ES2815681T3 - Ureas cíclicas como inhibidores de ROCK - Google Patents
Ureas cíclicas como inhibidores de ROCK Download PDFInfo
- Publication number
- ES2815681T3 ES2815681T3 ES16703378T ES16703378T ES2815681T3 ES 2815681 T3 ES2815681 T3 ES 2815681T3 ES 16703378 T ES16703378 T ES 16703378T ES 16703378 T ES16703378 T ES 16703378T ES 2815681 T3 ES2815681 T3 ES 2815681T3
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- Prior art keywords
- substituted
- independently selected
- alkyl
- heterocyclyl
- nrara
- Prior art date
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- -1 Cyclic ureas Chemical class 0.000 title description 117
- 239000011435 rock Substances 0.000 title description 40
- 239000003112 inhibitor Substances 0.000 title description 13
- 235000013877 carbamide Nutrition 0.000 title description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 167
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 164
- 150000001875 compounds Chemical class 0.000 claims abstract description 150
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 148
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 147
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 146
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 144
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 134
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 99
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 96
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 95
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 83
- 229910021481 rutherfordium Inorganic materials 0.000 claims abstract description 83
- 101150105130 RORB gene Proteins 0.000 claims abstract description 76
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 68
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 61
- 150000003839 salts Chemical class 0.000 claims abstract description 54
- 125000003118 aryl group Chemical group 0.000 claims abstract description 50
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 38
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 36
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 36
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 30
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 22
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 claims abstract description 19
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 6
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 201
- 229910052799 carbon Inorganic materials 0.000 claims description 69
- 238000011282 treatment Methods 0.000 claims description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 15
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 10
- 238000011321 prophylaxis Methods 0.000 claims description 9
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 9
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 8
- 208000035475 disorder Diseases 0.000 claims description 7
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 210000002460 smooth muscle Anatomy 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 230000002159 abnormal effect Effects 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 230000003176 fibrotic effect Effects 0.000 claims description 4
- 150000004885 piperazines Chemical class 0.000 claims description 4
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 4
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 230000002981 neuropathic effect Effects 0.000 claims 1
- 230000000771 oncological effect Effects 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 208000019553 vascular disease Diseases 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 304
- 238000000034 method Methods 0.000 description 222
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 187
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 178
- 239000011541 reaction mixture Substances 0.000 description 157
- 239000000243 solution Substances 0.000 description 154
- 238000005160 1H NMR spectroscopy Methods 0.000 description 151
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 132
- 235000019439 ethyl acetate Nutrition 0.000 description 124
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 79
- 239000000460 chlorine Substances 0.000 description 77
- 238000002360 preparation method Methods 0.000 description 77
- 238000004128 high performance liquid chromatography Methods 0.000 description 76
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- 239000011734 sodium Substances 0.000 description 69
- 239000002904 solvent Substances 0.000 description 68
- 239000012267 brine Substances 0.000 description 65
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 62
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- 239000000543 intermediate Substances 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 43
- 238000003818 flash chromatography Methods 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
- 239000012043 crude product Substances 0.000 description 37
- 238000002953 preparative HPLC Methods 0.000 description 37
- 229910000104 sodium hydride Inorganic materials 0.000 description 36
- 239000012391 XPhos Pd G2 Substances 0.000 description 35
- 239000000706 filtrate Substances 0.000 description 35
- 239000012044 organic layer Substances 0.000 description 35
- 239000000047 product Substances 0.000 description 34
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 27
- 239000012453 solvate Substances 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000010828 elution Methods 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 239000006184 cosolvent Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 238000004293 19F NMR spectroscopy Methods 0.000 description 16
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- 229910052717 sulfur Inorganic materials 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- 238000004808 supercritical fluid chromatography Methods 0.000 description 14
- FCXAYEPBCJFGPO-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(C(O)=O)N=C1 FCXAYEPBCJFGPO-UHFFFAOYSA-N 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 12
- 229910052796 boron Inorganic materials 0.000 description 12
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
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- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
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- 229940079593 drug Drugs 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000002950 monocyclic group Chemical group 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 8
- PHRJTGPFEAUEBC-UHFFFAOYSA-N 1-fluoro-3-(isocyanatomethyl)benzene Chemical compound FC1=CC=CC(CN=C=O)=C1 PHRJTGPFEAUEBC-UHFFFAOYSA-N 0.000 description 8
- SIOHQNFGXFYSHG-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)acetic acid Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)O)C1=CC(=CC=C1)OC)=O SIOHQNFGXFYSHG-UHFFFAOYSA-N 0.000 description 8
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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- 125000002971 oxazolyl group Chemical group 0.000 description 6
- PUBVIAHPSLGSFN-UHFFFAOYSA-N phenyl n-(5-bromopyridin-2-yl)carbamate Chemical compound N1=CC(Br)=CC=C1NC(=O)OC1=CC=CC=C1 PUBVIAHPSLGSFN-UHFFFAOYSA-N 0.000 description 6
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- QWGAJMDRYUIPIT-UHFFFAOYSA-N 1-(isocyanatomethyl)-3-methoxybenzene Chemical group COC1=CC=CC(CN=C=O)=C1 QWGAJMDRYUIPIT-UHFFFAOYSA-N 0.000 description 5
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 5
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- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 description 5
- 125000004438 haloalkoxy group Chemical group 0.000 description 5
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
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- CJWGCBRQAHCVHW-SSDOTTSWSA-N (1r)-1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC([C@@H](C)N)=C1 CJWGCBRQAHCVHW-SSDOTTSWSA-N 0.000 description 4
- SERVOTWJOQLFFE-QMMMGPOBSA-N (5S)-3-(4-bromophenyl)-5-(hydroxymethyl)imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N[C@H](C1=O)CO)=O SERVOTWJOQLFFE-QMMMGPOBSA-N 0.000 description 4
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| 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 |
| WO2017046739A1 (en) * | 2015-09-15 | 2017-03-23 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazolidinone derivatives as inhibitors of perk |
| AR107354A1 (es) | 2016-01-13 | 2018-04-18 | Bristol Myers Squibb Co | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock |
| US10562887B2 (en) | 2016-05-27 | 2020-02-18 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of ROCK |
| CN109661396B (zh) | 2016-07-07 | 2022-07-01 | 百时美施贵宝公司 | 作为rock抑制剂的螺稠合环状脲 |
| EP3481817B1 (en) | 2016-07-07 | 2020-08-19 | Bristol-Myers Squibb Company | Spirolactams as inhibitors of rock |
| US10730858B2 (en) | 2016-07-07 | 2020-08-04 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
| ES2829400T3 (es) | 2016-11-30 | 2021-05-31 | Bristol Myers Squibb Co | Inhibidores tricíclicos de Rho cinasa |
| 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 |
| CN110914257B (zh) | 2017-07-12 | 2023-05-26 | 百时美施贵宝公司 | 作为rock抑制剂的螺庚基乙内酰脲 |
| US11306081B2 (en) | 2017-07-12 | 2022-04-19 | Bristol-Myers Squibb Company | Phenylacetamides as inhibitors of rock |
| US11299488B2 (en) | 2017-07-12 | 2022-04-12 | Bristol-Myers Squibb Company | Five membered-aminoheterocycle 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 |
| US11192891B2 (en) | 2017-11-03 | 2021-12-07 | Bristol-Myers Squibb Company | Diazaspiro ROCK inhibitors |
| AU2019387370A1 (en) | 2018-11-30 | 2021-06-10 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
| CN112759550A (zh) * | 2019-11-04 | 2021-05-07 | 上海科技大学 | 一种平滑受体拮抗剂 |
| JP2021183586A (ja) * | 2020-05-22 | 2021-12-02 | 武田薬品工業株式会社 | 複素環化合物 |
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| CN119219603A (zh) * | 2023-06-28 | 2024-12-31 | 科辉智药(深圳)新药研究中心有限公司 | Sarm1酶活性抑制剂及其用途 |
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| WO2010036316A1 (en) * | 2008-09-24 | 2010-04-01 | Yangbo Feng | Urea and carbamate compounds and analogs as kinase inhibitors |
| US9000154B2 (en) * | 2010-10-19 | 2015-04-07 | Boehringer Ingelheim International Gmbh | Rho kinase inhibitors |
| EP2945943B1 (en) | 2013-01-18 | 2018-05-30 | Bristol-Myers Squibb Company | Phthalazinones and isoquinolinones as rock inhibitors |
| TW201444798A (zh) | 2013-02-28 | 2014-12-01 | 必治妥美雅史谷比公司 | 作爲強效ｒｏｃｋ１及ｒｏｃｋ２抑制劑之苯基吡唑衍生物 |
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| EP3239161A1 (en) | 2013-07-31 | 2017-11-01 | UDC Ireland Limited | Luminescent diazabenzimidazole carbene metal complexes |
| US9682960B2 (en) | 2013-12-19 | 2017-06-20 | Endorecherche, Inc. | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
| KR101861942B1 (ko) * | 2014-01-20 | 2018-06-29 | 에프. 호프만-라 로슈 아게 | 신경 발생을 자극할 수 있는 n-페닐-락탐 유도체 및 이의 신경 장애 치료에서의 용도 |
| US9902702B2 (en) | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
| CN107108581B (zh) | 2014-08-21 | 2020-06-23 | 百时美施贵宝公司 | 作为强效rock抑制剂的回接苯甲酰胺衍生物 |
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| CN107406426A (zh) | 2017-11-28 |
| EP3242873A1 (en) | 2017-11-15 |
| EP3242873B1 (en) | 2020-07-22 |
| JP2018501285A (ja) | 2018-01-18 |
| JP6779214B2 (ja) | 2020-11-04 |
| US20180000788A1 (en) | 2018-01-04 |
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