PROTEASOME ACTIVITY ENHANCING COMPOUNDS
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.
1 . A compound having the Formula (I):
or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof; wherein:
D is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;
-A is selected from the group consisting of, ═O, —OH, —C 1 -C 10 alkyl and —C 2 -C 12 alkenyl, wherein the —C 1 -C 10 alkyl and —C 2 -C 12 alkenyl are each optionally substituted;
Q 1 is C(R a ) or nitrogen;
each of Q 2 , Q 3 , Q 4 and Q 5 is independently selected from the group consisting of C(R 3 ) and nitrogen; wherein at least two of Q 2 , Q 3 , Q 4 and Q 5 are each independently C(R 3 );
each of R i and R 2 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;
each R 3 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, OR c , N 3 , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;
Z is selected from the group consisting of NR b R b , optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, and OR c ;
each R a is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;
each R b is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
each R c is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;
each R d is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or two geminal R d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
each R e is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; and
each n is independently 0, 1 or 2;
provided that when D is 4-chlorophenyl, -A is ═O, Q 1 is C(R a ), R a is methyl, Z is 1-piperidinyl, 4-hydroxy-1-piperidinyl or 1-pyrrolidinyl, and each of R i and R 2 is hydrogen, then at least one of Q 2 , Q 3 , Q 4 , and Q 5 is not CH; and
provided that when D is selected from the group consisting of phenyl, 4-chlorophenyl, 4-methylphenyl and 4-methoxyphenyl, -A is ═O, Q 1 is C(R a ), R a is methyl, Z is 1-piperidinyl or 4-morpholinyl, each of R i and R 2 is hydrogen, and Q 2 and Q 5 are CH, then Q 3 and Q 4 are not C(OCH 3 ) and C(Br), respectively.
2 . The compound of claim 1 , wherein -A is ═O.
3 . (canceled)
4 . The compound of claim 1 , wherein R i and R 2 are each independently selected from hydrogen and optionally substituted C 1 -C 10 alkyl.
5 . (canceled)
6 . (canceled)
7 . The compound of claim 1 , wherein D is optionally substituted phenyl.
8 . The compound of claim 1 , wherein Q 1 is C(R a ), and R a is selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.
9 . (canceled)
10 . The compound of claim 1 , wherein one or two of Q 2 , Q 3 , Q 4 and Q 5 is nitrogen and the remaining of Q 2 , Q 3 , Q 4 and Q 5 are each independently C(R 3 ).
11 - 15 . (canceled)
16 . The compound of claim 1 , wherein Z is an optionally substituted heterocyclic containing at least one ring nitrogen atom or NR b R b .
17 . The compound of claim 16 , wherein Z is an optionally substituted N-heterocyclic.
18 . The compound of claim 16 , wherein Z is selected from the group consisting of optionally substituted pyrrolidinyl and optionally substituted piperidinyl.
19 - 51 . (canceled)
52 . The compound of claim 1 , wherein the compound has the Formula (IV):
wherein:
R j is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic and optionally substituted heteroaryl.
53 . (canceled)
54 . The compound of claim 52 , wherein R i and R 2 are each independently selected from hydrogen and optionally substituted C 1 -C 10 alkyl.
55 . (canceled)
56 . The compound of claim 52 , wherein each of R 3b and R 3c is independently selected from the group consisting of hydrogen, halo, NR d R d , NO 2 , CN, optionally substituted C 1 -C 10 alkyl, C(O)OR c , C(O)R c NR d C(O)R c , OC(O)R c and OR c .
57 . (canceled)
58 . The compound of claim 56 , wherein R 3f is selected from the group consisting of hydrogen, halo, N 3 , C(O)OR c , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NO 2 and NR d R d .
59 . (canceled)
60 . (canceled)
61 . The compound of claim 52 , wherein R g and R 3b are both hydrogen and R 3c is optionally substituted C 1 -C 6 alkyl, CN and OR c .
62 . (canceled)
63 . The compound of claim 52 , wherein R g and R 3c are both hydrogen and R 3b is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, CN and OR c .
64 . The compound of claim 52 , wherein Z is selected from the group consisting of optionally substituted 1-pyrrolidinyl and optionally substituted 1-piperidinyl.
65 - 77 . (canceled)
78 . The compound of claim 1 , wherein the compound is selected from the group consisting of those shown in the Table below:
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
79 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.
80 . (canceled)
81 . (canceled)
82 . A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 1 .
83 - 93 . (canceled)