Granted Patent B2

US 12,421,228 · App. 17/605,094 · Granted Sep 23, 2025

Inventors: John Michael Ketcham (San Diego, CA); Aaron Craig Burns (San Diego, CA); Matthew Arnold Marx (San Diego, CA)

Assignee: MIRATI THERAPEUTICS, INC.

C07D471/04A61P35/00

Abstract

Claims (57)

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof,

wherein:

represents a single or a double bond;

A 1 , A 2 , A 3 and A 4 are each independently N or CR A , wherein no more than two of A 1 , A 2 , A 3 , and A 4 are N, and wherein at least one of A 2 , A 3 and A 4 is N;

Z is O or S;

X is O, CR 5 , CR 5 OH, or C(R 5 ) 2 , wherein:

when X is O, is a single bond;

when X is C(R 5 ) 2 , is a single bond;

when X is CR 5 OH, is a single bond; or

when X is CR 5 , is a double bond;

R 1 is aryl, heteroaryl, -L-cycloalkyl, —N(R 5 )heterocyclyl, or -L-heterocyclyl, wherein the aryl, the heteroaryl and the cyclyl portion of the -L-cycloalkyl, —N(R 5 )heterocyclyl, and -L-heterocyclyl are optionally substituted with one or more independently selected R 3 ;

R 2 is independently C1-C3 alkyl or halogen;

each R 3 is independently oxo, cyano, halogen, hydroxyl, —PO 3 (C1-C3 alkyl) 2 , alkoxy, hydroxyalkyl, heteroalkyl, aralkyl, haloalkyl, —COOR 5 , —Y 2 -haloalkyl, —Y 1 —C1-C6 alkyl, —Y 2 -C1-C6 alkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, —Y 1 -heterocyclyl, —Y 2 -heterocyclyl, -L-N(R 5 ) 2 , —O-L-N(R 5 ) 2 , —C(CF 3 )N(R 5 ) 2 , —Y 1 —N(R 5 ) 2 , or —Y 2 —N(R 5 ) 2 wherein the ring portion of the aralkyl, -L-cycloalkyl, -L-heteroaryl, -L-heterocyclyl, and —Y 1 -heterocyclyl is optionally substituted with one or more independently selected R 6 ;

R 4 is hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

L is a bond or C1-C4 alkylene;

Y 1 is a bond, —C(O)—, or —NHC(O)—;

Y 2 is a bond, —S—, —SO—, —SO 2 —, or —NR 5 SO 2 —,

each R 5 is independently hydrogen or C1-C3 alkyl;

each R 6 is oxo, cyano, hydroxyl, alkoxy, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, -L-N(R 5 ) 2 , C1-C6 alkyl, or —Y 1 -heterocyclyl, wherein —Y 1 -heterocyclyl is optionally substituted with one or more R 7 ;

each R 7 is independently hydrogen, C1-C3 alkyl, halogen, haloalkyl, hydroxyalkyl, or heteroalkyl;

each R A is independently hydrogen, alkoxy, heteroalkyl, —N(R 5 ) 2 , heteroalkylN(R 5 ) 2 , C1-C3 alkyl, S—C1-C3 alkyl, or aryl; and

n is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is N.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 and A 3 are each N.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 2 is CR A and R A is alkoxy.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 4 is CR A and R A is alkoxy.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 2 is N.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 2 and A 4 are each N.

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is CR A and R A is alkoxy, heteroalkyl, —N(R 5 ) 2 , heteroalkylN(R 5 ) 2 , C1-C3 alkyl, S—C1-C3 alkyl, or aryl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 2 and A 3 are each N.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 4 is N.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is N, A 4 is CR A and R A is alkoxy, —N(R 5 ) 2 , or aryl.

12. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is O.

13. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen.

15. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 2 is fluorine.

16. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is C(R 5 ) 2 and is a single bond.

17. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl optionally substituted with one or more independently selected R 3 .

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl optionally substituted with one or more independently selected R 3 .

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted with one, two or three R 3 .

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein the one, two or three R 3 are each independently halogen, hydroxyl, haloalkyl, —COOR 5 , —Y 1 —C1-C6 alkyl, —Y 2 —C1-C6 alkyl, -L-N(R 5 ) 2 , —O-L-N(R 5 ) 2 , —C(CF 3 )N(R 5 ) 2 , —Y 1 —N(R 5 ) 2 , —Y 2 —N(R 5 ) 2 , —Y 2 -haloalkyl, -L-heterocyclyl, or —Y 1 -heterocyclyl, wherein the heterocyclyl portion of the -L-heterocyclyl and —Y 1 -heterocyclyl is optionally substituted with one or more independently selected R 6 .

21. The compound according claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl optionally substituted with one or more independently selected R 3 .

22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl selected from pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazinyl, pyridyl, pyridinyl-2-one, pyrazinyl, pyridazinyl, pyrimidinyl, isoxazolyl, isoindolinyl, naphthridinyl, 1,2,3,4-tetrahydroisoquinolinyl, and 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, each optionally substituted with one or more independently selected R 3 .

23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted with one or more R 3 ; wherein each R 3 is independently cyano, halogen, —Y 1 -C1-C6 alkyl, —Y 2 -C1-C6 alkyl, alkoxy, hydroxyalkyl, heteroalkyl, haloalkyl, -L-cycloalkyl, -L-N(R 5 ) 2 , —Y 1 —N(R 5 ) 2 , -L-heteroaryl, -L-heterocyclyl, or —Y 1 -heterocyclyl, wherein the heteroaryl of the-L-heteroaryl and the heterocyclyl portion of the -L-heterocyclyl and —Y 1 -heterocyclyl are optionally substituted with one or more independently selected R 6 .

24. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Z is O;

n is 1;

R 2 is fluorine;

X is C(R 5 ) 2 and is a single bond; and

R 5 is hydrogen.

27. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted with one or more independently selected R 3 .

28. The compound of claim 26 , or a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl substituted with one or more independently selected R 3 .

29. The compound of claim 28 , or a pharmaceutically acceptable salt thereof, wherein R 1 is pyrazolyl or pyridyl, substituted with one or more independently selected R 3 .

Assignments (1)

Continuity (2)

References Cited (161)