EGFR inhibitor compounds
Disclosed herein are nitrogen-containing bicyclic compounds of Formula (I), including pharmaceutically acceptable salts thereof, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:
R 1 is selected from hydroxy and an unsubstituted C 1-4 alkoxy;
R 2
wherein R 2A is an unsubstituted bicyclo pentyl, a fluoro-substituted bicyclo pentyl, a chloro-substituted bicyclo pentyl or a cyano-substituted bicyclo pentyl; and wherein R 2 is optionally substituted with one or more substituents independently selected from halogen, cyano, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted C 1-4 alkoxy, an alkyl substituted mono-substituted amine and an alkyl substituted di-substituted amine;
R 3 is a substituted C 1-4 alkyl, wherein R 3 is substituted with —(CR 6A R 6B ) n NR 7A R 7B ;
X 1 is NR 4 ;
R 4 is selected from hydrogen and an unsubstituted C 1-4 alkyl;
R 6 A and R 6B are each hydrogen;
R 7A and R 7B are independently selected from hydrogen and an unsubstituted C 1-4 alkyl;
A 1 is CR 8 ;
R 8 is selected from hydrogen, fluoro, chloro and cyano;
m is 1; and
n is 0 or 1.
2. The compound of claim 1 , wherein R 2 is
wherein R 2A is an unsubstituted bicyclo pentyl.
3. The compound of claim 1 , wherein R 2 is
wherein R 2A is a fluoro-substituted bicyclo pentyl, a chloro-substituted bicyclo pentyl or a cyano-substituted bicyclo pentyl.
4. The compound of claim 1 , wherein R 4 is an unsubstituted C 1-4 alkyl.
5. The compound of claim 4 , wherein R 4 is methyl.
6. The compound of claim 1 , wherein R 3 is a substituted C 2 alkyl substituted by —(CR 6A R 6B ), NR 7A R 7B .
7. The compound of claim 6 , wherein n is 0.
8. The compound of claim 7 , wherein R 7A and R 7B are each an unsubstituted C 1-4 alkyl.
9. The compound of claim 8 , wherein the unsubstituted C 1-4 alkyl is methyl.
10. The compound of claim 1 , wherein R 1 is an unsubstituted C 1-4 alkoxy; and R 8 is hydrogen.
11. The compound of claim 10 , wherein the unsubstituted C 1-4 alkoxy is methoxy.
12. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
14. A method for ameliorating or treating a cancer comprising contacting a malignant growth or a tumor that is in a subject having the malignant growth or the tumor with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the malignant growth or tumor is due to a cancer selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a kidney carcinoma.
15. A method for inhibiting replication of a malignant growth or a tumor comprising contacting the growth or the tumor with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the malignant growth or tumor is due to a cancer selected from a lung cancer, a pancreatic cancer, a colon cancer, a breast cancer, a prostate cancer, a head and neck cancer, an ovarian cancer, a brain cancer and a kidney carcinoma.
16. A method for inhibiting the activity of EGFR comprising providing an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject or sample having a cancer cell selected from a lung cancer cell, a pancreatic cancer cell, a colon cancer cell, a breast cancer cell, a prostate cancer cell, a head and neck cancer cell, an ovarian cancer cell, a brain cancer cell and a kidney carcinoma cell, and wherein the EGFR has one or more selected from a deletion in exon 19, an insertion in exon 20, a mutation at L858R and an acquired EGFR T790M mutation.
17. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.