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-alcohol steatohepatitis disease (NASH).
1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof:
wherein;
X 1 and X 2 are independently C(R 8 ) or N;
X 3 is C(R 9 ) or N, in which R 9 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy or halo;
X 4 is S, O, or N(R 10 );
R 1 is selected from
wherein 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 3 , 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 3- to 8-membered heterocycloalkyl-alkyl;
13) Substituted or unsubstituted heteroaryl;
14) Substituted or unsubstituted heteroarylalkyl;
15) —N(R 6 )(R 7 );
16) —S(O) 2 N(R 6 )(R 7 );
17) —N(R 6 ) C(O)R 7 ;
18) —N(R 6 ) S(O) 2 R 6 ; and
9) —OR 6 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, 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 heterocycloalkyl group; and
R 10 is selected from the group consisting of hydrogen, —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each —C 1 -C 8 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylC(O)NH—, arylC(O)NH—, heteroarylC(O)NH—, —CN, alkoxy, —CF 3 , aryl, and heteroaryl.
2. The compound of claim 1 , represented by one of Formula IIa˜Formula IIh or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , and X 4 are as defined in claim 1 .
3. The compound of claim 1 , represented by one of Formula IIIa˜Formula IIId or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , X 3 , and X 4 are as defined in claim 1 .
4. The compound of claim 1 , represented by Formula IV or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 3 , X 3 , and X 4 are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula V or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , R 5 , X 3 , and X 4 are as defined in claim 1 .
6. The compound of claim 1 , represented by Formula VI or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , X 3 , and X 4 are as defined in claim 1 .
7. The compound of claim 1 , represented by Formula VII or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , and X 4 are as defined in claim 1 .
8. The compound of claim 1 , which is selected from compounds of Formula VIII or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 1:
TABLE 1
Compound
R 3
X 3
1
H
C—H
2
Methyl
C—H
3
—CF 3
C—H
4
Ethyl
C—H
5
Propyl
C—H
6
Allyl
C—H
7
i-Propyl
C—H
8
Butyl
C—H
9
t-Butyl
C—H
10
Benzyl
C—H
11
C—H
12
C—H
13
C—H
14
C—H
15
C—H
16
C—H
17
—NH 2
C—H
18
—NHMe
C—H
19
—NHCH 2 Ph
C—H
20
—NHCH(CH 3 ) 2
C—H
21
—N(CH 3 ) 2
C—H
22
—N(CH 2 CH 3 ) 2
C—H
23
—N[CH(CH 3 ) 2 ] 2
C—H
24
C—H
25
C—H
26
C—H
27
C—H
28
C—H
29
C—H
30
C—H
31
C—H
32
C—H
33
C—H
34
C—H
35
C—H
36
C—H
37
C—H
38
C—H
39
C—H
40
C—H
41
C—H
42
H
C—F
43
Methyl
C—F
44
—CF 3
C—F
45
Ethyl
C—F
46
Propyl
C—F
47
Allyl
C—F
48
i-Propyl
C—F
49
Butyl
C—F
50
t-Butyl
C—F
51
Benzyl
C—F
52
C—F
53
C—F
54
C—F
55
C—F
56
C—F
57
C—F
58
—NH 2
C—F
59
—NHMe
C—F
60
—NHCH 2 Ph
C—F
61
—NHCH(CH 3 ) 2
C—F
62
—N(CH 3 ) 2
C—F
63
—N(CH 2 CH 3 ) 2
C—F
64
—N[CH(CH 3 ) 2 ] 2
C—F
65
C—F
66
C—F
67
C—F
68
C—F
69
C—F
70
C—F
71
C—F
72
C—F
73
C—F
74
C—F
75
C—F
76
C—F
77
C—F
78
C—F
79
C—F
80
C—F
81
C—F
82
C—F
83
H
N
84
Methyl
N
85
—CF 3
N
86
Ethyl
N
87
Propyl
N
88
Allyl
N
89
i-Propyl
N
90
Butyl
N
91
t-Butyl
N
92
Benzyl
N
93
N
94
N
95
N
96
N
97
N
98
N
99
—NH 2
N
100
—NHMe
N
101
—NHCH 2 Ph
N
102
—NHCH(CH 3 ) 2
N
103
—N(CH 3 ) 2
N
104
—N(CH 2 CH 3 ) 2
N
105
—N[CH(CH 3 ) 2 ] 2
N
106
N
107
N
108
N
109
N
110
N
111
N
112
N
113
N
114
N
115
N
116
N
117
N
118
N
119
N
120
N
121
N
122
N
123
N .
9. The compound of claim 1 , which is selected from compounds of Formula IX or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 2:
TABLE 2
Compound
R 3
X 3
124
H
C—H
125
Methyl
C—H
126
—CF 3
C—H
127
Ethyl
C—H
128
Propyl
C—H
129
Allyl
C—H
130
i-Propyl
C—H
131
Butyl
C—H
132
t-Butyl
C—H
133
Benzyl
C—H
134
C—H
135
C—H
136
C—H
137
C—H
138
C—H
139
C—H
140
—NH 2
C—H
141
—NHMe
C—H
142
—NHCH 2 Ph
C—H
143
—NHCH(CH 3 ) 2
C—H
144
—N(CH 3 ) 2
C—H
145
—N(CH 2 CH 3 ) 2
C—H
146
—N[CH(CH 3 ) 2 ] 2
C—H
147
C—H
148
C—H
149
C—H
150
C—H
151
C—H
152
C—H
153
C—H
154
C—H
155
C—H
156
C—H
157
C—H
158
C—H
159
C—H
160
C—H
161
C—H
162
C—H
163
C—H
164
C—H
165
H
C—F
166
Methyl
C—F
167
—CF 3
C—F
168
Ethyl
C—F
169
Propyl
C—F
170
Allyl
C—F
171
i-Propyl
C—F
172
Butyl
C—F
173
t-Butyl
C—F
174
Benzyl
C—F
175
C—F
176
C—F
177
C—F
178
C—F
179
C—F
180
C—F
181
—NH 2
C—F
182
—NHMe
C—F
183
—NHCH 2 Ph
C—F
184
—NHCH(CH 3 ) 2
C—F
185
—N(CH 3 ) 2
C—F
186
—N(CH 2 CH 3 ) 2
C—F
187
—N[CH(CH 3 ) 2 ] 2
C—F
188
C—F
189
C—F
190
C—F
191
C—F
192
C—F
193
C—F
194
C—F
195
C—F
196
C—F
197
C—F
198
C—F
199
C—F
200
C—F
201
C—F
202
C—F
203
C—F
204
C—F
205
C—F
206
H
N
207
Methyl
N
208
—CF 3
N
209
Ethyl
N
210
Propyl
N
211
Allyl
N
212
i-Propyl
N
213
Butyl
N
214
t-Butyl
N
215
Benzyl
N
216
N
217
N
218
N
219
N
220
N
221
N
222
—NH 2
N
223
—NHMe
N
224
—NHCH 2 Ph
N
225
—NHCH(CH 3 ) 2
N
226
—N(CH 3 ) 2
N
227
—N(CH 2 CH 3 ) 2
N
228
—N[CH(CH 3 ) 2 ] 2
N
229
N
230
N
231
N
232
N
233
N
234
N
235
N
236
N
237
N
238
N
239
N
240
N
241
N
242
N
243
N
244
N
245
N
246
N.
10. The compound of claim 1 , which is selected from compounds of Formula X or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 3:
TABLE 3
Compound
R 3
X 3
247
H
C—H
248
Methyl
C—H
249
—CF 3
C—H
250
Ethyl
C—H
251
Propyl
C—H
252
Allyl
C—H
253
i-Propyl
C—H
254
Butyl
C—H
255
t-Butyl
C—H
256
Benzyl
C—H
257
C—H
258
C—H
259
C—H
260
C—H
261
C—H
262
C—H
263
—NH 2
C—H
264
—NHMe
C—H
265
—NHCH 2 Ph
C—H
266
—NHCH(CH 3 ) 2
C—H
267
—N(CH 3 ) 2
C—H
268
—N(CH 2 CH 3 ) 2
C—H
269
—N[CH(CH 3 ) 2 ] 2
C—H
270
C—H
271
C—H
272
C—H
273
C—H
274
C—H
275
C—H
276
C—H
277
C—H
278
C—H
279
C—H
280
C—H
281
C—H
282
C—H
283
C—H
284
C—H
285
C—H
286
C—H
287
C—H
288
H
C—F
289
Methyl
C—F
290
—CF 3
C—F
291
Ethyl
C—F
292
Propyl
C—F
293
Allyl
C—F
294
i-Propyl
C—F
295
Butyl
C—F
296
t-Butyl
C—F
297
Benzyl
C—F
298
C—F
299
C—F
300
C—F
301
C—F
302
C—F
303
C—F
304
—NH 2
C—F
305
—NHMe
C—F
306
—NHCH 2 Ph
C—F
307
—NHCH(CH 3 ) 2
C—F
308
—N(CH 3 ) 2
C—F
309
—N(CH 2 CH 3 ) 2
C—F
310
—N[CH(CH 3 ) 2 ] 2
C—F
311
C—F
312
C—F
313
C—F
314
C—F
315
C—F
316
C—F
317
C—F
318
C—F
319
C—F
320
C—F
321
C—F
322
C—F
323
C—F
324
C—F
325
C—F
326
C—F
327
C—F
328
C—F
329
H
N
330
Methyl
N
331
—CF 3
N
332
Ethyl
N
333
Propyl
N
334
Allyl
N
335
i-Propyl
N
336
Butyl
N
337
t-Butyl
N
338
Benzyl
N
339
N
340
N
341
N
342
N
343
N
344
N
345
—NH 2
N
346
—NHMe
N
347
—NHCH 2 Ph
N
348
—NHCH(CH 3 ) 2
N
349
—N(CH 3 ) 2
N
350
—N(CH 2 CH 3 ) 2
N
351
—N[CH(CH 3 ) 2 ] 2
N
352
N
353
N
354
N
355
N
356
N
357
N
358
N
359
N
360
N
361
N
362
N
363
N
364
N
365
N
366
N
367
N
368
N
369
N.
11. The compound of claim 1 , represented by Formula XI or a pharmaceutically acceptable salt thereof:
wherein R 3 , R 4 , X 3 , and X 4 are as defined in claim 1 .
12. The compound of claim 1 , represented by Formula XII or a pharmaceutically acceptable salt thereof:
wherein R 3 , X 3 , and X 4 are as defined in claim 1 .
13. The compound of claim 1 , which is selected from compounds of Formula XIII or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 4:
TABLE 4
Compound
R 3
X 3
370
H
C—H
371
Methyl
C—H
372
—CF 3
C—H
373
Ethyl
C—H
374
Propyl
C—H
375
Allyl
C—H
376
i-Propyl
C—H
377
Butyl
C—H
378
t-Butyl
C—H
379
Benzyl
C—H
380
C—H
381
C—H
382
C—H
383
C—H
384
C—H
385
C—H
386
—NH 2
C—H
387
—NHMe
C—H
388
—NHCH 2 Ph
C—H
389
—NHCH(CH 3 ) 2
C—H
390
—N(CH 3 ) 2
C—H
391
—N(CH 2 CH 3 ) 2
C—H
392
—N[CH(CH 3 ) 2 ] 2
C—H
393
C—H
394
C—H
395
C—H
396
C—H
397
C—H
398
C—H
399
C—H
400
C—H
401
C—H
402
C—H
403
C—H
404
C—H
405
C—H
406
C—H
407
C—H
408
C—H
409
C—H
410
C—H
411
H
C—F
412
Methyl
C—F
413
—CF 3
C—F
414
Ethyl
C—F
415
Propyl
C—F
416
Allyl
C—F
417
i-Propyl
C—F
418
Butyl
C—F
419
t-Butyl
C—F
420
Benzyl
C—F
421
C—F
422
C—F
423
C—F
424
C—F
425
C—F
426
C—F
427
—NH 2
C—F
428
—NHMe
C—F
429
—NHCH 2 Ph
C—F
430
—NHCH(CH 3 ) 2
C—F
431
—N(CH 3 ) 2
C—F
432
—N(CH 2 CH 3 ) 2
C—F
433
—N[CH(CH 3 ) 2 ] 2
C—F
434
C—F
435
C—F
436
C—F
437
C—F
438
C—F
439
C—F
440
C—F
441
C—F
442
C—F
443
C—F
444
C—F
445
C—F
446
C—F
447
C—F
448
C—F
449
C—F
450
C—F
451
C—F
452
H
N
453
Methyl
N
454
—CF 3
N
455
Ethyl
N
456
Propyl
N
457
Allyl
N
458
i-Propyl
N
459
Butyl
N
460
t-Butyl
N
461
Benzyl
N
462
N
463
N
464
N
465
N
466
N
467
N
468
—NH 2
N
469
—NHMe
N
470
—NHCH 2 Ph
N
471
—NHCH(CH 3 ) 2
N
472
—N(CH 3 ) 2
N
473
—N(CH 2 CH 3 ) 2
N
474
—N[CH(CH 3 ) 2 ] 2
N
475
N
476
N
477
N
478
N
479
N
480
N
481
N
482
N
483
N
484
N
485
N
486
N
487
N
488
N
489
N
490
N
491
N
492
N.
14. The compound of claim 1 , which is selected from compounds of Formula XIV or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 5:
TABLE 5
Compound
R 3
X 3
493
H
C—H
494
Methyl
C—H
495
—CF 3
C—H
496
Ethyl
C—H
497
Propyl
C—H
498
Allyl
C—H
499
i-Propyl
C—H
500
Butyl
C—H
501
t-Butyl
C—H
502
Benzyl
C—H
503
C—H
504
C—H
505
C—H
506
C—H
507
C—H
508
C—H
509
—NH 2
C—H
510
—NHMe
C—H
511
—NHCH 2 Ph
C—H
512
—NHCH(CH 3 ) 2
C—H
513
—N(CH 3 ) 2
C—H
514
—N(CH 2 CH 3 ) 2
C—H
515
—N[CH(CH 3 ) 2 ] 2
C—H
516
C—H
517
C—H
518
C—H
519
C—H
520
C—H
521
C—H
522
C—H
523
C—H
524
C—H
525
C—H
526
C—H
527
C—H
528
C—H
529
C—H
530
C—H
531
C—H
532
C—H
533
C—H
534
H
C—F
535
Methyl
C—F
536
—CF 3
C—F
537
Ethyl
C—F
538
Propyl
C—F
539
Allyl
C—F
540
i-Propyl
C—F
541
Butyl
C—F
542
t-Butyl
C—F
543
Benzyl
C—F
544
C—F
545
C—F
546
C—F
547
C—F
548
C—F
549
C—F
550
—NH 2
C—F
551
—NHMe
C—F
552
—NHCH 2 Ph
C—F
553
—NHCH(CH 3 ) 2
C—F
554
—N(CH 3 ) 2
C—F
555
—N(CH 2 CH 3 ) 2
C—F
556
—N[CH(CH 3 ) 2 ] 2
C—F
557
C—F
558
C—F
559
C—F
560
C—F
561
C—F
562
C—F
563
C—F
564
C—F
565
C—F
566
C—F
567
C—F
568
C—F
569
C—F
570
C—F
571
C—F
572
C—F
573
C—F
574
C—F
575
H
N
576
Methyl
N
577
—CF 3
N
578
Ethyl
N
579
Propyl
N
580
Allyl
N
581
i-Propyl
N
582
Butyl
N
583
t-Butyl
N
584
Benzyl
N
585
N
586
N
587
N
588
N
589
N
590
N
591
—NH 2
N
592
—NHMe
N
593
—NHCH 2 Ph
N
594
—NHCH(CH 3 ) 2
N
595
—N(CH 3 ) 2
N
596
—N(CH 2 CH 3 ) 2
N
597
—N[CH(CH 3 ) 2 ] 2
N
598
N
599
N
600
N
601
N
602
N
603
N
604
N
605
N
606
N
607
N
608
N
609
N
610
N
611
N
612
N
613
N
614
N
615
N.
15. The compound of claim 1 , which is selected from compounds of Formula XV or a pharmaceutically acceptable salt thereof:
wherein R 3 and X 3 are delineated for each compound in Table 6:
TABLE 6
Compound
R 3
X 3
616
H
C—H
617
Methyl
C—H
618
—CF 3
C—H
619
Ethyl
C—H
620
Propyl
C—H
621
Allyl
C—H
622
i-Propyl
C—H
623
Butyl
C—H
624
t-Butyl
C—H
625
Benzyl
C—H
626
C—H
627
C—H
628
C—H
629
C—H
630
C—H
631
C—H
632
—NH 2
C—H
633
—NHMe
C—H
634
—NHCH 2 Ph
C—H
635
—NHCH(CH 3 ) 2
C—H
636
—N(CH 3 ) 2
C—H
637
—N(CH 2 CH 3 ) 2
C—H
638
—N[CH(CH 3 ) 2 ] 2
C—H
639
C—H
640
C—H
641
C—H
642
C—H
643
C—H
644
C—H
645
C—H
646
C—H
647
C—H
648
C—H
649
C—H
650
C—H
651
C—H
652
C—H
653
C—H
654
C—H
655
C—H
656
C—H
657
H
C—F
658
Methyl
C—F
659
—CF 3
C—F
660
Ethyl
C—F
661
Propyl
C—F
662
Allyl
C—F
663
i-Propyl
C—F
664
Butyl
C—F
665
t-Butyl
C—F
666
Benzyl
C—F
667
C—F
668
C—F
669
C—F
670
C—F
671
C—F
672
C—F
673
—NH 2
C—F
674
—NHMe
C—F
675
—NHCH 2 Ph
C—F
676
—NHCH(CH 3 ) 2
C—F
677
—N(CH 3 ) 2
C—F
678
—N(CH 2 CH 3 ) 2
C—F
679
—N[CH(CH 3 ) 2 ] 2
C—F
680
C—F
681
C—F
682
C—F
683
C—F
684
C—F
685
C—F
686
C—F
687
C—F
688
C—F
689
C—F
690
C—F
691
C—F
692
C—F
693
C—F
694
C—F
695
C—F
696
C—F
697
C—F
698
H
N
699
Methyl
N
700
—CF 3
N
701
Ethyl
N
702
Propyl
N
703
Allyl
N
704
i-Propyl
N
705
Butyl
N
706
t-Butyl
N
707
Benzyl
N
708
N
709
N
710
N
711
N
712
N
713
N
714
—NH 2
N
715
—NHMe
N
716
—NHCH 2 Ph
N
717
—NHCH(CH 3 ) 2
N
718
—N(CH 3 ) 2
N
719
—N(CH 2 CH 3 ) 2
N
720
—N[CH(CH 3 ) 2 ] 2
N
721
N
722
N
723
N
724
N
725
N
726
N
727
N
728
N
729
N
730
N
731
N
732
N
733
N
734
N
735
N
736
N
737
N
738
N.
16. 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
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
17. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
18. A method for treating an ASK-1 mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of claim 1 .
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, Sjoegren's syndrome, stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, congestive heart failure, pathologic immune responses such as that caused by T cell activation, 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, including apoptosis-driven neurodegenerative disease, caused by traumatic injury, acute hypoxia, ischemia and glutamate neurotoxicity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
20. A pharmaceutical composition comprising a compound according to claim 16 and a pharmaceutically acceptable carrier.