Pyrimidyl sulphone amide derivatives as chemokine receptor modulators

1. A method for the treatment of a condition or disease selected from COPD, asthma, allergic rhinitis, and rheumatoid arthritis, comprising administering a compound of formula (1), or a pharmaceutically acceptable salt thereof, wherein:

wherein R 1 is a group selected from C 3-7 carbocyclyl, C 1-8 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, nitrile, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , phenyl or heteroaryl; wherein phenyl and heteroaryl are optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl and trifluoromethyl;

wherein R 2 is C 3-7 carbocyclyl, optionally substituted by 1, 2 or 3 substituents independently selected from:

(a) fluoro, —OR 4 , —NR 5 R 6 —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 ;

(b) a 3-8 membered ring optionally containing 1, 2 or 3 atoms selected from O, S, —NR 8 and whereby the ring is optionally substituted by C 1-3 alkyl or fluoro; or

(c) phenyl or heteroaryl, each of which is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —NR 8 COR 9 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl and trifluoromethyl;

or R 2 is a group selected from C 1-8 alkyl, C 2-6 alkenyl or C 2-6 alkynyl wherein the group is substituted by 1, 2 or 3 substituents independently selected from hydroxy, amino, C 1-6 alkoxy, C 1 -6 alkylamino, di(C 1-6 alkyl)amino, N—(C 1-6 alkyl)-N -(phenyl)amino, N—C 1-6 alkylcarbamoyl, N,N -di(C 1-6 alkyl)carbamoyl, N—(C 1-6 alkyl)-N-(phenyl)carbamoyl, carboxy, phenoxycarbonyl, —NR 8 COR 9 , —SO 2 R 10 , —SO 2 NR 5 R 6 and —NR 8 SO 2 R 9 ;

wherein R 3 is hydrogen or independently R 2 ;

R 4 is hydrogen or a group selected from C 1-6 alkyl and phenyl, wherein the group is optionally substituted by 1 or 2 substituents independently selected from halo, phenyl, —OR 11 and —NR 12 R 13 ;

R 5 and R 6 are independently hydrogen or a group selected from C 1-6 alkyl and phenyl wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, —OR 14 , —NR 15 R 16 , —COOR 14 , —CONR 15 R 16 , —NR 15 COR 16 , —SO2R 10 , —SONR 15 R 16 , and NR 15 SO 2 R 16 or

R 5 and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally containing a further heteroatom selected from oxygen and nitrogen atoms, which ring is optionally substituted by 1, 2 or 3 substituents independently selected from phenyl, —OR 14 , —COOR 14 , —NR 15 R 16 , —SO2R 10 , —SONR 15 R 16 , NR 15 SO 2 R 16 or C 1-6 alkyl (optionally substituted by 1 or 2 substituents independently selected from halo, —NR 15 R 16 and —OR 17 groups);

R 10 is hydrogen or a group selected from C 1-6 alkyl or phenyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, phenyl, —OR 17 and —NR 15 R 16 ; and

each of R 7 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 is independently hydrogen, C 1-6 alkyl or phenyl;

X is hydrogen, halo, cyano, nitro, hydroxy, C 1-6 alkoxy (optionally substituted by 1 or 2 substituents selected from halo, —OR 11 and —NR 12 R 13 ), —NR 5 R 6 , —COOR 7 , —NR 8 COR 9 , thio, C 1-6 alkylthio(optionally substituted by 1 or 2 substituents selected from halo, —OR 17 , —NR 15 R 16 ), —SO 2 R 10 or a group selected from C 3-7 carbocyclyl, C 1-8 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 and —NR 8 SO 2 R 9 ; and

R x is trifluoromethyl, —NR 5 R 6 , phenyl, napthyl, monocyclic or bicyclic heteroaryl wherein a heteroring may be partially or fully saturated and one or more ring carbon atoms may form a carbonyl group, and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7, —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl or trifluoromethyl;

or R x is a group selected from C 3-7 carbocyclyl, C 1-8 alkyl, C 2-6 alkenyl and C 2-6 alkynyl whereby the group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , phenyl or heteroaryl; and wherein each phenyl or heteroaryl group is optionally substituted by 1, 2 or 3 substituents independently selected from halo, cyano, nitro, —OR 4 , —NR 5 R 6 , —CONR 5 R 6 , —COR 7 , —COOR 7 , —NR 8 COR 9 , —SR 10 , —SO 2 R 10 , —SO 2 NR 5 R 6 , —NR 8 SO 2 R 9 , C 1-6 alkyl or trifluoromethyl.

2. The method according to claim 1 wherein R 1 is benzyl optionally substituted by 1, 2 or 3 substituents independently selected from fluoro, chloro, bromo, methoxy, methyl and trifluoromethyl.

3. The method according to claim 1 wherein R 3 is hydrogen.

4. The method according to claim 1 wherein X is hydrogen.

5. The method according to claim 1 wherein R x is methyl, 1-methylimidazolyl, 1,2-dimethylimidazolyl, N,N-dimethylamino, azetidinyl, pyrolidinyl, morpholinyl and piperidinyl.

6. The method according to claim 1 wherein the compound of formula (1) is selected from the group consisting of:

N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)methanesulfonamide;

N-[2-[(3-Chloro-2-fluorobenzyl)thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-4-morpholinesulfonamide;

N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1,2-dimethyl-1H-imidazole-4-sulfonamide;

N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)piperidine-1-sulfonamide;

N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)pyrrolidine-1-sulfonamide;

N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)azetidine-1-sulfonamide;

N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}morpholine-4-sulfonamide;

N-(2-[(2,3-Difluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)morpholine-4-sulfonamide;

N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)azetidine-1-sulfonamide;

N-{6-{[(1R)-2-Hydroxy-1-methylethyl]amino}-2-[(2,3,4-trifluorobenzyl)thio]-pyrimidin-4-yl}azetidine-1-sulfonamide;

N-(2-[(3-Chloro-2-fluorobenzyl)thio]-6-{[(1R)-2-hydroxy-1-methylethyl]amino}-pyrimidin-4-yl)-N,N-dimethylsulfamide; and

N-[2-[[(3-Chloro-2-fluorophenyl)methyl]thio]-6-[(R)-(2-hydroxy-1-methylethyl)amino]-4-pyrimidinyl]-1-methyl-1H-imidazole-4-sulfonamide;

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 wherein R 2 is C 1-8 alkyl optionally substituted by 1 or 2 hydroxy substituents.

8. The method according to claim 1 wherein the condition or disease is asthma.

9. The method according to claim 1 wherein the condition or disease is allergic rhinitis.

10. The method according to claim 1 wherein the condition or disease is COPD.

11. The method according to claim 1 wherein the condition or disease is rheumatoid arthritis.