Fused imidazole derivatives as IL-17 modulators

1 . A compound of Formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

A represents C—R 1 or N;

B represents C—R 2 or N;

D represents C—R 3 or N;

E represents C—R 4 or N;

Z represents —CH(R 5 )N(H)S(O) 2 R 6 or —CH(R 5 )N(H)R 7 ;

R 0 represents hydrogen or C 1-6 alkyl;

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 , —NR b R c , —NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 Re, —NHSO 2 NR b R c , —N═S(O)R 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 —S(O)(NR c )R a ; or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl(C 1-6 )alkyl, C 4-9 cycloalkenyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, C 3-7 hetero-cycloalkenyl, C 4-9 heterobicycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups are optionally substituted by one or more substituents;

R 5 represents C 3-9 cycloalkyl, which group is optionally substituted by one or more substituents;

R 5a represents C 3-7 cycloalkyl, C 4-9 bicycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and

R 5b represents hydrogen or C 1-6 alkyl; or

R 5a and R 5b , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl, C 4-9 bicycloalkyl or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;

R 6 represents —OR 6a or —NR 6b R 6c ; or R 6 represents C 6 alkyl, C 3-9 cycloalkyl, C 3-9 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 are optionally substituted by one or more substituents;

R 6a represents C 1-6 alkyl; or R 6a represents C 3-9 cycloalkyl, which group are optionally substituted by one or more substituents;

R 6b represents hydrogen or C 1-6 alkyl;

R 6c represents hydrogen or C 1-6 alkyl;

R 7 represents heteroaryl, which group is optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, difluoromethyl and tetrahydropyranyl;

R a represents trifluoromethyl; or R a represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-9 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 are optionally substituted by one or more substituents;

R b and R c independently represent hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-9 cycloalkyl, C 3-9 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 are 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 are optionally substituted by one or more substituents;

R d represents hydrogen; or R d represents C 1-6 alkyl, C 3-9 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups are optionally substituted by one or more substituents; and

R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups are optionally substituted by one or more substituents.

2 . The compound of claim 1 represented by Formula (IIA), an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

D, E, R 2 , R 5 and R 6 are as defined in claim 1 .

3 . The compound of claim 1 wherein R 6 represents heteroaryl, which group is optionally substituted by one or more substituents.

4 . The compound of claim 1 represented by Formula (IIB), an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

D, E, R 2 , R 5 and R 7 are as defined in claim 1 .

5 . The compound of claim 1 wherein R 2 represents C 3-7 heterocycloalkyl, which group is optionally substituted by one or more substituents.

6 . The compound of claim 1 wherein the compound is selected from:

(4-{2-[(S)-(Cyclopentyl){[6-(difluoromethyl)pyridazin-3-yl]amino}methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydrofuran-3-yl)(3,3-difluoroazetidin-1-yl)methanone;

(1-Benzyl-4-{4-fluoro-2-[(S)-(imidazo[1,2-c]pyrimidin-5-ylamino)(4-methylcyclohexyl)-methyl]-1H-benzimidazol-5-yl}pyrrolidin-3-yl)(3,3-difluoroazetidin-1-yl)methanone;

N-[(S)-{5-[(3SR,4RS)-4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydrofuran-3-yl]-4-fluoro-1H-benzimidazol-2-yl}[4-(trifluoromethyl)cyclohexyl]methyl]-2-ethyl-2H-pyrazole-3-sulfonamide;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl)(isoxazolo[4,5-b]pyridin-3-ylamino)methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)methanone;

(3,3-Difluoroazetidin-1-yl)[4-(2-{(S)-(4,4-difluorocyclohexyl)[(5-isopropyl-1,2,4-oxadiazol-3-yl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydropyran-4-yl]-methanone;

(3,3-Difluoroazetidin-1-yl)[4-(2-{(S)-(4,4-difluorocyclohexyl)[(5-methyl-1,2,4-oxadiazol-3-yl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydropyran-4-yl]methanone;

(3,3-Difluoroazetidin-1-yl)[4-(2-{(S)-(4,4-difluorocyclohexyl)[(5-methyl-1,3,4-oxadiazol-2-yl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)tetrahydropyran-4-yl]methanone;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl)(pyridin-2-ylamino)-methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)methanone;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl){[6-(difluoromethyl)-pyridazin-3-yl]amino}methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)-methanone;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl)(pyrazin-2-ylamino)-methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)methanone;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl){[3-(difluoromethyl)-pyridin-2-yl]amino}methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)-methanone;

(3,3-Difluoroazetidin-1-yl)(4-{2-[(S)-(4,4-difluorocyclohexyl){[5-(tetrahydropyran-4-yl)-1,2,4-oxadiazol-3-yl]amino}methyl]-4-fluoro-1H-benzimidazol-5-yl}tetrahydropyran-4-yl)methanone;

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2-methylpropane-1-sulfonamide;

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-1,5-dimethylpyrazole-4-sulfonamide;

N-[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-2,5-dimethylfuran-3-sulfonamide;

2-Chloro-N-[(S)-{5-[4-(3,3-difluoroazetidine-1-carbonyl)tetrahydropyran-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]thiazole-5-sulfonamide; and

1-(3,3-Difluoroazetidin-1-yl)-2-{2-[(S)-(4,4-difluorocyclohexyl){[6-(difluoromethyl)-pyridazin-3-yl]amino}methyl]-4-fluoro-1H-benzimidazol-5-yl}propan-1-one.

7 . A pharmaceutical composition comprising the compound of Formula (I) of claim 1 , an N-oxide thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

9 . A method of treating a disorder for which the administration of a modulator of IL-17 function is indicated, comprising administering to a patient in need of such treatment an effective amount of the compound of Formula (I) of claim 1 , an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

10 . A method for the treatment of an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment an effective amount of the compound of Formula (I) of claim 1 , an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 4 wherein R 2 represents C 3-7 heterocycloalkyl, which group is optionally substituted by one or more substituents.

12 . The compound of claim 1 wherein R 2 represents C 1-6 alkyl or C 3-7 heterocycloalkyl, which groups are optionally substituted by one or more substituents.

13 . The compound of claim 1 wherein R 2 represents C 1-6 alkyl or C 3-7 heterocycloalkyl, which groups are optionally substituted by one, two or three substituents independently selected from benzyl and difluoroazetidinyl.

14 . The compound of claim 1 wherein R 5 represents C 3-9 cycloalkyl, which group is optionally substituted by one, two or three substituents independently selected from halogen, C 1-6 alkyl and trifluoromethyl.