Imidazothiazoles and imidazoxazoles

1. A compound of formula (I)

pharmaceutically acceptable salts thereof, or pro-drugs thereof, wherein

X is O or S;

A is C or N;

D is O, N or NR b ;

E is N or CR a ;

G is N, NR b or CR c ;

Z is selected from the optionally substituted group consisting of phenyl, naphthyl, azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl or tropanyl;

R for each occurrence is independently H, F, Cl, or (C 1 -C 4 )alkyl;

R a is selected from the group consisting of H, NR 2 R 3 , pyridinyl and (C 1 -C 6 )alkyl;

R b is selected from the group consisting of H, —S(O) 2 —(C 1 -C 4 )alkyl, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 1 -C 6 )alkyl-R 1 , optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R c is H or R c is selected from the group consisting of, NR 2 R 3 , optionally substituted —C(O)—NH—(C 1 -C 4 )alkyl, —CO 2 —(C 1 -C 3 )alkyl, —(C 3 -C 4 )alkylamino, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 6 )cycloalkenyl, —(C 1 -C 6 )alkyl-R 1 , optionally substituted phenyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

wherein R c is optionally substituted by one or more substituents selected from the group consisting of CF 3 , CN, halo, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy, —C(O)—NH-optionally substituted (C 1 -C 3 )alkyl, —C(O)—NH-optionally substituted (C 1 -C 6 )alkyl-optionally substituted amino, —C(O)—OCH 3 , —NH—C(O)-optionally substituted (C 1 -C 3 )alkyl, OH, COOH, NR 2 R 3 , —C(O)—NH-optionally substituted (C 1 -C 5 )alkyl; —C(O)—NH-optionally substituted (C 3 -C 6 )cycloalkyl, —C(O)—NH-optionally substituted (C 1 -C 6 )alkyl-optionally substituted (C 3 -C 6 )cycloalkyl, —NH—C(O)—O-optionally substituted (C 1 -C 4 )alkyl, NH 2 , N(H)CH 3 , N(CH 3 ) 2 and —O—C(O)-optionally substituted (C 1 -C 3 )alkyl;

R 1 is selected from the optionally substituted group consisting of amino, phenyl, heteroaryl, heterocyclyl and (C 3 -C 6 )cycloalkyl;

R 2 and R 3 are independently selected from H and optionally substituted (C 1 -C 4 )alkyl;

R 4 is H, halo, CN, SO 2 , CONH—(C 1 -C 6 )alkyl, —CO—N(CH 3 ) 2 , —CO—N(H)-optionally substituted (C 1 -C 6 )alkyl, —CO—N(H)-optionally substituted (C 1 -C 6 )alkyl-NR 2 R 3 , —NHCO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkyl, CO—(C 1 -C 6 )alkyl, CO 2 —(C 1 -C 3 )alkyl or optionally substituted (C 1 -C 6 ) alkyl; and

n is 1, 2 or 3;

provided that the compound is not

1-methyl-6-[6-(6-methyl-pyridin-2-yl)]-imidazo[2,1-b]thiazol-5-yl-1H-benzotriazole;

2-methyl-5-[6-(6-methyl-pyridin-2-yl)]-imidazo[2,1-b]thiazol-5-yl-1H-benzotriazole;

2-methyl-5-[3-methyl-6-(6-methyl-pyridin-2-yl)]-imidazo[2,1-b]thiazol-5-yl-1H-benzotriazole; or

2-methyl-5-[2-methyl-6-(6-methyl-pyridin-2-yl)]-imidazo[2,1-b]thiazol-5-yl-1H-benzotriazole.

2. The compound of claim 1 wherein

X is O or S;

A is C or N;

D is N or NR b ;

E is N or CR a ;

G is N, NR b or CR c ;

Z is selected from the optionally substituted group consisting of phenyl, naphthyl, azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl or tropanyl;

R for each occurrence is independently selected from the group consisting of H, F, Cl, or (C 1 -C 4 )alkyl;

R a is selected from the group consisting of H, NR 2 R 3 , pyridinyl and (C 1 -C 6 )alkyl;

R b is selected from the group consisting of H, —S(O) 2 —(C 1 -C 4 )alkyl, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 1 -C 6 )alkyl-R 1 , optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R c is selected from the group consisting of H, NR 2 R 3 , optionally substituted —C(O)—NH—(C 1 -C 4 )alkyl, —CO 2 —(C 1 -C 3 )alkyl, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, —(C 1 -C 6 )alkyl-R 1 , optionally substituted phenyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R 1 is selected from the optionally substituted group consisting of amino, phenyl, heteroaryl, heterocyclyl and (C 3 -C 6 )cycloalkyl;

R 2 and R 3 are independently selected from H and (C 1 -C 4 )alkyl;

R 4 is H, halo, CN, SO 2 NH 2 , CONH—(C 1 -C 6 )alkyl, NHCO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkyl, CO—(C 1 -C 6 )alkyl, CO 2 —(C 1 -C 3 )alkyl or optionally substituted (C 1 -C 6 ) alkyl; and

n is 1, 2 or 3.

3. The compound of claim 2 wherein Z is optionally substituted phenyl.

4. The compound of claim 3 wherein D is N.

5. The compound of claim 4 wherein E is N.

6. The compound of claim 5 wherein A is N.

7. The compound of claim 6 wherein

G is CR c ; and

R c is NH 2 or is selected from the optionally substituted group consisting of —C(O)—NH—(C 1 -C 4 )alkyl, phenyl, heteroaryl, heterocyclyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, —(C 3 -C 4 )alkylamino and —CO 2 —(C 1 -C 4 )alkyl.

8. The compound of claim 7 wherein Z is phenyl substituted with one or more substituents each independently selected from CF 3 and halogen.

9. The compound of claim 8 wherein Z is phenyl substituted with one or more F;

R c is selected from the optionally substituted group consisting of phenyl, imidazolyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl and heterocyclyl;

n is 1; and

R is H.

10. The compound of claim 9 wherein X is O and R c is selected from the optionally substituted group consisting of phenyl, (C 1 -C 4 )alkyl and (C 3 -C 4 )cycloalkyl.

11. The compound of claim 10 wherein R c is optionally substituted by one or more substituents selected from the group consisting of CF 3 , CN, halo, optionally substituted (C 1 -C 3 )alkyl, optionally substituted (C 1 -C 3 )alkoxy, —C(O)—NH-optionally substituted (C 1 -C 3 )alkyl, —C(O)—NH-optionally substituted (C 1 -C 6 )alkyl-optionally substituted amino, —C(O)—OCH 3 and —NH—C(O)-optionally substituted (C 1 -C 3 )alkyl.

12. The compound of claim 11 wherein the compound is

13. The compound of claim 5 wherein A is C.

14. The compound of claim 13 wherein

G is NR b ; and

R b is H or is selected from the optionally substituted group consisting of phenyl, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl and (C 1 -C 6 )alkyl-R 1 .

15. The compound of claim 14 wherein R 1 is (C 3 -C 6 )cycloalkyl or phenyl.

16. The compound of claim 15 wherein Z is phenyl substituted with one or more F;

R b is selected from the optionally substituted group consisting of phenyl, (C 1 -C 6 )alkyl, —CH 2 -cyclopropyl;

X is O;

n is 1; and

R is H.

17. The compound of claim 16 wherein the compound is

18. The compound of claim 3 wherein E is CR a .

19. The compound of claim 18 wherein G is NR b .

20. The compound of claim 19 wherein

R a is NH 2 , (C 1 -C 4 )alkyl, heteroaryl or —NH—S(O) 2 -phenyl;

R b is H or a bond or is selected from the optionally substituted group consisting of (C 1 -C 5 )alkyl, —(C 1 -C 5 )alkyl-R 1 , (C 3 -C 6 )cycloalkyl and aryl; and

A is C.

21. The compound of claim 20 wherein

R a is NH 2 , CH 3 , pyridinyl or —NH—S(O) 2 -phenyl;

R b is a bond or is selected from the optionally substituted group consisting of (C 1 -C 5 )alkyl, —CH 2 -azetidinyl, —CH 2 -cyclohexyl, —CH 2 -cyclopropyl, —CH 2 -pyridinyl, —CH 2 -tetrahydropyranyl, —CH 2 -pyrrolidinyl, —CH 2 -pyrrolyl, benzyl, cyclopropyl, cyclohexyl, and phenyl;

R is H;

n is 1; and

Z is phenyl substituted with F.

22. The compound of claim 21 wherein the compound is

23. The compound of claim 3 wherein D is O, E is N, A is C and G is CR c ;

R c is NH 2 or R c is selected from the optionally substituted group consisting of —C(O)—NH—(C 1 -C 4 )alkyl, phenyl, heteroaryl, heterocyclyl, (C 1 -C 4 )alkyl, (C 3 -C 4 )cycloalkyl, —(C 3 -C 4 )alkylamino and —CO 2 —(C 1 -C 4 )alkyl;

n is 1;

R is H; and

Z is phenyl substituted with one or more F.

24. A method of treating a condition in a patient comprising administering a therapeutically effective amount of a compound of claim 1 or a physiologically acceptable salt thereof to a patient, wherein said condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease, psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn's disease, lupus, multiple sclerosis, juvenile chronic arthritis, Lyme arthritis, reactive arthritis, septic arthritis, systemic onset juvenile rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatoid arthritis associated interstitial lung disease, ankylosing spondylitis associated lung disease, gouty arthritis, psoriasis type 1, psoriasis type 2, rheumatoid spondylitis, polymyalgia rheumatica, polyarticular JRA, septic arthritis, and spondylitis ankylosans.

25. A pharmaceutical composition comprising a compound of Formula (I)

and a pharmaceutically acceptable carrier or excipient, wherein

X is O or S;

A is C or N;

D is O, N or NR b ;

E is N or CR a ;

G is N, NR b or CR c ;

Z is selected from the optionally substituted group consisting of phenyl, naphthyl azaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl or tropanyl;

R for each occurrence is independently H, F, Cl, or (C 1 -C 4 )alkyl;

R a is selected from the group consisting of H, NR 2 R 3 , pyridinyl and (C 1 -C 6 )alkyl;

R b is selected from the group consisting of H, —S(O) 2 —(C 1 -C 4 )alkyl, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 1 -C 6 )alkyl-R 1 , optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R c is selected from the group consisting of H, NR 2 R 3 , optionally substituted —C(O)—NH—(C 1 -C 4 )alkyl, —CO 2 —(C 1 -C 3 )alkyl, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted (C 3 -C 6 )cycloalkenyl, —(C 1 -C 6 )alkyl-R 1 , optionally substituted phenyl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R 1 is selected from the optionally substituted group consisting of amino, phenyl, heteroaryl, heterocyclyl and (C 3 -C 6 )cycloalkyl;

R 2 and R 3 are independently selected from H and (C 1 -C 4 )alkyl;

R 4 is H, halo, CN, SO 2 , CONH—(C 1 -C 6 )alkyl, —CO—N(CH 3 ) 2 , —CO—N(H)-optionally substituted (C 1 -C 6 )alkyl, —CO—N(H)-optionally substituted (C 1 -C 6 )alkyl-NR 2 R 3 , —NHCO—(C 1 -C 6 )alkyl, SO 2 —(C 1 -C 6 )alkyl, CO—(C 1 -C 6 )alkyl, CO 2 —(C 1 -C 3 )alkyl or optionally substituted (C 1 -C 6 ) alkyl; and

n is 1, 2 or 3.