Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof: which inhibit the Apoptosis signal-regulating kinase 1 (ASK-1), which associated with autoimmune disorders, neurodegenerative disorders, inflammatory diseases, chronic kidney disease, cardiovascular disease. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from ASK-1 related disease. The invention also relates to methods of treating an ASK-1 related disease in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention specifically relates to methods of treating ASK-1 associated with hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis disease (NASH).
1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof:
wherein R 1 is selected from
X 1 and X 2 are each independently C(R 8 ) or N;
X 3 is C(R 9 ) or N;
R 9 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy and halogen;
X 4 is S, S(O), or SO 2 ;
R 4 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
R 2 , R 5 and R 8 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) Cyano;
5) Substituted or unsubstituted —C 1 -C 8 alkyl;
6) Substituted or unsubstituted —C 2 -C 8 alkenyl;
7) Substituted or unsubstituted —C 2 -C 8 alkynyl;
8) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
9) Substituted or unsubstituted aryl;
10) Substituted or unsubstituted arylalkyl;
11) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
12) Substituted or unsubstituted heteroaryl;
13) Substituted or unsubstituted heteroarylalkyl;
14) —N(R 6 )(R 7 );
15) —S(O) 2 N(R 6 )(R 7 );
16) —N(R 6 )C(O)R 7 ; and
17) —N(R 6 )S(O) 2 R 6 ;
wherein R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, —C 1 -C 8 alkenyl, —C 1 -C 8 alkynyl, —C 3 -C 8 cycloalkyl, aryl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, all of which are optionally substituted with 1-3 substituents selected from halo, alkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl;
alternatively, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic;
R 3 is selected from the group consisting of:
1) Substituted or unsubstituted —C 1 -C 8 alkyl;
2) Substituted or unsubstituted —C 2 -C 8 alkenyl;
3) Substituted or unsubstituted —C 2 -C 8 alkynyl;
4) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
5) Substituted or unsubstituted aryl;
6) Substituted or unsubstituted arylalkyl;
7) Substituted or unsubstituted 3- to 8-membered heterocycloalkyl;
8) Substituted or unsubstituted heteroaryl;
9) Substituted or unsubstituted heteroarylalkyl;
10) —C(O)R 6 ;
11) —C(O)OR 6 ;
12) —C(O)N(R 6 )(R′);
13) —SO 2 R 6 ; and
14) hydrogen
R 10 and R 11 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 8 alkyl; alternatively, R 10 and R 11 are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl, cycloalkenyl or heterocyclic; and n is 0, 1 or 2.
2. The compound of claim 1 , wherein R 3 is one of the following groups,
wherein each group is optionally substituted.
3. The compound of claim 1 , wherein R 4 is one of the following groups,
wherein each group is optionally substituted.
4. The compound of claim 1 , represented by Formula Ib or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 10 , R 11 , X 1 , X 2 , X 3 and n are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula II or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 10 , R 11 , X 2 , X 3 , X 4 and n are as defined in claim 1 .
6. The compound of claim 1 represented by Formula III or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 10 , R, X 3 , X 4 and n are as defined in claim 1 .
7. The compound of claim 1 represented by Formula IV or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 3 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .
8. The compound of claim 1 represented by Formula V or Formula XIII, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , R 5 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .
9. The compound of claim 1 represented by Formula VII, Formula X, Formula XIV, or Formula XVII, or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 10 , R 11 , X 3 , X 4 and n are as defined in claim 1 .
10. The compound of claim 1 represented by Formula VIII, or Formula XI, Formula XV, or Formula XVIII, or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , X 4 and n are as defined in claim 1 .
11. The compound of claim 1 , which is selected from compounds of Formula IX, or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , and n are delineated for each compound in Table 1:
TABLE 1
compound
R 3
X 3
n
1
H
C—H
0
2
Methyl
C—H
0
3
Ethyl
C—H
0
4
Propyl
C—H
0
5
Allyl
C—H
0
6
i-Propyl
C—H
0
7
C—H
0
8
i-Butyl
C—H
0
9
sec-Butyl
C—H
0
10
t-Butyl
C—H
0
11
C—H
0
12
C—H
0
13
C—H
0
14
C—H
0
15
C—H
0
16
C—H
0
17
C—H
0
18
H
C—F
0
19
Methyl
C—F
0
20
Ethyl
C—F
0
21
Propyl
C—F
0
22
Allyl
C—F
0
23
i-Propyl
C—F
0
24
C—F
0
25
i-Butyl
C—F
0
26
sec-Butyl
C—F
0
27
t-Butyl
C—F
0
28
C—F
0
29
C—F
0
30
C—F
0
31
C—F
0
32
C—F
0
33
C—F
0
34
C—F
0
35
H
C—OMe
0
36
Methyl
C—OMe
0
37
Ethyl
C—OMe
0
38
Propyl
C—OMe
0
39
Allyl
C—OMe
0
40
i-Propyl
C—OMe
0
41
C—OMe
0
42
i-Butyl
C—OMe
0
43
sec-Butyl
C—OMe
0
44
t-Butyl
C—OMe
0
45
C—OMe
0
46
C—OMe
0
47
C—OMe
0
48
C—OMe
0
49
C—OMe
0
50
C—OMe
0
51
C—OMe
0
52
H
N
0
53
Methyl
N
0
54
Ethyl
N
0
55
Propyl
N
0
56
Allyl
N
0
57
i-Propyl
N
0
58
N
0
59
i-Butyl
N
0
60
sec-Butyl
N
0
61
t-Butyl
N
0
62
N
0
63
N
0
64
N
0
65
N
0
66
N
0
67
N
0
68
N
0
69
H
C—H
1
70
Methyl
C—H
1
71
Ethyl
C—H
1
72
Propyl
C—H
1
73
Allyl
C—H
1
74
i-Propyl
C—H
1
75
C—H
1
76
i-Butyl
C—H
1
77
sec-Butyl
C—H
1
78
t-Butyl
C—H
1
79
C—H
1
80
C—H
1
81
C—H
1
82
C—H
1
83
C—H
1
84
C—H
1
85
C—H
1
86
H
C—F
1
87
Methyl
C—F
1
88
Ethyl
C—F
1
89
Propyl
C—F
1
90
Allyl
C—F
1
91
i-Propyl
C—F
1
92
C—F
1
93
i-Butyl
C—F
1
94
sec-Butyl
C—F
1
95
t-Butyl
C—F
1
96
C—F
1
97
C—F
1
98
C—F
1
99
C—F
1
100
C—F
1
101
C—F
1
102
C—F
1
103
H
C—OMe
1
104
Methyl
C—OMe
1
105
Ethyl
C—OMe
1
106
Propyl
C—OMe
1
107
Allyl
C—OMe
1
108
i-Propyl
C—OMe
1
109
C—OMe
1
110
i-Butyl
C—OMe
1
111
sec-Butyl
C—OMe
1
112
t-Butyl
C—OMe
1
113
C—OMe
1
114
C—OMe
1
115
C—OMe
1
116
C—OMe
1
117
C—OMe
1
118
C—OMe
1
119
C—OMe
1
120
H
N
1
121
Methyl
N
1
122
Ethyl
N
1
123
Propyl
N
1
124
Allyl
N
1
125
i-Propyl
N
1
126
N
1
127
i-Butyl
N
1
128
sec-Butyl
N
1
129
t-Butyl
N
1
130
N
1
131
N
1
132
N
1
133
N
1
134
N
1
135
N
1
136
N
1.
12. The compound of claim 1 which is selected from compounds of Formula XII, or a pharmaceutically acceptable salt thereof,
wherein R 3 , X 3 , and n are delineated for each compound in Table 2:
TABLE 2
compound
R 3
X 3
n
137
H
C—H
0
138
Methyl
C—H
0
139
Ethyl
C—H
0
140
Propyl
C—H
0
141
Allyl
C—H
0
142
i-Propyl
C—H
0
143
C—H
0
144
i-Butyl
C—H
0
145
sec-Butyl
C—H
0
146
t-Butyl
C—H
0
147
C—H
0
148
C—H
0
149
C—H
0
150
C—H
0
151
C—H
0
152
C—H
0
153
C—H
0
154
H
C—F
0
155
Methyl
C—F
0
156
Ethyl
C—F
0
157
Propyl
C—F
0
158
Allyl
C—F
0
159
i-Propyl
C—F
0
160
C—F
0
161
i-Butyl
C—F
0
162
sec-Butyl
C—F
0
163
t-Butyl
C—F
0
164
C—F
0
165
C—F
0
166
C—F
0
167
C—F
0
168
C—F
0
169
C—F
0
170
C—F
0
171
H
C—OMe
0
172
Methyl
C—OMe
0
173
Ethyl
C—OMe
0
174
Propyl
C—OMe
0
175
Allyl
C—OMe
0
176
i-Propyl
C—OMe
0
177
C—OMe
0
178
i-Butyl
C—OMe
0
179
sec-Butyl
C—OMe
0
180
t-Butyl
C—OMe
0
181
C—OMe
0
182
C—OMe
0
183
C—OMe
0
184
C—OMe
0
185
C—OMe
0
186
C—OMe
0
187
C—OMe
0
188
H
N
0
189
Methyl
N
0
190
Ethyl
N
0
191
Propyl
N
0
192
Allyl
N
0
193
i-Propyl
N
0
194
N
0
195
i-Butyl
N
0
196
sec-Butyl
N
0
197
t-Butyl
N
0
198
N
0
199
N
0
200
N
0
201
N
0
202
N
0
203
N
0
204
N
0
205
H
C—H
1
206
Methyl
C—H
1
207
Ethyl
C—H
1
208
Propyl
C—H
1
209
Allyl
C—H
1
210
i-Propyl
C—H
1
211
C—H
1
212
i-Butyl
C—H
1
213
sec-Butyl
C—H
1
214
t-Butyl
C—H
1
215
C—H
1
216
C—H
1
217
C—H
1
218
C—H
1
219
C—H
1
220
C—H
1
221
C—H
1
222
H
C—F
1
223
Methyl
C—F
1
224
Ethyl
C—F
1
225
Propyl
C—F
1
226
Allyl
C—F
1
227
i-Propyl
C—F
1
228
C—F
1
229
i-Butyl
C—F
1
230
sec-Butyl
C—F
1
231
t-Butyl
C—F
1
232
C—F
1
233
C—F
1
234
C—F
1
235
C—F
1
236
C—F
1
237
C—F
1
238
C—F
1
239
H
C—OMe
1
240
Methyl
C—OMe
1
241
Ethyl
C—OMe
1
242
Propyl
C—OMe
1
243
Allyl
C—OMe
1
244
i-Propyl
C—OMe
1
245
C—OMe
1
246
i-Butyl
C—OMe
1
247
sec-Butyl
C—OMe
1
248
t-Butyl
C—OMe
1
249
C—OMe
1
250
C—OMe
1
251
C—OMe
1
252
C—OMe
1
253
C—OMe
1
254
C—OMe
1
255
C—OMe
1
256
H
N
1
257
Methyl
N
1
258
Ethyl
N
1
259
Propyl
N
1
260
Allyl
N
1
261
i-Propyl
N
1
262
N
1
263
i-Butyl
N
1
264
sec-Butyl
N
1
265
t-Butyl
N
1
266
N
1
267
N
1
268
N
1
269
N
1
270
N
1
271
N
1
272
N
1.
13. The compound of claim 1 , which is selected from compounds of Formula XIII, or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , and n are delineated for each compound in Table 3:
TABLE 3
compound
R 3
X 3
n
273
H
C—H
0
274
Methyl
C—H
0
275
Ethyl
C—H
0
276
Propyl
C—H
0
277
Allyl
C—H
0
278
i-Propyl
C—H
0
279
C—H
0
280
i-Butyl
C—H
0
281
sec-Butyl
C—H
0
282
t-Butyl
C—H
0
283
C—H
0
284
C—H
0
285
C—H
0
286
C—H
0
287
C—H
0
288
C—H
0
289
C—H
0
290
H
C—F
0
291
Methyl
C—F
0
292
Ethyl
C—F
0
293
Propyl
C—F
0
294
Allyl
C—F
0
295
i-Propyl
C—F
0
296
C—F
0
297
i-Butyl
C—F
0
298
sec-Butyl
C—F
0
299
t-Butyl
C—F
0
300
C—F
0
301
C—F
0
302
C—F
0
303
C—F
0
304
C—F
0
305
C—F
0
306
C—F
0
307
H
C—OMe
0
308
Methyl
C—OMe
0
309
Ethyl
C—OMe
0
310
Propyl
C—OMe
0
311
Allyl
C—OMe
0
312
i-Propyl
C—OMe
0
313
C—OMe
0
314
i-Butyl
C—OMe
0
315
sec-Butyl
C—OMe
0
316
t-Butyl
C—OMe
0
317
C—OMe
0
318
C—OMe
0
319
C—OMe
0
320
C—OMe
0
321
C—OMe
0
322
C—OMe
0
323
C—OMe
0
324
H
N
0
325
Methyl
N
0
326
Ethyl
N
0
327
Propyl
N
0
328
Allyl
N
0
329
i-Propyl
N
0
330
N
0
331
i-Butyl
N
0
332
sec-Butyl
N
0
333
t-Butyl
N
0
334
N
0
335
N
0
336
N
0
337
N
0
338
N
0
339
N
0
340
N
0
341
H
C—H
1
342
Methyl
C—H
1
343
Ethyl
C—H
1
344
Propyl
C—H
1
345
Allyl
C—H
1
346
i-Propyl
C—H
1
347
C—H
1
348
i-Butyl
C—H
1
349
sec-Butyl
C—H
1
350
t-Butyl
C—H
1
351
C—H
1
352
C—H
1
353
C—H
1
354
C—H
1
355
C—H
1
356
C—H
1
357
C—H
1
358
H
C—F
1
359
Methyl
C—F
1
360
Ethyl
C—F
1
361
Propyl
C—F
1
362
Allyl
C—F
1
363
i-Propyl
C—F
1
364
C—F
1
365
i-Butyl
C—F
1
366
sec-Butyl
C—F
1
367
t-Butyl
C—F
1
368
C—F
1
369
C—F
1
370
C—F
1
371
C—F
1
372
C—F
1
373
C—F
1
374
C—F
1
375
H
C—OMe
1
376
Methyl
C—OMe
1
377
Ethyl
C—OMe
1
378
Propyl
C—OMe
1
379
Allyl
C—OMe
1
380
i-Propyl
C—OMe
1
381
C—OMe
1
382
i-Butyl
C—OMe
1
383
sec-Butyl
C—OMe
1
384
t-Butyl
C—OMe
1
385
C—OMe
1
386
C—OMe
1
387
C—OMe
1
388
C—OMe
1
389
C—OMe
1
390
C—OMe
1
391
C—OMe
1
392
H
N
1
393
Methyl
N
1
394
Ethyl
N
1
395
Propyl
N
1
396
Allyl
N
1
397
i-Propyl
N
1
398
N
1
399
i-Butyl
N
1
400
sec-Butyl
N
1
401
t-Butyl
N
1
402
N
1
403
N
1
404
N
1
405
N
1
406
N
1
407
N
1
408
N
1.
14. The compound of claim 1 , which is selected from compounds of Formula XIX, or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , and n are delineated for each compound in Table 4:
TABLE 4
compound
R 3
X 3
n
409
H
C—H
0
410
Methyl
C—H
0
411
Ethyl
C—H
0
412
Propyl
C—H
0
413
Allyl
C—H
0
414
i-Propyl
C—H
0
415
C—H
0
416
i-Butyl
C—H
0
417
sec-Butyl
C—H
0
418
t-Butyl
C—H
0
419
C—H
0
420
C—H
0
421
C—H
0
422
C—H
0
423
C—H
0
424
C—H
0
425
C—H
0
426
H
C—F
0
427
Methyl
C—F
0
428
Ethyl
C—F
0
429
Propyl
C—F
0
430
Allyl
C—F
0
431
i-Propyl
C—F
0
432
C—F
0
433
i-Butyl
C—F
0
434
sec-Butyl
C—F
0
435
t-Butyl
C—F
0
436
C—F
0
437
C—F
0
438
C—F
0
439
C—F
0
440
C—F
0
441
C—F
0
442
C—F
0
443
H
C—OMe
0
444
Methyl
C—OMe
0
445
Ethyl
C—OMe
0
446
Propyl
C—OMe
0
447
Allyl
C—OMe
0
448
i-Propyl
C—OMe
0
449
C—OMe
0
450
i-Butyl
C—OMe
0
451
sec-Butyl
C—OMe
0
452
t-Butyl
C—OMe
0
453
C—OMe
0
454
C—OMe
0
455
C—OMe
0
456
C—OMe
0
457
C—OMe
0
458
C—OMe
0
459
C—OMe
0
460
H
N
0
461
Methyl
N
0
462
Ethyl
N
0
463
Propyl
N
0
464
Allyl
N
0
465
i-Propyl
N
0
466
N
0
467
i-Butyl
N
0
468
sec-Butyl
N
0
469
t-Butyl
N
0
470
N
0
471
N
0
472
N
0
473
N
0
474
N
0
475
N
0
476
N
0
477
H
C—H
1
478
Methyl
C—H
1
479
Ethyl
C—H
1
480
Propyl
C—H
1
481
Allyl
C—H
1
482
i-Propyl
C—H
1
483
C—H
1
484
i-Butyl
C—H
1
485
sec-Butyl
C—H
1
486
t-Butyl
C—H
1
487
C—H
1
488
C—H
1
489
C—H
1
490
C—H
1
491
C—H
1
492
C—H
1
493
C—H
1
494
H
C—F
1
495
Methyl
C—F
1
496
Ethyl
C—F
1
497
Propyl
C—F
1
498
Allyl
C—F
1
499
i-Propyl
C—F
1
500
C—F
1
501
i-Butyl
C—F
1
502
sec-Butyl
C—F
1
503
t-Butyl
C—F
1
504
C—F
1
505
C—F
1
506
C—F
1
507
C—F
1
508
C—F
1
509
C—F
1
510
C—F
1
511
H
C—OMe
1
512
Methyl
C—OMe
1
513
Ethyl
C—OMe
1
514
Propyl
C—OMe
1
515
Allyl
C—OMe
1
516
i-Propyl
C—OMe
1
517
C—OMe
1
518
i-Butyl
C—OMe
1
519
sec-Butyl
C—OMe
1
520
t-Butyl
C—OMe
1
521
C—OMe
1
522
C—OMe
1
523
C—OMe
1
524
C—OMe
1
525
C—OMe
1
526
C—OMe
1
527
C—OMe
1
528
H
N
1
529
Methyl
N
1
530
Ethyl
N
1
531
Propyl
N
1
532
Allyl
N
1
533
i-Propyl
N
1
534
N
1
535
i-Butyl
N
1
536
sec-Butyl
N
1
537
t-Butyl
N
1
538
N
1
539
N
1
540
N
1
541
N
1
542
N
1
543
N
1
544
N
1.
15. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
17. A method for treating an ASK-1 mediated disease or condition in a subject in need thereof, wherein the ASK-1 mediated disease or condition is an autoimmune disorder, a neurodegenerative disorder, an inflammatory disease, chronic kidney disease, renal disease, cardiovascular disease, a metabolic disease, or an acute or chronic liver disease, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
18. The method according to claim 17 wherein the ASK-1 mediated disease or condition is (a) a chronic liver disease selected from the group consisting of primary biliary cirrhosis (PBC), cerebrotendinous xanthomatosis (CTX), primary sclerosing cholangitis (PSC), drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis (PNAC), bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, or alpha 1-antitrypsin deficiency; (b) a renal disease selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease; (c) a cardiovascular disease selected from the group consisting of atherosclerosis, arteriosclerosis, reperfusion/ischemia in stroke, cardiac hypertrophy, respiratory diseases, heart attacks, and myocardial ischemia; or (d) a metabolic disease selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity.
19. A method for treating a disease selected from the group consisting of glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs. host disease, multiple sclerosis, Sjoegren's syndrome, ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathologic immune responses thrombin-induced platelet aggregation, osteoporosis, osteoarthritis, multiple myeloma-related bone disorder, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), epilepsy, seizures, Huntington's disease, polyglutamine diseases, traumatic brain injury, ischemic and hemorrhaging stroke, cerebral ischemias and neurodegenerative disease caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 .