ES2634628T3 - Derivados tricíclicos de pirido-carboxamida como inhibidores ROCK - Google Patents
Derivados tricíclicos de pirido-carboxamida como inhibidores ROCK Download PDFInfo
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- ES2634628T3 ES2634628T3 ES14740124.4T ES14740124T ES2634628T3 ES 2634628 T3 ES2634628 T3 ES 2634628T3 ES 14740124 T ES14740124 T ES 14740124T ES 2634628 T3 ES2634628 T3 ES 2634628T3
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- substituted
- independently selected
- alkyl
- chrd
- chromene
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- 239000011435 rock Substances 0.000 title description 39
- 239000003112 inhibitor Substances 0.000 title description 15
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical class NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- -1 bicyclic carbocyclyl Chemical group 0.000 claims abstract description 112
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 102
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 91
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 85
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 81
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 80
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 80
- 229910021481 rutherfordium Inorganic materials 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 43
- 125000003118 aryl group Chemical group 0.000 claims abstract description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 34
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 33
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 30
- 101150105130 RORB gene Proteins 0.000 claims abstract description 30
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 26
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 21
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 17
- 125000002837 carbocyclic group Chemical group 0.000 claims abstract description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 16
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 16
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 15
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 13
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims abstract description 7
- JBOYQZDFEWOILV-UHFFFAOYSA-N 5h-chromene Chemical compound O1C=CC=C2CC=CC=C21 JBOYQZDFEWOILV-UHFFFAOYSA-N 0.000 claims description 177
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 34
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 29
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 22
- 239000004202 carbamide Substances 0.000 claims description 20
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 13
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 claims description 9
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 238000011321 prophylaxis Methods 0.000 claims description 8
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 6
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 201000001881 impotence Diseases 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000335 thiazolyl group Chemical group 0.000 claims description 6
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
- PQQRHWFRZHFGFM-UHFFFAOYSA-N 1,3-thiazole-4-carboxamide Chemical compound NC(=O)C1=CSC=N1 PQQRHWFRZHFGFM-UHFFFAOYSA-N 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 206010003225 Arteriospasm coronary Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 208000003890 Coronary Vasospasm Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 201000011634 coronary artery vasospasm Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- OFLWZAHKUJNRML-UHFFFAOYSA-N 2,3-dihydroindole-1-carboxamide Chemical compound C1=CC=C2N(C(=O)N)CCC2=C1 OFLWZAHKUJNRML-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- GTKIGDZXPDCIKR-UHFFFAOYSA-N 2-phenylbenzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=CC=C1 GTKIGDZXPDCIKR-UHFFFAOYSA-N 0.000 claims description 2
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 2
- QDXGKRWDQCEABB-UHFFFAOYSA-N pyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=CN=C1 QDXGKRWDQCEABB-UHFFFAOYSA-N 0.000 claims description 2
- NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 201000006474 Brain Ischemia Diseases 0.000 claims 1
- 101150063022 CHRD gene Proteins 0.000 claims 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims 1
- 206010008120 Cerebral ischaemia Diseases 0.000 claims 1
- 208000035473 Communicable disease Diseases 0.000 claims 1
- 101100274355 Danio rerio chd gene Proteins 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 claims 1
- 208000001132 Osteoporosis Diseases 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 claims 1
- 125000002877 alkyl aryl group Chemical group 0.000 claims 1
- 206010008118 cerebral infarction Diseases 0.000 claims 1
- 230000004054 inflammatory process Effects 0.000 claims 1
- 208000031225 myocardial ischemia Diseases 0.000 claims 1
- 230000004770 neurodegeneration Effects 0.000 claims 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 104
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 58
- 238000000034 method Methods 0.000 description 51
- 239000000460 chlorine Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 33
- 239000002904 solvent Substances 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 24
- 239000012453 solvate Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000003814 drug Substances 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- 125000004429 atom Chemical group 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
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- 125000003226 pyrazolyl group Chemical group 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
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- 229920006395 saturated elastomer Polymers 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 10
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- HFNHAPQMXICKCF-USJMABIRSA-N urotensin-ii Chemical compound N([C@@H](CC(O)=O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@@H](C(C)C)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@@H](N)CCC(O)=O)[C@@H](C)O HFNHAPQMXICKCF-USJMABIRSA-N 0.000 description 1
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Classifications
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- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
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| US201361842084P | 2013-07-02 | 2013-07-02 | |
| US201361842084P | 2013-07-02 | ||
| PCT/US2014/045008 WO2015002926A1 (en) | 2013-07-02 | 2014-07-01 | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
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| ES2634628T3 true ES2634628T3 (es) | 2017-09-28 |
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| AR094929A1 (es) | 2013-02-28 | 2015-09-09 | Bristol Myers Squibb Co | Derivados de fenilpirazol como inhibidores potentes de rock1 y rock2 |
| CN105102448B (zh) | 2013-02-28 | 2018-03-06 | 百时美施贵宝公司 | 作为rock1和rock2抑制剂的苯基吡唑衍生物 |
| AR096788A1 (es) | 2013-07-02 | 2016-02-03 | Bristol Myers Squibb Co | Compuestos tricíclicos de carboxamida como inhibidores potentes de rock |
| WO2015002926A1 (en) | 2013-07-02 | 2015-01-08 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
| EP3054955B1 (en) | 2013-10-11 | 2018-05-30 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
| US9902702B2 (en) | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
| AR103990A1 (es) | 2015-01-09 | 2017-06-21 | Bristol Myers Squibb Co | Ureas cíclicas como inhibidoras de rock |
| TW201706265A (zh) | 2015-03-09 | 2017-02-16 | 必治妥美雅史谷比公司 | 做為Ｒｈｏ激酶（ＲＯＣＫ）抑制劑之內醯胺 |
| ES2740224T3 (es) | 2015-04-10 | 2020-02-05 | Bristol Myers Squibb Co | 6H-isocromeno[3,4-c]piridinas y benzo[c][1,7]naftiridin-6-(5H)-onas como inhibidores de la cinasa asociada a adaptador 1 (AAK1) |
| AR107354A1 (es) | 2016-01-13 | 2018-04-18 | Bristol Myers Squibb Co | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock |
| ES2781309T3 (es) | 2016-05-27 | 2020-09-01 | Bristol Myers Squibb Co | Triazolonas y tetrazolonas como inhibidores de ROCK |
| ES2821877T3 (es) | 2016-07-07 | 2021-04-28 | Bristol Myers Squibb Co | Espirolactamas como inhibidores de ROCK |
| EP3481816B1 (en) | 2016-07-07 | 2020-06-24 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
| JP7155102B2 (ja) * | 2016-07-07 | 2022-10-18 | ブリストル－マイヤーズ スクイブ カンパニー | Ｒｏｃｋ阻害剤としてのスピロ縮合環尿素 |
| WO2018102325A1 (en) * | 2016-11-30 | 2018-06-07 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
| EP3652165B1 (en) | 2017-07-12 | 2021-08-25 | Bristol-Myers Squibb Company | Five membered-aminoheterocyclic and 5,6-or 6,6-membered bicyclic aminoheterocyclic inhibitors of rock for the treatment of heart failure |
| US12060341B2 (en) | 2017-07-12 | 2024-08-13 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as ROCK inhibitors |
| CN110869360B (zh) | 2017-07-12 | 2023-12-15 | 百时美施贵宝公司 | 作为rock抑制剂的苯乙酰胺类 |
| EP3652167B1 (en) | 2017-07-12 | 2021-06-02 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as rock inhibitors |
| TW201908293A (zh) | 2017-07-12 | 2019-03-01 | 美商必治妥美雅史谷比公司 | 作為rock抑制劑之5員及雙環雜環醯胺 |
| WO2019089868A1 (en) | 2017-11-03 | 2019-05-09 | Bristol-Myers Squibb Company | Diazaspiro rock inhibitors |
| CA3121202A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| CN113354630B (zh) * | 2021-06-30 | 2022-11-01 | 江南大学 | 一种5,6-二氢苯并[h]喹唑啉类化合物及其应用 |
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-
2014
- 2014-07-01 WO PCT/US2014/045008 patent/WO2015002926A1/en not_active Ceased
- 2014-07-01 CN CN201480047826.1A patent/CN105518005B/zh not_active Expired - Fee Related
- 2014-07-01 JP JP2016524308A patent/JP6522602B2/ja not_active Expired - Fee Related
- 2014-07-01 US US14/900,228 patent/US9663529B2/en active Active
- 2014-07-01 EP EP14740124.4A patent/EP3016950B1/en not_active Not-in-force
- 2014-07-01 ES ES14740124.4T patent/ES2634628T3/es active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016523923A (ja) | 2016-08-12 |
| WO2015002926A1 (en) | 2015-01-08 |
| US20160152627A1 (en) | 2016-06-02 |
| CN105518005B (zh) | 2018-07-20 |
| JP6522602B2 (ja) | 2019-05-29 |
| EP3016950A1 (en) | 2016-05-11 |
| EP3016950B1 (en) | 2017-06-07 |
| US9663529B2 (en) | 2017-05-30 |
| CN105518005A (zh) | 2016-04-20 |
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