Allosteric EGFR inhibitors and methods of use thereof
The disclosure relates to compounds that act as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.
1. A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein:
A and A′ are each, independently, CH or N;
W and Z are each, independently, CH or C-halo;
R 1 is selected from the group consisting of:
R 3 is phenyl optionally substituted one time with piperidine, wherein piperidine is substituted one time with R 7 ;
R 6 is independently, at each occurrence, hydroxy or halo; and
R 7 is independently, at each occurrence, C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein R 1 is
3. The compound of claim 1 , wherein W is CH.
4. The compound of claim 1 , wherein Z is CF.
5. The compound of claim 1 , wherein there is one occurrence of R 3 , and R 3 is phenyl substituted one time with piperidine, wherein piperidine is substituted one time with R 7 .
6. The compound of claim 1 , wherein R 7 is C 1 -C 3 alkyl.
7. The compound of claim 1 , wherein the compound of Formula Ia is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound of Formula Ia is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 , wherein the compound of Formula Ia is
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , wherein the compound of Formula Ia is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
11. A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof;
wherein:
A and A′ are each, independently, CH, CR 8 , or N;
W and Z are each, independently, N, CH, C-halo, C—(C 1 -C 3 alkyl), or C—(C 1 -C 3 alkoxy);
provided that at least one of W or Z is CH;
R 1 is selected from the group consisting of:
all of which are optionally substituted with one, two, or three R 8
R 3 is independently, at each occurrence, selected from the group consisting of C 2 -C 6 alkynyl or C 6 -C 10 aryl, wherein alkynyl is optionally substituted one, two, or three times with R 4 , and wherein aryl is optionally substituted one, two, or three times with R 5 ;
R 4 is independently, at each occurrence, selected from the group consisting of H, (CH 2 ) 0-3 —(C 3 -C 7 cycloalkyl), (CH 2 ) 0-3 —(C 4 -C 7 cycloalkenyl), (CH 2 ) 0-3 —(C 6 -C 10 aryl), (CH 2 ) 0-3 -(5-6 membered heteroaryl), and (CH 2 ) 0-3 -(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 5 ;
R 5 is independently, at each occurrence, selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(C 1 -C 6 alkyl), O(CH 2 ) 1-3 —OH, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , OH, CN, (CH 2 ) 0-3 —(C 6 -C 10 aryl), (CH 2 ) 0-3 -(5-6 membered heteroaryl), and (CH 2 ) 0-3 -(5-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R 7 ;
R 6 is independently, at each occurrence, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylamine, halogen, OH, NO 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , (CH 2 ) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH 2 , or CN;
alternatively, two R 6 , together with the atoms to which they are attached, can form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl;
R 7 is independently, at each occurrence, selected from the group consisting of substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , SO 2 NH 2 , SO 2 NH(C 1 -C 6 alkyl), SO 2 N(C 1 -C 6 alkyl) 2 , (CH 2 ) 1-2 —OH, C(O)(CH 2 ) 1-2 —OH, C(O)(C 1 -C 6 alkyl), and C(O)O(C 1 -C 6 alkyl);
alternatively, two R 7 , together with the atoms to which they are attached, can form 5-10 membered heteroaryl, 6-10 membered aryl, 3-10 membered heterocycloalkyl, or 3-10 membered cycloalkyl; and
R 8 is independently, at each occurrence, selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 1 -C 3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO 2 , NH 2 , NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , (CH 2 ) 1-4 OH, S(O) 0-2 H, S(O) 0-2 NH 2 , or CN.
12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein:
A is CH and A′ is CH, CR 8 , or N;
W is CH and Z is N, CH, C-halo, C—(C 1 -C 3 alkyl), or C—(C 1 -C 3 alkoxy);
R 1 is benzimidazole optionally substituted with halogen;
R 3 is phenyl substituted one or two times with R 5 ;
R 5 is either halogen, piperidin-4-yl substituted with methyl, or 3-azabicyclo[4.1.0]heptan-6-yl substituted with methyl;
R 6 is independently, at each occurrence, selected from the group consisting of halogen and OH;
R 8 is or halogen.
13. The compound of claim 11 , wherein R 1 is
14. The compound of claim 11 , wherein W is CH.
15. The compound of claim 11 , wherein Z is CF.
16. The compound of claim 11 , wherein there is one occurrence of R 3 , and R 3 is phenyl substituted one time with piperidine, wherein piperidine is substituted one time with R 7 .
17. The compound of claim 11 , wherein R 7 is C 1 -C 3 alkyl.
18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
19. A pharmaceutical composition comprising a compound of claim 9 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
20. A pharmaceutical composition comprising a compound of claim 11 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
21. A method of treating an EGFR-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
22. The method according to claim 21 , wherein the cancer is non-small cell lung cancer (NSCLC).
23. The method of claim 21 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of osimertinib.
24. A method of treating an EGFR-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 11 .
25. The method according to claim 24 , wherein the cancer is non-small cell lung cancer (NSCLC).
26. The method of claim 24 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of osimertinib.
27. A method of treating an EGFR-mediated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 9 .
28. The method according to claim 27 , wherein the cancer is non-small cell lung cancer (NSCLC).
29. The method of claim 27 , wherein the method further comprises administering to the subject in need thereof a therapeutically effective amount of osimertinib.