Fused imidazole and pyrazole derivatives as modulators of TNF activity

Patent metadata

Field	Value
Publication number	US-9868749-B2
Application number	US-201415100825-A
Country	US
Kind code	B2
Filing date	Dec 8, 2014
Priority date	Dec 9, 2013
Publication date	Jan 16, 2018
Grant date	Jan 16, 2018

Abstract

A series of substituted benzimidazole, imidazo[1,2-a]pyridine and pyrazolo[1,5-a]pyridine derivatives, and analogues 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:

wherein
V represents C—R 22 or N;
R 21 represents hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, (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 )heterocycloalkyl, (C 4-9 )heterobicycloalkyl or (C 4-9 )spiroheterocycloalkyl, any of which groups may be optionally substituted by one, two or three substituents independently selected from halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, oxo, amino, 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;
D represents C—R 4 or N;
E represents —CH 2 — or —CH(CH 3 )—;
Y represents a group of formula

(Ya-1), (Ya-2), (Ya-3), (Yb-1), (Yb-2), (Yb-3), (Yb-4), (Yb-5), (Yb-6), (Yb-7), (Yc-1) or (Yd-1):

wherein
the asterisk (*) represents the point of attachment to the remainder of the molecule;
R 1g represents hydrogen, halogen, cyano, C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy, pentafluorothio, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkyl-aminocarbonyl, hydroxy(C 1-6 )alkylaminocarbonyl, (C 1-6 )alkoxy(C 1-6 )alkylaminocarbonyl, (C 3-7 )cycloalkylaminocarbonyl, heteroaryl(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, hydroxy(C 3-7 )heterocycloalkyl, (C 1-6 )alkoxy-(C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkylcarbonyl, hydroxy(C 3-7 )heterocycloalkyl-carbonyl, oxo(C 3-7 )heterocycloalkylcarbonyl, (C 1-6 )alkylsulphonyl(C 3-7 )heterocycloalkyl-carbonyl or (C 2-6 )alkoxycarbonyl(C 3-7 )heterocycloalkylcarbonyl;
R 2g and R 3g independently represent hydrogen or halogen;
R 2 represents hydrogen or halogen;
R 4 represents hydrogen;
R 5 represents C 1-6 alkyl, optionally substituted by halogen, hydroxy or C 1-6 alkoxy;
R 7a and R 7b independently represent hydrogen or C 1-6 alkyl;
R 8a and R 8b independently represent hydrogen, halogen or C 1-6 alkyl; or
R 8a and R 8b , when taken together with the carbon atom to which they are both attached, represent cyclopropyl; and
R 9a and R 9b independently represent hydrogen or C 1-6 alkyl.

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

3. The compound as claimed in claim 2 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), (IIF-C), (IIG-C), (IIH-C), (IIJ-C), (IIK-C) or (IIL-C), or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate 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 or C 2-6 alkylcarbonyl;
R 32 represents hydrogen, halogen, hydroxy, C 2-6 alkylcarbonyl or carboxy;
R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl or amino;
R 34 represents hydrogen, halogen, hydroxy or amino;
A represents C—R 2 or N;
D represents C—R 4 or N;
E represents —CH 2 — or —CH(CH 3 )—;
Y represents a group of formula (Ya-1), (Ya-2), (Ya-3), (Yb-1), (Yb-2), (Yb-3), (Yb-4), (Yb-5), (Yb-6), (Yb-7), (Yc-1) or (Yd-1):

wherein
the asterisk (*) represents the point of attachment to the remainder of the molecule;
R 1g represents hydrogen, halogen, cyano, C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy, pentafluorothio, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkyl-aminocarbonyl, hydroxy(C 1-6 )alkylaminocarbonyl, (C 1-6 )alkoxy(C 1-6 )alkylaminocarbonyl, (C 3-7 )cycloalkylaminocarbonyl, heteroaryl(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 alkyl][N—(C 1-6 (alkyl ]sulphoximinyl, hydroxy(C 3-7 )heterocycloalkyl, (C 1-6 )alkoxy-(C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkylcarbonyl, hydroxy(C 3-7 heterocycloalkyl-carbonyl, oxo(C 3-7 )heterocycloalkylcarbonyl, (C 1-6 )alkylsulphonyl(C 3 )heterocycloalkyl-carbonyl or (C 2-6 )alkoxycarbonyl(C 3-7 )heterocycloalkylcarbonyl;
R 2g and R 3g independently represent hydrogen or halogen;
R 2 represents hydrogen or halogen;
R 4 represents hydrogen;
R 5 represents C 1-6 alkyl, optionally substituted by halogen, hydroxy or C 1-6 alkoxy;
R 7a and R 7b independently represent hydrogen or C 1-6 alkyl;
R 8a and R 8b independently represent hydrogen, halogen or C 1-6 alkyl; or
R 8a and R 8b , when taken together with the carbon atom to which they are both attached, represent cyclopropyl; and
R 9a and R 9b independently represent hydrogen or C 1-6 alkyl.

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

5. A compound which is
4-{[6-(6-Methanesulfonylpyridin-3-yl)-2-methylimidazo[1,2-a]pyridin-3-yl]methyl}-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one;
8-Fluoro-4-({6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-methylimidazo[1,2-a]-pyridin-3-yl}methyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;
7-Fluoro-3-({6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-methylimidazo[1,2-a]-pyridin-3-yl}methyl)-2,3-dihydro-1,3-benzoxazol-2-one;
3-({6-[2-(2-Hydroxypropan-2-yl)pyrimidin-5-yl]-2-methylimidazo[1,2-a]pyridin-3-yl}methyl)-2H,3H-[1,3]oxazolo[4,5-d]pyrimidin-2-one;
8-Fluoro-4-{[6-(6-methanesulfonylpyridin-3-yl)-2-methylimidazo[1,2-a]pyridin-3-yl]-methyl}-3,4-dihydro-2H-1,4-benzoxazin-3-one;
tert-Butyl 4-(5-{3-[(8-Fluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)methyl]-2-methylimidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)piperazine-1-carboxylate;
8-Fluoro-4-({2-methyl-6-[2-(morpholin-4-yl)pyrimidin-5-yl]imidazo[1,2-a]pyridin-3-yl}methyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one;
8-Fluoro-4-({2-methyl-6-[2-(piperazin-1-yl)pyrimidin-5-yl]imidazo[1,2-a]pyridin-3-yl}-methyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one hydrochloride;
(2R)-8-Fluoro-4-({6-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2-methylimidazo[1,2-a]-pyridin-3-yl}methyl)-2-methyl-3,4-dihydro-2H-1,4

Assignees

• Ucb Biopharma Sprl

Inventors

• Alexander Rikki Peter
• Bentley Jonathan Mark
• Brace Gareth Neil
• Brookings Daniel Christopher
• Chovatia Prafulkumar Tulshibhai
• Deboves Hervé Jean Claude
• Johnstone Craig
• Jones Elizabeth Pearl
• Kroeplien Boris
• Lecomte Fabien Claude
• Madden James
• Miller Craig
• Porter John Robert
• Selby Matthew Duncan
• Shaw Michael Alan
• Vaidya Darshan Gunvant
• Yule Ian Andrew

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title