a，在步骤2中使用原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-2-羟基-苯甲酸(22A)
Figure PCTCN2016071778-appb-000054
相关表征数据如下：ESI-MS:[M+H]+＝444.1
1H-NMR(300MHz,CD3OD-d4)δ:ppm 8.07(d,1H,J＝8.4Hz),7.80(s,1H),7.48(m,2H),7.29-7.41(m,2H),7.10(s,1H),7.05(d,1H,J＝8.4Hz),6.69-6.80(m,2H)；和
(顺)-4-(3-(2，6-二氯-苯亚甲基)-4-氟-吲哚啉-2-酮-1-基)-2-羟基-苯甲酸(22B)
Figure PCTCN2016071778-appb-000055
相关表征数据如下：ESI-MS:[M+H]+＝444.1
1H-NMR(300MHz,CD3OD-d4)δ:ppm 8.01(d,1H,J＝8.4Hz),7.76(s,1H),7.44(m,2H),7.35(m,2H),6.97(m,3H),6.82(d,1H,J＝7.8Hz)。
实施例23:本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2c替代原料2a，原料3b替代原料3a，在步骤2中使用原料1b替代原料1a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-氯-吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000056
相关表征数据如下：ESI-MS:[M+H]+＝446.1
1H-NMR(300MHz,DMSO-d6)δ:ppm 12.99(brs,1H),8.31-7.78(m,3H),7.70-7.52(m,4H),7.43-7.26(m,3H),6.91-6.81(m,1H)。
实施例24：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中原料3c替代原料3a，得到(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-氯-苯甲酸
Figure PCTCN2016071778-appb-000057
相关表征数据如下：ESI-MS:[M+H]+＝464.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.01-7.79(m,2H),7.64-7.62(m,1H),7.54-7.49(m,1H),7.35-7.22(m,3H),7.05-6.93(m,2H),6.86-6.71(m,1H),1.76-1.71(m,1H),1.26(s,3H),0.87-0.83(m,2H),0.71-0.63(m,2H)。
实施例25：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中原料3d替代原料3a，得到(反)-4-(3-(2-氯-6-环丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-氟-苯甲酸
Figure PCTCN2016071778-appb-000058
相关表征数据如下：ESI-MS:[M+H]+＝448.9
1H-NMR(300MHz,DMSO-d6)δ:ppm 8.03(t,1H,J＝8.1Hz),7.89(s,1H),7.38-7.46(m,2H),7.22-7.36(m,3H),7.01(dd,2H,J＝7.5,18.3Hz),6.86(d,1H,J＝7.8Hz),2.64(s,3H),0.83-0.87(m,3H),0.63-0.70(m,2H)。
实施例26：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2g替代原料2a，得到(反)-4-(3-(2氯-6-溴-苯亚甲基)-4-三氟甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000059
相关表征数据如下：ESI-MS:[M+H]+＝500.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 11.71(brs,1H),7.98(S,1H),7.90-7.82(m,1H),7.57-7.48(m,2H),7.35-7.25(m,2H),7.19-7.10(m,1H),7.03-6.73(m,3H),5.36(s,1H),1.78-1.73(m,1H),1.49-1.46(m,2H),0.83-0.86(m,2H)。
实施例27：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2h替代原料2a，得到(反)-4-(3-(2氯-6-溴-苯亚甲基)-吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000060
相关表征数据如下：ESI-MS:[M+H]+＝432.0
1H-NMR(300MHz,CDCl3)δ:ppm 7.98-8.09(m,2H),7.31-7.37(m,2H),7.10-7.24(m,3H),6.89-6.99(m,3H),6.82-6.84(m,1H),1.89-2.00(m,1H),0.85-0.94(m,3H),0.64-0.76(m,1H)。
实施例28：(反)-4-(3-(2氯-6-溴-苯亚甲基)-吲哚啉-2-酮-1-基)-2-特戊酰氧基苯甲酸
Figure PCTCN2016071778-appb-000061
相关表征数据如下：ESI-MS:[M+H]+＝530.1
1H-NMR(300MHz,CDCl3)δ:ppm 8.18(d,2H,J＝8.4Hz),7.81(s,1H),7.43(dd,1H,J＝8.7Hz,J＝1.8Hz),7.16-7.28(m,5H),6.90-7.00(m,3H),2.69(s,3H),1.90-1.95(m,1H),1.35(s,9H),0.80-0.90(m,3H),0.52-0.60(m,1H)。
实施例29：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进 行,不同之处在于在步骤2中使用表1中起始原料1h替代原料1a，在步骤3中使用3b代替3a，得到(反)-4-(3-(2氯-6-甲基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000062
相关表征数据如下：ESI-MS:[M+H]+＝404.2
1H-NMR(300MHz,CDCl3)δ:ppm 8.19(d,J＝8.4Hz,2H),7.72(s,1H),7.56(d,J＝8.4Hz,2H),7.27～7.15(m,4H),6.98(d,J＝7.8Hz,1H),6.84(d,J＝7.5Hz,1H),2.69(s,3H),2.34(s,3H)。
实施例30：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤1中使用表1中起始原料2d替代原料2a，在步骤3中使用3b代替3a，得到(反)-4-(3-(2氯-6-甲基-苯亚甲基)-4-甲氧基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000063
相关表征数据如下：ESI-MS:[M+H]+＝446.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 13.06(brs,1H),8.08-8.06(m,3H),7.55-7.52(d,2H),7.35-7.21(m,3H),6.94-6.90(s,2H),6.58-6.55(d,1H),4.02(s,3H),1.93-1.87(m,1H),0.90-0.84(m,2H),0.73-0.67(m,1H),0.64-0.58(m,1H)。
实施例31：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1b替代原料1a，在步骤3中使用3b代替3a，得到(反)-4-(3-(2，6-二氯-苯亚甲基)-4-甲氧基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000064
相关表征数据如下：ESI-MS:[M+H]+＝440.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 12.99(s,1H),8.11(m,2H),7.84(s,1H), 7.69-7.51(m,4H),7.33(m,2H),6.93(d,J＝8.4Hz,1H),6.56(d,J＝7.8Hz,1H),4.03(s,3H)。
实施例32：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1f替代原料1a，在步骤3中使用3b代替3a，得到(反)-4-(3-(2氯-6-甲氧基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000065
相关表征数据如下：ESI-MS:[M+H]+＝420.2
1H-NMR(300MHz,CDCl3)δ:ppm 8.18(d,J＝8.4Hz,2H),8.61(s,1H),7.56(d,J＝8.4Hz,2H),7.24～7.14(m,2H),7.05(d,J＝7.5Hz,1H),,6.96(d,J＝7.8Hz,1H),6.85～6.79(m,2H),3.81(s,3H),2.68(s,3H)。
实施例33：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤3中使用3e代替3a，得到(反)-4-(3-(2氯-6-甲氧基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-氨基苯甲酸
Figure PCTCN2016071778-appb-000066
相关表征数据如下：ESI-MS:[M+H]+＝445.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.85-7.78(m,2H),7.31-7.21(m,3H),7.01-6.96(m,2H),6.79-6.77(m,2H),6.52-6.48(m,1H),2.63(s,3H),1.95-1.89(m,1H),0.87-0.83(m,2H),0.69-0.63(m,2H)。
实施例34：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1j替代原料1a，在步骤3中使用3b代替3a，得到(反)-4-(3-(2氯-6-环丁基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-苯甲酸
Figure PCTCN2016071778-appb-000067
相关表征数据如下：ESI-MS:[M+H]+＝444.2
1H-NMR(300MHz,DMSO-d6)δ:ppm 12.94(brs,1H),8.08-8.05(d,2H),7.77(s,1H),7.54-7.51(d,2H),7.34-7.22(m,4H),7.04-7.02(d,1H),6.79-6.76(d,1H),3.65-3.57(m,1H),2.62(s,3H),2.22-1.99(m,4H),1.92-1.70(m,2H)。
实施例35：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1j替代原料1a，得到(反)-4-(3-(2氯-6-环丁基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000068
相关表征数据如下：ESI-MS:[M+H]+＝460.3
1H-NMR(300MHz,DMSO-d6)δ:ppm 7.91-7.89(d,1H),7.76(s,1H),7.32-7.23(m,4H),7.04-6.93(m,3H),6.82-6.80(d,1H),3.62-3.59(m,1H),2.62(s,3H),2.21-1.99(m,4H),1.92-1.70(m,2H)。
实施例36：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1k替代原料1a，得到(反)-4-(3-(2氯-6-异丙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000069
相关表征数据如下：ESI-MS:[M+H]+＝448.3
1H-NMR(300MHz,CDCl3)δ:ppm 7.96(d,1H,J＝8.4Hz),7.75(s,1H),7.16-7.31(m,4H),7.09(s,1H),7.00(d,2H,J＝8.4Hz),6.91(d,1H,J＝8.4Hz),3.29(m 2H),2.61(s,3H),1.15(t,J＝7.5Hz,3H)。
实施例37：本实施例化合物的制备可以按照前述制备实施例1的类似的步骤方法进行,不同之处在于在步骤2中使用表1中起始原料1l替代原料1a，得到(反)-4-(3-(2氯-6-乙基-苯亚甲基)-4-甲基吲哚啉-2-酮-1-基)-2-羟基苯甲酸
Figure PCTCN2016071778-appb-000070
相关表征数据如下：ESI-MS:[M+H]+＝434.3
1H-NMR(300MHz,CD3OD)δ:ppm 7.99(d,1H,J＝8.4Hz),7.81(s,1H),7.19-7.27(m,4H),6.99(d,1H,J＝8.4Hz),6.89-6.94(m,2H),6.78(d,1H,J＝7.8Hz),2.69(s,3H),2.02(s,3H)。
本申请化合物的生物活性测试
1.体外生物活性筛选：TR-FRET筛选
本申请的化合物可以调节(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(时间分辨荧光能量共振转移)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。
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-RORγ-LBD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D22(Life Technologies#PV4386)等。
(1)本方法反应体系的终浓度和反应条件如下表：(表2)
Figure PCTCN2016071778-appb-000071
(2)实验方法
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。
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2)和2X Tb标记的抗GST抗体(4nM)的混合溶液，10μL/well加入到384-孔板(Corning 3376)中。
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/well加入到上述384-孔板中，混合均匀。阳性对照孔中加入5μL/well含有4％DMSO的完全缓冲液D(无待测化合物)。
使用完全缓冲液D配制4X RORγ-LBD(8nM)，5μL/well加入到上述384-孔板中，混合均匀。阴性对照孔中加入5μL/well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。
使用Tecan M1000Pro【厂家:Tecan】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；。
(3)数据分析
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IC50值，此数值越小说明化合物对受体RORγ调节(抑制)作用越强。
本申请的化合物对RORγ作用的IC50值见下表：(表3)
Figure PCTCN2016071778-appb-000072
Figure PCTCN2016071778-appb-000073
表3中，“+”表示IC50值为“1000-10000”，“++”表示IC50值为“100-1000”，“+++”表示IC50值为“<100”。
2，细胞实验：Th17细胞分化抑制实验
用5μg/mL小鼠CD3抗体(购自BD)包被96板(37℃，2-6小时)备用。用CD4+T cell isolation kitⅡ(购自MACS)分离C57小鼠淋巴结初始CD4阳性T细胞，以5x105细胞/孔/100μL接种于包被好的96孔板。用RMPI-1640培养基(Gibco,22440)梯度稀释待测样品，并使其为终浓度(1μM开始，10倍稀释，设置6个药物浓度)的4倍。将稀释好的待测样品以每孔50μL加入接种细胞的实验孔，阳性对照及阴性对照孔分别加入50μL RMPI-1640培养基。实验孔和阳性对照孔中每孔再加入50μL 4倍终浓度的刺激剂混合液(20ug/mL小鼠CD28抗体(购自BD)；40ug/mL小鼠IL-4抗体(购自BD)；40ug/mL小鼠IFNγ抗体(购自BD)； 4ng/mL小鼠TGF-β1(购自R&D)；200ng/mL小鼠IL-6(购自R&D)；20ng/mL小鼠IL-23(购自R&D))，阴性对照孔加入50μL RMPI-1640培养基。将加好的96孔板置于37℃，5％CO2培养箱培养66小时，之后每孔再加入50uL PMA(购自Sigma，工作浓度50ng/mL)和Ionomycin(购自Sigma，工作浓度1ug/mL)混合液,37℃继续培养6小时。培养结束后取细胞培养上清液用小鼠IL-17A ELISA试剂盒(购自达科为)测定上清液中的IL-17A含量，并计算抑制率及IC50。具体操作参照试剂盒说明(见下)：
(1)根据实验孔(空白和标准品)数量，确定所需的板条数目。提前20分钟将Washing buffer(50×)和即用溶液从试剂盒中取出，以平衡至室温。
(2)加样：100μL/well加入稀释后的Cytokine standard至标准品孔，100μL/well加入样品至样品孔，设置空白孔，用Dilutionbuffer R(1×)代替样本和标准品。
(3)加检测抗体：50μL/well加入稀释后的Biotinylated antibody。混匀后，盖上封板膜，37℃温育90分钟。
(4)洗板：扣去孔内液体，300μL/well加入1×washing buffer；停留1分钟后弃去孔内液体。重复4次，每一次在滤纸上扣干。
(5)加酶：100μL/well加入稀释后的Streptavidin-HRP。盖上封板膜，37℃温育30分钟。
(6)洗板：重复步骤5。
(7)显色：100μL/well加入TMB，37℃避光温育5-30分钟之间，根据孔内颜色的深浅(深蓝色)来判定终止反应。通常显色10-20分钟可以达到很好的效果。
(8)终止反应：100μL/well迅速加入Stop solution终止反应。
读板：终止后10分钟内，用检测波长(measurement wavelength)450nm读值。
本申请的部分化合物对Th17细胞分化的抑制活性(抑制率)见下表：(表4)
Figure PCTCN2016071778-appb-000074
3.大鼠抗关节炎模型CIA体内活性实验
受试动物：雌性Wistar大鼠，单只体重范围在180-220g克。
实验方法：(1)将牛Ⅱ型胶原(CII,2mg/ml，Chondrex,20022)与不完全弗氏佐剂(IFA,sigma-aldrich)1:1等体积混合，在冰浴条件下使二者充分乳化，形成乳剂，CII最终浓度为1mg/ml。(2)每只大鼠尾根部皮内注射200ul乳剂进行初次免疫，初次免疫后第7天每只大鼠尾根部皮内注射100ul乳剂进行加强免疫。(3)给药：初次免疫后第12天开始以口服灌胃的方式将受试药物(本发明的实施例1的化合物和实施例2的2A化合物)给予大鼠体内，每天2次给药；给药后观察并记录大鼠四肢关节病变程度，每2天记录1次。溶媒为二甲亚砜/土温80/PEG400/去离子水＝1/5/20/74。
评分标准：全身病变按5级评分法评价，根据4肢肢体的病变程度累积计分，计算出关节炎指数(severity score)。标准如下：0分，无红肿；1分，踝关节或跗骨关节红肿；2分，踝关节至跗骨关节肿胀；3分，踝关节至跖骨关节肿胀；4分，包括踝关节在内的全部足爪、关节肿胀。
结果：本申请的化合物与溶媒在大鼠抗关节炎CIA模型的体内活性如图1所示。关节炎指数(severity score)分值越低，表明对病变的治疗及缓解作用越强，化合物的体内活性越好。
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，本申请的范围包括后附的权利要求以及权利要求的等价物的全部范围。

Claims (17)

  1. 一种化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物具有结构式(I)：
    Figure PCTCN2016071778-appb-100001
    其中：
    A是5元或6元的芳基或杂芳基,所述杂芳基具有一个或多个选自N、O和S的杂原子；
    R6选自一个或多个以下基团：氢、烷基、环烷基、烷氧基、芳基、卤素、三氟甲基、氨基、氰基、羟基、羧基、卤代烷基、卤代烷氧基、烷基氨基、二烷基氨基、烷基磺酰基、氨基磺酰基、磺酰氨基、酰氨基、羰基、烷基氨基羰基或二烷基氨基羰基；
    B是芳基或杂芳基；所述杂芳基具有一个或多个选自N、O和S的杂原子；
    Q是芳基或杂芳基，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、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、硝基、羰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基氨基羰基、二烷基氨基羰基、烷基磺酰基或烷基羰基，所述烷基、环烷基、烷氧基、芳基、杂芳基可以任选地被1个或多个卤素取代；
    R1选自-C(＝O)OH、-C(＝O)O-烷基、酰氨基、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基或烷基磺酰基；
    R2选自氢、羟基、卤素、巯基、氨基、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-4)烷基C(＝O)O-,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
    m是0,1,2,3或4。
  2. 如权利要求1所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物具有结构式(Ia)：
    Figure PCTCN2016071778-appb-100002
    其中：
    A、B、R1、R2的定义同权利要求1；
    R3，R4，R5任意独立地选自H,卤素、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基磺酰基或烷基羰基；
    m是0,1,2,3或4；
    n是0,1,2或3。
  3. 如权利要求2所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物具有结构式(Ⅰb)：
    Figure PCTCN2016071778-appb-100003
    其中:
    A是苯基、吡啶基、噻吩基、呋喃基或嘧啶基，
    R1，R2，R3，R4，R5或R6的定义同权利要求2。
  4. 如权利要求3所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物具有结构式(Ⅰc)
    Figure PCTCN2016071778-appb-100004
    其中:
    R1选自-C(＝O)OH、-C(＝O)O-烷基、酰氨基、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、烷氧基、烷基氨基羰基、氨基磺酰基、磺酰氨基、烷基磺酰基；
    R2选自氢、羟基、氨基、巯基、卤素、氰基、硝基、(C1-4)烷基或(C1-4)烷氧基或(Cl-3)烷基C(＝O)O-,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
    R3，R4，R5可以任意独立地选自H,卤素、三氟甲基、烷基、环烷基、烷氧基、羟基、氨基、氰基、芳基、杂芳基、烷基氨基、二烷基氨基、烷基磺酰基或烷基羰基；
    R6选自氢、卤素、三氟甲基、烷基、环烷基、烷氧基、芳基、羟基、氨基、氰基或羰基。
  5. 如权利要求4所述的化合物，其中，式(Ic)中，
    R1是-C(＝O)OH、-C(＝O)NH2、-C(＝O)O-C1-6烷基、-C(＝O)NHR、-C(＝O)N(Ra)R(其中R和Ra都选自C1-6烷基)、5-四氮唑、HOC(CF3)2、磷酸基、磷酸酯基、氰基、羟基、氨基、C1-6烷氧基、氨基磺酰基、磺酰氨基、C1-6烷基磺酰基；
    R2选自氢、羟基、卤素、巯基、氨基；
    R3选自卤素、氨基、C1-6烷基氨基、二C1-6烷基氨基、C1-6烷基磺酰基、C1-6烷基羰基，
    R4选自H、卤素、三氟甲基、C1-6烷基、C3-6环烷基或C1-6烷氧基，且
    R5选自H，C1-6烷基、C3-6环烷基或C1-6烷氧基；
    R6选自卤素、三氟甲基、C1-6烷基、C3-6环烷基、C1-6烷氧基或C5-10芳基。
  6. 如权利要求1所述的化合物，其中，所述化合物由(Id)表示：
    Figure PCTCN2016071778-appb-100005
    其中，
    R2选自氢、羟基、卤素、氨基、(C1-4)烷基、(C1-4)烷氧基或(Cl-4)烷基C(＝O)O-,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
    R6选自以下基团：氢、卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基或C5-10芳基；
    R3和R4任意独立地选自卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基或(C3-4)环烷基。
  7. 如权利要求6所述的化合物，其中：
    R2任意选自氢、羟基、卤素、氨基、(C1-4)烷基、(C1-4)烷氧基或(Cl-4)烷基C(＝O)O-,所述(C1-4)烷基、(C1-4)烷氧基可以任选地被1个或多个卤素取代；
    R6选自以下基团：氢、卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基或C5-10芳基；
    R3选自卤素；且
    R4任意独立地选自卤素、三氟甲基、(C1-4)烷基、(C1-4)烷氧基、(C3-4)环烷基。
  8. 如权利要求6或7所述的化合物，其中：
    R2是氢、羟基或卤素；
    R6是氟、甲基、三氟甲基或甲氧基。
  9. 如权利要求8所述的化合物，其中：
    R2是羟基；
    R6是氟、甲基或甲氧基。
  10. 如权利要求1-9中任意一项所述的化合物，其中，R3是氯。
  11. 如权利要求10所述的化合物，其中:
    R2是羟基；
    R6是甲基；
    R3是氯；且
    R4是环丙基、三氟甲基或氯。
  12. 根据权利要求1-10中任一项所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，所述化合物选自以下：
    Figure PCTCN2016071778-appb-100006
    Figure PCTCN2016071778-appb-100007
    Figure PCTCN2016071778-appb-100008
  13. 一种药物组合物，包含权利要求1-12中任一项所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药，以及药学上可接受的赋形剂。
  14. 权利要求13所述的药物组合物，其还包含一种或多种选自以下的抗炎药：非甾体类抗炎药、非特异性或特异性环氧合酶-2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。
  15. 权利要求1至12中任一项所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药在制备作为RORγ调节剂的药物中的用途。
  16. 权利要求1至12中任一项所述的化合物、其立体异构体、互变异构体、其药学上可接受的盐、其溶剂化物或前药在制备预防或治疗RORγ介导的疾病的药物中的用途。
  17. 如权利要求16所述的用途，其中所述疾病选自：多发性硬化症、类风湿性关节炎、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。
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US10322108B2 (en) 2019-06-18
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