2-Arylthiazole Derivatives as CXCR3 Receptor Modulators

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

D is CR 4 or N;

R 3 is selected from the group consisting of: H, halo, C 1-4 alkyl, —CF 3 , —OCF 3 and —S(O) n CF 3 , wherein n is 0 or 2;

R 4 is selected from the group consisting of: H, halo, —OH, C 1-4 alkyl, —OCH 3 , —OCH 2 CF 3 and —CF 3 ;

or R 3 and R 4 may be joined together with the carbon atoms to which they are attached to form a five- or six-membered monocyclic ring, said rings containing oxygen or tetra-substituted with methyl groups as follows:

R 5 is selected from the group consisting of: —H, halo, C 1-4 alkyl, C 3-6 cycloalkyl, CF 3 , —CF 2 CH 3 , —OCF 3 and —SCF 3 ;

R 6 is selected from the group consisting of —H and —OCH 3 ,

or R 5 and R 6 may be joined together with the carbon atoms to which they are attached to form a monocyclic 5-membered ring, said ring di-substituted with methyl as follows:

and

is a 5 membered non-aromatic or aromatic ring or a 9 membered fused bicyclic partially aromatic or aromatic ring, each ring containing at least 1 nitrogen atom and optionally up to 3 additional heterotaoms selected from S, O and N, said rings optionally substituted with 1 to 3 substituents independently selected from the group consisting of: oxo, hydroxy, carboxy, —CF 3 , halo, —S(O) p —CH 3 , phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy; and

p is 0, 1 or 2.

2 . The compound according to claim 1 wherein:

is selected from the group consisting of:

wherein X, Y and Z are independently C or N,

R″ 2 , R″ 3 , R″ 4 and R″ 5 are independently selected from the group consisting of: —H, carboxy, —CF 3 , halo, methylthio, methylsulfonyl, phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy,

R″ 6 is H or OH, and

------ is an optional double bond.

3 . The compound according to claim 1 wherein D is N.

4 . The compound according to claim 1 wherein D is CR 4 .

5 . The compound according to claim 4 wherein:

R 3 and R 4 are joined together with the carbon atoms to which they are attached to form a six-membered monocyclic ring as follows:

6 . The compound according to claim 4 wherein:

R 3 is selected from the group consisting of H, halo, C 1-4 alkyl and —CF 3 ;

R 4 is selected from the group consisting of: H, halo, C 1-4 alkyl, —OCH 3 and —CF 3 ;

R 5 is selected from the group consisting of: H, halo, C 1-4 alkyl, CF 3 and —SCF 3 ; and

R 6 is H.

7 . The compound according to claim 6 wherein:

R 3 is selected from the group consisting of: H, Cl, Br, tert-butyl and —CF 3 ;

R 4 is selected from the group consisting of: H, Cl, Br, tert-butyl, —OCH 3 and —CF 3 ;

R 5 is selected from the group consisting of: H, Cl, Br, tert-butyl, CF 3 and —SCF 3 ; and

R 6 is H.

8 . The compound according to claim 1 wherein R 6 is —H.

9 . The compound according to claim 1 wherein:

D is CR 4 ;

R 3 is selected from the group consisting of: H, Cl, Br, tert-butyl and —CF 3 ;

R 4 is selected from the group consisting of: H, Cl, Br, tert-butyl, —OCH 3 and —CF 3 ;

or R 3 and R 4 may be joined together with the carbon atoms to which they are attached to form a six-membered monocyclic ring as follows:

R 5 is selected from the group consisting of H, Cl, Br, tert-butyl, CF 3 and —SCF 3 ; and

R 6 is —H.

10 . The compound according to claim 9 wherein:

(1) R 3 is tert-butyl, R 4 is H and R 5 is tert-butyl;

(2) R 3 is tert-butyl, R 4 is —OCH 3 and R 5 is tert-butyl;

(3) R 3 is —CF 3 , R 4 is —H and R 5 is —CF 3 ;

(4) R 3 is H, R 4 is —OCH3 and R 5 is H;

(5) R 3 is H, R 4 is tert-butyl and R 5 is H;

(6) R 3 is H, R 4 is Cl and R 5 is H;

(7) R 3 is H, R 4 is Br and R 5 is H;

(8) R 3 is H, R 4 is —CF 3 and R 5 is H;

(9) R 3 is H, R 4 is H and R 5 is Cl;

(10) R 3 is H, R 4 is H and R 5 is Cl;

(11) R 3 is H, R 4 is H and R 5 is —CF 3 ; or

(12) R 3 is Cl, R 4 is H and R 5 is Cl.

11 . The compound according to claim 9 wherein

is selected from the group consisting of

wherein X, Y and Z are independently C or N,

R′ 2 , R″ 3 , R″ 4 and R″ 5 are independently selected from the group consisting of: —H, carboxy, —CF 3 , halo, methylthio, methylsulfonyl, phenyl, C 1-3 alkoxy and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with carboxy or hydroxy,

R″ 6 is H or OH, and

------ is an optional double bond.

12 . The compound according to claim 11 wherein:

is

13 . The compound according to claim 9 wherein:

D is CR 4 ;

R 3 is tert-butyl;

R 4 is H or —OCH 3 ;

R 5 is tert-butyl; and

R 6 is H.

14 . A compound according to claim 1 selected from the following group:

(1) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl}piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-b]pyridine;

(2) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(2,5-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;

(3) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-methyl-1H-imidazol-5-yl]methanol;

(4) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methyl-1,3-dihydro-2H-imidazol-2-one;

(5) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,4-dimethyl-1,3-dihydro-2H-imidazol-2-one;

(6) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-4-methyl-1H-pyrazol-3-yl]acetate bis(hydrotrifluoroacetate);

(7) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[4-methyl-2-(methylsulfonyl)-1H-imidazol-1-yl]acetyl}piperidine;

(8) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,3-dihydro-2H-imidazol-2-one;

(9) Potassium — [3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]acetate;

(10) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-phenylimidazolidin-2-one;

(11) 3-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-3H-imidazo[4,5-b]pyridine;

(12) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1H-[(4-methoxy-1-imidazol-1-yl)acetyl]piperidine;

(13) 4-[2-(8-tert-butyl-4,4-dimethyl-3,4-dihydro-2H-chromen-6-yl)-1,3-thiazol-4-yl]-1-[(2,4-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;

(14) 1-[(4-chloro-2,5-dimethyl-1H-imidazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidine;

(15) 3-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-c]pyridine;

(16) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazo[4,5-c]pyridine;

(17) 3-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3H-imidazo[4,5-b]pyridine1;

(18) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazo[4,5-b]pyridine;

(19) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1-ethyl-4-methyl-1,3-dihydro-2H-imidazol-2-one;

(20) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-4-methyl-1,3-dihydro-2H-imidazol-2-one;

(21) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one;

(22) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(2-ethyl-4-methyl-1H-imidazol-1-yl)acetyl]piperidine;

(23) 2,6-di-tert-butyl-4-{4-[1-(1H-imidazo[4,5-c]pyridin-1-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;

(24) 2,6-di-tert-butyl-4-{4-[1-(3H-imidazo[4,5-c]pyridin-3-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;

(25) 2,6-di-tert-butyl-4-{4-[1-(3H-imidazo[4,5-b]pyridin-3-ylacetyl)piperidin-4-yl]-1,3-thiazol-2-yl}phenol;

(26) 2,6-di-tert-butyl-4-(4-{1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidin-4-yl}-1,3-thiazol-2-yl)phenol;

(27) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-4-methyl-1H-imidazol-5-yl]methanol;

(28) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{2-(methylthio)-1H-imidazol-1-yl]acetyl}piperidine;

(29) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{2-(methylsulfonyl)-1H-imidazol-1-yl]acetyl}piperidine;

(30) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl) 5-methyl-1H-imidazol-4-yl]acetic dihydrochloride;

(31) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-4-methyl-1H-imidazol-5-yl]acetic dihydrochloride;

(32) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;

(33) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;

(34) 4-[2(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(4-methyl-1-imidazol-1-yl)acetyl]piperidine;

(35) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(5-methyl-1-imidazol-1-yl)acetyl]piperidine;

(36) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-methylimidazolidin-2-one;

(37) 3-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-1,3-oxazolidin-2-one;

(38) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperidine;

(39) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperidine;

(40) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-pyrrolo[2,3-b]pyridine;

(41) 1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-1H-pyrrolo[2,3-b]pyridine;

(42) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-benzimidazole;

(43) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-2-methyl-1H-benzimidazole;

(44) 2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-1H-benzimidazole;

(45) 1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl}-2-methyl-1H-benzimidazole;

(46) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidine;

(47) 1-{[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;

(48) 4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;

(49) 1-[(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]-4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidine;

(50) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)imidazolidin-2-one;

(51) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl)-2-oxoethyl)-1H-imidazol-2-yl]metanol;

(52) [1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-benzimidazol-2-yl]metanol;

(53) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[2-(trifluoromethyl)-1H-imidazol-1-yl]acetyl}piperidine;

(54) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-{[2-methyl-1H-imidazol-1-yl]acetyl}piperidine;

(55) 4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]-1-(1H-imidazol-1-ylacetyl)piperidine;

(56) [1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-5-methyl-1H-pyrazol-3-yl]acetic acid;

(57) Potassium (1-{2-[4-(2-{3-tert-butyl-5-[(trifluoromethyl)thio]phenyl}-1,3-thiazol-4-yl)piperidin-1-yl]-2-oxoethyl)-5-methyl-1H-pyrazol-3-yl)acetate;

(58) 4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]-1-[(2,4-dimethyl-1H-imidazol-1-yl)acetyl]piperidine;

(59) 1-(2-{4-[2-(3,5-di-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(60) 3-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-3H-imidazo[4,5-b]pyridine;

(61) 4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}-1-[(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetyl]piperidine;

(62) 3-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-3H-imidazo[4,5-c]pyridine;

(63) 1-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-1H-imidazo[4,5-c]pyridine;

(64) 1-[2-(4-{2-[3,5-bis(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}piperidin-1-yl)-2-oxoethyl]-2-methyl-1H-imidazo[4,5-c]pyridine;

(65) 1-(2-{4-[2-(3,5-di-tert-butyl-4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1H-imidazole-2-carboxylic acid dihydrochloride;

(66) 1-ethyl-3-{2-oxo-2-{4-(2-phenyl-1,3-thiazol-4-yl)piperidin-1-yl]ethyl}-1,3-dihydro-2H-imidazol-2-one;

(67) 1-ethyl-3-(2-{4-[2-(4-methoxyphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-1,3-dihydro-2H-imidazol-2-one;

(68) 1-(2-{4-[2-(4-tert-butylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(69) 1-(2-{4-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(70) 1-(2-{4-[2-(4-bromophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(71) 1-(2-{4-[2-(4-trifluoromethylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(72) 1-(2-{4-[2-(3-chlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(73) 1-(2-{4-[2-(3-bromophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(74) 1-(2-{4-[2-(3-trifluoromethylphenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one;

(75) 1-(2-{4-[2-(3,5-dichlorophenyl)-1,3-thiazol-4-yl]piperidin-1-yl}-2-oxoethyl)-3-ethyl-1,3-dihydro-2H-imidazol-2-one; and

(76) 1-ethyl-3-{2-oxo-2-[4-(2-pyridin-4-yl-1,3-thiazol-4-yl)piperidin-1-yl]ethyl}-1,3-dihydro-2H-imidazol-2-one.

15 . A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

16 . A method for treating a disease or condition mediated by the CXCR3 chemokine receptor comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 .

17 . The method according to claim 16 wherein the disease or condition is selected from the group consisting of: acute and chronic transplant rejection, psoriasis, rheumatoid arthritis and multiple sclerosis.