Azaquinazoline pan-KRas inhibitors

Patent metadata

Field	Value
Publication number	US-12398154-B2
Application number	US-202117300930-A
Country	US
Kind code	B2
Filing date	Dec 15, 2021
Priority date	Dec 15, 2020
Publication date	Aug 26, 2025
Grant date	Aug 26, 2025

Abstract

The present invention relates to compounds that inhibit at least one of KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, pharmaceutical compositions comprising the compounds and methods of use therefor.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
W is:

A is naphthyl optionally substituted with 1-4 R 1 ;
B is:

Y 1 and Y 2 join to form:

where X is selected from: a bond, —S—, —O—, —N< bound to a fused ring, —CH 2 —, —CH 2 —N—, —CH 2 —N—CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 — and —S—CH 2 —;
each R 1 is independently halogen, cyano, hydroxy, C 1 -C 4 alkyl, —S—C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, —O—C1-C3 haloalkyl, —S—C1-C3 haloalkyl, C1-C3 alkoxy, hydroxyC1-C3 alkyl, —CH 2 C(═O)N(R 5 ) 2 , —C3-C4 alkynyl(NR 5 ) 2 , —N(R 5 ) 2 , deuteroC2-C4 alkynyl, (C1-C3 alkoxy)haloC1-C3 alkyl-, or C3-C6 cycloalkyl wherein said C3-C6 cycloalkyl is optionally substituted with halogen or C1-C3 alkyl;
each R 2 is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, -L-OC(O)N(R 5 ) 2 , —CO 2 R 5 , or —CO 2 N(R 5 ) 2 ;
each R 3 is independently hydrogen, hydroxy, halogen, C1-C3 alkyl, C1-C3 cyanoalkyl, C1-C3 hydroxyalkyl, HC(═O)—, -L-OC(O)N(R 5 ) 2 , —CO 2 R 5 , or —CO 2 N(R 5 ) 2 ;
each R 4 is independently hydrogen, halogen or C1-C3 alkyl;
each R 5 is independently hydrogen or C1-C3 alkyl;
each R 6 is independently hydrogen, hydroxy, C1-C4 hydroxyalkyl or heteroaryl, or two R 6 join to form C3-C6 cycloalkyl or heterocycle;
each R 7 is independently hydrogen, C1-C3 alkyl, hydroxy, halogen, C1-C3 haloalkyl, -L-NH 2 , —NH(C1-C3 alkyl), —N(C1-C3 alkyl) 2 , oxo (═O), —O—(C1-C3 alkyl), —(C1-C3 alkyl)-OH, —C(O)OH, —C(O)O(C1-C3 alkyl), —C(O)N(R 10 ) 2 , —CN, aryl, —(CH 2 )S(O) 2 N(R 10 ) 2 , or heteroaryl optionally independently substituted with 1-2 substituents independently selected from C1-C3 alkyl, —CN and C(O)NH 2 ,
two R 7 on the same atom optionally join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with 1-4 substituents independently selected from oxo (═O), halogen, hydroxy, C1-C3 alkyl and —O—(C1-C3 alkyl),
two R 7 on adjacent atoms optionally join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R 8 , heteroaryl optionally substituted with 1-4 R 8 , aryl optionally substituted with 1-4 R 8 , and heterocycle optionally substituted with 1-4 R 8 , and
two R 7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge;
each R 8 is independently C1-C3 alkyl, hydroxy, halogen, oxo (═O), —O—(C1-C3 alkyl), —(C1-C3 alkyl)-OH, —C(O)OH, —C(O)O(C1-C3 alkyl), —C(O)N(R10) 2 , or —CN;
each R 10 is hydrogen
L is a bond
each n is 0-3; and
p is 1-8.

2. The compound or salt of claim 1 , wherein:
X is selected from: —CH 2 —, —CH 2 —CH 2 — and —O—CH 2 .

3. The compound or salt of claim 2 , wherein each R 1 is independently selected from halogen, hydroxy, C1-C3 alkoxy and C1-C4 alkyl.

4. The compound or salt of claim 2 , wherein each R 2 , if present, is selected from hydrogen and halogen, and wherein each R 3 , if present, is selected from hydrogen and halogen.

5. The compound or salt of claim 2 , wherein each R 7 is independently selected from hydrogen, C1-C3alkyl, hydroxy, C1-C3 alkoxy, and wherein two R 7 on non-adjacent atoms optionally join to form a 1-2 carbon bridge.

6. The compound or salt of claim 2 , wherein each R 6 is independently hydrogen or hydroxy.

7. The compound or salt of claim 1 , wherein at least one R 1 is C1-C4 alkyl.

8. The compound or salt of claim 1 , wherein at least one R 1 is halogen.

9. The compound or salt of claim 8 , wherein said halogen is a fluorine.

10. The compound or salt of claim 1 , wherein at least one R 1 is hydroxy.

11. The compound or salt of claim 1 , wherein at least one R 2 is halogen.

12. The compound or salt of claim 11 , wherein said halogen is a fluorine.

13. The compound or salt of claim 1 , wherein at least one R 3 is C1-C4 alkyl.

14. The compound or salt of claim 1 , wherein at least one R 3 is halogen.

15. The compound or salt of claim 14 , wherein said halogen is fluorine.

16. The compound or salt of claim 1 , wherein R 4 is halogen.

17. The compound or salt of claim 16 , wherein said halogen is fluorine.

18. The compound or salt of claim 1 , wherein at least one R 5 is C1-C4 alkyl.

19. The compound or salt of claim 1 , wherein at least one R 5 is hydrogen.

20. The compound or salt of claim 1 , wherein one or both R 6 are hydrogen.

21. The compound or salt of claim 1 , wherein Y 1 and Y 2 join to form piperidine, azepane, azocane, thiazepine, diazepane, oxazepane, pyrrolidine, piperazine bound to a fused ring via nitrogen or thiomorpholine.

22. The compound or salt of claim 1 , wherein two R 7 on the same atom join to form a spirocyclic ring selected from C3-C6 cycloalkyl and heterocycle, where said spirocyclic ring is optionally substituted with one or more substituents selected from oxo (═O), halogen, hydroxy, C1-C3 alkyl and —O—(C1-C3 alkyl).

23. The compound or salt of claim 1 , wherein two R 7 on adjacent atoms join to form a bond or a fused ring selected from C3-C6 cycloalkyl optionally substituted with 1-4 R 8 heteroaryl optionally substituted with 1-4 R 8 ; aryl optionally substituted with 1-4 R 8 , and heterocycle optionally substituted with 1-4 R 8 .

24. The compound or salt of claim 1 , wherein two R 7 on nonadjacent atoms join to form a 1-2 carbon bridge.

25. A compound selected from:

Assignees

• Mirati Therapeutics Inc

Inventors

• Wang Xiaolun
• Kulyk Svitlana
• Lawson John David
• Marx Matthew Arnold
• Smith Christopher Ronald

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title

• C07D495/10

  Spiro-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title