2,4-disubstituted pyrimidine compounds useful as kinase inhibtors
The present invention provides 2,4-disubstituted pyrimidine compounds useful as kinase inhibitors, pharmaceutically acceptable compositions thereof, and methods of using the same.
1. A method for selectively inhibiting at least one mutant of epidermal growth factor receptor (EGFR) as compared to wild-type epidermal growth factor receptor (WT EGFR), in a biological sample or in a patient, comprising contacting the biological sample with, or administering to the patient, a compound of formula I-a
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, or 2;
m is 0, 1, or 2, wherein m and n are not simultaneously 0;
W is —O— or -NH-;
R l is —OR;
each R is independently C 1-4 alkyl or C 1-4 fluoroalkyl;
R 2 is —CF 3 , Cl, or Br;
G is —NR 3 - or —S(O) 2 -; and
R 3 is —C(O)-R, —C(O)OR, —C(O)NHR, —SO 2 -R, —SO 2 NH 2 , —C(O)—C 1-4 alkylene-OH or —SO 2 —C 1-4 alkylene-OH.
2. The method according to claim 1 , wherein said compound is sparing for WT EGFR.
3. The method according to claim 1 , wherein the at least one mutant is T790M.
4. The method according to claim 2 , wherein the at least one mutant is T790M.
5. The method according to claim 1 , wherein the at least one mutant of EGFR is an activating mutant.
6. The method according to claim 5 , wherein the activating mutant is a deletion mutant.
7. The method according to claim 5 , wherein the activating mutant is a point mutation.
8. The method according to claim 6 , wherein the deletion mutant is delE746-A750.
9. The method according to claim 7 , wherein the point mutation is L858R.
10. The method according to claim 7 , wherein the point mutation is G719S.
11. The method according to claim 1 , wherein the compound selectively inhibits at least one activating mutant and T790M.
12. The method according to claim 11 , wherein the at least one activating mutant is a deletion mutant.
13. The method according to claim 11 , wherein the at least one activating mutant is a point mutation.
14. The method according to claim 12 , wherein the deletion mutant is delE746-A750.
15. The method according to claim 13 , wherein the point mutation is L858R.
16. The method according to claim 13 , wherein the point mutation is G719S.
17. A method for modulating mutant epidermal growth factor receptor in a patient, comprising administering to the patient a compound of formula I-a:
or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, or 2;
m is 0, 1, or 2, wherein m and n are not simultaneously 0;
W is —O— or —NH—;
R l is —OR;
each R is independently C 1-4 alkyl or C 1-4 fluoroalkyl;
R 2 is —CF 3 , Cl, or Br;
G is —NR 3 — or —S(O) 2 —; and
R 3 is —C(O)—R, —C(O)OR, —C(O)NHR, —SO 2 —R, —SO 2 NH 2 , —C(O)—C 1-4 alkylene-OH or —SO 2 —C 1-4 alkylene-OH.
18. The method according to claim 17 , wherein the patient is suffering from a cancer.
19. The method according to claim 18 , wherein the cancer is non-small cell lung cancer.
20. The method according to claim 1 , wherein the compound is of formula III-a:
or a pharmaceutically acceptable salt thereof.
21. The method according to claim 20 , wherein W is —NH—.
22. The method according to claim 20 , wherein R 2 is —CF 3 .
23. The method according to claim 20 , wherein
R 2 is —CF 3 or Cl; and
R 3 is —C(O)CH 3 or —SO 2 CH 3 .
24. The method according to claim 21 , wherein:
R 2 is —CF 3 or Cl; and
R 3 is —C(O)CH 3 .
25. The method according to claim 21 , wherein:
R 2 is —CF 3 or Cl; and
R 3 is —SO 2 CH 3 .
26. The method according to claim 20 , wherein:
W is —O—;
R 2 is —CF 3 or Cl; and
R 3 is —C(O)CH 3 .
27. The method according to claim 20 , wherein:
W is —O—;
R 2 is —CF 3 or Cl; and
R 3 is —SO 2 CH 3 .
28. The method according to claim 1 , wherein the compound is selected from:
selected from:
or a pharmaceutically acceptable salt thereof.
29. The method according to claim 1 wherein the compound is:
or a pharmaceutically acceptable salt thereof.