Fused bicyclic RAF inhibitors and methods for use thereof
The present disclosure generally relates to improved synthesis of fused bicyclic Raf inhibitors of formula (I), (I-A), (I-B), (II), or (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. The disclosure also relates to method of using the compound of formula (I), (I-A), (I-B), (II), or (III), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, for treating diseases such as cancer, including colorectal cancer.
1. A compound of formula (II), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
X 1 and X 2 are each N or CH;
R 1 is a substituted C 1-8 alkyl, an unsubstituted C 5-8 alkyl, a substituted or unsubstituted C 1-8 haloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl; and
R 4 is —NR F C(O)R 5 , —NR F C(O)CH 2 R 5 , —NR F C(O)CH(CH 3 )R 5 , or —NR F R 5 ;
R 5 is a substituted or unsubstituted group selected from alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl; and
R F is H or C 1-3 alkyl.
2. The compound of claim 1 , wherein:
a) one of X 1 and X 2 is N; or
b) X 1 and X 2 are both CH.
3. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclyl, or a substituted or unsubstituted heteroaryl.
4. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyrimidinyl, or a substituted or unsubstituted thiophenyl.
5. The compound of claim 1 , wherein R 4 is —NHC(O)R 5 , —NHC(O)CH 2 R 5 , —NHC(O)CH(CH 3 )R 5 , or —NHR 5 .
6. The compound of claim 1 , wherein R 5 is a substituted or unsubstituted group selected from alkyl, 3-6 membered carbocyclyl, phenyl, 3-6 membered heterocyclyl, or 5-6 membered heteroaryl.
7. The compound of claim 1 , wherein R 5 is a substituted or unsubstituted group selected from methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyridine, thiazole, imidazole, pyrazole, or triazole.
8. The compound of claim 1 , wherein the substituent 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 .
9. The compound of claim 1 , wherein the compound has (R) or(S) stereochemistry at the carbon indicated by *.
10. The compound of claim 1 , wherein R 5 is substituted with one or more substituents selected from halogen, methyl, ethyl, propyl, isopropyl, —CN, —OH, or —NH 2 .
11. The compound of claim 1 , wherein the compound is selected from
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 at least one mutation of the BRAF kinase.
17. The method of claim 16 , wherein the cancer comprises a BRAF V600E mutation.
18. The method of claim 17 , wherein the cancer is BRAF V600E melanoma or BRAF V600E colorectal cancer.