Compounds and compositions as protein kinase inhibitors

1. A method to treat cancer mediated by Raf kinase, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a compound of Formula I:

wherein:

R1 is —X1NHC(O)OR1a, where X1 is a (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from (C1-C4)alkyl or halosubstituted(C1-C4)alkyl and R1a is (C1-C2)alkyl or halosubstituted(C1-C2)alkyl;

R1b is H or methyl;

R2 is H or F;

R3 is H, halogen, (C1-C2)alkoxy, (C1-C2)alkyl, halosubstituted(C1-C2)alkoxy, or halosubstituted(C1-C2)alkyl;

R4 is H or methyl;

R5 is (C1-C4)alkyl, (C3-C5)branched alkyl, halosubstituted(C1-C4)alkyl, or halosubstituted(C3-C6)branched alkyl;

R6 is H, (C1-C2)alkyl, or halogen; and

R7 is (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, or (C3-C6)branched alkyl;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein:

R1 is —X1NHC(O)OR1a, where X1 is (C1-C2)alkylene substituted with (C1-C2)alkyl and R1a is (C1-C2)alkyl;

R2 is H;

R3 is H, Cl, F, methoxy, methyl, or difluoromethoxy;

R4 is H;

R5 is methyl, ethyl, propyl, isopropyl, sec-butyl, isobutyl, trifluoromethyl, or 3,3,3-trifluoropropyl;

R6 is H, methyl, F, or Cl; and

R7 is t-butyl, cyclopropyl, or 1-methylcyclopropyl;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 , wherein R1 has the following formula (1a)

or a pharmaceutically acceptable salt thereof.

4. A method to treat cancer mediated by Raf kinase, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a compound of the formula:

wherein

R1 is

(i) (C1-C3)alkyl optionally substituted with cyano, —C(O)NH2, or hydroxy, or

(ii) —X1NHC(O)OR1a, where X1 is (C1-C4)alkylene optionally substituted with 1 to 3 groups each independently selected from halo, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl and R1a is H, (C1-C4)alkyl, or halosubstituted(C1-C4)alkyl;

R2 is H or halogen;

R3 is H, halogen, (C1-C4)alkoxy, (C1-C4)alkyl, halosubstituted(C1-C4)alkoxy, or halosubstituted(C1-C4)alkyl;

R4 is halogen, H, or (C1-C4)alkyl;

R5 is (C1-C6)alkyl, (C3-C8)branched alkyl, halosubstituted(C1-C6)alkyl, or halosubstituted(C3-C8)branched alkyl;

R6 is H, (C1-C4)alkyl, or halogen; and

R7 is H, (C1-C6)alkyl, (C3-C6)cycloalkyl, 1-methyl-(C3-C6)cycloalkyl, (C3-C8)branched alkyl, or phenyl, where said phenyl is optionally substituted with 1 to 3 substituents selected form halogen, (C1-C4)alkyl or halosubstituted(C1-C4)alkyl;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the compound is selected from the group consisting of:

(S)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(R)-Methyl 1-(4-(4-(2-chloro-5-fluoro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2,5-dichloro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(4-(2-chloro-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(2-cyclopropyl-4-(2-fluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

Methyl (2S)-1-(4-(2-cyclopropyl-4-(2,5-difluoro-3-(methylsulfonamido)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; and

(S)-Methyl 1-(4-(4-(2-chloro-5-methyl-3-(methylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 , wherein the compound is selected from the group consisting of:

(S)-Methyl 1-(4-(5-(5-chloro-3-(ethylsulfonamido)-2-fluorophenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(5-(5-chloro-2-fluoro-3-(3,3,3-trifluoropropylsulfonamido)phenyl)-2-cyclopropyl-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(4-(2-chloro-3-(ethylsulfonamido)-5-fluorophenyl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)-Methyl 1-(4-(5-(5-chloro-2-fluoro-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate; and

(S)-Methyl 1-(4-(5-(2-fluoro-5-methyl-3-(methylsulfonamido)phenyl)-2-(1-methylcyclopropyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , wherein R5 is (C1-C6)alkyl.

8. The method of claim 7 , wherein R5 is methyl.

9. The method of claim 1 , wherein said cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, and adenomas.

10. The method of claim 9 , further comprising administering to said subject an additional therapeutic agent.

11. The method of claim 10 , wherein said additional therapeutic agent is an anticancer drug, a pain medication, an antiemetic, an antidepressant, or an anti-inflammatory agent.

12. A method to treat a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

13. The method of claim 12 wherein the Raf kinase is a mutant b-Raf kinase.

14. The method of claim 13 , wherein said mutant b-Raf kinase is b-Raf(V600E).

15. The method of claim 14 , further comprising administering to said subject an additional therapeutic agent.

16. The method of claim 15 , wherein said additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK.