WILD TYPE KIT INHIBITORS
Disclosed is a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are defined herein. Compounds of Formula (I) are useful for inhibiting wild type c-kit kinase and for treating disorders and diseases mediated by wild type c-kit kinase in humans or non-humans.
1 . A method of treating a subject suffering from a disease or disorder, comprising administrating to the subject an effective amount of a compound having the structure of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from tetrazole or triazole, wherein said tetrazole or triazole is optionally substituted with R a ;
wherein R a is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 0-5 alkylphenyl, C 0-5 alkylC 3-6 cycloalkyl, C 0-5 alkylC 6-10 spirocycloalkyl, C 0-5 alkylC 5-10 bridgedbicycloalkyl, C 0-5 alkyl(4-6 membered heterocycle), C 0-5 alkyl(7-10 membered spiroheterocycle), and C 0-5 alkyl(5-10 membered bridgedbicycloheterocycle), wherein said heterocycle,
spiroheterocycle, and bridged bicylcoheterocycle contain at least one N or O, and said alkyl, haloalkyl, phenyl, cycloalkyl, spirocycloalkyl, bridgedbicycloalkyl, heterocycle, spiroheterocycle, or bridgedbicycloheterocycle is optionally substituted with 1-5 R b , wherein:
each R b is independently selected from OH, CN, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkoxy, SO 2 C 1-4 alkyl, SO 2 C 1-4 haloalkyl, C(O)OC 1-4 alkyl, SO 2 (C 0-2 alkyl)(4-6 membered heterocycle containing at least one O or N), SO 2 (C 1-4 alkyl)C 1-4 haloalkoxy, SO 2 (C 1-4 alkyl)C 1-4 alkoxy(C 0-1 alkoxy), SO 2 (C 1-4 alkyl)OH, SO 2 (C 0-2 alkyl)C 3-6 cycloalkyl, C 1-3 alkyl, C 1-5 haloalkyl, halogen, and C 1-2 alkylOH, further wherein said cycloalkyl is optionally substituted with C 1-3 alkyl;
each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 0-4 alkylOH, C 6-10 spirocycloalkyl, C 0-6 alkylC 1-6 alkoxy, C 0-4 alkylC 1-6 haloalkoxy, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NH-(4-6 membered heterocycle or 5-6 membered heteroaryl containing at least one O or N), 4-6 membered heterocycle, 7-10 membered fused bicycloheterocycle, 7-10 membered spiroheterocycle, and 5-6 membered heteroaryl containing at least two N, wherein said heterocycle, fused bicycloheterocycle, and spiroheterocycle contain at least one N or O, and said alkyl, haloalkyl, alkoxy, cycloalkyl, spirocycloalkyl, heterocycle, or heteroaryl is optionally substituted with 1-3 R e ;
each R e is independently selected from deuterium, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, C 0-3 alkyl-S(O) 2 C 1-3 alkyl, C 0-3 alkyl-S(O)(NH)C 1-3 alkyl, (C 1-4 alkyl)P(O)(C 1-3 alkyl) 2 , C 1-4 alkyl, CN, CHF 2 , C 3-6 cycloalkyl, C 1-4 haloalkyl, C 0-4 alkylOH, C 1-4 alkyl(OH)(C 1 -C 4 alkoxy), C 0-4 alkylC 1-4 alkoxy, C 1-3 alkoxyC 1-3 alkoxy, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and (C 0-4 alkyl)-(4-6 membered heterocycle containing at least one O or N),
wherein said heterocycle is optionally substituted with 1-3 C 0-3 alkylOH;
each R 9 is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, halogen, CN, and C 3-4 cycloalkyl;
n is 1 or 2; and
p is 0, 1 or 2;
wherein the disease or disorder is selected from urticaria, atopic dermatosis, allergic asthma, prurigo nodularis, allergic conjunctivitis, allergic rhinitis, amyotrophic lateral sclerosis (AML), chronic rhinosinusitis with nasal polyps, irritable bowel syndrome (IBS), food allergies, eosinophilic esophagitis and mast cell activation syndrome (MCAS).
2 . The method of claim 1 , wherein
each R e is independently selected from deuterium, deuterated C 1-4 alkyl, deuterated C 1-4 alkoxy, C 1-4 haloalkoxy, halogen, C 0-3 alkyl-S(O) 2 C 1-3 alkyl, C 0-3 alkyl-S(O)(NH)C 1-3 alkyl,
(C 1-4 alkyl)P(O)(C 1-3 alkyl) 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 0-4 alkylOH, C 1-4 alkyl(OH)(C 1 -C 4 alkoxy),
C 0-4 alkylC 1-4 alkoxy, C 1-3 alkoxyC 1-3 alkoxy, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , and
(C 0-4 alkyl)-(4-6 membered heterocycle containing at least one O or N), wherein said heterocycle is optionally substituted with 1-3 C 0-3 alkylOH.
3 . The method of claim 1 , wherein the compound has the structure of Formula (IIa):
or a pharmaceutically acceptable salt thereof.
4 . The method of claim 1 , wherein the compound has the structure of Formula (IIb):
or a pharmaceutically acceptable salt thereof.
5 . The method of claim 1 , wherein the compound has the structure of Formula (IIIa):
or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein the compound has the structure of Formula (IIIb):
or a pharmaceutically acceptable salt thereof.
7 . The method of claim 1 , wherein p is 0.
8 . The method of claim 1 , wherein p is 1 or 2.
9 . The method of claim 1 , wherein:
R a is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 0-3 alkylphenyl,
C 0-4 alkylC 3-6 cycloalkyl, C 0-3 alkylC 6-10 spirocycloalkyl, C 0-3 alkyl(C 5-8 bridgedbicycloalkyl),
C 0-5 alkyl(4-6 membered heterocycle containing at least one N or O), C 0-3 alkyl(7-10 membered spiroheterocycle containing at least one N or O), and C 0-3 alkyl(5-10 membered bridged bicycloheterocycle containing at least one O or N), wherein:
i) said alkyl or haloalkyl is optionally substituted with 1-5 R b each independently selected from C 1-5 alkoxy, C 1-5 haloalkoxy, OH and CN;
ii) said cycloalkyl, spirocycloalkyl, or phenyl is optionally substituted with 1-2 R b each independently selected from methyl, halogen, C 1-3 haloalkyl, C 1-3 alkoxy, and C 0-3 alkylOH; and
iii) said heterocycle is optionally substituted with one R b selected from SO 2 C 1-4 alkyl,
SO 2 C 1-4 haloalkyl, C(O)OC 1-4 alkyl, SO 2 (4-6 membered heterocycle containing at least one O or N), SO 2 (C 1-3 alkyl)C 1-3 haloalkoxy, SO 2 (C 1-3 alkyl)C 1-3 alkoxy, SO 2 (C 1-4 alkyl)OH,
SO 2 (C 1-3 alkyl)C 1-3 alkoxy(methoxy), SO 2 (C 0-2 alkyl)C 3-6 cycloalkyl and C 1-4 haloalkyl, further wherein said cycloalkyl is optionally substituted with C 1-2 alkyl.
10 . The method of claim 1 , wherein each R 9 is independently selected from CH 3 , Cl, F, CD 3 , CN, and cyclopropyl.
11 . The method of claim 1 , wherein the compound is selected from any one of the compounds in the table below:
Compound
No
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
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
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
12 . The method of claim 1 , wherein the disease or disorder is chronic urticaria.
13 . The method of claim 12 , wherein the chronic urticaria is chronic spontaneous urticaria (CSU).
14 . The method of claim 13 , wherein the subject is resistant to antihistamine treatment (i.e., the subject remains symptomatic despite antihistamine treatment).