Benzene sulfonamide thiazole and oxazole compounds

1. A compound of formula (I)

wherein:

a is 0, 1, 2 or 3;

each R 1 is the same or different and is independently selected from halo, alkyl, haloalkyl, —OR 6 , —CO 2 R 6 , —NR 6 R 7 , and —CN;

Ring A is selected from C 3-6 cycloalkyl, phenyl, 5-6 membered heterocycle and 5-6 membered heteroaryl, said heterocycle and said heteroaryl each having 1 or 2 heteroatoms selected from N, O and S;

each of Q 1 , Q 2 , Q 3 and Q 4 is CH, C—R 2 or N, wherein not more than one of Q 1 , Q 2 , Q 3 , and Q 4 is N;

each R 2 is the same or different and is independently selected from halo, alkyl, haloalkyl, and —OR 6 ;

W is selected from —O— and —S—;

R 3 is selected from H, alkyl, haloalkyl-, -alkylene-OH, —NR 6 R 7 , —C 3-6 cycloalkyl, -alkylene-C(O)—OH, -alkylene-NH 2 , and Het;

wherein said R 3 C 3-6 cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, OH, O—C 1-3 alkyl, oxo, S(C 1-3 alkyl), SO 2 , NH 2 , N(H)C 1-3 alkyl and N(C 1-3 alkyl) 2 ;

Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1 or 2 substituents which are the same or different and are each independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, O—C 1-3 alkyl, C 1-3 alkylene-O—C 1-3 alkyl, OH, C 1-3 alkylene-OH, oxo, SO 2 (C 1-3 alkyl), C 1-3 alkylene-SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl, N(C 1-3 alkyl) 2 , CN, and —CH 2 CN;

R 4 is selected from H, alkyl, haloalkyl, alkenyl, —OR 6 , —R 5 —OR 6 , —R 5 —CO 2 R 6 , —R 5 —SO 2 R 6 , —R 5 —Het, —R 5 —C(O)—Het, —N(H)R 8 , —N(CH 3 )R 8 , and —R 5 —NR 6 R 7 ;

each R 5 is the same or different and is independently C 1-4 olkylene;

each R 6 and each R 7 is the same or different and is independently selected from H, alkyl, haloalkyl, —C(O)-alkyl, and —C(O)-cycloalkyl;

R 8 is selected from H, alkyl (optionally substituted by —OH), haloalkyl, C 3-6 cycloalkyl, —R 5 —C 3-6 cycloalkyl, Het 2 , —R 5 —Het 2 , —R 5 —OR 6 , —R 5 —O—R 5 —OR 6 , —R 5 —C(O) 2 R 6 , —R 5 —C(O)NR 6 R 7 , —R 5 —N(H)C(O)—R 6 , —R 5 —N(H)C(O)—R 5 —OR 6 , —R 5 —N(H)C(O) 2 —R 6 , —R 5 —NR 6 R 7 , —R 5 —S(O) 2 R 6 , —R 5 —CN, and —R 5 —N(H)S(O) 2 R 6 ;

wherein said R 8 C 3-6 cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, OH, O—C 1-3 alkyl, oxo, S(C 1-3 alkyl), SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl and N(C 1-3 alkyl) 2 , and N(H)SO 2 C 1-3 alkyl; and

Het 2 is a 4-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1, 2, 3, 4 or 5 C 1-3 alkyl or 1 or 2 substituents which are the same or different and are each independently selected from halo, C 1-3 alkyl, haloC 1-3 alkyl, O—C 1-3 alkyl,

C 1-3 alkylene-O—C 1-3 alkyl, OH, C 1-3 alkylene-OH, oxo, SO 2 (C 1-3 alkyl), C 1-3 alkylene-SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl, N(C 1-3 alkyl) 2 , N(H)SO 2 C 1-3 alkyl, C(O)(C 1-3 alkyl), CO 2 (C 1-4 alkyl), CN, and —CH 2 CN;

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein each R 1 is the same or different and is independently selected from halo, alkyl, haloalkyl, and —OR 6 .

3. The compound according to claim 1 , wherein Ring A is phenyl, 5-6 membered heterocycle or 5-6 membered heteroaryl.

4. The compound according to claim 1 , wherein each of Q 1 , Q 2 , Q 3 , and Q 4 is CH or C—R 2 , wherein at least two of Q 1 , Q 2 , Q 3 , and Q 4 are CH.

5. The compound according to claim 1 , wherein each R 2 is the same or different and is independently halo or C 1-3 alkyl.

6. The compound according to claim 1 wherein each of Q 1 , Q 2 , and Q 3 is CH and Q 4 is C—F or C—Cl.

7. A compound of formula (I):

wherein:

a is 0, 1, 2 or 3;

each R 1 is the same or different and is independently selected from halo, alkyl, haloalkyl, —OR 6 , —CO 2 R 6 , —NR 6 R 7 , and —CN;

Ring A is selected from C 3-6 cycloalkyl, phenyl, 5-6 membered heterocycle and 5-6 membered heteroaryl, said heterocycle and said heteroaryl each having 1 or 2 heteroatoms selected from N, O and S;

each of Q 1 , Q 2 , Q 3 and Q 4 is CH, C—R 2 or N, wherein not more than one of Q 1 , Q 2 , Q 3 , and Q 4 is N;

each R 2 is the same or different and is independently halo, alkyl, haloalkyl, or —OR 6 ;

W is —O— or —S—;

R 3 is H, alkyl, haloalkyl, alkylene-OH, NR 6 R 7 , C 3-6 cycloalkyl, or Het;

wherein said R 3 C 3-6 cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, OH, O—C 1-3 alkyl, oxo, S(C 1-3 alkyl), SO 2 , NH 2 , N(H)C 1-3 alkyl and N(C 1-3 alkyl) 2 ;

Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1 or 2 substituents which are the same or different and are each independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, O—C 1-3 alkyl, C 1-3 alkylene-O—C 1-3 alkyl, OH, C 1-3 alkylene-OH, oxo, SO 2 (C 1-3 alkyl), C 1-3 alkylene-SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl, N(C 1-3 alkyl) 2 , CN, and —CH 2 CN;

R 4 is H, alkyl, haloalkyl, alkenyl, —OR 6 , —R 5 —OR 6 , —R 5 —CO 2 R 6 , —R 5 —SO 2 R 6 , —R 5 —Het, —N(H)R 8 , —N(CH 3 )R 8 , or —R 5 —NR 6 R 7 ;

each R 5 is the same or different and is independently C 1-4 alkylene;

each R 6 and each R 7 is the same or different and is independently H, alkyl or haloalkyl; and

R 8 is selected from H, alkyl, haloalkyl, C 3-6 cycloalkyl, —R 5 —C 3-6 cycloalkyl, Het 2 , —R 5 —Het 2 ,

—R 5 —OR 6 , —R 5 —O—R 5 —OR 6 , —R 5 —C(O) 2 R 6 , —R 5 —C(O)NR 6 R 7 , —R 5 —N(H)C(O)—R 6 , —R 5 —N(H)C(O)—R 5 —OR 6 , —R 5 —N(H)C(O) 2 —R 6 , —R 5 —NR 6 R 7 , —R 5 —S(O) 2 R 6 , and —R 5 —N(H)S(O) 2 R 6 ;

wherein said R 8 C 3-6 cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo,

C 1-3 alkyl, haloC 1-3 alkyl, OH, O—C 1-3 alkyl, oxo, S(C 1-3 alkyl), SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl and N(C 1-3 alkyl) 2 , and N(H)SO 2 C 1-3 alkyl; and

Het 2 is a 4-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1, 2, 3, 4 or 5 C 1-3 alkyl or 1 or 2 substituents which are the same or different and are each independently selected from halo, C 1-3 alkyl, haloC 1-3 alkyl, O—C 1-3 alkyl,

C 1-3 alkylene-O—C 1-3 alkyl, OH, C 1-3 alkylene-OH, oxo, SO 2 (C 1-3 alkyl), C 1-3 alkylene-SO 2 (C 1-3 alkyl), NH 2 , N(H)C 1-3 alkyl, N(C 1-3 alkyl) 2 , N(H)SO 2 C 1-3 alkyl, C(O)(C 1-3 alkyl), CO 2 (C 1-4 -alkyl), CN, and —CH 2 CN;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 , wherein the compound of formula (I) is a compound of formula (I-iii-a):

wherein Q 4 is CH or C—R 2 .

9. The compound according to claim 7 , wherein the compound of formula (I) is a compound of formula (I-iii-b):

wherein Q 4 is CH or C—R 2 .

10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

11. A method for treating melanoma in a human in need thereof, said method comprising administering to the human a therapeutically effective amount of a compound according to claim 1 .

12. A process for preparing a compound according to claim 1 , said process comprising reacting a compound of formula (VIII):

wherein R 10 is halo or thiomethyl;

with one of:

i) molecular hydrogen

ii) an alkyl metal reagent or alkenyl metal reagent

iii) an alcohol, or

iv) a compound of formula (IX): N(R a )—R 8 , wherein R a is H or CH 3 , to prepare a compound of formula (I).

13. A process for preparing a compound according to claim 1 comprising reacting a compound of formula (XVIII):

with a compound of formula (VII):

to prepare a compound of formula (I).

14. The method according to claim 11 , wherein said melanoma is metastatic melanoma having a mutation encoding a V600E amino acid substitution.