Difluorocyclohexyl derivatives as IL-17 modulators

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

wherein

A represents C—R 1 or N;

E represents C—R 2 or N;

R 1 represents hydrogen or fluoro;

R 2 represents hydrogen or fluoro;

R 3 represents —NR 3a R 3b ; or R 3 represents a group of formula (Wa):

in which the asterisk (*) represents the point of attachment to the remainder of the molecule;

W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or

W represents the residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or

W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;

R 3a represents hydrogen or C 1-6 alkyl;

R 3b represents 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;

R 4a represents hydrogen, fluoro or hydroxy; or R 4a represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents; and

R 4b represents hydrogen, fluoro or C 1-6 alkyl; or

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

R 16 represents methyl, ethyl, isopropyl or cyclopropyl.

2 . A compound as claimed in claim 1 wherein R 3 represents —NR 3a R 3b ; and R 3b represents C 1-6 alkyl or C 3-7 cycloalkyl(C 1-6 )alkyl, either of which groups is optionally substituted by one or more substituents.

3 . A compound as claimed in claim 1 wherein R 3 represents a group of formula (Wa), in which the group of formula (Wa) represents azetidin-1-yl or pyrrolidin-1-yl, either of which rings is optionally substituted by one or more substituents.

4 . A compound as claimed in claim 1 wherein R 4a represents C 1-6 alkyl, which group is optionally substituted by one, two or three substituents independently selected from halogen, C 1-6 alkoxy and C 1-6 alkylsulfonyl.

5 . A compound as claimed in claim 1 wherein R 4a and R 4b together with the carbon atom to which they are both attached represent cyclobutyl, cyclohexyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups is optionally substituted by one or more substituents.

6 . A compound as claimed in claim 1 which is

Methyl (3S)-3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate;

Methyl (3R)-3-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)-amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate;

N—[(S)-{5-[1-(3,3-Difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-{5-[(1S)-1-(3,3-Difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-{5-[(1R)-1-(3,3-Difluoroazetidine-1-carbonyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-{5-[1-(3,3-Difluoroazetidine-1-carbonyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)propyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-{[(1R)-2-methyl-1-(methylcarbamoyl)propyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-1-{[(1R)-1-(dimethylcarbamoyl)-2-methyl-propyl]carbamoyl}-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl)-{5-[(1R)-1-{[(1R)-1-(dimethylcarbamoyl)-2-methyl-propyl]carbamoyl}-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[3,3,3-trifluoro-1-(3,3,3-trifluoropropyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl)(5-{1-[(2,2-difluorocyclopropyl)methylcarbamoyl]-3,3,3-trifluoropropyl}-4-fluoro-1H-benzimidazol-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—{(S)-(4,4-Difluorocyclohexyl)[4-fluoro-5-(3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl)-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-{5-[4-(3,3-Difluoroazetidine-1-carbonyl)piperidin-4-yl]-4-fluoro-1H-benzimidazol-2-yl}(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

Methyl 4-(3,3-difluoroazetidine-1-carbonyl)-4-(2-{(S)-(4,4-difluorocyclohexyl)[(4-methyl-1,2,5-oxadiazole-3-carbonyl)amino]methyl}-4-fluoro-1H-benzimidazol-5-yl)-piperidine-1-carboxylate;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)tetrahydropyran-4-yl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

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

N—[(S)-(4,4-Difluorocyclohexyl)(5-{4-[(2,2-difluorocyclopropyl)methylcarbamoyl]-tetrahydropyran-4-yl}-1H-imidazo[4,5-b]pyridin-2-yl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3-(ethylsulfonyl)-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-ethyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1S)-3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){4-fluoro-5-[(1R)-3,3,3-trifluoro-1-(2,2,2-trifluoroethyl-carbamoyl)propyl]-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-1-(2,2-difluoroethylcarbamoyl)-3,3,3-trifluoro-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide monoformate salt;

N—[(S)-(4,4-Difluorocyclohexyl){5-[3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—{(S)-(4,4-Difluorocyclohexyl)[5-(3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]-carbamoyl}propyl)-4-fluoro-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-{[(1S)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—{(S)-(4,4-Difluorocyclohexyl)[5-(3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]-carbamoyl}propyl)-4-fluoro-1H-benzimidazol-2-yl]methyl}-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1S)-3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(4,4-Difluorocyclohexyl){5-[(1R)-3,3-difluoro-1-{[(1R)-2,2,2-trifluoro-1-methylethyl]carbamoyl}propyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

N—[(S)-(5-{1-[(1-Cyclopropyl-2,2,2-trifluoroethyl)carbamoyl]-3,3-difluoropropyl}-4-fluoro-1H-benzimidazol-2-yl)(4,4-difluorocyclohexyl)methyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3-difluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{(1R)-3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl)(4-fluoro-5-{(1S)-3,3,3-trifluoro-1-[(2-fluoro-2-methylpropyl)carbamoyl]propyl}-1H-benzimidazol-2-yl)methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-4-fluoro-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide;

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1S)-1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide; or

4-Cyclopropyl-N—[(S)-(4,4-difluorocyclohexyl){4-fluoro-5-[(1R)-1-(methoxymethyl)-2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-1H-benzimidazol-2-yl}methyl]-1,2,5-oxadiazole-3-carboxamide.

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

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

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