Compositions and methods for treating KIT- and PDGFRA-mediated diseases
The present disclosure provides compounds of Formula I, pharmaceutical salts thereof, and/or solvates of any of the foregoing, which are useful for treating diseases and conditions related to mutant KIT and PDGFRα and present an advantageously non-brain penetrant profile for treating diseases and conditions related to mutant KIT and PDGFRα. The present disclosure also provides methods for treating gastrointestinal stromal tumors and systemic mastocytosis.
1. A compound of Formula I:
a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein:
A is
R 3 is chosen from hydrogen and methyl;
R 4 is chosen from hydrogen and methyl, or
R 3 and R 4 taken together form a cyclopropyl;
R 5 is chosen from hydrogen and methyl;
R 6 is chosen from hydrogen and methyl, or
R 5 and R 6 taken together form a cyclopropyl, or
R 4 taken together with R 6 forms a cyclobutyl; and
R 7 is hydrogen.
2. The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein:
A is:
R 3 is chosen from hydrogen and methyl;
R 4 is chosen from hydrogen and methyl, or R 3 and R 4 taken together form a cyclopropyl;
R 5 is chosen from hydrogen and methyl;
R 6 is chosen from hydrogen and methyl; or
R 5 and R 6 taken together form a cyclopropyl, and
R 7 is hydrogen.
3. The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
4. The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
5. The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
6. The compound of claim 5 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
7. The compound of claim 6 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
8. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
9. The compound of claim 8 ,
10. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
11. The compound of claim 10
12. A pharmaceutical composition comprising:
a compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
13. A pharmaceutical composition comprising:
a compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
14. A pharmaceutical composition comprising:
a compound of claim 10 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
15. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
16. The method of claim 15 , wherein the disease or condition is systemic mastocytosis.
17. The method of claim 16 , wherein the systemic mastocytosis is chosen from indolent systemic mastocytosis and smoldering systemic mastocytosis.
18. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
19. The compound of claim 18 ,
20. A pharmaceutical composition comprising:
a compound of claim 18 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
21. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 18 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
22. The method of claim 21 , wherein the disease or condition is indolent systemic mastocytosis.
23. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
24. The compound of claim 23 ,
25. A pharmaceutical composition comprising:
a compound of claim 23 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
26. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 23 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
27. The method of claim 26 , wherein the disease or condition is indolent systemic mastocytosis.
28. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
29. The compound of claim 28 ,
30. A pharmaceutical composition comprising:
a compound of claim 28 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
31. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 28 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
32. The method of claim 31 , wherein the disease or condition is indolent systemic mastocytosis.
33. A compound
or a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing.
34. The compound of claim 33 ,
35. A pharmaceutical composition comprising:
a compound of claim 33 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing; and
a pharmaceutically acceptable excipient.
36. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 33 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
37. The method of claim 36 , wherein the disease or condition is indolent systemic mastocytosis.
38. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
39. The method of claim 38 , wherein the disease or condition is indolent systemic mastocytosis.
40. A method of treating a disease or condition in a patient in need thereof, wherein the method comprises administering to the patient a compound of claim 10 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
41. The method of claim 40 , wherein the disease or condition is indolent systemic mastocytosis.