Heterocyclic compounds, preparation methods and uses thereof
Provided herein are novel compounds, for example, compounds having a Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. Also provided herein are methods of preparing the compounds and methods of using the compounds, for example, in inhibiting KRAS G12C in a cell, and/or in treating various cancer such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer).
1. A compound of Formula I-1 or I-2, or a pharmaceutically acceptable salt thereof:
wherein:
X is O, S, N, or NR 10 ,
wherein R 10 is hydrogen, an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
each of A 3 , A 4 , and A 5 is independently CR 30 or N,
wherein R 30 at each occurrence is independently hydrogen, F, Cl, C 1-4 alkyl, or C 1-4 alkoxy;
R 2 and R 3 are each independently hydrogen, halogen, —OH, —CN, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or optionally substituted C 1-4 alkoxy;
Het is a 4-10 membered heterocyclic ring, optionally substituted with independently selected R 4 group(s), (R 4 ) n , wherein n is 0, 1, 2, or 3, and R 4 at each occurrence is independently C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3 or 4 membered ring, fluorine substituted C 1-4 alkyl, hydroxyl substituted C 1-4 alkyl, or cyano substituted C 1-4 alkyl;
or two R 4 groups can join together to form a 3-6 membered ring structure;
R 7 is hydrogen, halogen, CN, a 3-4 membered ring, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, or optionally substituted C 1-4 alkoxy;
R 8 is an optionally substituted aryl or optionally substituted heteroaryl;
each of J 1 and J 2 is independently selected from O, S, N, CR 40 , and NR 41 , wherein each of R 40 and R 41 at each occurrence is independently hydrogen, OH, CN, halogen, an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, an optionally substituted C 1-4 alkoxy, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring,
R 5 and R 6 are each independently hydrogen, halogen, —CN, —COOR 23A , —CONR 21A R 22A , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted phenyl, optionally substituted 5 or 6 membered heteroaryl, or optionally substituted 4 to 7 membered heterocyclic ring, or R 5 and R 6 can join together to form an optionally substituted C 3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring, wherein each of R 21A and R 22A at each occurrence is independently hydrogen, an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group; and R 23A at each occurrence is independently hydrogen, an optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, optionally substituted C 1-4 heteroalkyl, optionally substituted C 3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
wherein the dotted line indicates that the respective connection is a single or double bond, provided that the bicyclic ring as a whole is aromatic.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, characterized as having Formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C:
wherein A 2 is CH or N, and each of R 10 , R 40 and R 41 at each occurrence is independently hydrogen or a C 1-4 alkyl.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently selected from hydrogen, C 1-4 alkyl optionally substituted with 1-3 fluorine, C 3-6 cycloalkyl, and halogen.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are both isopropyl or both cyclopropyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein,
the moiety of
is represented by
wherein n is 0, 1, or 2, wherein when n is 1 or 2, R 4 at each occurrence is independently methyl, ethyl, —CF 3 , —CF 2 H, —CH 2 OH, or —CH 2 CN.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is N, A 4 is CH, and A 5 is N.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, F, Cl, methyl, or CF 3 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a phenyl optionally substituted with 1-3 groups each independently selected from F, C 1 , —OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3 or 4 membered ring, C 1-4 alkoxy, fluorine substituted C 1-4 alkyl, and fluorine substituted C 1-4 alkoxy.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a bicyclic heteroaryl optionally substituted with 1-3 groups each independently selected from F, Cl, —OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3 or 4 membered ring, C 1-4 alkoxy, fluorine substituted C 1-4 alkyl, and fluorine substituted C 1-4 alkoxy.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from:
11. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
12. A method of inhibiting KRAS G12C mutant protein in a cell, the method comprising contacting the cell with the compound of claim 1 or a pharmaceutically acceptable salt thereof.
13. A method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the cancer is a hematologic malignancy, lung cancer, pancreatic cancer, endometrial cancer, gall bladder cancer, thyroid cancer, bile duct cancer, and/or colorectal cancer.
15. The method of claim 13 , further comprising treating the subject with an additional therapy.
16. The method of claim 15 , wherein the additional therapy is a chemotherapeutic agent, therapeutic antibody, radiation, cell therapy, or immunotherapy.
17. The method of claim 13 , wherein the subject has a G12C mutation of KRAS, HRAS and/or NRAS.