Allosteric EGFR inhibitors and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12391671-B2
Application number	US-202217741206-A
Country	US
Kind code	B2
Filing date	May 10, 2022
Priority date	Nov 11, 2019
Publication date	Aug 19, 2025
Grant date	Aug 19, 2025

Abstract

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.

First claim

The invention claimed is:

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 comprise

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Scott David A
• Heppner David
• Gero Thomas
• Cullis Courtney A
• To Ciric
• Huang Shih-Chung
• Hu Yongbo
• Stroud Steve
• Beyett Tyler
• Eck Michael
• Gray Nathanael S

Classifications

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title