Fused bicyclic RAF inhibitors and methods for use thereof

1. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

ring A is an imidazole, a pyrazole, or a triazole;

one of R 1 or R 2 is a substituted C 1-8 alkyl, an unsubstituted C 5-8 alkyl, a substituted or unsubstituted C 1-8 haloalkyl, a substituted monocyclic aryl, substituted monocyclic heteroaryl, unsubstituted tetrahydropyran, substituted indazole, or substituted benzoimidazole, and the other R 1 or R 2 is H;

or alternatively, R 1 and R 2 together with the atoms to which they are attached forms a 5- or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the ring is substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —C(O)CH 3 , —CN, —OH, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —CH 2 NH 2 , —CH 2 NH(C 1-3 alkyl), or —CH 2 N(C 1-3 alkyl) 2 ; and

wherein when ring A is an imidazole, then the substituted monocyclic aryl of R 1 or R 2 is not

2. The compound of claim 1 , wherein

ring A is

3. The compound of claim 1 having the structure of formula (I-A) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein:

one of R 1 or R 2 is a substituted or unsubstituted C 5-8 alkyl, a substituted or unsubstituted C 1-8 haloalkyl, a substituted monocyclic aryl, substituted monocyclic heteroaryl, unsubstituted tetrahydropyran, substituted indazole, or substituted benzoimidazole, and the other R 1 or R 2 is H;

or alternatively, R 1 and R 2 together with the atoms to which they are attached forms a 5- or 6-membered saturated, partially unsaturated, or unsaturated ring containing 0, 1, or 2 heteroatoms selected from N, O, or S, wherein the ring is substituted with 1 or 2 substituents selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —C(O)CH 3 , —CN, —OH, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —CH 2 NH 2 , —CH 2 NH(C 1-3 alkyl), or —CH 2 N(C 1-3 alkyl) 2 ; and

wherein the substituted monocyclic aryl of R 1 or R 2 is not

4. The compound of claim 1 , wherein R 1 and R 2 together with the atoms to which they are attached forms a substituted phenyl ring, a substituted pyridyl ring, or a substituted tetrahydropyridyl ring.

5. The compound of claim 1 , wherein the compound has the structure of formula (I-B), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,

wherein R 1 is a substituted monocyclic aryl, a substituted monocyclic heteroaryl, unsubstituted tetrahydropyran, substituted indazole, or substituted benzoimidazole; and

wherein the substituted monocyclic aryl is not

6. The compound of claim 1 , wherein R 1 is a substituted monocyclic aryl, substituted monocyclic heteroaryl, substituted indazole, or substituted benzoimidazole.

7. The compound of claim 6 , wherein:

a) R 1 is a substituted phenyl or a substituted 5- or 6-membered N-heteroaryl;

b) R 1 is a substituted phenyl, a substituted pyridyl, a substituted pyrazole, a substituted pyrimidinyl, or a substituted thiophenyl;

c) R 1 is a monocyclic substituted aryl or a monocyclic substituted heteroaryl;

d) R 1 is a substituted monocyclic aryl; or

e) R 1 is a substituted indazole or a substituted benzoimidazole.

8. The compound of claim 5 , wherein R 1 is an unsubstituted tetrahydropyran.

9. The compound of claim 1 , wherein the substituent of the substituted monocyclic aryl, the substituted monocyclic heteroaryl, the substituted indazole, and the substituted benzoimidazole is selected from halogen, methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, t-butyl, cyclopropyl, methoxy, ethoxy, isopropoxy, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —C(O)CH 3 , —CN, —OH, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 , —CH 2 NH 2 , —CH 2 NH(C 1-3 alkyl), or —CH 2 N(C 1-3 alkyl) 2 .

10. The compound of claim 1 , wherein the compound has (R) or (S) stereochemistry at the carbon indicated by *.

11. A compound having the structure

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient or carrier.

13. The pharmaceutical composition of claim 12 , further comprising an additional therapeutic agent.

14. The pharmaceutical composition of claim 13 , wherein the additional therapeutic agent is an antiproliferative or an antineoplastic drug, a cytostatic agent, an anti-invasion agent, an inhibitor of growth factor function, an antiangiogenic agent, a steroid, a targeted therapy agent, or an immunotherapeutic agent.

15. A method of treating cancer, comprising administering an effective amount of the compound of claim 1 to a subject in need thereof, wherein the cancer is colorectal cancer or melanoma.

16. The method of claim 15 , wherein the cancer comprises a BRAF V600E mutation.

17. The method of claim 16 , wherein the cancer is BRAF V600E melanoma or BRAF V600E colorectal cancer.