Compounds and compositions as protein kinase inhibitors

1. A compound of Formula I:

in which:

X 1 is selected from CH and N;

Y is selected from S and NR 5 ; wherein R 5 is selected from hydrogen and C 1-6 alkyl;

Z is selected from C and S(O);

R 1 is selected from hydrogen and C 1-6 alkyl;

R 2 is selected from C 6-12 aryl and —NR 3 R 4 ;

R 3 is selected from hydrogen and C 1-6 alkyl;

R 4 is —XR 5 ; wherein X is selected from a bond, C 1-6 alkylene and C 1-10 heterarylene; wherein R 5 is selected from C 6-10 aryl and C 1-10 heteroaryl;

wherein said aryl or heteroaryl of R 5 is optionally substituted with 1 to 3 radicals independently selected from C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 3-8 heterocycloalkyl, —C(O)NR 6 R 7 and —NR 6 C(O)R 7 ; wherein R 6 is selected from hydrogen and C 1-6 alkyl; and R 7 is selected from C 6-10 aryl and C 1-10 heteroaryl;

wherein said aryl or heteroaryl of R 7 is optionally substituted with 1 to 3 radicals independently selected from —R 8 and —OR 8 ; wherein R 8 is selected from C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 6-12 aryl, C 1-10 heteroaryl and C 3-8 heterocycloalkyl-C 0-4 alkyl; wherein said aryl, heteroaryl and heterocycloalkyl substituents of R 8 are optionally substituted with C 1-6 alkyl;

or R 3 and R 4 , together with the atoms to which R 3 and R 4 are attached, form C 3-8 heterocycloalkyl optionally substituted with —C(O)NR 6 R 9 ; wherein R 6 is selected from hydrogen and C 1-6 alkyl; and R 9 is selected from C 6-10 aryl and C 1-10 heteroaryl; and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 of Formula Ia:

in which:

X 1 is selected from CH and N;

Y is selected from S and NR 5 ; wherein R 5 is selected from hydrogen and C 1-6 alkyl;

n is selected from 0, 1 and 2;

R 1 is selected from hydrogen and C 1-6 alkyl; and

R 12 is selected from hydrogen, C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 3-8 heterocycloalkyl, —C(O)NR 6 R 7 and —NR 6 C(O)R 7 ; wherein R 6 is selected from hydrogen and C 1-6 alkyl; and R 7 is selected from C 6-10 aryl and C 1-10 heteroaryl;

wherein said aryl or heteroaryl of R 7 is optionally substituted with 1 to 3 radicals independently selected from —R 8 and —OR 8 ; wherein R 8 is selected from C 1-6 alkyl, halo-substituted-C 1-6 alkyl, C 6-12 aryl, C 1-10 heteroaryl and C 3-8 heterocycloalkyl-C 0-4 alkyl; wherein said aryl, heteroaryl and heterocycloalkyl substituents of R 8 are optionally substituted with C 1-6 alkyl.

3. The compound of claim 2 in which: X 1 is selected from CH and N; Y is selected from S and N(CH 3 ); and R 1 is hydrogen.

4. The compound of claim 3 in which R 12 is hydrogen, methyl, —C(O)NHR 7 , —NHC(O)R 7 , —N(CH 3 )C(O)R 7 and morpholino; wherein R 7 is selected from phenyl and isoxazolyl; wherein said phenyl or oxazolyl of R 7 is optionally substituted with 1 to 2 radicals selected from iso-butyl, trifluoromethyl, phenoxy, ethyl-piperazinyl-methyl, methyl-piperazinyl-methyl, methyl-imidazolyl and morpholino-methyl.

5. The compound of claim 1 selected from: 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 1-Methyl-1,6-dihydro-1,5,6-triaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid phenylamide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid 3-trifluoromethyl-benzylamide; Morpholin-4-yl-(6H-1-thia-5,6-diaza-as-indacen-2-yl)-methanone; 2-Benzenesulfonyl-1-methyl-1,6-dihydro-1,5,6-triaza-as-indacene; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [2-methyl-5-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {2-methyl-5-[methyl-(3-trifluoromethyl-benzoyl)-amino]-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {5-[4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-2-methyl-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [2-methyl-5-(3-morpholin-4-ylmethyl-5-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {2-methyl-5-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-benzoylamino]-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [5-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-2-methyl-phenyl]-amide; 4-(6H-1-Thia-5,6-diaza-as-indacene-2-carbonyl)-piperazine-1-carboxylic acid (4-phenoxy-phenyl)-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {1-[3-(3-trifluoromethyl-benzoylamino)-phenyl]-1H-imidazol-2-yl}-amide; 1-Methyl-1,6-dihydro-1,5,6-triaza-as-indacene-2-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 1-Methyl-1,6-dihydro-1,5,6-triaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 1-Methyl-1,6-dihydro-1,5,6-triaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6,7-triaza-as-indacene-2-carboxylic acid [3-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6,7-triaza-as-indacene-2-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6,7-triaza-as-indacene-2-carboxylic acid [2-methyl-5-(4-morpholin-4-ylmethyl-3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-methoxy-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-methoxy-5-(3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [3-methoxy-5-(4-morpholin-4-ylmethyl-3-trifluoromethyl-phenylcarbamoyl)-phenyl]-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {3-methoxy-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylcarbamoyl]-phenyl}-amide; 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid {3-[4-(4-ethyl-piperazin-1-yl)-3-trifluoromethyl-phenylcarbamoyl]-5-methoxy-phenyl}-amide; and 6H-1-Thia-5,6-diaza-as-indacene-2-carboxylic acid [2-methyl-5-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-phenyl]-amide.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient.

7. A method for the inhibition of kinase activity, which method comprises administering to an animal a compound of claim 1 .

8. The method of claim 7 in which the kinase is selected from Abl, Bcr-Abl, Aurora-A, SGK, Tie-2, Trk-B, FGFR3, c-kit, b-RAF, c-RAF, DYRK2, Fins, Fyn and PDGFRα and PDGFRβ.