IP Library › Granted Patent US 12,269,824

Granted Patent B2

US 12,269,824 · App. 18/603,567 · Granted Apr 8, 2025

Wild type kit inhibitors

Inventors: Jason D. Brubaker (Cambridge, MA); Yinghui Dai (Cambridge, MA); Thomas A. Dineen (Cambridge, MA); Guangyan Du (Cambridge, MA); Cheng Fang (Cambridge, MA); Andrew Marc Haidle (Somerville, MA); Joseph L. Kim (Cambridge, MA); Emanuele Perola (Cambridge, MA); Thiwanka Samarakoon (Cambridge, MA); Douglas Wilson (Cambridge, MA)

Assignee: Blueprint Medicines Corporation

C07D471/04 A61K31/437 A61K31/4545 A61K31/496 A61K31/4985 A61K31/5377 A61K31/675 C07D519/00 C07F9/6524

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Quick Facts

Patent No.: US 12,269,824
App. No.: 18/603,567
Granted: Apr 8, 2025
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

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.

Claims (350)

1. 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, and C 0-5 alkyl(4-6 membered heterocycle), or C 0-5 alkyl(7-10 membered spiroheterocycle) or C 0-5 alkyl(5-10 membered bridgedbicycloheterocycle, each containing at least one N or O, wherein 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), and 4-6 membered heterocycle or 7-10 membered fused bicycloheterocycle or 7-10 membered spiroheterocycle, each containing at least one O or N, or 5-6 membered heteroaryl containing at least two N, wherein 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), C 1-4 alkyl, CN, CHF 2 , C 3-6 cycloalkyl, C 1-4 haloalkyl, C 0-4 alkylOH, C 2-5 alkyl(OH) 2 , C 1-4 alkyl(OH)(C 1 -C 4 alkoxy), C 2-5 alkyl(OH)(C 1-5 alkoxy)(C 1-5 alkoxy), C 0-4 alkylC 1-4 alkoxy, C 1-3 alkyoxyC 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, or C 1-3 alkyl;

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.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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), 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 alkyoxyC 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 compound of claim 1 or a pharmaceutically acceptable salt thereof, 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), 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 alkyoxyC 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.

4. The compound of claim 1 having the structure of Formula (IIa):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 having the structure of Formula (IIb):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 having the structure of Formula (IIIa):

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 having the structure of Formula (IIIb):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 0.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 0-4 alkylOH, C 0-4 alkylC 1-6 alkoxy, C 0-4 alkylC 1-6 haloalkoxy, C 3-4 cycloalkyl, NH 2 , NHC 1-5 alkyl, N(C 1-3 alkyl) 2 , NH-(4-6 membered heterocycle containing at least one O), NH-(5-6 membered heteroaryl containing at least one N), 4-6 membered heterocycle or 7-9 membered fused bicycloheterocycle or 7-10 membered spiroheterocycle, each containing at least one O or N, and 5-6 membered heteroaryl containing at least two N, wherein:

i) said alkyl, haloalkyl, or alkoxy is optionally substituted with 1-3 R e each independently selected from deuterium, deuterated C 1-3 alkoxy, C 1-3 alkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 1-2 alkyoxyC 1-2 alkoxy, OH, halogen, and 4-6 membered heterocycle containing at least one O or N;

ii) said heterocycle or cycloalkyl is optionally substituted with 1-3 R e each independently selected from deuterated C 1-3 alkyl, di(C 1-3 alkyl)amine, S(O) 2 C 1-3 alkyl, halogen, 4-6 membered heterocycle containing one O, C 1-3 alkyl, C 0-4 alkylOH, and C 1-2 alkylC 1-3 alkoxy; and

iii) said heteroaryl is optionally substituted with 1-3 R e each independently selected from C 1-4 alkyl, CN, CHF 2 , cyclopropyl, C 1-4 alkylOH, C 2-5 alkyl(OH) 2 , C 2-4 alkyl(OH)(methoxy), C 2-5 alkyl(OH)(C 1-5 alkoxy) (C 1-5 alkoxy), S(O) 2 C 1-3 alkyl, C 1-3 alkyl-S(O)(NH)C 1-3 alkyl, (C 1-3 alkyl)P(O)(C 1-3 alkyl) 2 , and (C 1-3 alkyl)-(4-6 membered heterocycle containing at least one O or N),wherein said heterocycle is optionally substituted with 1-2 OH or C 1-3 alkyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from CH 3 , Cl, F, CD 3 , CN, and cyclopropyl.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds in the table below:

Com-

pound

Structure

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

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

14. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or excipient.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

16. The compound of claim 1 , wherein the compound is:

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

18. The compound of claim 1 , wherein the compound is:

19. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

20. The compound of claim 1 , wherein the compound is:

21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

22. The compound of claim 1 , wherein the compound is:

23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

24. The compound of claim 1 , wherein the compound is:

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

26. The compound of claim 1 , wherein the compound is:

27. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

28. The compound of claim 1 , wherein the compound is:

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

30. The compound of claim 1 , wherein the compound is:

31. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

32. The compound of claim 1 , wherein the compound is:

33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is:

34. The compound of claim 1 , wherein the compound is:

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 30, 2024

From: BRUBAKER, JASON D.; DAI, YINGHUI; DINEEN, THOMAS A.; DU, GUANGYAN; FANG, CHENG; HAIDLE, ANDREW MARC; KIM, JOSEPH L.; PEROLA, EMANUELE; SAMARAKOON, THIWANKA; WILSON, DOUGLAS

To: BLUEPRINT MEDICINES CORPORATION

Reel/Frame 067263/0771 →

Continuity (4)

Continuation PCTUS2023081773 · Nov 30, 2023

Provisional Application 63445787 · Feb 15, 2023

Provisional Application 63428804 · Nov 30, 2022

Related Publication 20240262826A1 · Aug 8, 2024

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