Spirocyclic indane analogues as IL-17 modulators

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein

ring A represents C 4 -C 6 heterocycloalkyl which group is optionally substituted by one or more substituents;

B represents C—R 2 ;

D represents C—R 3 or N;

E represents C—R 4 ;

—X—Y— represents —C(X 1 )(X 2 )—O—, —C(X 1 )(X 2 )—N(Y 3 )—, —C(X 1 )(X 2 )—C(Y 1 )(Y 2 )—, —C(O)—O—, or —C(X 1 )═C(Y′)—;

R 1 represents —COR a ;

R 2 represents hydrogen, halogen, cyano, C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkyl-sulphinyl or C 1-6 alkylsulphonyl;

R 3 represents hydrogen, halogen, cyano, C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkyl-sulphinyl or C 1-6 alkylsulphonyl;

R 4 represents hydrogen, halogen, cyano, C 1-6 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkyl-sulphinyl or C 1-6 alkylsulphonyl;

R a represents —CH(R 5 )N(H)C(O)R 6 or —C(═CR 5a R 5b )N(H)C(O)R 6 ;

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 is 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 is optionally substituted by one or more substituents;

R 6 represents aryl or heteroaryl, each of which groups is optionally substituted by one or more substituents;

X 1 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, (C 1-6 )alkoxy-(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl;

X 2 represents hydrogen, halogen or C 1-6 alkyl;

Y 1 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, (C 1-6 )alkoxy-(C 1-6 )alkyl, amino(C 1-6 )alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl or heteroaryl;

Y 2 represents hydrogen, halogen or C 1-6 alkyl; and

Y 3 represents hydrogen or C 1-6 alkyl.

2. A compound as claimed in claim 1 represented by formula (I-1) or (I-3), or a pharmaceutically acceptable salt thereof:

wherein A, X, Y, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .

3. A compound as claimed in claim 1 represented by formula (I-11), (I-12), (I-13), (I-14) or (I-15), or a pharmaceutically acceptable salt thereof:

wherein A, B, D, E, X 1 , X 2 , Y 1 , Y 2 , Y 3 and R 1 are as defined in claim 1 .

4. A compound as claimed in claim 1 represented by formula (IIA), or a pharmaceutically acceptable salt thereof:

wherein

W represents O, S, S(O), S(O) 2 , S(O)(NH) or N—R 17 ;

R 17 represents hydrogen or C 1-6 alkyl;

X, Y, R 2 , R 3 , R 5 and R 6 are as defined in claim 1 .

5. A compound as claimed in claim 4 wherein R 5 represents C 3-9 cycloalkyl, which group may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl.

6. A compound as claimed in claim 1 represented by formula (IIB), or a pharmaceutically acceptable salt thereof:

wherein

X, Y, R 2 , R 5 and R 6 are as defined in claim 1 ; and

W represents O, S, S(O), S(O) 2 , S(O)(NH) or N—R 17 .

7. A compound as claimed in claim 6 wherein R 5 represents C 3-9 cycloalkyl, which group may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl.

8. A compound as claimed in claim 6 wherein R 6 represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from C 1 -C 6 alkyl, (C 1 -C 6 )alkylsulfonyl-(C 1 -C 6 )alkyl, dioxoisothiazolidinyl, tetrahydropyranyl, C 1 -C 6 alkylsulfonylamino and di(C 1 -C 6 )alkylsulfoximinyl.

9. A compound as claimed in claim 1 wherein R 5 represents C 3-9 cycloalkyl, which group may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl.

10. A compound as claimed in claim 9 wherein R 6 represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from C 1 -C 6 alkyl, (C 1 -C 6 )alkylsulfonyl-(C 1 -C 6 )alkyl, dioxoisothiazolidinyl, tetrahydropyranyl, C 1 -C 6 alkylsulfonylamino and di(C 1 -C 6 )alkylsulfoximinyl.

11. A compound as claimed in claim 1 wherein R 6 represents aryl or heteroaryl, either of which groups may be optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, (C 1-6 )alkylsulfonyl(C 1-6 )alkyl, dioxoisothiazolidinyl, tetrahydropyranyl, C 1-6 alkylsulfonylamino and di(C 1-6 )alkyl-sulfoximinyl.

12. A compound as claimed in claim 1 which is

2-Cyclooctyl-2-[(3-methylisoxazol-4-yl)formamido]-N-(spiro[indene-1,4′-oxane]-5-yl)-acetamide;

2-(5-Chlorobicyclo[4.2.0]octa-1,3,5-trien-7-ylidene)-2-[(1-ethyl-1H-pyrazol-5-yl)-formamido]-N-(spiro[indene-1,4′-oxane]-5-yl)acetamide;

N-[1-Cyclooctyl-2-oxo-2-(spiro[indane-1,4′-tetrahydropyran]-5-ylamino)ethyl]-3-methyl-isoxazole-4-carboxamide;

N-{1-Cyclooctyl-2-[(2-fluorospiro[indene-1,4′-tetrahydropyran]-5-yl)amino]-2-oxo-ethyl}-3-methylisoxazole-4-carboxamide;

N-[1-Cyclooctyl-2-oxo-2-(spiro[indoline-3,4′-tetrahydropyran]-6-ylamino)ethyl]-3-methylisoxazole-4-carboxamide;

2-Ethyl-N-[(1S)-1-(4-methylcyclohexyl)-2-oxo-2-(spiro[indoline-3,4′-tetrahydropyran]-6-ylamino)ethyl]pyrazole-3-carboxamide (trans isomer);

N-{1-Cyclooctyl-2-oxo-2-[(2-oxo-2′,3′,5′,6′-tetrahydro-2H-spiro[benzofuran-3,4′-pyran]-6-yl)amino]ethyl}-3-methylisoxazole-4-carboxamide;

N-[1-Cyclooctyl-2-oxo-2-(spiro[2H-benzofuran-3,4′-tetrahydropyran]-6-ylamino)ethyl]-3-methylisoxazole-4-carboxamide;

3-(1,1-Dioxo-1,2-thiazolidin-2-yl)-N-{(1S)-2-[(4-fluorospiro[indoline-3,4′-tetrahydro-pyran]-6-yl)amino]-1-(trans-4-methylcyclohexyl)-2-oxoethyl}benzamide;

N-{(1S)-2-[(4-Fluorospiro[indoline-3,4′-tetrahydropyran]-6-yl)amino]-1-(trans-4-methyl-cyclohexyl)-2-oxoethyl}-3-(methylsulfonylmethyl)benzamide;

N-{(1S)-2-[(4-Fluorospiro[indoline-3,4′-tetrahydropyran]-6-yl)amino]-1-(trans-4-methyl-cyclohexyl)-2-oxoethyl}-3-(methanesulfonamido)benzamide;

4-Ethyl-N-{(1S)-2-[(4-fluorospiro[indoline-3,4′-tetrahydropyran]-6-yl)amino]-1-(trans-4-methylcyclohexyl)-2-oxoethyl}-1,2,5-oxadiazole-3-carboxamide;

3-{[Dimethyl(oxo)-λ 6 -sulfanylidene]amino}-N-{(1S)-2-[(4-fluorospiro[indoline-3,4′-tetrahydropyran]-6-yl)amino]-1-(trans-4-methylcyclohexyl)-2-oxoethyl}benzamide;

(2S)-2-[(1-Ethyl-1H-pyrazol-5-yl)formamido]-N-(4-fluoro-1,2-dihydrospiro[indole-3,4′-oxane]-6-yl)-2-(trans-4-methylcyclohexyl)acetamide;

(2S)-2-{[1-(Propan-2-yl)-1H-pyrazol-5-yl]formamido}-2-(trans-4-methylcyclohexyl)-N-(spiro[indene-1,4′-oxane]-5-yl)acetamide;

3-{[Dimethyl(oxo)-λ 6 -sulfanylidene]amino}-N-[(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-(spiro[indene-1,4′-tetrahydropyran]-5-ylamino)ethyl]benzamide;

2-Ethyl-N-[(1S)-1-(trans-4-methylcyclohexyl)-2-oxo-2-(spiro[1,2-dihydropyrrolo[3,2-c]-pyridine-3,4′-tetrahydropyran]-6-ylamino)ethyl]pyrazole-3-carboxamide;

N-[(1S)-1-(trans-4-Methylcyclohexyl)-2-oxo-2-(spiro[indene-1,4′-tetrahydropyran]-5-ylamino)ethyl]-1-(tetrahydropyran-4-yl)pyrazole-4-carboxamide; or

a pharmaceutically acceptable salt thereof.

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

14. A pharmaceutical composition as claimed in claim 13 further comprising an additional pharmaceutically active ingredient.

15. A method for the treatment of psoriasis, psoriatic arthritis or ankylosing spondylitis, 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 a pharmaceutically acceptable salt thereof.