Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer
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, isotopic form or prodrug thereof, wherein R 1 , L 1 , L 2 , L 3 , A 1 , A 2 , A 3 , A 4 , G 1 , G 2 , E, W, X, Y, Z, m, and n 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 the following structure (I):
or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
indicates an aromatic ring;
A 1 , A 2 , A 3 and A 4 are, at each occurrence, independently CR 4a R 4b or NR 5 ;
X, Y and Z are each, independently, N, CR 3a or NR 3b provided that at least one of at least one of X, Y and Z is N or NR 3b ;
W is CR 2 or N;
G 1 and G 2 are each independently CR′ or N, provided that G 1 is CR′ when at least one of A 1 and A 2 is NR 5 , and provided that G 2 is CR′ when at least one of A 3 and A 4 is NR 5 ;
L 1 is a bond or —NR 5 —;
L 2 is a bond or C 1 -C 6 alkylene;
L 3 is a bond, alkenylene, cycloalkylene, alkynylene, CR 4a R 4b , —S—, —O—, C(═O), —S(O) 2 —, —S(O)—, —C(═O)NR 5 —, —S(O) 2 NR 5 —, —NR 5 C(═O)NR 5 —, —NR 5 S(O) 2 NR 5 — or —NR 5 —;
R′ is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkylalkyl;
R 1 is aryl, cycloalkyl, heterocyclyl or heteroaryl;
R 2 is H, cyano, hydroxyl, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, aminylalkyl, alkylaminyl, aminylcarbonyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl or heteroaryl;
R 3a is H, cyano, amino, oxo, alkyl, cycloalkyl, haloalkyl, alkynyl, alkenyl, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, alkylsulfonylaminyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclylthioether, aminylalkyl, aminylalkynyl, aminylalkylaminyl, aminylalkoxy, alkylcarbonylaminyl, heterocyclyl, heterocyclylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkylaminyl, heterocyclylalkoxy, heterocyclylcarbonylaminyl, aryl, arylalkyl, arylalkylaminyl, arylalkoxy, arylalkylaminyl, arylcarbonylaminyl, heteroaryl, heteroarylaminyl, heteroaryloxy, heteroarylalkyl, heteroarylalkylaminyl, heteroarylalkoxy or heteroarylcarbonylaminyl;
R 3b is H, cyano, alkyl, cycloalkyl, haloalkyl, alkynyl, alkenyl, aminylcarbonyl, aminylsulfonyl, alkylcarbonyl, aminylalkylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aminylalkylsulfonyl, cycloalkylsulfonyl, heterocyclylsulfonyl, alkylthioether, aminylalkylthioether, cycloalkylthioether, heterocyclylthioether, aminylalkyl, aminylalkynyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, or R 4a and R 4b , when attached to the same carbon, join to form oxo or a carbocyclic or heterocyclic ring, or R 4a and R 4b , when attached to different carbons, join to form a carbocyclic or heterocyclic ring;
R 5 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 haloalkyl or C 3 -C 8 cycloalkylalkyl;
m is 2;
n is 1 or 2; and
E has the following structure:
wherein:
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl;
when is a double bond then R 9 and R 10 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl;
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl,
wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic and heteroaryl rings is optionally substituted with one or more substituents unless otherwise specified.
2. The compound of claim 1 , wherein the compound has one of the following structures (Ia), (Ib), (Ic) or (Id):
3. The compound of claim 1 , wherein the compound has one of the following structures (Ia1), (Ia2), (Ia3), (Ia4), (Ia5), (Ia6) or (Ia7):
4. The compound of claim 1 , wherein the compound has one of the following structures (Ib1), (Ib2), (Ib3), (Ib4), (Ib5), (Ib6) or (Ib7):
5. The compound of claim 1 , wherein the compound has one of the following structures (Ic1), (Ic2), (Ic3), (Ic4), (Ic5), (Ic6) or (Ic7):
6. The compound of claim 1 , wherein the compound has one of the following structures (Id1), (Id2), (Id3), (Id4), (Id5), (Id6) or (Id7):
7. The compound of claim 1 , 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.
8. The compound of claim 1 , wherein R 1 has one of the following structures:
9. The compound of claim 1 , wherein R 1 has one of the following structures:
10. The compound of claim 1 , wherein R 1 has one of the following structures:
11. The compound of claim 1 , wherein R 2 is H, cyano, hydroxyl, halo, C 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkyl, C 3 -C 8 cycloalkyl, aminylalkyl, alkylaminyl or aminylcarbonyl.
12. The compound of claim 1 , wherein R 2 has one of the following structures:
13. The compound of claim 12 , wherein R 2 is cyano.
14. The compound claim 1 , wherein at least one occurrence of R 3a is cyano, oxo, haloalkyl, aminylcarbonyl, aminylcarbonylalkoxy, aminylsulfonyl, heterocyclyl, heterocyclylcarbonyl, heterocyclylcarbonylalkoxy, aminylalkyl, aminylalkynyl, aminylalkylaminyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkoxy, heteroaryl, heteroarylalkoxy or heteroarylcarbonylaminyl.
15. The compound of claim 1 , wherein at least one occurrence of R 3a has one of the following structures:
16. The compound of claim 1 , wherein R 3b has one of the following structures:
17. The compound of claim 1 , wherein each R 4a and R 4b are H at each occurrence.
18. The compound of claim 1 , wherein at least one R 4a is C 1 -C 6 alkyl.
19. The compound of claim 1 , wherein at least one occurrence of R 4a and R 4b join to form oxo.
20. The compound of claim 1 , wherein Q is —C(═O)—.
21. The compound of claim 1 , wherein E has one of the following structures:
22. The compound of claim 1 , wherein L 1 is a bond.
23. The compound of claim 1 , wherein L 2 is a bond.
24. The compound of claim 1 , wherein L 3 has one of the following structures:
25. The compound of claim 1 , having one of the following structures:
26. A substantially purified atropisomer according to claim 1 .
27. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
28. A method for treatment of cancer mediated by a KRAS, HRAS, or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.
29. A method for inhibiting tumor metastasis mediated by a KRAS, HRAS, or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 27 to a subject in need thereof.