WO2015139621A1 - Acide benzoïque 4-hétéroaryle substitué ou composé de benzamides - Google Patents

Acide benzoïque 4-hétéroaryle substitué ou composé de benzamides Download PDF

Info

Publication number
WO2015139621A1
WO2015139621A1 PCT/CN2015/074415 CN2015074415W WO2015139621A1 WO 2015139621 A1 WO2015139621 A1 WO 2015139621A1 CN 2015074415 W CN2015074415 W CN 2015074415W WO 2015139621 A1 WO2015139621 A1 WO 2015139621A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
alkoxy
halogen
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2015/074415
Other languages
English (en)
Chinese (zh)
Inventor
薛海
于飞
马涛
车美英
Original Assignee
北京韩美药品有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 北京韩美药品有限公司 filed Critical 北京韩美药品有限公司
Publication of WO2015139621A1 publication Critical patent/WO2015139621A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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 arthritis, multiple sclerosis 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 block the proliferation and growth of TH17 cells by inhibiting the function of ROR ⁇ , and inhibit the production of cytokine IL-17 to block the occurrence and development of inflammation.
  • ROR ⁇ inverse agonists
  • 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):
  • Q is selected from:
  • Y represents CH or N
  • n 0, 1, 2, 3 or 4;
  • R is a carbocyclic group, a heterocyclic group, a 6-12 membered aryl group or a 5-12 membered heteroaryl group, and the carbocyclic group, heterocyclic group, aryl group or heteroaryl group is optionally independently one or Multiple groups substituted: halogen, trifluoromethyl, amino, cyano, carboxy, alkyl, alkoxy, alkylamino, dialkylamino, alkylsulfonyl, aminosulfonyl, sulfonylamino, acyl Amino or carbonyl;
  • the (C 1-4 )alkyl or (C 1-4 )alkoxy group may be optionally substituted with one or more halogen atoms;
  • a 1 , A 2 , A 3 , and A 4 are optionally independently selected from O, S, NR a1 or CR b1 , CR b2 , CR b3 , CR b4 , respectively, provided that there are no more than 2 A 1 -A 4
  • the position is simultaneously selected from O or S or NR a1 ;
  • R a1 is hydrogen, (C 1-4 )alkyl, C 3-6 cycloalkyl, 5-10 membered aryl or heteroaryl; or R a1 is absent;
  • An alkyl or (C 1-4 ) alkoxy group, the (C 1-4 ) alkyl group or (C 1-4 ) alkoxy group may be optionally substituted by one or more halogen atoms;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • all of the alkyl groups in R and R 1 are C 1-6 alkyl groups.
  • Q is selected from:
  • Y represents CH or N
  • R is a C 3-7 carbocyclic group, a 3-7 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group, which is optionally independently one or more of the following Substituted for: halogen, trifluoromethyl, amino, cyano, carboxy, alkyl, alkoxy, alkylamino, dialkylamino, alkylsulfonyl, aminosulfonyl, sulfonylamino, amido Or a carbonyl group, the alkyl group in R is a C 1-6 alkyl group;
  • the (C 1-4 )alkyl or (C 1-4 )alkoxy group may be optionally substituted with one or more halogen atoms;
  • a 1 , A 2 , A 3 , A 4 are optionally independently selected from O, S, NR a1 or CR b1 , CR b2 , CR b3 , CR b4 , provided that A 1 -A 4 is not more than 2 positions Is selected from O or S or NR a1 at the same time;
  • R a1 is hydrogen, (C 1-4 )alkyl, C 3-6 cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; or R a1 is absent;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S;
  • n is an integer from 1 to 4.
  • X, Y, n, R, R 1 and R 2 have the same meanings as above.
  • R is selected from phenyl, which is optionally substituted by one or more of the following: halo, trifluoromethyl, amino, cyano, carboxy, alkyl, alkoxy, alkylamino, dialkylamino
  • halo trifluoromethyl
  • amino, cyano carboxy, alkyl, alkoxy, alkylamino, dialkylamino
  • X, Y, n and R 2 are as defined above;
  • R' is H or (C 1-3 )alkyl.
  • some of the compounds of formula (I) and (Ia), (Ib), (Ic) provided herein are selected from the group consisting of:
  • R 3 is selected from halogen, trifluoromethyl, amino, cyano, carboxy, alkyl, alkoxy, alkylamino, dialkylamino, alkylsulfonyl, aminosulfonyl, sulfonylamino, amido or a carbonyl group, the alkyl group in R 3 is a C 1-6 alkyl group;
  • n 0, 1, 2, 3, 4 or 5.
  • Q is selected from:
  • Y represents CH or N
  • R is a C 3-7 carbocyclic group, a 3-7 membered heterocyclic group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group, which is optionally independently one or more of the following Substituted for: halogen, trifluoromethyl, amino, cyano, carboxy, alkyl, alkoxy, alkylamino, dialkylamino, alkylsulfonyl, aminosulfonyl, sulfonylamino, amido Or a carbonyl group, the alkyl group in R is a C 1-6 alkyl group;
  • the (C 1-4 )alkyl or (C 1-4 )alkoxy group may be optionally substituted with one or more halogen atoms;
  • a 1 and A 2 are optionally independently selected from O, S, NR a1 or CR b1 , CR b2 , and A 3 is selected from O, S, NR a1 or CR b3 , provided that A 1 -A 3 is not more than 2 Where the positions are simultaneously selected from O or S or NR a1 , and A 3 is S, A 1 and A 2 may not be simultaneously selected from CR b1 and/or CR b2 ;
  • R a1 is hydrogen, (C 1-4 )alkyl, C 3-6 cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; or R a1 is absent;
  • the heterocyclic or heteroaryl group has one or more heteroatoms selected from N, O and S.
  • a 1 is selected from the group consisting of O and S
  • a 3 is selected from the group consisting of NR a1 and CR b3 .
  • Y is selected from N.
  • a 1 is selected from the group consisting of O and S
  • a 3 is selected from the group consisting of NR a1 and CR b3 .
  • R is phenyl substituted by two substituents ortho to the phenyl group;
  • R 2 is optionally independently selected from hydrogen, halogen, hydroxy, C 1-6 alkoxy;
  • Y is selected from N;
  • n is 1 or 2.
  • 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, 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.
  • Some embodiments of the present application relate to a compound, a stereoisomer, a tautomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a prodrug thereof of the present application for the preparation of a medicament for preventing or treating a disease mediated by ROR ⁇ Use in.
  • 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 disease described herein may be an autoimmune disease and/or an inflammatory disease.
  • the disease for prevention or treatment described herein is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, asthma, systemic lupus erythematosus, chronic obstructive pulmonary disease, Tissue graft rejection and rejection of transplanted organs, scleroderma, purpura, autoimmune hemolytic and thrombocytopenic symptoms, irritable bowel syndrome, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, mucosa Leesman's disease, bronchitis, allergic rhinitis, atopic dermatitis, cystic fibrosis, lung metabolic rejection, rheumatoid arthritis in children, ankylosing spondylitis, pancreatitis, autoimmune diabetes, autoimmune eye disease Ulcerative colitis, sjorgen's syndrome, optic neuritis, diabetes, optic neuromyelitis, myasthenia grav
  • 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 6-12 aryl means an aryl group as defined below having a total of from 6 to 12 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.
  • the "carbon atom” means that the number of ring atoms of the group is from 3 to 7, such as ", for example, "membered heterocyclic group” means that the number of ring atoms of the heterocyclic group is from 3 to 7.
  • 5-tetrazole is represented.
  • HOC(CF 3 ) 2 is a representation
  • 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, preferably fluoro or chloro.
  • alkyl group as a group or a part of another group (ie, an alkyl group alone or an alkyl group bonded to another group), the term "alkyl group” means only a carbon atom and a hydrogen atom.
  • the alkyl group may have, for example, 1 to 18, preferably 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, hexyl, heptyl, 2-methyl A hexyl group, a 3-methylhexyl group, an octyl group, a decyl group, a fluorenyl group and the like.
  • 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, preferably 2 to 10, More preferably a linear or branched hydrocarbon chain group of 2 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 And but-2-enyl, 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 straight or branched hydrocarbon chain group of up to 14, preferably 2 to 10, more preferably 2 to 8 carbon atoms and attached to the remainder of the molecule by a single bond.
  • alkynyl groups 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 only carbon atoms and a non-aromatic monocyclic or polycyclic hydrocarbon group composed of a hydrogen atom, which may include a fused ring system, a bridged ring system or a spiro ring system having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, having 3 to 8 carbon atoms, 3-7 carbon atoms, and which are saturated or unsaturated and can be attached to the remainder of the molecule via a single bond via any suitable carbon atom.
  • 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 (preferably 6 to 10) carbon atoms and at least one aromatic ring.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system which can comprise a fused ring or a bridged ring system.
  • the 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.
  • Aromatic ring The subunit is linked to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthracenyl, 2-benzoxazolinone, 2H-1,4-benzoxazine-3(4H)-one-
  • a 7-group or the like is preferably a phenyl group.
  • heteroaryl as a group or part of another group means having from 1 to 15 (preferably from 1 to 10) carbon atoms and from 1 to 4 selected from nitrogen and oxygen in the ring. And a hetero atom of sulfur, and a 5- to 16-membered ring system group of at least one aromatic ring.
  • a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system or a bridged ring system, provided that the point of attachment is an aromatic ring atom .
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a 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 an amount of a compound of the present application which is sufficient to effectively prevent or treat a disease in a mammal (e.g., a human) when the compound of the present application is based on a mammal (e.g., a human). .
  • constitute The amount of a compound of the present application in an anti- or therapeutically effective amount depends on the particular compound employed, the particular condition being treated, the cause of the condition, the target of the drug, the severity of the disease, the mode of administration, and the age of the mammal to be treated , body weight, physical condition, etc., but can be routinely determined by those skilled in the art based on their own knowledge and the content disclosed in the present application.
  • prevention includes reducing the likelihood of developing or worsening a disease or condition.
  • treatment includes the following meanings:
  • ROR ⁇ -mediated disease refers to a condition in which ROR ⁇ is produced or altered by ROR ⁇ itself, or by causing another cytokine such as, but not limited to, IL-17 or IL-23. Any disease or other harmful condition that releases and acts.
  • 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 invention is the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug The factors such as the point and the mode of administration are determined.
  • the dose for parenteral administration may be 1-200 mg/kg, and the dose for oral administration may be 1-1000 mg/kg.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups 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 a1 is hydrogen or alkyl; m is 0, 1, 2, 3 or 4, preferably 0 or 1; Hal is I, Br, Cl, preferably I or Br; others are as previously described.
  • the nitrogen-containing heteroaromatic ring As a starting material (Hal represents halogen, preferably bromine or iodine), first under various conditions (sodium hydride or potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, etc.) with various substitutions or non- The substituted acid chloride, sulfonyl chloride or sulfinyl chloride is reacted to obtain a substituted nitrogen-containing heteroaryl ring intermediate, and then the substituted benzene ring is bonded to the nitrogen-containing heteroaromatic ring under the conditions of the Lingmu coupling reaction to obtain the target compound.
  • Hal represents halogen, preferably bromine or iodine
  • the unit of temperature is Celsius (°C); the definition of room temperature is 18-25 ° C;
  • the identification of the final product was performed by nuclear magnetic resonance (Bruker AVANCE 300, 300 MHz) and LC-MS (Bruker esquine 6000, Agilent 1200 series).
  • Example 1 The detailed synthesis steps of Example 1 are as follows:
  • the compounds 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 the TR-FRET screening system.
  • Nuclear receptor cofactors coactivators and cosuppressors
  • the method uses Life Technologies' LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) technique to determine the ability of a compound to modulate the interaction of RORy with its coactivator (agonism or reverse agonism).
  • Tb-labeled anti-GST antibody (Life Technologies #PV3550) was indirectly labeled by binding to the GST tag of RORy-LBD (Life Technologies #PV5887).
  • ROR ⁇ can continue to bind to fluorescein-labeled coactivators.
  • agonists bind to ROR ⁇ , they can enhance the interaction of ROR ⁇ with fluorescein-labeled coactivators.
  • Inverse agonists can inhibit ROR ⁇ by binding to ROR ⁇ .
  • 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 Fluorescein-SRC1-2 (Life Technologies #PV4578), Fluorescein-SRC1-4 (Life Technologies #PV4582), and the like.
  • Complete TR-FRET Coregulator Buffer D (hereinafter referred to as complete buffer D): DTT (Life Technologies #P2325) was added to TR-FRET Coregulator Buffer D (Life Technologies #PV4420) to a final DTT concentration of 5 mM.
  • 2X Fluorescein-SRC1-2 (0.3 ⁇ M, refer to Table 1 when using other co-activator peptides) and 2X Tb-labeled anti-GST antibody (4 nM) were mixed in complete buffer D, and 10 ⁇ L/well was added to the 384-well plate. (Corning 3376).
  • 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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé utilisable en tant que modificateur du récepteur γ orphelin gamma (RORγ) lié à l'acide rétinoïque, une composition pharmaceutique de celui-ci, son utilisation dans la préparation de médicaments, et une méthode de traitement ou de prévention de maladies induites par RORγ chez des mammifères (notamment chez l'homme) à l'aide du composé. Le composé a une structure de formule I:
PCT/CN2015/074415 2014-03-18 2015-03-17 Acide benzoïque 4-hétéroaryle substitué ou composé de benzamides WO2015139621A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410097627.3 2014-03-18
CN201410097627 2014-03-18

Publications (1)

Publication Number Publication Date
WO2015139621A1 true WO2015139621A1 (fr) 2015-09-24

Family

ID=54143760

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/074415 WO2015139621A1 (fr) 2014-03-18 2015-03-17 Acide benzoïque 4-hétéroaryle substitué ou composé de benzamides

Country Status (1)

Country Link
WO (1) WO2015139621A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016128908A1 (fr) * 2015-02-12 2016-08-18 Advinus Therapeutics Limited Composés bicycliques, compositions et applications médicinales correspondantes
JP2018510135A (ja) * 2015-02-11 2018-04-12 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害剤としての置換ピラゾール化合物及びその使用
JP2018531957A (ja) * 2015-10-27 2018-11-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害薬としての置換二環式ピラゾール化合物及びその使用
JP2018535958A (ja) * 2015-10-27 2018-12-06 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害薬としての置換インダゾール化合物及びその使用
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106995A1 (fr) * 2011-02-11 2012-08-16 Merck Sharp & Dohme Corp. Inhibiteurs de rorgammat
WO2014026327A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2015008234A1 (fr) * 2013-07-17 2015-01-22 Glenmark Pharmaceuticals S.A. Composés hétécycliques bicycliques utilisés en tant que modulateurs des ror-gamma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106995A1 (fr) * 2011-02-11 2012-08-16 Merck Sharp & Dohme Corp. Inhibiteurs de rorgammat
WO2014026327A1 (fr) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. Composés d'acide benzoïque à substitution 4-hétéroaryle en tant qu'inhibiteurs de rorgammat et leurs utilisations
WO2015008234A1 (fr) * 2013-07-17 2015-01-22 Glenmark Pharmaceuticals S.A. Composés hétécycliques bicycliques utilisés en tant que modulateurs des ror-gamma

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10221142B2 (en) 2015-02-11 2019-03-05 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof
JP2018510135A (ja) * 2015-02-11 2018-04-12 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害剤としての置換ピラゾール化合物及びその使用
EP3256450A4 (fr) * 2015-02-11 2018-05-30 Merck Sharp & Dohme Corp. Composés pyrazole substitués utilisés en tant qu'inhibiteurs de rorgammat et utilisations desdits composés
AU2016219183B2 (en) * 2015-02-11 2020-06-11 Merck Sharp & Dohme Corp. Substituted pyrazole compounds as RORgammaT inhibitors and uses thereof
WO2016128908A1 (fr) * 2015-02-12 2016-08-18 Advinus Therapeutics Limited Composés bicycliques, compositions et applications médicinales correspondantes
EP3368516A4 (fr) * 2015-10-27 2019-04-03 Merck Sharp & Dohme Corp. Composés pyrazoles bicycliques substitués en tant qu'inhibiteurs de rorgammat et leurs utilisations
JP2018535958A (ja) * 2015-10-27 2018-12-06 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害薬としての置換インダゾール化合物及びその使用
US10287272B2 (en) 2015-10-27 2019-05-14 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
US10344000B2 (en) 2015-10-27 2019-07-09 Merck Sharp & Dohme Corp. Substituted bicyclic pyrazole compounds as RORgammaT inhibitors and uses thereof
US10584121B2 (en) 2015-10-27 2020-03-10 Merck Sharp & Dohme Corp. Heteroaryl substituted benzoic acids as RORgammaT inhibitors and uses thereof
JP2018531957A (ja) * 2015-10-27 2018-11-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ＲＯＲγＴ阻害薬としての置換二環式ピラゾール化合物及びその使用
US10689369B2 (en) 2015-10-27 2020-06-23 Merck Sharp & Dohme Corp. Substituted indazole compounds as RORgammaT inhibitors and uses thereof
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

Similar Documents

Publication Publication Date Title
WO2015139621A1 (fr) Acide benzoïque 4-hétéroaryle substitué ou composé de benzamides
WO2020094104A1 (fr) Composé inhibiteur de shp2 hétérocyclique fusionné contenant de l'azote, procédé de préparation et utilisation
JP6238980B2 (ja) 補体経路モジュレーターおよびその使用
JP5813734B2 (ja) ５員複素環アミドおよび関連化合物
JP5527745B2 (ja) シクロヘキシルアミド誘導体およびｃｒｆ−１受容体アンタゴニストとしてのその使用
WO2015139619A1 (fr) Composé servant de modulateur rorγ
JP5677719B2 (ja) ２，３置換ピラジンスルホンアミド
ES2527849T3 (es) Derivados de ciclohexilamida como antagonistas del receptor de CRF
BRPI0718505A2 (pt) Composto, composição farmacêutica, e, uso de um composto
JP2016528197A (ja) Ｉｄｏ阻害剤
BRPI0710231A2 (pt) composto, composição farmacêutica, e, intermediário para a preparação de um composto
TW200838539A (en) Pyridopyrimidinone compounds useful in treating sodium channel-mediated diseases or conditions
JPH07500108A (ja) 抗アレルギー、抗炎症および腫瘍壊死因子抑制活性を有するシクロペンタンおよびシクロペンテン誘導体
BR112017022158B1 (pt) Compostos, composições farmacêuticas e uso de um composto
US11970484B2 (en) LXR modulators with bicyclic core moiety
JP6831376B2 (ja) トリアゾール誘導体
WO2017190708A1 (fr) Dérivés de pyrazole-triazine, procédé pour leur préparation, composition pharmaceutique et utilisation correspondantes
CN109071434A (zh) 酰基磺酰胺NaV1.7抑制剂
BR112020017739A2 (pt) Compostos que modulam a função do receptor ampa
TWI640522B (zh) 吲嗪類衍生物、組合物及使用方法
WO2016119641A1 (fr) Dérivé de benzopyrroline-2-one substitué par groupe n-benzoate et son utilisation
WO2021244542A1 (fr) Composé 3,4-dihydroisoquinoléine et son utilisation
WO2020011086A1 (fr) Composé hétérocyclique de benzodiazépine, son procédé de préparation et son utilisation
JP2010195688A (ja) Ｎｐｙｙ５受容体拮抗作用を有するアミド及びウレア誘導体
BR112016030018B1 (pt) Sal composto de heterocíclico substituído com halogênio, antagonista do receptor de lpa, composição farmacêutica e uso do referido sal

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15765510

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 13/02/2017)

122 Ep: pct application non-entry in european phase

Ref document number: 15765510

Country of ref document: EP

Kind code of ref document: A1