Fused Bicyclic Heteroaromatic Derivatives As Modulators of TNF Activity

Patent metadata

Field	Value
Publication number	US-2016304470-A1
Application number	US-201415101283-A
Country	US
Kind code	A1
Filing date	Dec 8, 2014
Priority date	Dec 9, 2013
Publication date	Oct 20, 2016
Grant date	—

Abstract

A series of substituted heteroaromatic compounds containing two fused six-membered rings, tivity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

First claim

1 . A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:

wherein
q is zero or 1;
A represents C—R 2 or N;
B represents C—R 3 or N;
D represents C—R 4 or N;
G represents the residue of a six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
E represents a covalent bond; or E represents —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 5 )— or —N(R 5 )—; or E represents an optionally substituted straight or branched C 1-4 alkylene chain;
Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 6 )—, —N(R 6 )—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —S(O) 2 N(R 6 )— or —N(R 6 )S(O) 2 —; or Q represents an optionally substituted straight or branched C 1-6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 6 )—, —N(R 6 )—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —S(O) 2 N(R 6 )— and —N(R 6 )S(O) 2 —;
Y represents C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z 1 —Z 2 or —Z 1 —C(O)—Z 2 , either of which moieties may be optionally substituted by one or more substituents;
Z 1 represents a divalent radical derived from an aryl, C 3-7 heterocycloalkyl or heteroaryl group;
Z 2 represents aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl;
R 1 , R 2 , R 3 and R 4 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —SF 5 , —NR b R c , —NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R c , —N(SO 2 R c ) 2 , —NHSO 2 NR b R c , —COR d , —CO 2 R d , —CONR b R c , —CON(OR a )R b , —SO 2 NR b R c or —SO(NR b )R e ; or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 heterocycloalkenyl, C 4-9 heterobicycloalkyl, heteroaryl, heteroaryl(C 1-6 )alkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-aryl-, heteroaryl(C 3-7 )heterocycloalkyl-, (C 3-7 )cycloalkyl-heteroaryl-, (C 3-7 )cycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 4-7 )cycloalkenyl-heteroaryl-, (C 4-9 )bicycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 3-7 )heterocycloalkenyl-heteroaryl-, (C 4-9 )heterobicycloalkyl-heteroaryl- or (C 4-9 )spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents;
R 5 and R 6 independently represent hydrogen or C 1-6 alkyl;
R a represents C 1-6 alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
R b and R c , when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents;
R d represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

2 . The compound as claimed in claim 1 represented by formula (IIA), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:

wherein
R 11 represents halogen or cyano; or R 11 represents C 1-6 alkyl, C 2-6 alkynyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, heteroaryl, (C 3-7 )heterocycloalkyl-(C 1-6 )alkyl-aryl-, heteroaryl(C 3-7 )heterocycloalkyl-, (C 3-7 )cycloalkyl-heteroaryl-, (C 3-7 )cycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 4-7 )cycloalkenyl-heteroaryl-, (C 4-6 )bicycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 3-7 )heterocycloalkenyl-heteroaryl-, (C 4-6 )heterobicycloalkyl-heteroaryl- or (C 4-6 )spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents; and
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, arylamino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 )alkylaminosulfonyl.

3 . The compound as claimed in claim 2 wherein R 11 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.

4 . The compound as claimed in claim 2 represented by formula (IIB), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:

wherein
V represents C—R 22 or N;
R 21 represents hydrogen, halogen, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoro-methyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, (C 1-6 )alkoxy-(C 1-6 )alkyl, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C 3-7 )cycloalkyl-oxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, (C1.6)alkylsulphonyl(C 1-6 )alkyl, amino, amino-(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, N—[(C 1-6 )-alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino-(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, N—[(C 1-6 )alkyl]-N-[carboxy(C 1-6 )alkyl]amino, carboxy(C 3-7 )cycloalkylamino, carboxy(C 3-7 )cycloalkyl(C 1-6 )alkylamino, C 1-6 alkylsulphonylamino, C 1-6 alkylsulphonylamino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, (C 2-6 )alkylcarbonyloxy(C 1-6 )alkyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, C 2-6 alkoxycarbonyl-methylidenyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkyl-sulphoximinyl or [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl; or R 21 represents (C 3-7 )cycloalkyl, (C 3-7 )cy

Assignees

• Ucb Biopharma Sprl

Inventors

• Alexander Rikki Peter
• Foulkes Gregory
• Hutchings Martin Clive
• Jackson Victoria Elizabeth
• Kroeplien Boris
• Reuberson James Thomas
• Rook Sarah Margaret
• Zhu Zhaoning

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title