RAF inhibitor compounds

1. A compound of the formula:

wherein:

Ri is hydrogen, Ci-C 4 alkyl, or halo;

R 2 is Ci-C 4 alkyl or hydrogen;

R 3 is Ci-C 4 alkyl, hydrogen, —C(O)R 8 , oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and wherein the C 1 -C 4 alkyl is optionally substituted with hydroxyl, C 1 -C 2 alkoxy, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, N-azetidinyl, N-piperazinyl, C5-C 6 heteroaryl, N-morpholino, N-piperidinyl, N-pyrrolidinyl, or (C 1 -C 4 alkyl) n amino- wherein n is 0, 1, or 2; and wherein each of the rings as substituents on a C 1 -C 4 alkyl are further optionally substituted with one to three of the same or different C 1 -C 4 alkyl, fluoro, C1-C4 alkoxy, —C(0)Rg, or (C1-C4 alkyl) m amino, where m is 0, 1 or 2;

Rt is R5-(CH 2 )—, or C 4 -C 6 cycloalkyl optionally substituted with one or two of the same or different methyl, ethyl, or fluoro;

Rs is —CHR 6 R7 or C3-C 6 cycloalkyl optionally substituted with one or two of the same or different C 1 -C 2 alkyl;

R6 is hydrogen or hydroxyl, or C 1 -C 4 alkoxy;

R 7 is isopropyl, t-butyl, 1-fluoro-1-methyl-ethyl, 1-cyano-1-methyl-ethyl, 1-(Ci-C 4 alkoxy)-1-methyl-ethyl, 1-(Ci-C 4 alkyl)-cycloprop-1-yl, 1-(fluoro(Ci-C 2 alkyl)cycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl where fluoro(Ci-C 2 alkyl) has one to five fluoro substituents;

Rs is hydrogen, Ci-C 6 linear or branched alkyl, or (Ci-C 4 ) p amino where p is 0, 1, or 2, and each alkyl is optionally substituted with the same or different Ci-C 4 alkoxy, hydroxyl, or (Ci-C 4 alkyl) q amino and q is 0, 1, or 2;

provided that the following substituents as a group are not simultaneously allowed:

Ri is methyl;

R 2 is methyl;

R 3 is methyl;

R, is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein:

Ri is hydrogen, methyl, fluoro or bromo;

R 2 is hydrogen or methyl;

R3 is hydrogen, methyl, ethyl, acetyl, 2-methoxy ethyl, 2-hydroxy ethyl, oxetan-3-yl, 2-dimethylaminoethyl, N-morpholinoethyl, (1-methylimidazol-4-yl)methyl;

R4 is R 5 —(CH 2 )—, or 3,3-dimethylcyclobutyl;

R 5 is —CHR 6 R 7 , or 2,2-dimethylcycloprop-1-yl);

Re is hydrogen or hydroxyl;

R 7 is t-butyl, 1-fluoro-1-methyl-ethyl, 1-cyano-1-methyl-ethyl, 1-methoxy-1-methyl-ethyl, 1-methylcycloprop-1-yl, 1-trifluoromethylcycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein:

Ri is hydrogen, methyl or fluoro;

R 2 is hydrogen or methyl;

R 3 is hydrogen, methyl, acetyl, 2-hydroxyethyl, or N-morpholinoethyl;

R 4 is R 5 —(CH 2 )—, or 3,3-dimethylcyclobutyl;

R 5 is —CHR 6 R 7 ;

Re is hydrogen or hydroxyl;

R 7 is t-butyl, 1-cyano-1-methyl-ethyl, 1-methylcycloprop-1-yl, 1-trifluoromethylcycloprop-1-yl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl;

or a pharmaceutically acceptable salt thereof.

4. A compound of any one of claims 1 to 3 wherein:

Ri is hydrogen;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

5. A compound of any one of claims 1 to 3 wherein:

Ri is methyl;

R 2 is methyl;

R 3 is hydrogen;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

6. A compound of any one of claims 1 to 3 wherein:

Ri is fluoro;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

7. A compound of any one of claims 1 to 3 wherein: Ri is methyl;

R 2 is hydrogen;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

8. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is 1-cyano-1-methyl-ethyl;

or a pharmaceutically acceptable salt thereof.

9. A compound of any one of claims 1 to 3 wherein:

Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R3 is methyl;

R 4 is 3,3-dimethylcyclobutyl;

or a pharmaceutically acceptable salt thereof.

10. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is 1-methylcycloprop-1-yl;

or a pharmaceutically acceptable salt thereof.

11. A compound of any one of claims 1 to 3 wherein: Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is 1-trifluoromethylcycloprop-1-yl;

or a pharmaceutically acceptable salt thereof.

12. A compound of any one of claims 1 to 3 wherein:

Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R 3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is 2,2,2-trifluoro-1,1-dimethyl-ethyl;

or a pharmaceutically acceptable salt thereof.

13. A compound of any one of claims 1 to 3 wherein:

Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R 3 is 2-hydroxyethyl;

R4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydrogen;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

14. A compound of any one of claims 1 to 3 wherein:

Ri is hydrogen, methyl, or fluoro;

R 2 is methyl;

R3 is methyl;

R 4 is R 5 —(CH 2 )—;

R 5 is —CHR 6 R 7 ;

Re is hydroxyl;

R 7 is t-butyl;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

16. A method of treating a cancer which is thyroid cancer, ovarian cancer, melanoma, AML or colorectal cancer in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method of treating melanoma in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.