Pyrazolyl guanidine F
View Patent ↗The invention provides pyrazolyl guanidine compounds that inhibit F 1 F o -ATPase, and methods of using pyrazolyl guanidine compounds as therapeutic agents to treat medical disorders, such as an immune disorder, inflammatory condition, or cancer.
1. A compound represented by Formula I:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenylene or a six-membered heteroarylene;
A 2 is
R 1 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 8 , —C(O)R 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 N(R 10 )(R 11 ), —C(O)N(R 10 )(R 11 ), —N(R 10 )(R 11 ), or —N(R 8 )C(O)(R 9 );
R 2 is hydrogen or alkyl;
R 3 is aryl, aralkyl, cycloalkyl, —(C(R 8 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, —(C(R 8 ) 2 ) m -heterocycloalkyl, alkyl, haloalkyl, hydroxyalkyl, —(C(R 8 ) 2 ) m -alkoxyl, —(C(R 8 ) 2 ) m —O—(C(R 8 ) 2 ) m -alkoxyl, or —(C(R 8 ) 2 ) m —CN, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C 1 -C 6 alkoxy, cyano, and —C 1 -C 6 alkylene-CO 2 R 8 ;
R 4 is hydrogen, alkyl, or —C(O)R 9 ; or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
R 5 is hydrogen or alkyl;
R 6 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl, —CO 2 R 8 , or —C(O)N(R 10 )(R 11 ), wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, hydroxyalkyl, C 1 -C 6 alkoxy, —O-aralkyl, and cyano;
R 7 is hydrogen, halogen, alkyl, or haloalkyl;
R 8 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 8 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 9 represents independently for each occurrence alkyl or cycloalkyl;
R 10 and R 11 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
n is 1, 2, or 3; and
m is 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein A 1 is phenylene.
3. The compound of claim 1 , wherein A 2 is
4. The compound of claim 1 , wherein R 1 is halogen or haloalkyl.
5. The compound of claim 1 , wherein R 1 is chloro, fluoro, or trifluoromethyl.
6. The compound of claim 1 , wherein R 2 and R 4 are hydrogen.
7. The compound of claim 1 , wherein R 3 is alkyl or cycloalkyl.
8. The compound of claim 1 , wherein R 3 is —(C(R 8 ) 2 ) m -alkoxyl.
9. The compound of claim 1 , wherein R 3 is aryl or aralkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
10. The compound claim 1 , wherein R 3 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
11. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
12. The compound of claim 1 , wherein R 3 is benzyl optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, alkyl, and cycloalkyl.
13. The compound of claim 1 , wherein R 5 is hydrogen.
14. The compound of claim 1 , wherein R 6 is alkyl, haloalkyl, cyano, or aryl, wherein said aryl is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, and alkyl.
15. The compound of claim 1 , wherein R 6 is haloalkyl.
16. The compound of claim 1 , wherein R 6 is trifluoromethyl.
17. The compound of claim 1 , wherein R 6 is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and hydroxyl.
18. The compound of claim 1 , wherein R 7 is hydrogen.
19. The compound of claim 1 , wherein n is 1 or 2.
20. A compound represented by Formula I-A1:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
R 1 and R 2 each represent independently for each occurrence hydrogen, chloro, fluoro, or —CF 3 ;
R 3 is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or C 1 -C 6 alkylene-C 1 -C 6 alkoxy, wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano; and
R 4 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, C 1 -C 6 alkoxy, and cyano.
21. The compound of claim 20 , wherein R 1 and R 2 are chloro or fluoro.
22. The compound of claim 20 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
23. The compound of claim 20 , wherein R 4 is trifluoromethyl.
24. A compound represented by Formula II:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenylene or a six-membered heteroarylene;
X is —[C(R 5 ) 2 ] m or —[C(R 5 ) 2 ] p —C(O)-[C(R 5 ) 2 ] p ;
R 1 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 6 , —C(O)R 7 , —S(O)R 7 , —SO 2 R 7 , —SO 2 N(R 8 )(R 9 ), —C(O)N(R 8 )(R 9 ), —N(R 8 )(R 9 ), or —N(R 6 )C(O)(R 7 );
R 2 is hydrogen or alkyl;
R 3 is hydrogen, aryl, aralkyl, cycloalkyl, —(C(R 6 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, —(C(R 6 ) 2 ) m -heterocycloalkyl, alkyl, haloalkyl, hydroxyalkyl, —(C(R 6 ) 2 ) m -alkoxyl, —(C(R 6 ) 2 ) m —O—(C(R 6 ) 2 ) m -alkoxyl, or —(C(R 6 ) 2 ) m —CN, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C 1 -C 6 alkoxy, cyano, and —C 1 -C 6 alkylene-CO 2 R 6 ; or R 3 and a single occurrence of R 5 are taken together with the atoms to which they are attached to form a saturated heterocyclic ring;
R 4 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl, —CO 2 R 6 , or —C(O)N(R 8 )(R 9 ), wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, hydroxyalkyl, C 1 -C 6 alkoxy, —O-aralkyl, and cyano;
R 5 represents independently for each occurrence hydrogen or alkyl; or R 3 and a single occurrence of R 5 are taken together with the atoms to which they are attached to form a saturated heterocyclic ring;
R 6 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 6 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 7 represents independently for each occurrence alkyl or cycloalkyl;
R 8 and R 9 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
n is 1, 2, or 3;
m represents independently for each occurrence 1, 2, 3, 4, or 5; and
p represents independently for each occurrence 0, 1, or 2.
25. The compound of claim 1 , wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:
Com-
pound
No.
Chemical Structure
A-1
A-2
A-3
A-4
A-5
A-6
A-7
A-8
A-9
A-10
A-11
A-12
A-13
A-14
A-15
A-16
A-17
A-18
A-19
A-20
A-21
A-22
A-23
A-24
A-25
A-26
A-27
A-28
A-29
A-30
A-31
A-32
A-33
A-34
A-35
A-36
A-37
A-39
A-40
A-41
A-42
A-43
A-44
A-45
A-46
A-47
A-48
A-49
A-50
A-51
A-52
A-53
A-54
A-55
A-56
A-57
A-58
A-59
A-60
A-61
A-62
A-63
A-64
A-65
A-66
A-67
A-68
A-69
A-70
A-71
A-72
A-73
A-74
A-75
A-76
A-77
A-78
A-79
A-80
A-81
A-82
A-83
A-84
A-85
A-86
A-87
A-88
A-89
A-90
A-91
A-92
A-93
A-94
A-95
A-96
A-97
A-98
A-99
A-100
A-101
A-102
A-103
A-104
A-105
A-106
A-107
A-108
A-109
A-110
A-111
A-112
A-113
A-114
A-115
A-116
A-117
A-118
A-119
A-120
A-121
A-122
A-123
A-124
A-125
A-126
A-127
A-128
A-129
A-130
A-131
A-132
A-133
A-134
A-135
A-136
A-137
A-138
A-139
A-140
A-141
A-142
A-143
A-144
A-145
A-146
A-147
A-148
A-149
A-150
A-151
A-152
A-153
A-154
A-155
A-156
A-157
A-158
A-159
A-160
A-161
A-162
A-163
A-164
A-165
A-166
A-167
A-168
A-169
A-170
A-171
A-172
A-173
A-174
A-175
A-176
A-177
A-178
A-179
A-180
A-181
A-182
A-183
A-184
A-185
A-186
A-187
A-188
A-189
A-190
A-191
A-192
A-193
A-194
A-195
A-196
A-197
A-198
A-199
A-200
A-201
A-202
A-203
A-204
A-205
A-206
A-207
A-208
A-209
A-210
A-211
A-212
A-213
A-214
A-215
A-216
A-217
A-218
A-219
A-220
A-221
A-222
A-223
A-224
A-225
A-226
A-227
A-228
A-229
A-230
A-231
A-232
A-233
A-234
A-235
A-236
A-237
A-238
A-239
A-240
A-241
A-242
A-243
A-244
A-245
A-246
A-247
A-248
A-249
A-250
A-251
A-252
A-253
A-254
A-255
A-256
A-257
A-258
A-259
A-260
A-261
A-262
A-263
A-264
A-265
A-266
A-267
A-268
A-269
A-270
A-271
A-272
A-273
A-274
A-275
A-276
A-277
A-278
A-279
A-280
A-281
A-282
A-283
A-284
A-285
A-286
A-287
A-288
A-289
A-290
A-291
A-292
A-293
A-294
A-295
A-296
A-297
A-298
A-299
A-300
A-301
A-302
A-303
A-304
A-305
A-306
A-307
A-308
A-309
A-310
A-311
A-312
A-313
A-314
A-315
A-316
A-317
A-318
A-319
A-320
A-321
A-322
A-323
A-324
A-325
A-326
A-327
A-328
A-329
A-330
A-331
A-332
A-333
A-334
A-335
A-336
A-337
A-338
A-339
A-340
A-341
A-342
A-343
A-344
A-345
A-346
A-347
A-348
A-349
A-350
A-351
A-352
A-353
A-354
A-355
A-356
A-357
A-358
A-359
A-360
A-361
A-362
A-363
A-364
A-365
A-366
A-367
A-368
A-369
A-370
A-371
A-372
A-373
A-374
A-375
A-376
A-377
A-378
A-379
A-380
A-381
A-382
A-383
A-384
A-385
A-386
A-387
A-388
A-389
A-390
A-391
A-392
A-393
A-394
A-395
A-396
A-397
A-398
A-399
A-400
A-401
A-402
A-403
A-404
A-405
A-406
A-407
A-408
A-409
A-410
A-411
A-412
A-413
A-414
A-415
A-416
A-417
A-418
A-419
A-420
A-421
A-422
A-423
A-424
A-426
A-427
A-428
A-429
A-430
A-431
A-432
A-433
A-434
A-435
A-436
A-437
A-438
A-439
A-440
A-441
A-442
A-443
A-444
A-445
A-446
A-447
A-448
A-449
A-450
A-451
A-452
A-453
A-454
A-455
A-456
A-457
A-458
A-459
A-460
A-461
A-462
A-463
A-464
A-465
A-466
A-467
A-468
A-469
A-470
A-471
A-472
A-473
A-474
A-475
A-476
A-477
A-478
A-479
A-480
A-481
A-482
A-483
A-484
A-485
A-486
A-487
A-488
A-489
A-490
A-491
A-492
A-493
A-494
A-495
A-496
A-497
A-498
A-499
A-500
A-501
A-502
A-503
A-504
A-505
A-506
A-507
A-508
A-509
A-510
A-511
A-512
A-513
A-514
A-515
A-516
A-517
A-518
A-519
A-520
A-521
A-522
A-523
A-524
A-525
A-526
A-527
A-528
A-529
A-530
A-531
A-532
A-533
A-534
A-535
A-536
A-537
A-538
A-539
A-540
A-541
A-542
A-543
A-546
A-547
A-548
A-549
A-550
A-551
A-552
A-553
A-554
A-555
A-556
A-557
A-558
A-559
A-560
A-561
A-562
A-563
A-564
A-565
A-566
A-567
A-570
A-571
A-572
A-573
A-574
A-575
A-576
A-577
A-578
A-579
A-580
A-581
A-582
A-583
A-584
A-585
26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
27. A method of treating a disorder selected from the group consisting of an immune disorder, inflammatory disorder, cardiovascular disease, myeloma, lymphoma, cancer, and bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 in order to ameliorate a symptom of the disorder.
28. A method of inhibiting a F 1 F 0 -ATPase, comprising exposing a F 1 F 0 -ATPase to a compound claim of 1 to inhibit said F 1 F 0 -ATPase.
29. The compound of claim 1 , wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:
No.
A
X
Y
Z
I-1
3-chlorophenyl
H
3-chlorophenyl
I-2
4-chlorophenyl
H
4-chlorophenyl
I-3
3-fluorophenyl
H
3,5-dichlorophenyl
I-4
4-fluorophenyl
H
3-chloro-4-fluorophenyl
I-5
3,4-dichlorophenyl
H
3-chloro-5-fluorophenyl
I-6
3,4-difluorophenyl
H
3-trifluoromethylphenyl
I-7
4-trifluoromethylphenyl
H
3-cyclopropylphenyl
I-8
3-chlorophenyl
H
3-tert-butylphenyl
I-9
4-chlorophenyl
H
2-cyclopropylphenyl
I-10
3-fluorophenyl
H
2-cyclopropyl-4- fluorophenyl
I-11
4-fluorophenyl
H
3-chlorobenzyl
I-12
3,4-dichlorophenyl
H
4-chlorobenzyl
I-13
3,4-difluorophenyl
H
3-fluorobenzyl
I-14
4-trifluoromethylphenyl
H
4-fluorobenzyl
I-15
3-chlorophenyl
H
3-chloro-5-fluorobenzyl
I-16
4-chlorophenyl
H
3,5-dichlorobenzyl
I-17
3-fluorophenyl
H
3,5-difluorobenzyl
I-18
4-fluorophenyl
H
3-cyclopropylbenzyl
I-19
3,4-dichlorophenyl
H
3-trifluoromethylbenzyl
I-20
3,4-difluorophenyl
H
4-trifluoromethylbenzyl
I-21
4-trifluoromethylphenyl
H
cyclopropyl
I-22
3-chlorophenyl
H
cyclopentyl
I-23
4-chlorophenyl
H
cyclohexyl
I-24
3-fluorophenyl
H
4-methylcyclohexyl
I-25
4-fluorophenyl
H
ethyl
I-26
3,4-dichlorophenyl
H
tert-butyl
I-27
3,4-difluorophenyl
H
2,2,2-trifluoroethyl
I-28
4-trifluoromethylphenyl
H
1-methylcyclobutyl
I-29
3-chlorophenyl
H
3-chloro-4-fluorophenyl
I-30
4-chlorophenyl
H
3-chloro-5-fluorophenyl
I-31
3-fluorophenyl
H
3-chlorophenyl
I-32
4-fluorophenyl
H
4-chlorophenyl
I-33
3,4-dichlorophenyl
H
3,5-dichlorophenyl
I-34
3,4-difluorophenyl
H
3-chloro-4-fluorophenyl
I-35
4-trifluoromethylphenyl
H
3-chloro-5-fluorophenyl
I-36
3-chlorophenyl
H
3-trifluoromethylphenyl
I-37
4-chlorophenyl
H
3-chlorophenyl
I-38
3-fluorophenyl
H
4-chlorophenyl
I-39
4-fluorophenyl
H
3,5-dichlorophenyl
I-40
3-chlorophenyl
—C(O)Me
3-chlorophenyl
I-41
4-chlorophenyl
—C(O)Me
4-chlorophenyl
I-42
3-trifluorophenyl
—C(O)Me
3-chloro-4-fluorophenyl
I-43
3-fluorophenyl
—CH 3
3-chlorophenyl
I-44
4-fluorophenyl
—CH 3
4-chlorophenyl
I-45
3-trifluorophenyl
—CH 3
3-chloro-4-fluorophenyl
I-47
H
3-chloro-4-fluorophenyl
I-48
H
4-chlorophenyl
I-49
H
3-chloro-4-fluorophenyl
I-51
H
3-chloro-4-fluorophenyl
I-52
H
4-chlorophenyl
I-53
H
3-chloro-4-fluorophenyl
I-55
H
3-chloro-4-fluorophenyl
I-56
4-trifluoromethylphenyl
H
tert-butyl
I-57
H
tert-butyl
I-58
H
tert-butyl
I-59
H
I-60
H
tert-butyl.
30. The compound of claim 21 , wherein R 3 is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of chloro, fluoro, and trifluoromethyl; and R 4 is trifluoromethyl.
31. A pharmaceutical composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier.
32. A compound represented by Formula I:
including all stereoisomers, geometric isomers, and tautomers; or a pharmaceutically acceptable salt or solvate of any of the foregoing; wherein:
A 1 is phenyl or a six-membered heteroaryl;
A 2 is
R 1 represents independently for each occurrence halogen, haloalkyl, alkyl, cycloalkyl, heterocycloalkyl, hydroxyl, C 1 -C 6 alkoxy, cyano, —CO 2 R 8 , —C(O)R 9 , —S(O)R 9 , —SO 2 R 9 , —SO 2 N(R 10 )(R 11 ), —C(O)N(R 10 )(R 11 ), —N(R 10 )(R 11 ), or —N(R 8 )C(O)(R 9 );
R 2 is hydrogen or alkyl;
R 3 is aryl, aralkyl, cycloalkyl, —(C(R 8 ) 2 ) m -cycloalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, —(C(R 8 ) 2 ) m -heterocycloalkyl, alkyl, haloalkyl, hydroxyalkyl, —(C(R 8 ) 2 ) m -alkoxyl, —(C(R 8 ) 2 ) m —O—(C(R 8 ) 2 ) m -alkoxyl, or —(C(R 8 ) 2 ) m —CN, wherein said aryl, aralkyl, cycloalkyl, heteroaryl, heteroaralkyl, and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, hydroxyalkyl, C 1 -C 6 alkoxy, cyano, and —C 1 -C 6 alkylene-CO 2 R 8 ;
R 4 is hydrogen, alkyl, or —C(O)R 9 ; or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
R 5 is hydrogen or alkyl;
R 6 is alkyl, cycloalkyl, haloalkyl, cyano, aryl, aralkyl, heteroaryl, heteroaralkyl, —CO 2 R 8 , or —C(O)N(R 10 )(R 11 ), wherein said cycloalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, hydroxyalkyl, C 1 -C 6 alkoxy, —O-aralkyl, and cyano;
R 7 is hydrogen, halogen, alkyl, or haloalkyl;
R 8 represents independently for each occurrence hydrogen, alkyl, or cycloalkyl; or two occurrences of R 8 attached to the same carbon atom are taken together with said carbon atom to form a saturated carbocylic ring;
R 9 represents independently for each occurrence alkyl or cycloalkyl;
R 10 and R 11 each represent independently for each occurrence hydrogen, alkyl, or cycloalkyl; or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a 3 to 7 membered heterocyclic ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, and C 1 -C 6 alkoxy;
n is 0; and
m is 1, 2, 3, 4, or 5.