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US 9,850,262 B2Granted
Proteasome activity enhancing compounds
AssigneeProteostasis Therapeutics, Inc.
InventorsMatthew Cullen, Sheila Hauck, Bolin Geng, Megan Foley, Cecilia M. Bastos, Benito Munoz, Markus Haeberlein
Life of this patent
Estimating the term…
Abstract
The present invention is directed to compounds having the Formula (I), (II), (III), (IV), and (V), compositions thereof, and methods for the treatment of a condition associated with a dysfunction in proteostasis.
Claims25
A compound having the Formula (IV):
- or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof;
- wherein
- Z is an optionally substituted N-heterocyclic;
- R1 and R2 are each independently selected from hydrogen and optionally substituted C1-C10 alkyl;
- R3f is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, halo, N3, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)C(O)ORc, NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc(C═NRd)Rc, OC(O)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
- each of R3b and R3c is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, halo, N3, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)C(O)ORc, NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc(C═NRd)Rc, OC(O)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
- and
- Rg is selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, halo, N3, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)C(O)ORc, NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc(C═NRd)Rc, OC(O)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
- Rj is optionally substituted C1-C4 alkyl;
- each Rc is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
- each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C1-C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
- or two geminal Rd groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
- and
- each n is independently, 1or 2.
11 more elements
A compound having the Formula (V):
- or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof, wherein
- Ri is an optionally substituted C1-C4 alkyl;
- R3f is selected from the group consisting of halo, N3, C(O)ORc, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NO2 and NRdRd;
- R1 and R2 are each independently selected from hydrogen and optionally substituted C1-C10 alkyl;
- one of R3b and R3c is hydrogen and the other of R3b and R3c is selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted aryl, halo, N3, ORc, NRdRd, C(O)ORc, NO2, CN, C(O)Rc, C(O)C(O)Rc, C(O)NRdRd, NRdC(O)Rc, NRdS(O)nRc, N(Rd)C(O)ORc, NRdC(O)C(O)Rc, NRdC(O)NRdRd, NRdS(O)nNRdRd, NRdS(O)nRc, S(O)nRc, S(O)nNRdRd, OC(O)ORc, (C═NRd)Rc, OC(O)Rc, optionally substituted heterocyclic and optionally substituted heteroaryl;
- Z2 is selected from the group consisting of optionally substituted 1-pyrrolidinyl and 1-piperdinyl;
- each Rc is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
- each Rd is independently selected from the group consisting of hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted C1-C10 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
- or two terminal Rd groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
- and
- each n is independently 0, 1 or 2.
8 more elements
A compound selected from the group consisting of those shown in the Table below, or a pharmaceutically acceptable salt thereof:
- 30
- 31
- 34
- 86
- 87
- 88
- 98
- 104
- 106
- 108
- 115
- 116
- 118
- 119
- 120
- 123
- 125
- 126
- 127
- 128
- 130
- 131
- 132
- 133
- 141
- 142
- 144
- 145
- 146
- 147
- 148
- 149
- 150
- 151
- 152
- 153
- 154
- 155
- 156
- 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
- 230
- 231
- 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
- 290
- 291
- 292
- 294
- 295
- 296
- 297
- 298
- 299
- 300
- 301
- 302
- 303
- 304
- 305
- 306
- 307
- 308
- 309
- 310
- 311
- 312
- 314
- 315
- 318
- 319
- 320
- 321
- 324
- 325
- 326
- 327
- 328
- 329
- 330
- 331
- 332
- 335
- 336
- 337
- 338
- 339
- 340
- 341
- 342
- 343
- 344
- 345
- 346
- 347
- 348
- 349
- 350
- 351
- 352
- 353
- 354
- 355
- 356
- 357
- 359
- 360
- 361
- 362
- 363
- 364
- 365
- 366
- 367
- 368
- 369
- 370
- 371
- 372
- 373
- 374
- 381
- 382
- 383
- 384
- 385
- 386
- 387
- 388
- 389
- 390
- 391
- 392
- 393
- 394
- 395
- 396
- 397
- 398
- 399
- 400
- 401
- 402
254 more elements
Dependencies are inferred from the claim text.