US2023030115A1PendingUtilityA1
Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
Assignee: BEIJING TIDE PHARMACEUTICAL CO LTDPriority: Jun 30, 2017Filed: Jul 6, 2021Published: Feb 2, 2023
Est. expiryJun 30, 2037(~11 yrs left)· nominal 20-yr term from priority
Inventors:Yanping ZhaoHongjun WangGong LiYuanyuan JiangXiang LiBin LiuWeiting ZhongKai LiuFajie LiLiying ZhouYanan Liu
C07D 471/10C07D 403/14C07D 487/04C07D 495/04C07D 491/048C07D 453/02A61P 27/02A61K 31/506A61P 33/00C07F 9/65583A61P 37/06C07D 401/14C07D 519/00A61P 29/00A61P 35/00A61P 31/10A61K 31/416A61P 37/00A61P 21/04A61P 7/02C07D 513/04A61P 19/02C07D 405/14C07D 471/04C07D 413/14A61P 37/08A61P 3/00A61P 11/00A61P 5/50C07D 417/14C07D 409/14A61P 9/00A61P 17/00A61P 17/06A61P 19/10A61P 13/12A61P 31/12A61P 3/10A61P 9/10A61P 25/00A61P 1/18
62
PatentIndex Score
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Cited by
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References
0
Claims
Abstract
The present invention relates to a Rho-associated protein kinase inhibitor of formula (I), a pharmaceutical composition comprising the same, a preparation method thereof, and a use of the same in preventing or treating a disease mediated by Rho-associated protein kinase (ROCK).
Claims
exact text as granted — not AI-modified1 - 18 . (canceled)
19 . A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein the compound has the structure of Formula (I):
wherein:
X and Y are each independently selected from the group consisting of a direct bond, C(═O), O, S(═O) i and NR, provided that at least one of X and Y is not a direct bond;
R is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, saturated or partially unsaturated C 3-10 cyclic hydrocarbyl, saturated or partially unsaturated 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl, and at most 2 ring members in the cyclic hydrocarbyl and heterocyclyl are C(═O);
ring A and ring B are each independently selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O); provided that when ring B is a heterocycle containing a nitrogen atom, ring B is not attached to X via the nitrogen atom;
ring C is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);
ring D is absent, or is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);
ring E is selected from the group consisting of
ring F is selected from the group consisting of saturated or partially unsaturated C 3-10 hydrocarbon ring, saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aromatic ring and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the hydrocarbon ring and heterocycle are C(═O);
R 1 is selected from the group consisting of H, —NH 2 , C 1-6 alkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, N-methylpyrrolidinyl, N-methylpiperidinyl,
—C(═O)—(C 1-6 alkylene) n -CF 3 , —C(═O)—(C 1-6 alkylene) n -CN, —C(═O)-(saturated or partially unsaturated C 3-10 cyclic hydrocarbyl), —NHC(═O)-(saturated or partially unsaturated C 3-10 cyclic hydrocarbyl), —C(═O)-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), —C(═O)—C 1-6 alkylene-(saturated or partially unsaturated 3- to 10-membered heterocyclyl), —C(═O)-(5- to 14-membered heteroaryl), —C(═O)—C 1-6 alkylene-NH(C 1-6 alkyl), —C(═O)—C 1-6 alkylene-N(C 1-6 alkyl) 2 , N-methylpiperazine substituted acetyl, —S(═O) 2 R 1a , —P(═O)R 1a R 1b ,
provided that when one of R 1 and R 10 is C 1-6 alkyl, and the other is FI or C 3-10 cyclic hydrocarbyl, then at least one of X and Y is a direct bond, and ring C is not a 5-membered heteroaromatic ring; when one of R 1 and R 10 is H, and the other is
then ring C is not a 5-membered heteroaromatic ring; when both R 1 and R 10 are H, then ring A contains at least one nitrogen atom, and is not a 5- or 6-membered ring; when one of R 1 and R 10 is H, and the other is
then ring C is not a 5-membered heteroaromatic ring; and when one of R 1 and R 10 is H, and the other is FI or acetyl, then ring D is absent;
R 1a and R 1b are each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 , —C 1-6 alkylene-OR 5 and —O—C 1-6 alkylene-NR 5 R 6 , provided that when one of R 1a and R 1b is n-propyl, the other is not H; or R 1a and R 1b together with the atom to which they are attached form a 3- to 12-membered heterocycle or heteroaromatic ring;
R 2 , R 3 , R 4 , R 7 , R 8 , R 9 and R 10 , at each occurrence, are each independently selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 , —C 1-6 alkylene-O(P═O)(OH) 2 and —O—C 1-6 alkylene-NR 5 R 6 ;
the above alkyl, alkylene, alkenyl, alkynyl, cyclic hydrocarbyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaromatic ring and aralkyl, at each occurrence, are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, ═N—OR 5 , —C(═NH)NH 2 , —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 alkylene-NR 5 R 6 , and the alkyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, oxo, amino, cyano, nitro, C 1-6 alkyl, C 3-6 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
R 5 and R 6 , at each occurrence, are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
m, at each occurrence, is each independently an integer selected from 0, 1, 2 and 3;
n is an integer selected from 0, 1 and 2;
i is an integer selected from 0, 1 and 2; and
g is an integer selected from 0, 1, 2, 3 and 4.
20 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein X and Y are each independently selected from the group consisting of a direct bond, C(═O), O, S, S(═O), S(═O) 2 , NH and NCH 3 , and at least one of X and Y is a direct bond, provided that at least one of X and Y is not a direct bond.
21 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position,
wherein:
represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;
Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CR 9 , C(R 9 ) 2 , CR 10 , C(R 10 ) 2 , C(═O), N, NR 9 , NR 10 , O and S; and
j is 0, 1, 2, 3 or 4;
provided that at most two groups among Z 1 -Z 9 are simultaneously C(═O), and the atom attached to X is not a nitrogen atom;
R 9 and R 10 , at each occurrence, are each independently selected from the group consisting of halogen, methyl, ethyl, propyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, —CH 2 CHF 2 , acetyl, —OCH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 —O(P═O)(OH) 2 ,
and —CH 2 CH 2 —N(CH 3 ) 2
22 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
R 7 and R 8 , at each occurrence, are each independently selected from the group consisting of F, Cl, Br, I, cyano, —N(CH 3 ) 2 , methyl, ethyl, propyl, methoxy, trifluoromethyl, phenyl, —CH 2 -Ph, —NH-Ph, —O-Ph, —CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 —NHCH 3 , —C(═O)CH 3 , —C(═O)OH, —C(═O)OCH 2 CH 3 , —C(═O)NH 2 , —O—CH 2 CH 2 —N(CH 3 ) 2 and —CH 2 CH 2 —N(CH 3 ) 2
23 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein ring E is
R 3 and R 4 , at each occurrence, are each independently selected from the group consisting of H, F, Cl, Br, I, —OH, methyl, ethyl, propyl, methoxy, —NH 2 , —N(CH 3 ) 2 , and —O-ethylene-N(CH 3 ) 2 .
24 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein R 1 is selected from the group consisting of methyl, —CH 2 OH,
—C(═O)CF 3 , —C(═O)CH 2 CF 3 , —C(═O)CH 2 CN, —C(═O)OCH 3 , —C(═O)OC(CH 3 ) 3 ,
—S(═O) 2 CH 2 CH 3 ,
—C(═O)CH 2 N(CH 3 ) 2 ,
25 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein R 1a and R 1b are each independently selected from the group consisting of H, methyl, —CF 3 , ethyl, —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH(CH 3 )CF 3 , n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -ethylene-O-methyl, —CH 2 CN, —CH 2 CH 2 CN, —CH 2 CH 2 OH,
or R 1a and R 1b together with the atom to which they are attached form a group selected from the group consisting of:
26 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein the compound has a structure selected from the group consisting of the following formulae:
wherein:
Z is selected from the group consisting of O, S(═O) i and NR;
ring A′ and ring B′ are each independently selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycles and 5- to 14-membered heteroaromatic rings, and at most 2 ring members in the heterocycle are C(═O); provided that when ring B′ is a heterocycle containing a nitrogen atom, ring B′ is not attached to X via the nitrogen atom;
R 7′ is selected from the group consisting of H, halogen, —NH 2 , —OH, C 1-6 alkyl and —OR 5 ;
R 11 is selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 alkylene-NR 5 R 6 ; and
each of the remaining groups is as defined in claim 19 .
27 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein the compound has the structure of formula (XVII) or formula (XVIF):
wherein:
R is selected from the group consisting of H and C 1-6 alkyl;
ring D is selected from the group consisting of a saturated or partially unsaturated 3- to 10-membered heterocycle, C 6-10 aryl and a 5- to 10-membered heteroaromatic ring;
R 2 is selected from the group consisting of H and C 1-6 alkyl;
R 3 , R 4 , R 7 , R 7′ and R 8 , at each occurrence, are each independently selected from the group consisting of H, halogen, —NH 2 , —OH, C 1-6 alkyl and —OR 5 ;
R 9 and R 10 , at each occurrence, are each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 and —C 1-6 alkylene-O(P═O)(OH) 2 ;
wherein any of the above alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, heteroaromatic ring and aralkyl, at each occurrence, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl and —OR 5 ;
R 5 and R 6 , at each occurrence, are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl and C 6-12 aralkyl;
m, at each occurrence, is independently an integer selected from 0, 1, 2 and 3; and
n is an integer selected from 0, 1 and 2.
28 . The compound according to claim 19 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein the compound is selected from the group consisting of:
No.
Structural Formula
TDI01102
TDI01103
TDI01104
TDI01105
TDI01106
TDI01107
TDI01108
TDI01109
TDI01110
TDI01111
TDI01112
TDI01113
TDI01114
TDI01115
TDI01116
TDI01117
TDI01118
TDI01119
TDI01120
TDI01121
TDI01122
TDI01127
TDI01128
TDI01129
TDI01130
TDI01131
TDI01132
TDI01133
TDI01134
TDI01135
TDI01136
TDI01139
TDI01140
TDI01141
TDI01142
TDI01143
TDI01144
TDI01145
TDI01146
TDI01147
TDI01148
TDI01149
TDI01150
TDI01151
TDI01152
TDI01153
TDI01154
TDI01155
TDI01156
TDI01157
TDI01158
TDI01159
TDI01160
TDI01161
TDI01162
TDI01163
TDI01164
TDI01165
TDI01166
TDI01167
TDI01168
TDI01169
TDI01171
TDI01172
TDI01173
TDI01174
TDI01175
TDI01176
TDI01177
TDI01178
TDI01179
TDI01180
TDI01181
TDI01182
TDI01183
TDI01184
TDI01185
TDI01186
TDI01187
TDI01188
TDI01189
TDI01190
TDI01191
TDI01192
TDI01193
TDI01194
TDI01195
TDI01196
TDI01197
TDI01198
TDI01199
TDI01200
TDI01201
TDI01209
TDI01211
TDI01212
TDI01213
TDI01214
TDI01215
TDI01216
TDI01217
TDI01218
TDI01219
TDI01220
TDI01211
TDI01222
TDI01223
TDI01224
TDI01225
TDI01226
TDI01227
TDI01228
TDI01229
TDI01230
TDI01231
TDI01232
TDI01233
TDI01234
TDI01235
TDI01236
TDI01237
TDI01238
TDI01239
TDI01240
TDI01241
TDI01242
TDI01243
TDI01244
TDI01245
TDI01246
TDI01247
TDI01248
TDI01249
TDI01250
TDI01251
TDI01253
TDI01254
TDI01255
TDI01256
TDI01257
TDI01258
TDI01259
TDI01260
TDI01261
TDI01262
TDI01263
TDI01264
TDI01265
TDI01266
TDI01267
TDI01268
TDI01271
TDI01272
TDI01273
TDI01274
TDI01275
TDI01276
TDI01277
TDI01278
TDI01280
TDI01281
TDI01282
TDI01283
TDI01285
TDI01286
TDI01287
TDI01288
TDI01289
TDI01290
TDI01291
TDI01292
TDI01294
TDI01295
TDI01296
TDI01297
TDI01298
TDI01299
TDI01300
TDI01310
TDI01311
TDI01312
TDI01314
TDI01315
TDI01316
TDI01317
TDI01318
TDI01319
TDI01320
TDI01321
TDI01322
TDI01323
TDI01324
TDI01325
TDI01326
TDI01327
TDI01328
TDI01329
TDI01330
TDI01331
TDI01332
TDI01333
TDI01334
TDI01335
TDI01336
TDI01337
TDI01338
TDI01339
TDI01340
TDI01341
TDI01342
TDI01343
TDI01344
TDI01345
TDI01346
TDI01347
TDI01348
TDI01348P-2
TDI01350
TDI01351
TDI01353
TDI01354
TDI01355
TDI01356
TDI01357
TDI01358
TDI01360
TDI01360P-1
TDI01361
TDI01362
TDI01363
TDI01364
TDI01365
TDI01366
TDI01367
TDI01368
TDI01369
TDI01370
TDI01371
TDI01372
TDI01373
TDI01374
TDI01375
TDI01376
TDI01379
TDI01380
TDI01381
TDI01382
TDI01383
TDI01384
TDI01385
TDI01386
TDI01387
TDI01388
TDI01389
TDI01399
TDI01391
TDI01392
TDI01393
TDI01394
TDI01395
TDI01396
TDI01397
TDI01398
TDI01399
TDI01400
TDI01402
TDI01344-2A
TDI01403
TDI01404
TDI01405
TDI01406
TDI01407
TDI01408
TDI01410
TDI01411
TDI01415
TDI01416
TDI01417
TDI01418
TDI01419
TDI01420
TDI01421
TDI01422
TDI01423
TDI01424
TDI01425
TDI01426
TDI01427
TDI01428
TDI01429
TDI01430
TDI01431
TDI01432
TDI01433
TDI01434
TDI01435
TDI01436
TDI01437
TDI01438
TDI01439
TDI01440
TDI01441
TDI01442
TDI01443
TDI01444
TDI01445
TDI01446
TDI01447
TDI01448
TDI01449
TDI01450
TDI01451
TDI01452
TDI01453
TDI01454
TDI01455
TDI01456
TDI01457
TDI01458
TDI01459
TDI01460
TDI01461
TDI01462
TDI01463
TDI01464
TDI01465
TDI01466
TDI01467
TDI01468
TDI01469
TDI01470
TDI01471
TDI01472
TDI01473
TDI01474
TDI01475
TDI01476
TDI01477
TDI01478
TDI01479
TDI01480
TDI01481
TDI01482
TDI01483
TDI01484
TDI01485
TDI01486
TDI01487
TDI01488
TDI01489
TDI01490
TDI01491
TDI01492
TDI01493
TDI01494
TDI01495
TDI01496
TDI01497
TDI01498
TDI01499
TDI01500
TDI01501
TDI01502
TDI01503
TDI01504
TDI01505
TDI01506
TDI01507
TDI01508
TDI01509
TDI01510
TDI01511
TDI01512
TD101513
TDI01514
TDI01515
TDI01516
TDI01517
TDI01518
TDI01519
TDI01520
TDI01521
TDI01522
TDI01523
TDI01524
TDI01525
TDI01526
TDI01529
TDI01530
TDI01531
TDI01532
TDI01533
TDI01534
TDI01535
TDI01536
TDI01537
TDI01538
TDI01543
TDI01544
TDI01545
TDI01546
TDI01547
TDI01550
TDI01551
TDI01552
TDI-1553
TDI01554
TDI01555
TDI01556
TDI01557
TDI01557B
TDI01558
TDI01559
TDI01560
TDI01561
TDI01562
TDI01563
TDI01564
TDI01565
TDI01566
TDI01567
TDI01567B
TDI01567C
TDI01569
TDI01570
TDI01571
TDI01571B
TDI01572
TDI01573
TDI01574
TDI01575
TDI01578
TDI01579
TDI01580
TDI01581
TDI01582
TDI01583
TDI01584
TDI01585
TDI01586
TDI01587
TDI01588
TDI01589
TDI01590
TDI01591
TDI01592
TDI01593
TDI01594
TDI01594B
TDI01596
TDI01596B
TDI01597
TDI01597B
TDI01598
TDI01609
TDI01611
TDI01613
TDI01615
TDI01617
TDI01618A
TDI01620
TDI01621
TDI01622
TDI01623
TDI01628
TDI01633
TDI01634
TDI01653
TDI01654
TDI01655
TDI01656
TDI01657
TDI01658
TDI01659
TDI01662
TDI01665
TDI01666
TDI01667
TDI01668
TDI01670
TDI01672
TDI01673
TDI01674
TDI01675
TDI01676
TDI01678
TDI01681
TDI01682
TDI01683
TDI01684
TDI01689
TDI01690
TDI01691
TDI01692
TDI01693
TDI01694
TDI01695
TDI01698
TDI01706
TDI01708
TDI01709
TDI01710
TDI01712
TDI01714
TDI01715
TDI01721
TDI01801
TDI01802
TDI01803
TDI01804
TDI01806
TDI01807
TDI01808
TDI01809
TDI01810
TDI01811
TDI01812
TDI01813
TDI01814
TDI01815
TDI01816
TDI01816B
TDI01818
TDI01819
TDI01820
TDI01821
TDI01822
TDI01823
TDI01824
TDI01825
TDI01825B
TDI01825C
TDI01826
TDI01827
TDI01829
TDI01829B
TDI01829C
TDI01830
TDI01831
TDI01832
TDI01833
TDI01834
TDI01835
TDI01836
TDI01837
TDI01838
TDI01839
TDI01840
TDI01841
TDI01842
TDI01842B
TDI01843
TDI01844
TDI01845
TDI01846
TDI01847
TDI01847B
TDI01848
TDI01849
TDI01849B
TDI01850
TDI01851
TDI01852
TDI01853
TDI01854
TDI01855
TDI01856
TDI01861
TDI01862
TDI01863
TDI01864
TDI01865
TDI01867
TDI01868
TDI01869
TDI01870
TDI01871
TDI01872
TDI01873
TDI01874
TDI01875
TDI01876
TDI01876B
TDI01877
TDI01878
TDI01879
TDI01880
TDI01881
TDI01882
TDI01883
TDI01884
TDI01885
TDI01886
TDI01887
TDI01888
TDI01890
TDI01891
TDI01892
TDI01893
TDI01894
TDI01898
TDI01898B
TDI01899
TDI01900
TDI01901
TDI01902
TDI01903
TDI01904
TDI01905
TDI01906
TDI01907
TDI01908
TDI01909
TDI01910
TDI01911
TDI01912
TDI01913
TDI01914
TDI01915
TDI01916
TDI01917
TDI01918
TDI01919
TDI01920
TDI01921
TDI01923
TDI01924
TDI01925
TDI01926
TDI01927
TDI01928
TDI01929
TDI01930
TDI01931
TDI01932
TDI01933
TDI01934
TDI01935
TDI01936
TDI01937B
TDI01938
TDI01939
TDI01940
TDI01941
TDI01942
TDI01943
TDI01944
TDI01945
TDI01946
TDI01947
TDI01948
TDI01949
TDI01950
TDI01951
TDI01952
TDI01953
TDI01954
TDI01955
TDI01956
TDI01957
TDI01958
TDI01959
TDI01960
TDI01962
TDI01965
TDI01966
TDI01967
TDI01968A
TDI01968B
TDI01969
TDI01972
TDI01973
TDI01974
TDI01975
TDI01976
TDI01978
TDI01979
TDI01989
TDI01990
TDI01991
TDI01995
TDI01996
TDI01998
and
TDI01999
29 . A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound according to claim 19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound.
30 . A method of inhibiting a Rho-associated protein kinase (ROCK), preferably ROCK2, comprising administering an effective amount of the compound according to claim 19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof to a subject in need thereof.
31 . A method for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, to a subject in need thereof, wherein the disease is selected from an autoimmune disorder selected from rheumatoid arthritis, systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn's disease, atopic dermatitis, eczema, and graft-versus-host disease (GVHD); a cardiovascular disorder selected from hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, or erectile dysfunction); inflammation (associated with or comprising asthma, cardiovascular inflammation, ulcerative colitis, and renal inflammation); a central nervous system disorder selected from neuronal degeneration or spinal cord injury; or a central nervous system disorder selected from Huntington's disease, Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), or multiple sclerosis; an arterial thrombotic disorder selected from platelet aggregation, and leukocyte aggregation; a fibrotic disorder selected from liver fibrosis, lung fibrosis, and kidney fibrosis; a neoplastic disease or cancer; a metabolic syndrome; insulin resistance; hyperinsulinemia; type 2 diabetes; glucose intolerance; osteoporosis; an ocular disorder selected from ocular hypertension, age related macular degeneration (AMD), choroidal neovascularization (CNV), diabetic macular edema (DME), iris neovascularization, uveitis, glaucoma (including primary open-angle glaucoma, acute angle-closure glaucoma, pigmentary glaucoma, congenital glaucoma, normal tension glaucoma, secondary glaucoma or neo vascular glaucoma), or retinitis of prematurity (ROP).
32 . A method for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK), comprising administering an effective amount of the compound according to claim 19 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof to a subject in need thereof, wherein the disease is selected from lupus nephritis, atherosclerosis, rheumatoid arthritis (RA), hemangioma, angiofibroma, lung fibrosis, psoriasis, corneal graft rejection, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Crohn's disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograft rejection, allergic inflammation, contact dermatitis, delayed hypersensitivity, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, neuronal inflammation, Osier-Weber syndrome, restenosis, fungal infection, parasitic infection and viral infection.
33 . A method for the preparation of a compound of Formula (II), wherein the method comprises the following steps:
wherein:
R 2 is H;
Hal 1 and Hal 2 are same or different halogens;
PG 1 is a carboxy protecting group;
PG 2 is H or an amino protecting group;
R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;
the remaining groups are as defined in claim 19 ;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, to obtain compound c-1; and
step 3: reacting compound c-1 with compound REG-2, to obtain the compound of Formula (II);
alternatively, the method comprises the following steps:
wherein each of the groups is as defined above;
the reaction conditions for each step are as follows:
step 1: reacting compound a-2 with compound REG-2, to obtain compound b-2;
step 2: reacting compound b-2 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound c-2; and
step 3: reacting compound c-2 with compound REG-1 under the catalysis of a palladium catalyst, to obtain the compound of Formula (II); or
alternatively, the method comprises the following steps:
wherein each of the groups is as defined above;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: deprotecting compound b-1 under a condition corresponding to PG 1 , to obtain compound c-3;
step 3: reacting compound c-3 with compound REG-2, to obtain compound d-3; and
step 4: reacting compound d-3 with compound REG-1 under the catalysis of a palladium catalyst, to obtain the compound of Formula (II).
34 . A method for the preparation of a compound of Formula (XII), wherein the method comprises the following steps:
wherein:
R 2 is H;
Hal 1 and Hal 2 are same or different halogens;
PG 1 is a carboxy protecting group;
PG 2 is H or an amino protecting group;
R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;
the remaining groups are as defined in claim 19 ;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: reacting compound b-1 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain compound c-1′; and
step 3: reacting compound c-1′ with compound REG-2′, to obtain the compound of Formula (XII).
35 . A method for the preparation of a compound of Formula (XIII), wherein the
wherein:
R 2 is H;
Hal 1 and Hal 2 are same or different halogens;
PG 1 is a carboxy protecting group;
PG 2 is H or an amino protecting group;
R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;
the remaining groups are as defined in claim 19 ;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: reacting compound b-1 with compound REG-1 under the catalysis of a palladium catalyst, to obtain compound c-1; and
step 3: reacting compound c-1 with compound REG-2′, to obtain the compound of Formula (XIII).
36 . A method for the preparation of a compound of Formula (XIV), wherein the method comprises the following steps:
wherein:
R 2 is H;
Hal 1 and Hal 2 are same or different halogens;
PG 1 is a carboxy protecting group;
PG 2 is FI or an amino protecting group;
R a and R a′ , at each occurrence, are each independently selected from the group consisting of H and C 1-6 alkyl; or R a and R a′ together with the group to which they are attached form a 5- to 10-membered ring system;
the remaining groups are as defined in claim 19 ;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: reacting compound b-1 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain compound c-1′; and
step 3: reacting compound c-1′ with compound REG-2, to obtain the compound of Formula (XIV); or
alternatively, the method comprises the following steps:
wherein each of the groups is as defined above;
the reaction conditions for each step are as follows:
step 1: reacting compound a-2 with compound REG-2, to obtain compound b-2;
step 2: reacting compound b-2 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound c-2; and
step 3: reacting compound c-2 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain the compound of Formula (XIV); or
alternatively, the method comprises the following steps:
wherein each of the groups is as defined above;
the reaction conditions for each step are as follows:
step 1: reacting compound a-1 with a boric acid or borate under the catalysis of a palladium catalyst, to obtain compound b-1;
step 2: deprotecting compound b-1 under a condition corresponding to PG 1 , to obtain compound c-3;
step 3: reacting compound c-3 with compound REG-2, to obtain compound d-3; and
step 4: reacting compound d-3 with compound REG-1′ under the catalysis of a palladium catalyst, to obtain the compound of Formula (XIV).
37 . The compound according to claim 21 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCH 3 , CH 2 , C(CH 3 ) 2 , C—OCH 3 , C(═O), N, NH, NCH 3 , NCH 2 CH 3 , NCH(CH 3 ) 2 , NCH═CH 2 , NCH 2 F, NCHF 2 , NCH 2 CHF 2 , NC(═O)CH 3 , NCH 2 OH, NCH 2 OMe, NCH 2 CH 2 OMe, NCH 2 —O(P═O)(OH) 2 ,
NCH 2 CH 2 —N(CH 3 ) 2 , O and S.
38 . The compound according to claim 21 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position,
wherein:
represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;
Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CR 9 , C(R 9 ) 2 , CR 10 , C(R 10 ) 2 , C(═O), N, NR 9 , NR 10 , O and S; and
j is 0, 1, 2, 3 or 4;
provided that at most two groups among Z 1 -Z 9 are simultaneously C(═O), and the atom attached to X is not a nitrogen atom.
39 . The compound according to claim 38 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 and Z 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCH 3 , CH 2 , C(CH 3 ) 2 , C—OCH 3 , C(═O), N, NH, NCH 3 , NCH 2 CH 3 , NCH(CH 3 ) 2 , NCH═CH 2 , NCH 2 F, NCHF 2 , NCH 2 CHF 2 , NC(═O)CH 3 , NCH 2 OH, NCH 2 OMe, NCH 2 CH 2 OMe, NCH 2 —O(P═O)(OH) 2 ,
NCH 2 CH 2 —N(CH 3 ) 2 , O and S.
40 . The compound according to claim 21 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein at least one of ring A and ring B is selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycle and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the heterocycle are C(═O).
41 . The compound according to claim 21 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
wherein ring A′ and ring B′ are each independently selected from the group consisting of saturated or partially unsaturated 3- to 10-membered heterocycle and 5- to 14-membered heteroaromatic ring, and at most 2 ring members in the heterocycle are C(═O); provided that when ring B′ is a heterocycle containing a nitrogen atom, ring B′ is not attached to X via the nitrogen atom.
42 . The compound according to claim 41 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
43 . The compound according to claim 41 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
44 . The compound according to claim 21 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
is selected from the group consisting of
the above group is attached to X at either of the two positions labeled # or ##, and is attached to R 1 at the other position, provided that the atom attached to X is not a nitrogen atom.
45 . The compound according to claim 22 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position,
wherein:
represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;
V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CR 7 , C(R 7 ) 2 , CR 8 , C(R 8 ) 2 , C(═O), N, NR 7 , NR 8 , O and S; and
k is 0, 1, 2, 3 or 4;
provided that at most two groups among V 1 -V 9 are simultaneously C(═O).
46 . The compound according to claim 22 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position,
wherein:
represents either a single or a double bond, and the adjacent bonds are not double bonds simultaneously;
V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CR 7 , C(R 7 ) 2 , CR 8 , C(R 8 ) 2 , C(═O), N, NR 7 , NR 8 , O and S; and
k is 0, 1, 2, 3 or 4;
provided that at most two groups among V 1 -V 9 are simultaneously C(═O).
47 . The compound according to claim 45 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCN, CCH 3 , C—OCH 3 , CCF 3 , C—CH 2 -Ph, C—NH-Ph, C—O-Ph, C—CH 2 OCH 3 , C—CH 2 —NHCH 3 , C—N(CH 3 ) 2 , C—CH 2 NH 2 , C—C(═O)OH, C—C(═O)OCH 2 CH 3 , C—C(═O)NH 2 , —CO—CH 2 CH 2 —N(CH 3 ) 2 , CH 2 , C(═O), N, NH, NCH 3 , N—C(═O)CH 3 , N-Ph, —N—CH 2 CH 2 —N(CH 3 ) 2 , O and S.
48 . The compound according to claim 46 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 and V 9 , at each occurrence, are each independently selected from the group consisting of C, CH, CF, CCl, CCN, CCH 3 , C—OCH 3 , CCF 3 , C—CH 2 -Ph, C—NH-Ph, C—O-Ph, C—CH 2 OCH 3 , C—CH 2 —NHCH 3 , C—N(CH 3 ) 2 , C—CH 2 NH 2 , C—C(═O)OH, C—C(═O)OCH 2 CH 3 , C—C(═O)NH 2 , —CO—CH 2 CH 2 —N(CH 3 ) 2 , CH 2 , C(═O), N, NH, NCH 3 , N—C(═O)CH 3 , N-Ph, —N—CH 2 CH 2 —N(CH 3 ) 2 , O and S.
49 . The compound according to claim 22 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
50 . The compound according to claim 22 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
51 . The compound according to claim 22 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
is selected from the group consisting of
the above group is attached to Y at either of the two positions labeled * or **, and is attached to X at the other position.
52 . The compound according to claim 23 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein ring E is
53 . The compound according to claim 23 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein ring E is selected from the group consisting of
54 . The compound according to claim 24 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein
wherein R 11 is selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 , alkylene-NR 5 R 6 .
55 . The compound according to claim 24 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein R 1 is selected from the group consisting of
wherein R 11 is selected from the group consisting of H, halogen, amino, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 14-membered heteroaryl, C 6-12 aralkyl, —C(═O)R 5 , —OC(═O)R 5 , —C(═O)OR 5 , —OR 5 , —SR 5 , —S(═O)R 5 , —S(═O) 2 R 5 , —S(═O) 2 NR 5 R 6 , —NR 5 R 6 , —C(═O)NR 5 R 6 , —NR 5 —C(═O)R 6 , —NR 5 —C(═O)OR 6 , —NR 5 —S(═O) 2 —R 6 , —NR 5 —C(═O)—NR 5 R 6 , —C 1-6 alkylene-NR 5 R 6 and —O—C 1-6 alkylene-NR 5 R 6 .
56 . The compound according to claim 25 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein R 1a and R 1b together with the atom to which they are attached form a group selected from the group consisting of
57 . The compound according to claim 27 , or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or an isotopically labeled compound thereof, wherein ring D is selected from the group consisting of
phenyl ring, N-methylpyrrole ring, furan ring and thiophene ring.
58 . The method of claim 31 , wherein the cancer is selected from lymphoma, carcinoma, squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, bladder cancer, liver cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulval cancer, thyroid cancer, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, head and neck cancer, leukemia, astrocytoma, soft tissue sarcoma, sarcoma, and blastoma.Join the waitlist — get patent alerts
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