Fused imidazole and pyrazole derivatives as modulators of TNF activity

Patent metadata

Field	Value
Publication number	US-10004737-B2
Application number	US-201415039092-A
Country	US
Kind code	B2
Filing date	Dec 8, 2014
Priority date	Dec 9, 2013
Publication date	Jun 26, 2018
Grant date	Jun 26, 2018

Abstract

A series of substituted benzimidazole, imidazo[1,2-α]pyridine and pyrazolo[1,5-α]pyridine derivatives, and analogs thereof, being potent modulators of human TNFα activity, 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-A), (IIB-B) or (IIB-C), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal 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, (C 4-9 )bicycloalkyl, (C 3-7 )heterocycloalkyl or (C 4-9 )heterobicycloalkyl, any of which groups is optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, oxo, carboxy and C 2-6 alkoxycarbonyl;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy;
A represents C—R 2 or N;
Y represents a group of formula (Ya):

the asterisk (*) represents the point of attachment to the remainder of the molecule;
E represents —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 5 )— or —N(R 5 )—;
G represents the residue of an optionally substituted benzene ring; or an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl and triazolyl; or an optionally substituted six-membered heteroaromatic ring selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl;
Q represents —CH 2 —, —CH(OH)—, —CH 2 O—, —CH 2 S— or —CH 2 OCH 2 —;
Z represents hydrogen or methyl;
R 2 represents hydrogen or halogen;
R 5 represents hydrogen or C 1-6 alkyl;
R 7a represents hydrogen, C 1-6 alkyl or trifluoromethyl; and
R 7b represents hydrogen or C 1-6 alkyl; or
R 7a and R 7b , when taken together with the carbon atom to which they are both attached, represent carbonyl (C═O); or
R 7a and R 7b , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.

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

3. A compound as claimed in claim 1 represented by formula (IIC-A), (IID-A), (IIE-A), (IIF-A), (IIG-A), (IIH-A), (IIJ-A), (IIK-A), (IIL-A), (IIC-B), (IID-B), (IIE-B), (IIF-B), (IIG-B), (IIH-B), (IIJ-B), (IIK-B), (IIL-B), (IIC-C), (IID-C), (IIE-C), (IIG-C), (IIH-C), (IIH-C), (IIJ-C), (IIK-C) or (IIL-C), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof:

wherein
T represents —CH 2 — or —CH 2 CH 2 —;
U represents C(O) or S(O) 2 ;
W represents O, N(R 31 ) or C(R 32 )(R 33 );
-M- represents —CH 2 — or —CH 2 CH 2 —;
R 31 represents hydrogen, C 1-6 alkyl, carboxy or C 2-6 alkoxycarbonyl;
R 32 represents carboxy or C 2-6 alkoxycarbonyl;
R 33 represents hydrogen or C 1-6 alkyl;
R 34 represents hydrogen.

4. The compound as claimed in claim 1 wherein Y represents a group of formula (Ya-1) or (Ya-2):

wherein
the asterisk (*) represents the point of attachment to the remainder of the molecule; and
R 8a and R 8b independently represent C 1-6 alkyl, halogen, cyano, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, C 2-6 alkylcarbonyl, amino, C 1-6 alkylamino or di(C 1-6 )alkylamino.

5. A compound that is,
2-{5-[7-Fluoro-2-methyl-3-(3H-spiro[2-benzofuran-1,1′-cyclopropan]-3-yl)imidazo[1,2-a]pyridin-6-yl]pyrimidin-2-yl}propan-2-ol;
2-(5-{3-[(1S,3R)-3-Ethyl-1,3-dihydroisobenzofuran-1-yl]-7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
2-(5-{3-[(1S,3S)-3-Ethyl-1,3-dihydroisobenzofuran-1-yl]-7-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
2-(5-{7-Fluoro-2-methyl-3-[(3R)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
Potassium (1R,5S,6R)-3-(5-{2-methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)bicyclo[3.1.0]hexane-6-carboxylate;
2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]-6-[2-(piperazin-1-yl)-pyrimidin-5-yl]imidazo[1,2-a]pyridine;
2-(5-{2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]-pyridin-6-yl}pyridin-2-yl)propan-2-ol;
2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]-6-[6-(piperazin-1-yl)-pyridin-3-yl]imidazo[1,2-a]pyridine;
2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]-6-[2-(morpholin-4-yl)-pyridin-5-yl]imidazo[1,2-a]pyridine;
2-(5-{2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}-pyrimidin-2-yl)propan-2-ol;
2-(5-{2-Methyl-3-[(1R,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}-pyrimidin-2-yl)propan-2-ol;
Methyl (1R,5S)-3-(5-{2-methyl-3-[(3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]pyridin-2-yl}-3-azabicyclo[3.2.1]-octane-8-carboxylate;
(1R,5S)-3-(5-{2-Methyl-3-[(3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]-pyridin-6-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid;
(1R,5S)-3-(5-{2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid;
(1R,5S)-3-(5-{2-Methyl-3-[(1R,3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid;
2-(5-{7-Fluoro-2-methyl-3-[(3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
1-{5-[2-Methyl-3-(3-methyl-1,3-dihydro-isobenzofuran-1-yl)imidazo[1,2-a]pyridin-6-yl]-pyrimidin-2-yl}-1,4-diazepan-5-one;
Ethyl 4-methyl-1-{5-[2-methyl-3-(3-methyl-1,3-dihydroisobenzofuran-1-yl)imidazo[1,2-a]pyridin-6-yl]pyrimidin-2-yl}piperidine-4-carboxylate;
4-Methyl-1-{5-[2-methyl-3-(3-methyl-1,3-dihydroisobenzofuran-1-yl)imidazo[1,2-a]pyridin-6-yl]pyrimidin-2-yl}piperidine-4-carboxylic acid;
3-{6-[2-(1-Hydroxy-1-methylethyl)pyrimidin-5-yl]-2-methylimidazo[1,2-a]pyridin-3-yl}-2-methylisoindolin-1-one;
2-(5-{2-Methyl-3-[(1R,3R)-3-methylisoindolin-1-yl]imidazo[1,2-a]pyridin-6-yl}-pyrimidin-2-yl)propan-2-ol2-(5-{2-Methyl-3-[(1S,3S)-3-methylisoindolin-1-yl]-imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
2-(5-{2-Methyl-3-[(1R,3S)-3-methylisoindolin-1-yl]imidazo[1,2-a]pyridin-6-yl}-pyrimidin-2-yl)propan-2-ol2-(5-{2-Methyl-3-[(1S,3R)-3-methylisoindolin-1-yl]-imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)propan-2-ol;
trans-4-(5-{2-Methyl-3-[(1S,3S)-3-methyl-1,3-dihydro-2-benzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)cyclohexanecarboxylic acid;
Methyl (1R,5S)-3-(5-{2-(hydroxymethyl)-3-[(1R,3S)-3-methyl-1,3-dihydroisobenzofuran-1-yl]imidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylate;
Methyl (1R,

Assignees

• Ucb Biopharma Sprl

Inventors

• Brown Julien Alistair
• Calmiano Mark Daniel
• Jones Elizabeth Pearl
• Kroeplien Boris
• Reuberson James Thomas
• Selby Matthew Duncan
• Shaw Michael Alan
• Zhu Zhaoning

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

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