Fused bicyclic heteroaromatic derivatives as modulators of TNF activity

Patent metadata

Field	Value
Publication number	US-9815797-B2
Application number	US-201415101283-A
Country	US
Kind code	B2
Filing date	Dec 8, 2014
Priority date	Dec 9, 2013
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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

The invention claimed is:

1. A compound represented by formula (IIB), or a pharmaceutically acceptable salt thereof:

wherein
V represents C—R 22 or N;
R 21 represents hydroxy(C 1-6 )alkyl or R 21 represents (C 3-7 )cycloalkyl, which group is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, (C 2-6 )alkoxycarbonylamino-(C 1-6 )alkyl, C 1-6 alkyl sulphonylamino, (C 1-6 )alkyl-sulphonylamino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonyl-aminosulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl and hydroxyoxadiazolyl;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy;
q is zero or 1;
A represents C—R 2 or N;
G represents the residue of a six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;
E represents —O—, —CH 2 —, or —CH(CH 3 );
Q represents —CH 2 — or —CH 2 O;
Z represents hydrogen or methyl;
R 2 represents hydrogen or halogen;
R 15 represents hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy or difluoromethoxy; and
R 16 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, difluoromethoxy or amino.

2. The compound as claimed in claim 1 wherein R 21 represents hydroxy(C 1-6 )alkyl.

3. The compound as claimed in claim 1 represented by formula (IIF), (IIG), (IIH), or (IIJ), or a pharmaceutically acceptable salt thereof:

wherein
W represents C(R 32 )(R 33 );
R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonyl-aminosulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl;
R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, amino or carboxy;
R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkyl-amino, (C 2-6 )alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, (C 1-6 )alkyl-sulphonylamino or (C 1-6 )alkylsulphonylamino(C 1-6 )alkyl;
q is zero or 1.

4. The compound as claimed in claim 3 wherein R 34 represents hydrogen, fluoro or hydroxy.

5. The compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.

6. A compound that is
2-{5-[3-Methyl-4-(1-phenylethyl)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol,
2-(5-{4-[2-(Difluoromethoxy)benzyl]-3-methylcinnolin-6-yl}pyrimidin-2-yl)propan-2-ol, or
2-{5-[3-Methyl-4-(2-methylphenoxy)cinnolin-6-yl]pyrimidin-2-yl}propan-2-ol.

7. A pharmaceutical composition comprising a compound of formula (IIB) as defined in claim 1 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

8. The pharmaceutical composition as claimed in claim 7 further comprising an additional pharmaceutically active ingredient.

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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