Inhibitors of RAF kinases

1. A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

wherein,

R is selected from the group consisting of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C4-C8 cycloalkylalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C4-C8 heterocyclylalkyl, optionally substituted C6 aryl, optionally substituted 5- or 6-membered heteroaryl, and —CON(R 1 ) 2 ;

R 1 is selected from H or optionally substituted C1-C8 alkyl, wherein, optionally, two R 1 substituents join to form a ring;

X is H or F;

Z is selected from:

(a) —NR a R b , wherein R a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and R b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl;

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and

each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —S-alkyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups together form an oxo;

wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl); and

each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R 11 groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; n1 is 0, 1, or 2 provided both m1 and n1 are not both 0; p is 0, 1, or 2; and q is 0, 1 or 2;

W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl), CH 2 , CHR 11 , or C(R 11 ) 2 ; and

each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R 11 groups together form an oxo;

wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 1, or 2; p is 0, 1, 2, or 3; W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl), CH 2 , CHR 11 , —CH 2 —CH 2 —, —CH 2 —CHR 11 —, —CH 2 —C(R 11 ) 2 —, —CHR 11 —CH 2 —, —C(R 11 ) 2 —CH 2 —, —NH—CH 2 —, —NH—CHR 11 —, —NH—C(R 11 ) 2 —, —CH 2 —NH—, —CHR 11 —NH—, —C(R 11 ) 2 —NH—, —N(R 11 )—CH 2 —, —N(R 11 )—CHR 11 —, —N(R 11 )—C(R 11 ) 2 —, —CH 2 —N(R 11 )—, —CHR 11 —N(R 11 )—, —C(R 11 ) 2 —N(R 11 )—, —O—CH 2 —, or —CH 2 —O—; each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R 11 groups together form an oxo; and R 12 and R 13 are each independently selected from H, or optionally substituted C1-C6 alkyl;

or

wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl), CH 2 , CHR 11 , or C(R 11 ) 2 ; each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R 11 groups together form an oxo; and R 12 and R 13 are each independently selected from H, or optionally substituted C1-C6 alkyl;

wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —S-alkyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups together form an oxo;

wherein m is 1, 2, or 3; n is 1, 2, or 3; p is 0, 1, or 2; and

each R 13 or R 14 is independently selected from hydrogen, halogen, —CN, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R 11 is independently selected from —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or

wherein m is 0, 1, or 2; n is 0, 1, or 2; m1 is 0, 1, or 2; p is 0, 1, or 2; and q is 0, 1 or 2; W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl), CH 2 , CHR 11 , or C(R 11 ) 2 ; and each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two geminal R 11 groups together form an oxo.

2. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein Z is

wherein m is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and

each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —S-alkyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups together form an oxo.

3. The compound of claim 2 , or pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

4. The compound of claim 2 , or pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

5. The compound of claim 2 , or pharmaceutically acceptable salt or solvate thereof, wherein R 11 is optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl.

6. The compound of claim 5 , or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl is substituted with at least a halogen.

7. The compound of claim 5 , or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl is an optionally substituted C2 alkyl substituted with at least one halogen.

8. The compound of claim 7 , or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C2 alkyl is a 3,3,3-trifluoroethyl group.

9. The compound of claim 2 , or pharmaceutically acceptable salt or solvate thereof, wherein Z is 3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl.

10. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein Z is —NR a R b , wherein R a is selected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; and R b is selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl, or optionally substituted heterocyclylalkyl.

11. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein Z is

wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; W is O, S, S(O), SO 2 , NH or N (optionally substituted C1-C6 alkyl); and each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, or two R 11 groups together form an oxo.

12. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein Z is

wherein m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, or 4; and each R 11 is independently selected from amino, alkylamino, dialkylamino, —OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted —S-alkyl, optionally substituted —SO 2 alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or two R 11 groups together form an oxo.

13. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C1-C8 alkyl.

14. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C2-C8 alkenyl.

15. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C2-C8 alkynyl.

16. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C6 cycloalkyl.

17. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted C3-C6 heterocyclyl.

18. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted 5-membered heteroaryl.

19. The compound of claim 18 , or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 5-membered heteroaryl is an optionally substituted pyrazole, oxazole, or thiazole.

20. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is optionally substituted 6-membered heteroaryl.

21. The compound of claim 20 , or pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted 6-membered heteroaryl is an optionally substituted pyridine or pyrimidine.

22. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein R is —CON(R 1 ) 2 , and R 1 is selected from H or optionally substituted C1-C8 alkyl.

23. The compound of claim 12 , or pharmaceutically acceptable salt or solvate thereof, wherein n is 1; m is 1; p is 1; and R 11 is optionally substituted C1-C6 alkyl.

24. The compound of claim 23 , or pharmaceutically acceptable salt or solvate thereof, wherein R 11 is a —CF 3 group.

25. The compound of claim 23 , or pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted pyrazole.

26. The compound of claim 25 , or pharmaceutically acceptable salt or solvate thereof, wherein R is an optionally substituted pyrazol-4-yl, or optionally substituted pyrazol-5-yl.

27. The compound of claim 26 , or pharmaceutically acceptable salt or solvate thereof, wherein R is

or

28. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein X is F.

29. The compound of claim 1 , or pharmaceutically acceptable salt or solvate thereof, wherein X is H.

30. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt or solvate thereof, as described in claim 1 , and a pharmaceutically acceptable excipient.