COMPOSITIONS AND METHODS FOR TREATING KIT- AND PDGFRA-MEDIATED DISEASES
The present disclosure provides compounds of Formula (I-0), 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:
is chosen from a single bond and double bond;
is chosen from a single bond and double bond;
Z is chosen from CH and NH;
Y is chosen from C and N;
X 1 is chosen from CH, C, and N;
X 2 is chosen from CH, C, and N;
provided that when X 1 and X 2 are both N, then Y is not N and Z is not CH;
A is
R 1 is chosen from hydrogen and methyl;
R 2 is chosen from hydrogen and methyl, or
R 1 and R 2 taken together form a cyclopropyl;
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
one or R 2 or R 4 taken together with R 6 forms a cyclobutyl;
R 7 is hydrogen, or one of R 2 , R 4 , or R 6 taken together with R 7 forms a ring chosen from oxetane, tetrahydrofuran, and tetrahydropyran, wherein said tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl;
m is 0 or 1;
n is 0 or 1; and
B is selected from OH and NH 2 .
2 . The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the compound is of Formula (II):
3 . The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the compound is of Formula (III):
4 . The compound of claim 3 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein X 1 is N and is a single bond and X 2 is C and is a double-bond.
5 . The compound of claim 3 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein X 1 is C and is a double bond and X 2 is N and is a single bond.
6 . The compound of claim 3 , 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; or
R 5 and R 6 taken together form a cyclopropyl, and
R 7 is hydrogen.
7 . The compound of claim 3 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein:
A is
w is 1 or 2;
t is 1 or 2; and
s is 0 or 1.
8 . The compound of claim 6 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein B is NH 2 .
9 . The compound of claim 6 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein B is OH.
10 . The compound of claim 8 a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
11 . The compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
12 . The compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
13 . The compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
14 . The compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is chosen from
15 . The compound of claim 8 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein A is
16 . The compound of claim 1 , a pharmaceutically acceptable salt thereof, and/or a solvate of any of the foregoing, wherein the compound is selected from:
No.
Chemical Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
14-A
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
17 . 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.
18 . 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, gastrointestinal stromal tumors, acute myeloid leukemia, melanoma, seminoma, intercranial germ cell tumors, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK/T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.
19 . The method of claim 18 , wherein the disease or condition is systemic mastocytosis.
20 . The method of claim 19 , wherein the systemic mastocytosis is chosen from indolent systemic mastocytosis and smoldering systemic mastocytosis.
21 . (canceled)