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:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R a -R s are each independently selected from hydrogen and deuterium;
R 1 is —C(R 2 ) 3 , wherein each R 2 is independently selected from hydrogen and deuterium;
A is selected from,
wherein R 3 -R 6 are each independently selected from hydrogen, deuterium and C(R 19 ) 3 , wherein each R 19 is independently selected from hydrogen and deuterium; and
R 7 -R 18 are each independently selected from hydrogen and deuterium;
provided that at least one of R a -R s or R 1-19 is deuterium.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein: A is selected from
wherein R 3 -R 6 are each independently selected from hydrogen and deuterium.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from
4 . The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein A is
5 . The compound of any one of claims 2 - 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 -R 19 are deuterium.
6 . The compound of any one of claims 2 - 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 -R 19 are hydrogen.
7 . The compound of any one of claims 1 - 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein A is selected from
8 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R f , R g , R h , R i , R j , R k , R l , and R m are each deuterium.
9 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R f , R g , R h , R i , R j , R k , R l , and R m are each hydrogen.
10 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R f , R g , R h and R i , are each deuterium.
11 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R f , R g , R h , and R i , are each hydrogen.
12 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R j , R k , R l , and R m , are each deuterium.
13 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt or solvate thereof, wherein R j , R k , R l , and R m , are each hydrogen.
14 . The compound of any one of claims 1 - 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is —CD 3 .
15 . The compound of any one of claims 1 - 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein R l is —CH 3 .
16 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein R p , R q , R r , and R s are each deuterium.
17 . The compound of any one of claims 1 - 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein R p , R q , R r , and R s are each hydrogen.
18 . The compound of any one of claims 1 - 17 , or a pharmaceutically acceptable salt or solvate thereof, wherein R n and R o are each deuterium.
19 . The compound of any one of claims 1 - 17 or a pharmaceutically acceptable salt or solvate thereof, wherein R n and R o are each hydrogen.
20 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R c , R d , and R e are each deuterium.
21 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R c , R d , and R e are each hydrogen.
22 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R c and R d are each hydrogen.
23 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R c and R d are each deuterium.
24 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R e is hydrogen.
25 . The compound of any one of claims 1 - 19 , or a pharmaceutically acceptable salt or solvate thereof, wherein R e is deuterium.
26 . The compound of any one of claims 1 - 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R a and R b are each deuterium.
27 . The compound of any one of claims 1 - 25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R a and R b are each hydrogen.
28 . A pharmaceutical composition comprising:
a compound of any one of the claims 1 - 27 , a pharmaceutically acceptable salt or a solvate thereof; and
a pharmaceutically acceptable excipient.
29 . 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 any one of the claims 1 - 27 a pharmaceutically acceptable salt or a solvate thereof, or the pharmaceutical composition of claim 28 , wherein the disease or condition is chosen from systemic mastocytosis and gastrointestinal stromal tumors.
30 . The method of claim 29 , wherein the disease or condition is systemic mastocytosis.
31 . The method of claim 30 , wherein the systemic mastocytosis is chosen from indolent systemic mastocytosis and smoldering systemic mastocytosis.