Compounds useful as inhibitors of ATR kinase
The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention. The compounds of this invention have formula I-A or I-B: wherein the variables are as defined herein.
1. A compound of Formula I-B:
or a pharmaceutically acceptable salt thereof, wherein:
each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 is independently hydrogen or deuterium; provided at least one of Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 is deuterium;
each X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 is independently selected from 12 C or 13 C; and
X 3 is independently selected from — 12 C(O)— or — 13 C(O)—.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are independently selected from hydrogen or deuterium.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are hydrogen.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are 12 C; and
X 3 is — 12 C(O)—.
5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are 12 C;
X 3 is — 13 C(O)—; and
X 2 is 13 C.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , and Y 10 are independently selected from hydrogen or deuterium.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , and Y 10 are hydrogen.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are independently selected from hydrogen or deuterium.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Y 2 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are hydrogen.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 12 , Y 13 , Y 18 , and Y 19 are deuterium and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 14 , Y 15 , Y 16 , and Y 17 are hydrogen or deuterium.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein Y 12 , Y 13 , Y 18 , and Y 19 are deuterium and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 14 , Y 15 , Y 16 , and Y 17 are hydrogen.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are deuterium, and Y 1 , Y 2 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are independently selected from deuterium or hydrogen.
13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , and Y 11 are deuterium, and Y 1 , Y 2 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are hydrogen.
14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 and Y 11 are deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium or hydrogen.
15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein Y 2 and Y 11 are deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are hydrogen.
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 2 is deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are deuterium or hydrogen.
17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein Y 2 is deuterium, and Y 1 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are hydrogen.
18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , X 4 , X 5 , X 6 , X 7 , and X 8 are 12 C;
X 3 is — 12 C(O)—; and
X 9 is 13 C.
19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 2 , X 8 , and X 9 are 12 C;
X 3 is — 12 C(O)—; and
X 4 , X 5 , X 6 , and X 7 are 13 C.
20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein:
X 2 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are 12 C;
X 3 is — 12 C(O)—; and
X 1 is 3 C.
21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein:
X 2 , X 4 , X 5 , X 6 , X 7 , and X 9 are 12 C;
X 3 is — 13 C(O)—; and
X 1 and X 8 are 13 C.
22. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y 1 is deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are independently selected from hydrogen or deuterium.
23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein Y 11 is deuterium, and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Y 10 , Y 11 , Y 12 , Y 13 , Y 14 , Y 15 , Y 16 , Y 17 , Y 18 , and Y 19 are hydrogen.
24. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein:
X 1 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are 12 C;
X 3 is — 12 C(O)—; and
X 2 is 3 C.
25. A compound selected from the following:
or a pharmaceutically acceptable salt thereof.