Inhibitors of RAS and methods of use thereof
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R″, Q, W, X, Y, Z, n 1 , n 2 and are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
1. A compound having one of the following structures (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Is), (It), (Iu), (Iv), (Iw), (Ix), (Iy), (Iz), (Iaa), (Ibb), (Icc), (Idd), (Tee), (Iff), (Igg), (Ihh), (Iii) or (Ijj):
or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
L is absent or a linker selected from the group consisting of —O—, —S—, —NR c —, —NR c C(═O)—, —NR c S(═O) 2 — and —S(═O) 2 —, wherein R c is H or C 1 -C 6 alkyl;
L 2 is a bond or alkylene;
Q is —C(═O)—, —C(═NR 7 )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R′ is H, C 1 -C 6 alkyl, —CONR a R b , —C 1 -C 6 alkylene-CONR a R b , C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 aminylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl or heteroaryl, wherein R a and R b are independently H or C 1 -C 6 alkyl;
R 1 is aryl, cycloalkyl, heterocyclyl or heteroaryl;
R 2a , R 2b and R 2c are independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocyclylalkyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form oxo, a carbocyclic ring or a heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form oxo, a carbocyclic ring or a heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
when is a double bond then R 5 and R 6 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 5 and R 6 join to form a carbocyclic, heterocyclic or heteroaryl ring;
when is a triple bond then R 5 is absent and R 6 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl; and
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl,
wherein each alkyl, alkylene, haloalkyl, hydroxylalkyl, aminylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, alkylamino, alkoxy, haloalkoxy; heterocyclylalkyl, alkynyl, alkenyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl and alkoxyalkyl, is independently optionally substituted with one or more substituents.
2. The compound of claim 1 , wherein R 1 is optionally substituted aryl.
3. The compound of claim 2 , wherein R 1 is optionally substituted phenyl or optionally substituted naphthyl.
4. The compound of claim 1 , wherein R 1 is optionally substituted heteroaryl.
5. The compound of claim 4 , wherein R 1 comprises nitrogen.
6. The compound of claim 4 , wherein R 1 is optionally substituted indazolyl, optionally substituted indolyl, optionally substituted benzimidazolyl, optionally substituted benzotriazolyl or optionally substituted quinolinyl.
7. The compound of claim 1 , wherein R 1 is optionally substituted heterocyclyl.
8. The compound of claim 7 , wherein R 1 is optionally substituted piperidinyl or optionally substituted pyrrolidinyl.
9. The compound of claim 1 , wherein R 1 is substituted with one or more substituents.
10. The compound of claim 9 , wherein R 1 is substituted with halo, amino, hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —OC(═O)R or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.
11. The compound of claim 9 , wherein R 1 is substituted with fluoro, chloro, amino, hydroxyl, cyano, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.
12. The compound of claim 1 , wherein R 1 has one of the following structures:
13. The compound of claim 1 , wherein R 2a is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2c are each H.
14. The compound of claim 1 , wherein, R 2b is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2a and R 2c are each H.
15. The compound of claim 1 , wherein, R 2c is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2b are each H.
16. The compound of claim 1 , wherein each R 3a , R 3b , R 4a and R 4b is H.
17. The compound of claim 1 , wherein at least one occurrence of R 3a , R 3b , R 4a or R 4b is C 1 -C 6 alkyl.
18. The compound of claim 17 , wherein C 1 -C 6 alkyl is methyl.
19. The compound of claim 1 , wherein Q is —C(═O)—.
20. The compound of claim 1 , wherein each of R 5 and R 6 are H.
21. The compound of claim 1 , wherein
has one of the following structures:
22. The compound of claim 1 , wherein
23. The compound of claim 1 , wherein L 2 is a bond.
24. The compound of claim 1 , wherein L is absent.
25. The compound of claim 1 , wherein L is —O—, —NH—, —NHC(═O)—, —NHS(═O) 2 — or —S(═O) 2 —.
26. The compound of claim 1 , having one of the following structures:
27. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
28. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.
29. The method of claim 28 , wherein the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.
30. The method of claim 28 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.
31. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.