2-substituted quinazoline compounds comprising a substituted heterocyclic group 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 R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , A, G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , n, X and E are as defined herein and, wherein at least one of R 3a , R 3b , R 4a or R 4b is not H. 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 or stereoisomer thereof, wherein:
A is N, CH or C—CN;
G 1 and G 2 are each independently N or CH;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, 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 or 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 or 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;
R 5a and R 5b are, at each occurrence, independently H, hydroxyl, halo or C 1 -C 6 alkyl, or R 5a and R 5b join to form oxo;
R 6 is amino, cyano, hydroxyl, alkyl, haloalkyl, hydroxylalkyl, alkoxy, aminylalkyl, C 1 -C 6 alkylphosphoryl, C 1 -C 6 alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyloxy or heteroarylalkylaminyl when X is a bond, —NR 7 — or —S—; or R 6 is amino, cyano, C 1 -C 6 alkyl, haloalkyl, hydroxylalkyl, alkoxy, —NR a R b , C 1 -C 6 alkylphosphoryl, C 1 -C 6 alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyloxy or heteroarylalkylaminyl when X is —O—, wherein R a is H or C 1 -C 6 alkyl, and R b is C 1 -C 6 alkyl, provided that R a is H or C 2 -C 6 alkyl, and R b is C 1 -C 6 alkyl when n is 2 and one of R 3a , R 3b , R 4a or R 4b is methyl;
R 7 is, at each occurrence, independently H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocycloalkyl;
m 1 and m 2 are each independently 1, 2 or 3;
n is an integer from 0 to 6;
X is a bond, —O—, —NR 7 — or —S—; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein,
wherein each occurrence of alkyl, alkynyl, alkenyl, alkylene, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkylaminyl, haloalkyl, alkoxy, alkoxyalkyl, haloalkoxy, cycloalkyl, heterocyclylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl, alkylphosphoryl, alkylphosphorylaminyl, and carbocyclic and heterocyclic rings is optionally substituted with one or more substituents unless otherwise specified, the optional substituents being selected from the group consisting of amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C 1 -C 12 alkyl, C 1 -C 6 alkylaminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 12 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, cyanoC 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxylalkyl, C 2 -C 6 alkenylcarbonylaminyl, C 1 -C 6 thioalkyl, aryl, aralkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, heteroarylalkyl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, or —OC(=O)R, or combinations thereof, wherein R is C 1 -C 6 alkyl; and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring, and
provided that at least one occurrence of R 3a , R 3b , R 4a or R 4b is not H.
2. The compound of claim 1 , wherein the compound has the following structure (I′a):
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, aminylalkyl, 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, or R 9 and R 10 join to form a carbocyclic, heterocyclic or heteroaryl ring; and
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, aminylalkyl, 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.
3. The compound of claim 2 , wherein the compound has one of the following structures (I′b), (I′c), (I′d) or (I′e):
4. The compound of claim 1 , wherein R 1 is aryl.
5. The compound of claim 4 , wherein R 1 is phenyl or naphthyl.
6. The compound of claims 4 , wherein R 1 is substituted with one or more substituents.
7. The compound of claim 6 , 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 or —OC(═O)R, or combinations thereof, wherein R is C 1 -C 6 alkyl.
8. The compound of claim 7 , wherein R 1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropyl, trifluoromethyl or methoxy, or combinations thereof.
9. The compound of claim 1 , wherein R 1 has one of the following structures:
10. The compound of claim 1 , wherein R 1 is heteroaryl.
11. The compound of claim 10 , wherein R 1 is substituted with cyano, nitro, —NH 2 , —(C═O)NH 2 , hydroxyl, hydroxylalkyl, halo or C 1 -C 6 alkyl, or combinations thereof.
12. The compound of claim 10 , wherein R 1 has one of the following structures:
13. The compound of claim 1 , wherein R 2c is H.
14. The compound of claim 1 , wherein R 2a and R 2b are each independently halo, haloalkyl, alkyl, or alkoxy.
15. The compound of claim 1 , wherein R 2a is fluoro, chloro or methoxy.
16. The compound of claim 1 , wherein R 2b is chloro, fluoro or CF 3 .
17. The compound of claim 1 , wherein n is 0, X is a bond and R 6 is heterocyclyl.
18. The compound of claim 17 , wherein R 6 is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
19. The compound of claim 17 , wherein R 6 is substituted.
20. The compound of claim 19 , wherein R 6 is substituted with C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, heterocyclyl or spiro-heterocyclyl, or combinations thereof.
21. The compound of claim 17 , wherein R 6 has one of the following structures:
22. The compound of claim 1 , wherein n is an integer from 1 to 6, X is —O—and R 6 is heterocyclyl or heteroaryl.
23. The compound of claim 22 , wherein R 6 is azetidinyl, triazolyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl, pyridinonyl, pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl, thiomorpholinyl, pyrrolopyridinyl, imidazolyl, benzoimidazolyl, or an oxidized analogue thereof, dioxolanyl, or tetrahydropyranyl.
24. The compound of claim 22 , wherein R 6 is substituted.
25. The compound of claim 24 , wherein R 6 is substituted with oxo, cyano, halo, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, heteroaryl, or combinations thereof.
26. The compound of claim 22 , wherein R 6 has one of the following structures:
27. The compound of claim 1 , wherein n is an integer from 1 to 6, X is —NR 7 —and R 6 is heterocyclyl or heteroaryl.
28. The compound of claim 1 , wherein n is 0, X is —O—and R 6 is cycloalkyl, heterocyclyl or heteroaryl.
29. The compound of claim 1 , wherein n is 0, X is —NR 7 —and R 6 is heterocyclyl or heteroaryl.
30. The compound of claim 1 , wherein X is —O—, n is an integer from 1 to 6 and R 6 is heterocyclyl, heteroarylalkylaminyl, cyano, amino or —NR a R b .
31. The compound of claim 1 , wherein X is a bond, n is 0 and R 6 is amino, cyano or hydroxyl.
32. The compound of claim 1 , wherein X is a bond, n is an integer from 1 to 3 and R 6 is heteroarylalkyloxy or heteroarylalkylaminyl.
33. The compound of claim 1 , wherein at least two of R 3a , R 3b , R 4a and R 4b are not H.
34. The compound of claim 1 , wherein the compound has one of the following structures:
wherein R 3a and R 4a are independently —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.
35. The compound of claim 1 , wherein one of R 3a , R 3b , R 4a or R 4b is C 1 -C 6 alkyl.
36. The compound of claim 1 , wherein two of R 3a , R 3b , R 4a and R 4b are C 1 -C 6 alkyl.
37. The compound of claim 35 , wherein C 1 -C 6 alkyl is methyl.
38. The compound of claim 2 , wherein Q is —C(═O)—.
39. The compound of claim 2 , wherein each of R 9 and R 10 are H.
40. The compound of claim 1 , wherein E has one of the following structures:
41. The compound of claim 40 , wherein E is
42. The compound of claim 1 , wherein L 1 is a bond.
43. The compound of claim 1 , wherein L 2 is a bond.
44. The compound of claim 1 , wherein A is N.
45. The compound of claim 1 , wherein the compound has one of the following structures:
46. A substantially purified atropisomer of the compound of claim 1 .
47. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
48. A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 47 to a subject in need thereof.
49. The method of claim 48 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.