2-aminothiazole-4-carboxylic amides as protein kinase inhibitors

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein the dashed line indicates an optional and additional bond and wherein:

R 1 is

and G is —H halo or alkoxy;

R 2 is H, alkyl, aryl, heteroaryl, —C(O)-alkyl or —C(O)-aryl, wherein the aryl, heteroaryl or aryl moiety or a —C(O)-aryl group can be substituted with up to 3 substituents, which may be the same or different, and are independently selected from halo, alkyl, —C(O)OH, and —O-alkyl;

each occurrence of R 3 is independently H, alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)—R 9 (alkylene) m -N(R 9 ) 2 , or R 3 and the ring carbon atom to which it is attached, combine to form a carbonyl group;

R 4 is H alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)—R 9 (alkylene) m -N(R 9 ) 2 , or R 3 and R 3a , together with the common carbon atom to which each are attached, join to form a carbonyl, cycloalkyl or heterocycyl group;

R 4a is H alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)—R 9 (alkylene) m -N(R 9 ) 2 ;

each occurrence of R 5 is independently H alkyl (alkylene) m -aryl (alkylene) m -heteroaryl (alkylene) m -heterocyclyl (alkylene) m -N(R 9 ) 2 (alkylene) m -OH (alkylene) m -NHC(O)R 9 , hydroxyalkyl, haloalkyl, —C(O)R 6 , —C(O)OR 9 , —C(O)-(alkylene) m -N(R 9 ) 2 (alkylene) m -NHC(O)R 7 , —NHC(O)OR 9 or —NHS(O) 2 R 7 ;

R 6 is H, alkyl, aryl, heteroaryl or —NHOH;

R 7 is H, alkyl or haloalkyl;

R 8 is H, —OH, alkyl, —O-alkyl, or haloalkyl;

R 9 is H, alkyl, aryl, heterocyclyl, heteroaryl or cycloalkyl;

R 10 is H alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)R 9 (alkylene) m -N(R 9 ) 2 , or R 10 and R 10a , together with the common carbon atom to which each are attached, join to form a carbonyl, cycloalkyl or heterocycyl group;

R 10a is H, alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)—R 9 (alkylene) m -N(R 9 ) 2 ;

each occurrence of R 11 is independently H, alkyl, haloalkyl, hydroxyalkyl (alkylene) m -C(O)N(R 8 ) 2 (alkylene) m -NHC(O)—R 9 (alkylene) m -N(R 9 ) 2 , or R 11 and the ring carbon atom to which it is attached, combine to form a carbonyl group;

each occurrence of R 12 is independently H (alkylene) m -aryl (alkylene) m -heteroaryl (alkylene) m -heterocyclyl, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 -heteroaryl, hydroxyalkyl, —C(O)R 9 or —C(O)OR 9 ;

Ar is arylene or heteroarylene, wherein the arylene or heteroarylene is joined via any 2 of its adjacent ring carbon atoms, and wherein the arylene or heteroarylene group can be optionally substituted with up to 4 substituents, which may be the same or different, and are independently selected from halo, alkyl, alkoxy, aryloxy, —NH 2 , —NH-alkyl, —N(alkyl) 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 , —C(O)OR 8 , —C(O)N(R 8 ) 2 , —NHC(O)R 8 , haloalkyl, —CN and NO 2 , such that when Ar is tetrahydronaphthylene, R 3 and R 4 are each other than hydrogen;

W is —N(R 12 ) 2 —, —S—, —O— or —C(R 5 ) 2 —, wherein both R 5 groups and the common carbon atom to which they are attached can combine to form a cycloalkyl or heterocyclyl group;

Y is H, halo, alkyl or —CN;

Z is —C(R 8 )— or —N—, such that when the optional additional bond is present, Z is —C(R 8 )—;

each occurrence of m is independently 0 or 1;

n is an integer ranging from 0 to 2; and

p is 0 or 1.

2. The compound of claim 1 , wherein R 2 is —H or alkyl.

3. The compound of claim 1 , wherein n is 1.

4. The compound of claim 3 , wherein R 3 and R 3a are each —H, and Z is —N—.

5. The compound of claim 4 , wherein W is NH.

6. The compound of claim 4 , wherein W is —CH(NH 2 )—, —C(R 4 )(NH 2 )— or

—CH(OH)—.

7. The compound of claim 1 , wherein Ar is:

8. The compound of claim 1 , wherein Ar is

9. The compound of claim 1 , wherein Z is —N—, Ar is phenyl, and R 3 is H.

10. The compound of claim 1 , wherein Z is —N—, Ar is pyridyl, and R 3 is H.

11. The compound of claim 1 , wherein the group

12. A compound having the formula:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein

R 1 aryl arylalkyl benzofused cycloalkyl heteroaryl benzofused heteroaryl benzofused heterocyclenyl; and

R 2 is —H alkyl.

13. A compound having the formula:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein W is —N(R 12 ) 2 —, —S—, —O— or —C(R 5 ) 2 —, and wherein each occurrence of R 12 is independently H (alkylene) m -aryl (alkylene) m -heteroaryl (alkylene) m -heterocyclyl, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 -heteroaryl, hydroxyalkyl, —C(O)R 9 or —C(O)OR 9 ; both R 5 groups and the common carbon atom to which they are attached can combine to form a cycloalkyl or heterocyclyl group; Q 1 , Q 2 and Q 3 are each independently H, alkyl, heteroaryl or —C(O)OH; n is an integer ranging from 0 to 2; and each of X a and X b is independently CH or N.

14. The compound of claim 13 , wherein X b is CH, W is NH, Q 1 is COOH and n is 1.

15. A compound having the formula:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 6 is alkyl or aryl, wherein the aryl group can be substituted with up to 3 substituents, which may be the same or different, and are independently selected halo alkyl, —C(O)OH, alkoxy; R 1 is H, alkyl, alkenyl, alkynyl (alkylene) m -aryl (alkylene) m -cycloalkyl (alkylene) m -heteroaryl (alkylene) m -heterocyclyl (alkylene) m -heterocyclenyl, wherein any aryl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclenyl group can be optionally and independently substituted on a ring carbon or ring nitrogen atom with up to 3 substituents selected from halo, alkyl, —O-alkyl (alkylene) m -NR( 9 ) 2 , —C(O)OR 7 , —CN, —OH (alkylene) m -heteroaryl (alkylene) m -aryl; and wherein any aryl or heteroaryl substituent group can be substituted with up to 5 substituents, which may be the same or different, and are selected halo, —OH, alkyl, —C(O)OH, —C(O)O-alkyl, —N(R 9 ) 2 , and —O-alkyl; and wherein any aryl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclenyl group can be optionally fused to an aryl, cycloalkyl, heteroaryl, heterocyclyl or heterocyclenyl group; and W is —N(R 12 ) 2 —, —S—, —O— or —C(R 5 ) 2 —, wherein both R 5 groups and the common carbon atom to which they are attached can combine to form a cycloalkyl or heterocyclyl group.

16. A compound having the formula:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof, wherein R 2 is —H alkyl.

17. A compound having the structure:

or a pharmaceutically acceptable salt, ester or stereoisomer thereof.