JP2022506572A - Rockキナーゼ阻害剤 - Google Patents
Rockキナーゼ阻害剤 Download PDFInfo
- Publication number
- JP2022506572A JP2022506572A JP2021523997A JP2021523997A JP2022506572A JP 2022506572 A JP2022506572 A JP 2022506572A JP 2021523997 A JP2021523997 A JP 2021523997A JP 2021523997 A JP2021523997 A JP 2021523997A JP 2022506572 A JP2022506572 A JP 2022506572A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- mixture
- mmol
- residue
- compound according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000011435 rock Substances 0.000 title claims abstract 5
- 229940043355 kinase inhibitor Drugs 0.000 title description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 274
- 238000000034 method Methods 0.000 claims abstract description 44
- 230000000694 effects Effects 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 208000031464 Cavernous Central Nervous System Hemangioma Diseases 0.000 claims abstract description 18
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 9
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 5
- -1 cyano, hydroxyl Chemical group 0.000 claims description 60
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 239000000460 chlorine Substances 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 21
- 229920006395 saturated elastomer Polymers 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 210000002464 muscle smooth vascular Anatomy 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 208000034656 Contusions Diseases 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 5
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 claims description 4
- 125000005955 1H-indazolyl group Chemical group 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
- 208000010228 Erectile Dysfunction Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000032382 Ischaemic stroke Diseases 0.000 claims description 4
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 201000011634 coronary artery vasospasm Diseases 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 201000001881 impotence Diseases 0.000 claims description 4
- 238000001727 in vivo Methods 0.000 claims description 4
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 229950000688 phenothiazine Drugs 0.000 claims description 4
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 claims description 3
- 208000034526 bruise Diseases 0.000 claims description 3
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 230000003834 intracellular effect Effects 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000006442 vascular tone Effects 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 324
- 239000000203 mixture Substances 0.000 description 221
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 160
- 239000011541 reaction mixture Substances 0.000 description 131
- 239000007787 solid Substances 0.000 description 124
- 239000000243 solution Substances 0.000 description 124
- 235000019439 ethyl acetate Nutrition 0.000 description 122
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 122
- 239000011734 sodium Substances 0.000 description 88
- 239000012044 organic layer Substances 0.000 description 85
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 229910004298 SiO 2 Inorganic materials 0.000 description 80
- 239000003208 petroleum Substances 0.000 description 80
- 239000012299 nitrogen atmosphere Substances 0.000 description 76
- 238000004440 column chromatography Methods 0.000 description 75
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 62
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 45
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 238000002953 preparative HPLC Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- 238000000746 purification Methods 0.000 description 24
- 239000012267 brine Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- RWYPIJXEMMDPDH-UHFFFAOYSA-N 1-oxo-2H-isoquinoline-5-sulfonyl chloride Chemical compound C1=CNC(=O)C2=C1C(S(=O)(=O)Cl)=CC=C2 RWYPIJXEMMDPDH-UHFFFAOYSA-N 0.000 description 20
- 239000012043 crude product Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000005457 ice water Substances 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 14
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 14
- 239000003643 water by type Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 10
- 102000020233 phosphotransferase Human genes 0.000 description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 7
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 7
- LAFGPNHTRJDGQR-UHFFFAOYSA-N 1-chloroisoquinoline-5-sulfonyl chloride Chemical compound C1=CC=C2C(Cl)=NC=CC2=C1S(Cl)(=O)=O LAFGPNHTRJDGQR-UHFFFAOYSA-N 0.000 description 6
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 6
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- HSLNYVREDLDESE-UHFFFAOYSA-N 6-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=C2CCNC2=C1 HSLNYVREDLDESE-UHFFFAOYSA-N 0.000 description 5
- 102100035197 Cerebral cavernous malformations 2 protein Human genes 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 102100022422 cGMP-dependent protein kinase 1 Human genes 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 210000002460 smooth muscle Anatomy 0.000 description 5
- DKDQINLFUWFZCB-UHFFFAOYSA-N 2,3-dihydro-1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2CCNC2=C1 DKDQINLFUWFZCB-UHFFFAOYSA-N 0.000 description 4
- YCJCSDSXVHEBRU-UHFFFAOYSA-N 4-bromo-2,3-dihydro-1h-indole Chemical compound BrC1=CC=CC2=C1CCN2 YCJCSDSXVHEBRU-UHFFFAOYSA-N 0.000 description 4
- JAYGEXFKJUWRML-UHFFFAOYSA-N 4-bromo-5-nitroisoquinoline Chemical compound N1=CC(Br)=C2C([N+](=O)[O-])=CC=CC2=C1 JAYGEXFKJUWRML-UHFFFAOYSA-N 0.000 description 4
- INGNEZHNSSPYSA-UHFFFAOYSA-N 4-chloro-5-nitroisoquinoline Chemical compound N1=CC(Cl)=C2C([N+](=O)[O-])=CC=CC2=C1 INGNEZHNSSPYSA-UHFFFAOYSA-N 0.000 description 4
- RDIJVEJSTUYLCI-UHFFFAOYSA-N 4-methyl-5-nitroisoquinoline Chemical compound C1=CC([N+]([O-])=O)=C2C(C)=CN=CC2=C1 RDIJVEJSTUYLCI-UHFFFAOYSA-N 0.000 description 4
- JHXVHTVZWRBEBJ-UHFFFAOYSA-N 4-methylisoquinoline-5-sulfonyl chloride Chemical compound C1=CC(S(Cl)(=O)=O)=C2C(C)=CN=CC2=C1 JHXVHTVZWRBEBJ-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 101000737028 Homo sapiens Cerebral cavernous malformations 2 protein Proteins 0.000 description 4
- 101001091610 Homo sapiens Krev interaction trapped protein 1 Proteins 0.000 description 4
- 101000602149 Homo sapiens Programmed cell death protein 10 Proteins 0.000 description 4
- 101001046426 Homo sapiens cGMP-dependent protein kinase 1 Proteins 0.000 description 4
- 102100035878 Krev interaction trapped protein 1 Human genes 0.000 description 4
- 102000016349 Myosin Light Chains Human genes 0.000 description 4
- 108010067385 Myosin Light Chains Proteins 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- INJCMVBJBXONMM-UHFFFAOYSA-N N-(6-cyano-2,3-dihydro-1H-indol-4-yl)acetamide Chemical compound C(#N)C1=CC(=C2CCNC2=C1)NC(C)=O INJCMVBJBXONMM-UHFFFAOYSA-N 0.000 description 4
- 241000209094 Oryza Species 0.000 description 4
- 235000007164 Oryza sativa Nutrition 0.000 description 4
- 102100037594 Programmed cell death protein 10 Human genes 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 101710203837 Replication-associated protein Proteins 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 235000009566 rice Nutrition 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 3
- KARDFUTWMFZBDV-UHFFFAOYSA-N 1-methoxy-4-methylisoquinoline-5-sulfonyl chloride Chemical compound COC1=NC=C(C=2C(=CC=CC1=2)S(=O)(=O)Cl)C KARDFUTWMFZBDV-UHFFFAOYSA-N 0.000 description 3
- OHRPKGVOHMLKIN-UHFFFAOYSA-N 1-oxo-2H-phthalazine-5-sulfonyl chloride Chemical compound O=C1NN=CC=2C(=CC=CC1=2)S(=O)(=O)Cl OHRPKGVOHMLKIN-UHFFFAOYSA-N 0.000 description 3
- KOCACHRXWDMCSG-UHFFFAOYSA-N 1-oxo-2h-isoquinoline-5-sulfonic acid Chemical compound C1=CC=C2C(O)=NC=CC2=C1S(O)(=O)=O KOCACHRXWDMCSG-UHFFFAOYSA-N 0.000 description 3
- UJCADMLSXYYQJX-UHFFFAOYSA-N 2,3-dihydro-1h-pyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound N#CC1=CN=C2CCNC2=C1 UJCADMLSXYYQJX-UHFFFAOYSA-N 0.000 description 3
- SCRBSGZBTHKAHU-UHFFFAOYSA-N 4-bromoisoquinoline Chemical compound C1=CC=C2C(Br)=CN=CC2=C1 SCRBSGZBTHKAHU-UHFFFAOYSA-N 0.000 description 3
- SPQAGLCCKNZRJK-UHFFFAOYSA-N 4-chloro-1-methoxyisoquinoline-5-sulfonyl chloride Chemical compound ClC1=CN=C(C=2C=CC=C(C1=2)S(=O)(=O)Cl)OC SPQAGLCCKNZRJK-UHFFFAOYSA-N 0.000 description 3
- TXIBMTPLWKDOCV-UHFFFAOYSA-N 4-cyclopropyl-2,3-dihydro-1h-indole Chemical compound C1CC1C1=CC=CC2=C1CCN2 TXIBMTPLWKDOCV-UHFFFAOYSA-N 0.000 description 3
- OTKZBJOKTOFPFG-UHFFFAOYSA-N 7-chloroisoquinoline-5-sulfonyl chloride Chemical compound ClC=1C=C(C=2C=CN=CC=2C=1)S(=O)(=O)Cl OTKZBJOKTOFPFG-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 0 CN1c2ccccc2C(*)(*)C1 Chemical compound CN1c2ccccc2C(*)(*)C1 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 229910004373 HOAc Inorganic materials 0.000 description 3
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 102100032791 cAMP-dependent protein kinase catalytic subunit alpha Human genes 0.000 description 3
- 201000000760 cerebral cavernous malformation Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 125000001786 isothiazolyl group Chemical group 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 2
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 2
- CLLCZHHQZKCOHF-UHFFFAOYSA-N 1,4-dichloro-5-nitroisoquinoline Chemical compound N1=CC(Cl)=C2C([N+](=O)[O-])=CC=CC2=C1Cl CLLCZHHQZKCOHF-UHFFFAOYSA-N 0.000 description 2
- TZTZCFYSSUAVNZ-UHFFFAOYSA-N 1-(1-chloroisoquinolin-5-yl)sulfonyl-2,3-dihydroindol-5-ol Chemical compound ClC1=NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC(=CC=C12)O TZTZCFYSSUAVNZ-UHFFFAOYSA-N 0.000 description 2
- AHFKISRZWSDVQC-UHFFFAOYSA-N 1-(1-methoxy-4-methylisoquinolin-5-yl)sulfonyl-2,3-dihydropyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound COC1=NC=C(C2=C(C=CC=C12)S(=O)(=O)N1CCC2=NC=C(C=C21)C#N)C AHFKISRZWSDVQC-UHFFFAOYSA-N 0.000 description 2
- QUJIBVQVTYBNHL-UHFFFAOYSA-N 1-(1h-indol-4-yl)ethanol Chemical compound CC(O)C1=CC=CC2=C1C=CN2 QUJIBVQVTYBNHL-UHFFFAOYSA-N 0.000 description 2
- ZIWVQRNNLZNGAF-UHFFFAOYSA-N 1-(4-chloro-1-methoxyisoquinolin-5-yl)sulfonyl-2,3-dihydropyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound ClC1=CN=C(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=NC=C(C=C21)C#N)OC ZIWVQRNNLZNGAF-UHFFFAOYSA-N 0.000 description 2
- WWOXSZSFCBKJPI-UHFFFAOYSA-N 1-(4-chloroisoquinolin-5-yl)sulfonyl-2,3-dihydroindole-6-carbonitrile Chemical compound ClC1=CN=CC2=CC=CC(=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N WWOXSZSFCBKJPI-UHFFFAOYSA-N 0.000 description 2
- ONNGIICTGMYSDV-UHFFFAOYSA-N 1-(4-methylisoquinolin-5-yl)sulfonyl-2,3-dihydroindole-6-carbonitrile Chemical compound CC1=CN=CC2=CC=CC(=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N ONNGIICTGMYSDV-UHFFFAOYSA-N 0.000 description 2
- CUHYHGFTSPAKRN-UHFFFAOYSA-N 1-(7-chloroisoquinolin-5-yl)sulfonyl-2,3-dihydroindole-6-carbonitrile Chemical compound ClC1=CC(=C2C=CN=CC2=C1)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N CUHYHGFTSPAKRN-UHFFFAOYSA-N 0.000 description 2
- KURSAALWTFPVJZ-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]-2,3-dihydropyrrolo[3,2-c]pyridine-6-carboxylic acid Chemical compound C(C)(C)(C)OC(=O)N1CCC=2C=NC(=CC=21)C(=O)O KURSAALWTFPVJZ-UHFFFAOYSA-N 0.000 description 2
- QVQYQNJRRHODAZ-UHFFFAOYSA-N 1-[(4-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound ClC1=CNC(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N)=O QVQYQNJRRHODAZ-UHFFFAOYSA-N 0.000 description 2
- YMJUHMGAXHVDQT-UHFFFAOYSA-N 1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound OC1=NC=C(C2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N)C YMJUHMGAXHVDQT-UHFFFAOYSA-N 0.000 description 2
- YXFXHJHRIFJWMD-UHFFFAOYSA-N 1-chloro-5-(2,3-dihydroindol-1-ylsulfonyl)isoquinoline Chemical compound ClC1=NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC=CC=C12 YXFXHJHRIFJWMD-UHFFFAOYSA-N 0.000 description 2
- DKRGGDYJSYKUHO-UHFFFAOYSA-N 1-chloro-5-[(3,3-dimethyl-2H-indol-1-yl)sulfonyl]isoquinoline Chemical compound ClC1=NC=CC2=C(C=CC=C12)S(=O)(=O)N1CC(C2=CC=CC=C12)(C)C DKRGGDYJSYKUHO-UHFFFAOYSA-N 0.000 description 2
- HYHYMHMTXREMDC-UHFFFAOYSA-N 1-chloro-5-[(6-methyl-2,3-dihydroindol-1-yl)sulfonyl]isoquinoline Chemical compound ClC1=NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C HYHYMHMTXREMDC-UHFFFAOYSA-N 0.000 description 2
- DHJRQCFVLCCHEZ-UHFFFAOYSA-N 1-methoxy-4-methyl-5-nitroisoquinoline Chemical compound C1=CC=C2C(OC)=NC=C(C)C2=C1[N+]([O-])=O DHJRQCFVLCCHEZ-UHFFFAOYSA-N 0.000 description 2
- ONGGPSBEAIGEGU-UHFFFAOYSA-N 1-methoxy-4-methylisoquinolin-5-amine Chemical compound COc1ncc(C)c2c(N)cccc12 ONGGPSBEAIGEGU-UHFFFAOYSA-N 0.000 description 2
- IJPGABMGWMKYHP-UHFFFAOYSA-N 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile Chemical compound N#Cc1cc2NCCc2cn1 IJPGABMGWMKYHP-UHFFFAOYSA-N 0.000 description 2
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 2
- KOBKMLXDYFODDD-UHFFFAOYSA-N 3-hydroxy-4-nitro-2,3-dihydroisoindol-1-one Chemical compound C1=CC([N+]([O-])=O)=C2C(O)NC(=O)C2=C1 KOBKMLXDYFODDD-UHFFFAOYSA-N 0.000 description 2
- QUWCDANYAUHCRM-UHFFFAOYSA-N 3-hydroxy-4-nitro-3h-2-benzofuran-1-one Chemical compound C1=CC([N+]([O-])=O)=C2C(O)OC(=O)C2=C1 QUWCDANYAUHCRM-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- RUYIDRGITHKTKM-UHFFFAOYSA-N 4-amino-1-[(4-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound NC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C(=CNC(C2=CC=C1)=O)Cl RUYIDRGITHKTKM-UHFFFAOYSA-N 0.000 description 2
- GVVLZZCZADOGLJ-UHFFFAOYSA-N 4-amino-1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound NC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C(=CNC(C2=CC=C1)=O)C GVVLZZCZADOGLJ-UHFFFAOYSA-N 0.000 description 2
- ALWCMYAKSPSBAN-UHFFFAOYSA-N 4-amino-1h-indole-6-carbonitrile Chemical compound NC1=CC(C#N)=CC2=C1C=CN2 ALWCMYAKSPSBAN-UHFFFAOYSA-N 0.000 description 2
- LIXMZLHXLYDHRO-UHFFFAOYSA-N 4-bromo-1h-indole-6-carbonitrile Chemical compound BrC1=CC(C#N)=CC2=C1C=CN2 LIXMZLHXLYDHRO-UHFFFAOYSA-N 0.000 description 2
- GQTMHYNSELTLBW-UHFFFAOYSA-N 4-chloro-1-methoxy-5-nitroisoquinoline Chemical compound ClC1=CN=C(C2=CC=CC(=C12)[N+](=O)[O-])OC GQTMHYNSELTLBW-UHFFFAOYSA-N 0.000 description 2
- DIHDIZJKCNRZLT-UHFFFAOYSA-N 4-chloro-1-methoxyisoquinolin-5-amine Chemical compound ClC1=CN=C(C=2C=CC=C(C1=2)N)OC DIHDIZJKCNRZLT-UHFFFAOYSA-N 0.000 description 2
- MVFNHWOPSMJBQF-UHFFFAOYSA-N 4-chloroisoquinolin-5-amine Chemical compound N1=CC(Cl)=C2C(N)=CC=CC2=C1 MVFNHWOPSMJBQF-UHFFFAOYSA-N 0.000 description 2
- LBEQEEIDWHKVAR-UHFFFAOYSA-N 4-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=CN=CC2=C1 LBEQEEIDWHKVAR-UHFFFAOYSA-N 0.000 description 2
- IVRAWSOJSGNOIC-UHFFFAOYSA-N 4-chloroisoquinoline-5-sulfonyl chloride Chemical compound C1=CC(S(Cl)(=O)=O)=C2C(Cl)=CN=CC2=C1 IVRAWSOJSGNOIC-UHFFFAOYSA-N 0.000 description 2
- CBUGKXLIVHICRQ-UHFFFAOYSA-N 4-cyclopropyl-1H-indole-6-carbonitrile Chemical compound C1(CC1)C1=C2C=CNC2=CC(=C1)C#N CBUGKXLIVHICRQ-UHFFFAOYSA-N 0.000 description 2
- UEHCZLGUARZVFU-UHFFFAOYSA-N 4-fluoro-5-nitroisoquinoline Chemical compound N1=CC(F)=C2C([N+](=O)[O-])=CC=CC2=C1 UEHCZLGUARZVFU-UHFFFAOYSA-N 0.000 description 2
- WSUBMVBAMAKLFM-UHFFFAOYSA-N 4-fluoroisoquinolin-5-amine Chemical compound N1=CC(F)=C2C(N)=CC=CC2=C1 WSUBMVBAMAKLFM-UHFFFAOYSA-N 0.000 description 2
- VFFQGPWQVYUFLV-UHFFFAOYSA-N 4-fluoroisoquinoline Chemical compound C1=CC=C2C(F)=CN=CC2=C1 VFFQGPWQVYUFLV-UHFFFAOYSA-N 0.000 description 2
- UZUCKWMDQGESLP-UHFFFAOYSA-N 4-fluoroisoquinoline-5-sulfonyl chloride Chemical compound C1=CC(S(Cl)(=O)=O)=C2C(F)=CN=CC2=C1 UZUCKWMDQGESLP-UHFFFAOYSA-N 0.000 description 2
- HISJDVJIZZWKGW-UHFFFAOYSA-N 4-methoxy-2,3-dihydro-1H-indole-6-carbonitrile Chemical compound COc1cc(cc2NCCc12)C#N HISJDVJIZZWKGW-UHFFFAOYSA-N 0.000 description 2
- UMUWHMGBEVBIQW-UHFFFAOYSA-N 4-methyl-1-(4-methylisoquinolin-5-yl)sulfonyl-2,3-dihydroindole-6-carbonitrile Chemical compound CC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C(=CN=CC2=CC=C1)C UMUWHMGBEVBIQW-UHFFFAOYSA-N 0.000 description 2
- JVTVHILSTXFLCS-UHFFFAOYSA-N 4-methyl-1h-indole-6-carbonitrile Chemical compound CC1=CC(C#N)=CC2=C1C=CN2 JVTVHILSTXFLCS-UHFFFAOYSA-N 0.000 description 2
- BSRIUSPUGCAPHE-UHFFFAOYSA-N 4-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=CC2=C1CCN2 BSRIUSPUGCAPHE-UHFFFAOYSA-N 0.000 description 2
- AHYRKDKBOIYXFE-UHFFFAOYSA-N 4-methylisoquinolin-5-amine Chemical compound C1=CC(N)=C2C(C)=CN=CC2=C1 AHYRKDKBOIYXFE-UHFFFAOYSA-N 0.000 description 2
- RDAJRYOAFSPSPC-UHFFFAOYSA-N 4-prop-1-en-2-yl-2,3-dihydro-1H-indole Chemical compound CC(=C)c1cccc2NCCc12 RDAJRYOAFSPSPC-UHFFFAOYSA-N 0.000 description 2
- LRTAHCUSBZEOBO-UHFFFAOYSA-N 5,7-dichloroisoquinoline Chemical compound C1=CN=CC2=CC(Cl)=CC(Cl)=C21 LRTAHCUSBZEOBO-UHFFFAOYSA-N 0.000 description 2
- WPWODMYEKDCEHF-UHFFFAOYSA-N 5-[(4-ethenyl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound C(=C)C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O WPWODMYEKDCEHF-UHFFFAOYSA-N 0.000 description 2
- VZGUMDJAHKCISU-UHFFFAOYSA-N 5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]-4-methylisoquinoline Chemical compound ClC1=CC=C2CCN(C2=C1)S(=O)(=O)C1=C2C(=CN=CC2=CC=C1)C VZGUMDJAHKCISU-UHFFFAOYSA-N 0.000 description 2
- PJCMURZRUATYFM-UHFFFAOYSA-N 5-amino-2h-phthalazin-1-one Chemical compound C1=NNC(=O)C2=C1C(N)=CC=C2 PJCMURZRUATYFM-UHFFFAOYSA-N 0.000 description 2
- ZDRVCGZEWGFKSV-UHFFFAOYSA-N 5-nitro-2h-phthalazin-1-one Chemical compound C1=NNC(=O)C2=C1C([N+](=O)[O-])=CC=C2 ZDRVCGZEWGFKSV-UHFFFAOYSA-N 0.000 description 2
- LVGDYCWVNJBMLC-UHFFFAOYSA-N 7-chloro-5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]isoquinoline Chemical compound ClC1=CC(=C2C=CN=CC2=C1)S(=O)(=O)N1CCC2=CC=C(C=C12)Cl LVGDYCWVNJBMLC-UHFFFAOYSA-N 0.000 description 2
- YOMNAMATBRCQNB-UHFFFAOYSA-N 7-chloroisoquinolin-5-amine Chemical compound N1=CC=C2C(N)=CC(Cl)=CC2=C1 YOMNAMATBRCQNB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- MNDJEEXSXPBGBN-UHFFFAOYSA-N C1=CC([N+]([O-])=O)=C2C(C)=CN=C(Cl)C2=C1 Chemical compound C1=CC([N+]([O-])=O)=C2C(C)=CN=C(Cl)C2=C1 MNDJEEXSXPBGBN-UHFFFAOYSA-N 0.000 description 2
- WFLNRHUXWYCIQM-UHFFFAOYSA-N C=Cc1cccc2NCCc12 Chemical compound C=Cc1cccc2NCCc12 WFLNRHUXWYCIQM-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- QLPUTPLSFBYUJO-LZYBPNLTSA-N ClC1=CC(/C=N/CC(OCC)OCC)=CC(Cl)=C1 Chemical compound ClC1=CC(/C=N/CC(OCC)OCC)=CC(Cl)=C1 QLPUTPLSFBYUJO-LZYBPNLTSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 101100397746 Homo sapiens PRKACA gene Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- WPFWCVQPWQTIRA-UHFFFAOYSA-N N-(6-cyano-1H-indol-4-yl)acetamide Chemical compound C(#N)C1=CC(=C2C=CNC2=C1)NC(C)=O WPFWCVQPWQTIRA-UHFFFAOYSA-N 0.000 description 2
- NZDLPUTULLJIIO-UHFFFAOYSA-N N-(7-chloroisoquinolin-5-yl)-1,1-diphenylmethanimine Chemical compound ClC1=CC(=C2C=CN=CC2=C1)N=C(C1=CC=CC=C1)C1=CC=CC=C1 NZDLPUTULLJIIO-UHFFFAOYSA-N 0.000 description 2
- JWLMQZXJJUPPJE-UHFFFAOYSA-N N-[1-(4-chloro-1-methoxyisoquinolin-5-yl)sulfonyl-6-cyano-2,3-dihydroindol-4-yl]acetamide Chemical compound ClC1=CN=C(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=C(C=C(C=C12)C#N)NC(C)=O)OC JWLMQZXJJUPPJE-UHFFFAOYSA-N 0.000 description 2
- QHZSDXGRWVFDRA-UHFFFAOYSA-N N-[6-cyano-1-(1-methoxy-4-methylisoquinolin-5-yl)sulfonyl-2,3-dihydroindol-4-yl]acetamide Chemical compound C(#N)C1=CC(=C2CCN(C2=C1)S(=O)(=O)C1=C2C(=CN=C(C2=CC=C1)OC)C)NC(C)=O QHZSDXGRWVFDRA-UHFFFAOYSA-N 0.000 description 2
- NEKIKQXEJXLMBM-UHFFFAOYSA-N N-[6-cyano-1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindol-4-yl]acetamide Chemical compound C(#N)C1=CC(=C2CCN(C2=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O)NC(C)=O NEKIKQXEJXLMBM-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 2
- MPOUPYSWAXMUIB-UHFFFAOYSA-N [7-chloro-5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]isoquinolin-1-yl] acetate Chemical compound C(C)(=O)OC1=NC=CC2=C(C=C(C=C12)Cl)S(=O)(=O)N1CCC2=CC=C(C=C12)Cl MPOUPYSWAXMUIB-UHFFFAOYSA-N 0.000 description 2
- MLLDRPYPFIQNCO-UHFFFAOYSA-N [7-chloro-5-[(6-cyano-2,3-dihydroindol-1-yl)sulfonyl]isoquinolin-1-yl] acetate Chemical compound C(C)(=O)OC1=NC=CC2=C(C=C(C=C12)Cl)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N MLLDRPYPFIQNCO-UHFFFAOYSA-N 0.000 description 2
- ILUFFAUMGWWRGY-UHFFFAOYSA-N [O-][N+]1=CC(Cl)=C2C([N+](=O)[O-])=CC=CC2=C1 Chemical compound [O-][N+]1=CC(Cl)=C2C([N+](=O)[O-])=CC=CC2=C1 ILUFFAUMGWWRGY-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 125000002755 pyrazolinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- UASJEOFUIJKIJQ-UHFFFAOYSA-N tert-butyl 6-carbamoyl-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylate Chemical compound C(N)(=O)C1=CC2=C(C=N1)CCN2C(=O)OC(C)(C)C UASJEOFUIJKIJQ-UHFFFAOYSA-N 0.000 description 2
- FUDBNGZQHOMXHH-UHFFFAOYSA-N tert-butyl 6-chloro-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylate Chemical compound N1=C(Cl)C=C2N(C(=O)OC(C)(C)C)CCC2=C1 FUDBNGZQHOMXHH-UHFFFAOYSA-N 0.000 description 2
- HUHGCVLIUOIYAR-UHFFFAOYSA-N tert-butyl 6-cyano-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylate Chemical compound C(#N)C1=CC2=C(C=N1)CCN2C(=O)OC(C)(C)C HUHGCVLIUOIYAR-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 208000019553 vascular disease Diseases 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 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 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- RUBNGGWBJUGNNA-UHFFFAOYSA-N 1-(1h-indol-4-yl)ethanone Chemical compound CC(=O)C1=CC=CC2=C1C=CN2 RUBNGGWBJUGNNA-UHFFFAOYSA-N 0.000 description 1
- OVMFOWMDXKYHMV-UHFFFAOYSA-N 1-(2,3-dihydro-1H-indol-4-yl)ethanol Chemical compound CC(O)C1=CC=CC2=C1CCN2 OVMFOWMDXKYHMV-UHFFFAOYSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- UJLQPDDENUHWTN-UHFFFAOYSA-N 1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound O=C1NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N UJLQPDDENUHWTN-UHFFFAOYSA-N 0.000 description 1
- BFWWXDWCPOMLPT-UHFFFAOYSA-N 1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydropyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound O=C1NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=NC=C(C=C21)C#N BFWWXDWCPOMLPT-UHFFFAOYSA-N 0.000 description 1
- UTRZMSRXBYUJJR-UHFFFAOYSA-N 1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydropyrrolo[3,2-c]pyridine-6-carbonitrile Chemical compound O=C1NC=CC2=C(C=CC=C12)S(=O)(=O)N1CCC=2C=NC(=CC=21)C#N UTRZMSRXBYUJJR-UHFFFAOYSA-N 0.000 description 1
- GSGTZNMCUXPEOU-UHFFFAOYSA-N 1-[(1-oxo-2H-phthalazin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound O=C1NN=CC2=C(C=CC=C12)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N GSGTZNMCUXPEOU-UHFFFAOYSA-N 0.000 description 1
- LVSNHJTXBFIPTI-UHFFFAOYSA-N 1-[(4-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydropyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound ClC1=CNC(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=NC=C(C=C21)C#N)=O LVSNHJTXBFIPTI-UHFFFAOYSA-N 0.000 description 1
- DELOYJAHQCXTBN-UHFFFAOYSA-N 1-[(4-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-4-(dimethylamino)-2,3-dihydroindole-6-carbonitrile Chemical compound ClC1=CNC(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=C(C=C(C=C12)C#N)N(C)C)=O DELOYJAHQCXTBN-UHFFFAOYSA-N 0.000 description 1
- IGXLPPAZGXCYNY-UHFFFAOYSA-N 1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydropyrrolo[3,2-b]pyridine-6-carbonitrile Chemical compound CC1=CNC(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=NC=C(C=C21)C#N)=O IGXLPPAZGXCYNY-UHFFFAOYSA-N 0.000 description 1
- VPNPAMYQSXNEMG-UHFFFAOYSA-N 1-[(7-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound ClC1=CC(=C2C=CNC(C2=C1)=O)S(=O)(=O)N1CCC2=CC=C(C=C12)C#N VPNPAMYQSXNEMG-UHFFFAOYSA-N 0.000 description 1
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 1
- CEUFGDDOMXCXFW-UHFFFAOYSA-N 1h-indole-4-carbonitrile Chemical compound N#CC1=CC=CC2=C1C=CN2 CEUFGDDOMXCXFW-UHFFFAOYSA-N 0.000 description 1
- SZSZDBFJCQKTRG-UHFFFAOYSA-N 1h-indole-6-carbonitrile Chemical compound N#CC1=CC=C2C=CNC2=C1 SZSZDBFJCQKTRG-UHFFFAOYSA-N 0.000 description 1
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 1
- MPCXQPXCYDDJSR-UHFFFAOYSA-N 2,3-dihydro-1h-indol-5-ol Chemical compound OC1=CC=C2NCCC2=C1 MPCXQPXCYDDJSR-UHFFFAOYSA-N 0.000 description 1
- YFTHTJAPODJVSL-UHFFFAOYSA-N 2-(1-benzothiophen-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(SC=C2)C2=C1 YFTHTJAPODJVSL-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical group C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- SRCCLYMWDRNUAF-UHFFFAOYSA-N 3,3-dimethyl-1,2-dihydroindole Chemical compound C1=CC=C2C(C)(C)CNC2=C1 SRCCLYMWDRNUAF-UHFFFAOYSA-N 0.000 description 1
- CASRSOJWLARCRX-UHFFFAOYSA-N 3,5-dichlorobenzaldehyde Chemical compound ClC1=CC(Cl)=CC(C=O)=C1 CASRSOJWLARCRX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BFQARNDIMKOOQQ-UHFFFAOYSA-N 3-methyl-2,3-dihydro-1h-indole Chemical compound C1=CC=C2C(C)CNC2=C1 BFQARNDIMKOOQQ-UHFFFAOYSA-N 0.000 description 1
- NIXGYRHZQFZCCV-UHFFFAOYSA-N 4,6-dichloro-1h-indole Chemical compound ClC1=CC(Cl)=C2C=CNC2=C1 NIXGYRHZQFZCCV-UHFFFAOYSA-N 0.000 description 1
- UTAHVVGXBARLMT-UHFFFAOYSA-N 4-(dimethylamino)-1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound CN(C1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C(=CNC(C2=CC=C1)=O)C)C UTAHVVGXBARLMT-UHFFFAOYSA-N 0.000 description 1
- FOCIDGZBJANSEG-UHFFFAOYSA-N 4-(trifluoromethyl)-2,3-dihydro-1h-indole Chemical compound FC(F)(F)C1=CC=CC2=C1CCN2 FOCIDGZBJANSEG-UHFFFAOYSA-N 0.000 description 1
- HUPCAULNNCKSGY-UHFFFAOYSA-N 4-amino-1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound NC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O HUPCAULNNCKSGY-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- IOBRMERVPJBVGE-UHFFFAOYSA-N 4-cyclopropyl-1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound C1(CC1)C1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O IOBRMERVPJBVGE-UHFFFAOYSA-N 0.000 description 1
- RBZUCQSAPMCWHU-UHFFFAOYSA-N 4-cyclopropyl-2,3-dihydro-1H-indole-6-carbonitrile Chemical compound C1(CC1)C1=C2CCNC2=CC(=C1)C#N RBZUCQSAPMCWHU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- NIKFRZJCTGHKMW-UHFFFAOYSA-N 4-methoxy-1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound COC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O NIKFRZJCTGHKMW-UHFFFAOYSA-N 0.000 description 1
- OQXNIQGRPYJOAM-UHFFFAOYSA-N 4-methyl-1-[(1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound CC1=C2CCN(C2=CC(=C1)C#N)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O OQXNIQGRPYJOAM-UHFFFAOYSA-N 0.000 description 1
- ONKKSAMZYQGMCZ-UHFFFAOYSA-N 4-methyl-1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindole-6-carbonitrile Chemical compound OC1=NC=C(C2=C(C=CC=C12)S(=O)(=O)N1CCC2=C(C=C(C=C12)C#N)C)C ONKKSAMZYQGMCZ-UHFFFAOYSA-N 0.000 description 1
- MQXPPUHKRXFQSN-UHFFFAOYSA-N 4-methyl-2,3-dihydro-1H-indole-6-carbonitrile Chemical compound Cc1cc(cc2NCCc12)C#N MQXPPUHKRXFQSN-UHFFFAOYSA-N 0.000 description 1
- IFKCCURHRRCLCS-UHFFFAOYSA-N 4-nitro-1h-indole-6-carbonitrile Chemical compound [O-][N+](=O)C1=CC(C#N)=CC2=C1C=CN2 IFKCCURHRRCLCS-UHFFFAOYSA-N 0.000 description 1
- BONIIQYTWOPUQI-UHFFFAOYSA-N 4-nitroisoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(=O)NC2=O BONIIQYTWOPUQI-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- JGKSPZSVOZJQIQ-UHFFFAOYSA-N 5-(2,3-dihydroindol-1-ylsulfonyl)-2H-isoquinolin-1-one Chemical compound N1(CCC2=CC=CC=C12)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O JGKSPZSVOZJQIQ-UHFFFAOYSA-N 0.000 description 1
- DUYUDKVGCYTTQS-UHFFFAOYSA-N 5-[(3,3-dimethyl-2H-indol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound CC1(CN(C2=CC=CC=C12)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O)C DUYUDKVGCYTTQS-UHFFFAOYSA-N 0.000 description 1
- GYOSJUZXBGVUMO-UHFFFAOYSA-N 5-[(4-cyclopropyl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound C1(CC1)C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O GYOSJUZXBGVUMO-UHFFFAOYSA-N 0.000 description 1
- CWROKKPJTUFBTO-UHFFFAOYSA-N 5-[(4-ethyl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound C(C)C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O CWROKKPJTUFBTO-UHFFFAOYSA-N 0.000 description 1
- HMOOPYXJVRXYBS-UHFFFAOYSA-N 5-[(4-methyl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound CC1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O HMOOPYXJVRXYBS-UHFFFAOYSA-N 0.000 description 1
- LJLKPSYWOYVHGI-UHFFFAOYSA-N 5-[(4-prop-1-en-2-yl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound C(=C)(C)C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O LJLKPSYWOYVHGI-UHFFFAOYSA-N 0.000 description 1
- FGUTUGZLJCBMSU-UHFFFAOYSA-N 5-[(5-hydroxy-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound OC=1C=C2CCN(C2=CC=1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O FGUTUGZLJCBMSU-UHFFFAOYSA-N 0.000 description 1
- AADGETRCCFOYFG-UHFFFAOYSA-N 5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]-4-fluoro-2H-isoquinolin-1-one Chemical compound ClC1=CC=C2CCN(C2=C1)S(=O)(=O)C1=C2C(=CN=C(C2=CC=C1)O)F AADGETRCCFOYFG-UHFFFAOYSA-N 0.000 description 1
- RIYOKPRIRMKFBE-UHFFFAOYSA-N 5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]-4-fluoroisoquinoline Chemical compound ClC1=CC=C2CCN(C2=C1)S(=O)(=O)C1=C2C(=CN=CC2=CC=C1)F RIYOKPRIRMKFBE-UHFFFAOYSA-N 0.000 description 1
- VUGUHPNAABCHID-UHFFFAOYSA-N 5-[(6-fluoro-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound FC1=CC=C2CCN(C2=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O VUGUHPNAABCHID-UHFFFAOYSA-N 0.000 description 1
- COWLGBMVZUAQIE-UHFFFAOYSA-N 5-[(6-methyl-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound CC1=CC=C2CCN(C2=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O COWLGBMVZUAQIE-UHFFFAOYSA-N 0.000 description 1
- AHXWXQMGRSWDIX-UHFFFAOYSA-N 5-[[4-(1-hydroxyethyl)-2,3-dihydroindol-1-yl]sulfonyl]-2H-isoquinolin-1-one Chemical compound OC(C)C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O AHXWXQMGRSWDIX-UHFFFAOYSA-N 0.000 description 1
- JMPPTEKUMMFWLB-UHFFFAOYSA-N 5-[[4-(hydroxymethyl)-2,3-dihydroindol-1-yl]sulfonyl]-2H-isoquinolin-1-one Chemical compound OCC1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O JMPPTEKUMMFWLB-UHFFFAOYSA-N 0.000 description 1
- KLORCVDRVTXLNJ-UHFFFAOYSA-N 5-[[4-(trifluoromethyl)-2,3-dihydroindol-1-yl]sulfonyl]-2H-isoquinolin-1-one Chemical compound FC(C1=C2CCN(C2=CC=C1)S(=O)(=O)C1=C2C=CNC(C2=CC=C1)=O)(F)F KLORCVDRVTXLNJ-UHFFFAOYSA-N 0.000 description 1
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 1
- WSJKRCBUBLIDBF-UHFFFAOYSA-N 6-chloro-2,3-dihydro-1h-pyrrolo[3,2-c]pyridine Chemical compound C1=NC(Cl)=CC2=C1CCN2 WSJKRCBUBLIDBF-UHFFFAOYSA-N 0.000 description 1
- PBLNKUULIMDAIC-UHFFFAOYSA-N 6-fluoro-2,3-dihydro-1h-indole Chemical compound FC1=CC=C2CCNC2=C1 PBLNKUULIMDAIC-UHFFFAOYSA-N 0.000 description 1
- GYHSHGUXLJLVAR-UHFFFAOYSA-N 6-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=C2CCNC2=C1 GYHSHGUXLJLVAR-UHFFFAOYSA-N 0.000 description 1
- XTYNDTWVGCQENH-UHFFFAOYSA-N 7-chloro-5-[(6-chloro-2,3-dihydroindol-1-yl)sulfonyl]-2H-isoquinolin-1-one Chemical compound ClC1=CC(=C2C=CNC(C2=C1)=O)S(=O)(=O)N1CCC2=CC=C(C=C12)Cl XTYNDTWVGCQENH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical compound NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010005746 Blood pressure fluctuation Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010059109 Cerebral vasoconstriction Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 208000016988 Hemorrhagic Stroke Diseases 0.000 description 1
- 101001000061 Homo sapiens Protein phosphatase 1 regulatory subunit 12A Proteins 0.000 description 1
- 101000994496 Homo sapiens cAMP-dependent protein kinase catalytic subunit alpha Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010089704 Lim Kinases Proteins 0.000 description 1
- 102000008020 Lim Kinases Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- KSXKDZKYFDGEDH-UHFFFAOYSA-N N-[1-[(4-chloro-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-6-cyano-2,3-dihydroindol-4-yl]acetamide Chemical compound ClC1=CNC(C2=CC=CC(=C12)S(=O)(=O)N1CCC2=C(C=C(C=C12)C#N)NC(C)=O)=O KSXKDZKYFDGEDH-UHFFFAOYSA-N 0.000 description 1
- YZDWQHXMVJSQTH-UHFFFAOYSA-N N-[6-cyano-1-[(4-methyl-1-oxo-2H-isoquinolin-5-yl)sulfonyl]-2,3-dihydroindol-4-yl]acetamide Chemical compound C(#N)C1=CC(=C2CCN(C2=C1)S(=O)(=O)C1=C2C(=CNC(C2=CC=C1)=O)C)NC(C)=O YZDWQHXMVJSQTH-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100036547 Protein phosphatase 1 regulatory subunit 12A Human genes 0.000 description 1
- 102100024147 Protein phosphatase 1 regulatory subunit 14A Human genes 0.000 description 1
- 101710081981 Protein phosphatase 1 regulatory subunit 14A Proteins 0.000 description 1
- 101150111584 RHOA gene Proteins 0.000 description 1
- 108091027967 Small hairpin RNA Proteins 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000009443 Vascular Malformations Diseases 0.000 description 1
- BBAWTPDTGRXPDG-UHFFFAOYSA-N [1,3]thiazolo[4,5-b]pyridine Chemical compound C1=CC=C2SC=NC2=N1 BBAWTPDTGRXPDG-UHFFFAOYSA-N 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000005512 benztetrazolyl group Chemical group 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 101710143429 cGMP-dependent protein kinase 1 Proteins 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DXRFTDFNLITJMV-UHFFFAOYSA-N cyclopentyl(diphenyl)phosphane Chemical compound C1CCCC1P(C=1C=CC=CC=1)C1=CC=CC=C1 DXRFTDFNLITJMV-UHFFFAOYSA-N 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- LFVPBERIVUNMGV-UHFFFAOYSA-N fasudil hydrochloride Chemical compound Cl.C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 LFVPBERIVUNMGV-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 102000044469 human AKT1 Human genes 0.000 description 1
- 102000053038 human ROCK1 Human genes 0.000 description 1
- 102000053046 human ROCK2 Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000035874 hyperreactivity Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- GZZCYMXZJQCAJU-UHFFFAOYSA-N isoquinoline-1-sulfonamide Chemical class C1=CC=C2C(S(=O)(=O)N)=NC=CC2=C1 GZZCYMXZJQCAJU-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000026267 regulation of growth Effects 0.000 description 1
- 108010041788 rho-Associated Kinases Proteins 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Ophthalmology & Optometry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
別段の定義がない限り、本明細書で使用されるすべての技術用語および科学用語は、本発明が属する分野の当業者によって一般に理解される意味と同じ意味を有する。本明細書で言及されるすべての特許、特許出願、および刊行物は、それらが本開示と一致する程度で参照により組み込まれる。用語および範囲は、別段の明示的な定義がない限り、一般に定義される定義を有する。
化合物
別の態様では、本発明は、本発明によるROCKキナーゼ阻害剤および薬学的に許容される担体、賦形剤、または希釈剤を含む薬学的組成物を提供する。本発明の化合物は、当該技術分野で周知の任意の方法によって配合することができ、限定されないが、非経口、経口、舌下、経皮、局所、皮下、鼻腔内、気管内、または直腸内を含む任意の経路による投与のために調製することができる。特定の実施形態では、本発明の化合物は、病院環境において静脈内投与される。特定の他の実施形態では、投与は、好ましくは経口経路によるものであり得る。
さらに別の態様では、本発明は、細胞内のROCK活性を阻害するための方法であって、ROCK活性の阻害が望まれる細胞を、治療有効量の式(Ia)、式(Ib)、式(IIa)、もしくは式(IIb)の化合物、その薬学的に許容される塩、または化合物もしくはその薬学的に許容される塩を含む薬学的組成物と接触させることを含む、方法を提供する。
本発明の化合物は、本明細書に記載の合成方法および反応スキームを使用する市販の試薬を使用して、または当業者に周知の他の試薬および従来の方法を使用して調製することができる。
実施例1:DCM(10mL)中の1-ヒドロキシイソキノリン-5-スルホニルクロリド(150mg、615.6μmol)の溶液に、TEA(128.5μL、923.4μmol)および4-メチルインドリン(90.1mg、677.1μmol)を添加した。混合物を、N2雰囲気下、15℃で5時間撹拌した。反応混合物を、H2O(60mL)で希釈し、DCM(200mL×2)で抽出した。合わせた有機層を飽和ブライン(80mL)で洗浄し、無水Na2SO4上で乾燥させ、濾過し、減圧下で濃縮して残留物を得た。残留物を、カラムクロマトグラフィー(SiO2、石油エーテル:酢酸エチル=10:1~1:1)によって精製した。
実施例1、5-(4-メチルインドリン-1-イル)スルホニル-2H-イソキノリン-1-オン(90mg、252μmol、41.1%収率)を、白色の固体として得た。LC-MS:[M+1]340.09.
実施例8、5-[4-(トリフルオロメチル)インドリン-1-イル]スルホニル-2H-イソキノリン-1-オン(20mg、44.2μmol、7.18%収率)を、白色の固体として得た。LC-MS:[M+1]394.06.
化合物19-3、5,7-ジクロロイソキノリン(8g、40.3mmol、39.0%収率)を、黄色の固体として得た。
化合物19-4、N-(7-クロロ-5-イソキノリル)-1,1-ジフェニル-メタンイミン(40mg、116.6μmol、11.5%収率)を、黄色の固体として得た。
化合物19-7、7-クロロ-5-(6-クロロインドリン-1-イル)スルホニル-イソキノリン(80mg、210.9μmol、27.6%収率)を、黄色の固体として得た。
実施例20、1-[(7-クロロ-1-オキソ-2H-イソキノリン-5-イル)スルホニル]インドリン-6-カルボニトリル(2mg、4.7μmol、10.2%収率)を、白色の固体として得た。LC-MS:[M+1]385.03.
化合物22-1、4-ブロモ-5-ニトロ-イソキノリン(75g、296.3mmol、77.0%収率)を、黄色の固体として得た。
化合物23-1、4-メチル-1-[(4-メチル-5-イソキノリル)スルホニル]インドリン-6-カルボニトリル(50mg、粗製)を、黄色の固体として得た。
1H NMR(400MHz,DMSO-d6):δ 11.71(br,1H),8.59(d,J=8Hz,1H),7.88(d,J=7.6Hz,1H),7.53(t,J=8Hz,1H),7.39(s,1H),7.26~7.25(m,1H),7.09(s,1H),4.22(t,J=8Hz,2H)2.61(s,6H)(2Hは、水ピークと重複し得る)。
化合物25-4、5-ニトロ-2H-フタラジン-1-オン(6g、31.3mmol、61.2%収率)を、黄色の固体として得た。
化合物25-5、5-アミノ-2H-フタラジン-1-オン(3g、18.6mmol、59.3%の収率)を、黄色の固体として得た。
化合物30-4、N-(6-シアノインドリン-4-イル)アセトアミド(400mg、1.99mmol、66.00%収率)を、淡黄色の固体として得た。
化合物40-2、1-[(4-クロロ-1-メトキシ-5-イソキノリル)スルホニル]-2,3-ジヒドロピロロ[3,2-b]ピリジン-6-カルボニトリル(30mg、74.84μmol、72.88%収率)を、白色の固体として得た。
インドリン試薬
化合物4-シクロプロピルインドリン-6-カルボニトリル(20mg、108.6μmol、39.5%収率)を、黄色の固体として得た。
この実施例は、本発明の例示的な化合物が、ROCK1および/またはROCK2酵素活性を阻害することを示す。
Claims (36)
- 式(Ia)、式(Ib)、式(IIa)、もしくは式(IIb):
Xが、部分飽和アザ含有ヘテロアリールであり、
Yが、NまたはCHであり、
各R1が、シアノ、ヒドロキシル、ヒドロキシアルキル、ハロゲン、ハロアルキル、アルコキシ、Q-C1~C3アルキル、-N(R4)2、-NR4C(O)C1~C3アルキル、またはシクロアルキルであり、
Qが、結合、O、またはNR4であり、
各R2が、水素またはハロゲンであり、
各R3が、水素、ハロゲン、またはC1~C3アルキルであり、
各R4が、水素またはC1~C3アルキルであり、
mが、0、1、2、または3である。]
の化合物、またはその薬学的に許容される塩。 - 前記アザ含有ヘテロアリールが、インドリジニル、インドリル、イソインドリル、3H-インドリル、インドリニル、インダゾリル、1H-インダゾリル、ベンズイミダゾリル、ベンズチアゾリル、プリニル、4H-キノリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、1,8-ナフチリジニル、プテリジニル、キヌクリジニル、カルバゾリル、アクリジニル、フェナジミル、フェノチアジニル、フェノキサジニル、2H-ピロリル、ピロリル、2-ピロリニル、3-ピロリニル、オキサゾリル、チアゾリル、イミダゾリル、2-イミダゾリニル、ピラゾリル、2-ピラゾリニル、イソキサゾリル、イソチアゾリル、1,2,3-オキサジアゾリル、1,2,3-トリアゾリル、1,3,4-チアジアゾリル、ピリジル、ピリダジニル、ピリミジニル、または1,3,5-トリアジニルである、請求項1に記載の化合物。
- mが、1であり、R1が、シアノ、ヒドロキシル、ヒドロキシアルキル、ハロゲン、ハロアルキル、アルコキシ、Q-C1~C3アルキル、-N(R4)2、-NR4C(O)C1~C3アルキル、またはシクロアルキルである、請求項3に記載の化合物。
- 前記ハロゲンが、塩素またはフッ素である、請求項4に記載の化合物。
- 前記ハロアルキルが、トリフルオロメチルである、請求項4に記載の化合物。
- 前記Qが、結合であり、前記C1~C3アルキルが、メチル、エチル、またはイソプロピルである、請求項4に記載の化合物。
- 前記Qが、Oであり、前記C1~C3アルキルが、メチル、エチル、またはイソプロピルである、請求項4に記載の化合物。
- 前記Qが、Nであり、前記C1~C3アルキルが、メチル、エチル、またはイソプロピルである、請求項4に記載の化合物。
- 前記-N(R4)2の各R4基が、水素である、請求項4に記載の化合物。
- 前記-N(R4)2の各R4基が、C1~C3アルキルである、請求項4に記載の化合物。
- 前記ヒドロキシアルキルが、ヒドロキシメチルである、請求項4に記載の化合物。
- 前記シクロアルキルが、シクロプロピルである、請求項4に記載の化合物。
- mが、2であり、各R1が、独立して、シアノ、ハロゲン、C1~C3アルキル、またはシクロアルキルである、請求項3に記載の化合物。
- 各R1が、ハロゲンである、請求項14に記載の化合物。
- 一方のR1が、シアノであり、他方のR1が、ヒドロキシル、ヒドロキシアルキル、ハロゲン、ハロアルキル、アルコキシ、Q-C1~C3アルキル、-N(R4)2、-NR4C(O)C1~C3アルキル、またはシクロアルキルである、請求項14に記載の化合物。
- 各R1が、メチルである、請求項17に記載の化合物。
- R2が、ハロゲンである、請求項1~18のいずれか一項に記載の化合物。
- 前記ハロゲンが、塩素である、請求項19に記載の化合物。
- R3が、ハロゲンまたはC1~C3アルキルである、請求項1~20のいずれか一項に記載の化合物。
- 前記ハロゲンが、フッ素である、請求項21に記載の化合物。
- 前記C1~C3アルキルが、メチルである、請求項21に記載の化合物。
- 有効量の請求項1~24のいずれか一項に記載の化合物、および薬学的に許容される賦形剤を含む、薬学的組成物。
- 細胞内のROCK活性を阻害するための方法であって、ROCK活性の阻害が所望される前記細胞を、治療有効量の請求項1に記載の化合物と接触させることを含む、方法。
- 前記接触が、インビボで起こる、請求項26に記載の方法。
- 前記化合物の前記治療有効量が、1日あたり約0.01~300mg/kgである、請求項26または27に記載の方法。
- 前記化合物の前記治療有効量が、1日あたり約0.1~100mg/kgである、請求項28に記載の方法。
- 脳海綿状血管腫症候群(CCM)を有する患者を治療するための方法であって、前記患者に、治療有効量の請求項1に記載の化合物を単独で、または薬学的に許容される担体、賦形剤、もしくは希釈剤と組み合わせて投与することを含む、方法。
- 前記化合物の前記治療有効量が、1日あたり約0.01~300mg/kgである、請求項30に記載の方法。
- 前記化合物の前記治療有効量が、1日あたり約0.1~100mg/kgである、請求項31に記載の方法。
- 増加した血管緊張に関連する心血管疾患を治療する方法であって、それを必要とする患者に、治療有効量の請求項1に記載の化合物を単独で、または薬学的に許容される担体、賦形剤、もしくは希釈剤と組み合わせて投与することを含む、方法。
- 前記心血管疾患が、高血圧、アテローム性動脈硬化症、虚血性脳卒中、冠動脈血管痙攣、脳血管痙攣、狭心症、または勃起不全である、請求項33に記載の方法。
- 上昇した非血管平滑筋収縮性を伴う疾患を治療する方法であって、それを必要とする患者に、治療有効量の請求項1に記載の化合物を単独で、または薬学的に許容される担体、賦形剤、もしくは希釈剤と組み合わせて投与することを含む、方法。
- 上昇した非血管平滑筋収縮性を伴う前記疾患が、喘息または緑内障である、請求項35に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862756202P | 2018-11-06 | 2018-11-06 | |
US62/756,202 | 2018-11-06 | ||
PCT/US2019/059992 WO2020097158A1 (en) | 2018-11-06 | 2019-11-06 | Rock kinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2022506572A true JP2022506572A (ja) | 2022-01-17 |
Family
ID=70459339
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021523997A Pending JP2022506572A (ja) | 2018-11-06 | 2019-11-06 | Rockキナーゼ阻害剤 |
Country Status (13)
Country | Link |
---|---|
US (1) | US10745381B2 (ja) |
EP (1) | EP3877364A4 (ja) |
JP (1) | JP2022506572A (ja) |
KR (1) | KR20210093269A (ja) |
CN (1) | CN113227054A (ja) |
AU (1) | AU2019377087A1 (ja) |
BR (1) | BR112021008883A2 (ja) |
CA (1) | CA3118738A1 (ja) |
EA (1) | EA202191164A1 (ja) |
IL (1) | IL282941A (ja) |
MX (1) | MX2021005273A (ja) |
SG (1) | SG11202104446UA (ja) |
WO (2) | WO2020097158A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113582926B (zh) * | 2021-09-09 | 2022-03-01 | 安徽有吉医药科技有限公司 | 4-氟异喹啉-5-磺酰氯或其药学上可接受的盐的合成方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030171341A1 (en) * | 2001-11-19 | 2003-09-11 | Dongxu Sun | Modulators of Rho C activity |
WO2017038856A1 (ja) * | 2015-08-31 | 2017-03-09 | 興和株式会社 | 眼圧下降増強剤 |
JP2017513919A (ja) * | 2014-04-28 | 2017-06-01 | メッドシャイン ディスカバリー インコーポレイテッド | Rhoキナーゼ阻害剤としてのイソキノリンスルホン誘導体 |
WO2018118109A1 (en) * | 2016-12-21 | 2018-06-28 | BioAxone BioSciences, Inc. | Rho kinase inhibitor ba-1049 (r) and active metabolites thereof |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050014783A1 (en) | 2003-05-29 | 2005-01-20 | Schering Aktiengesellschaft | Use of Rho-kinase inhibitors in the treatment of aneurysm and cardiac hypertrophy |
EP1878732B1 (en) * | 2005-04-25 | 2009-02-25 | D. Western Therapeutics Institute | HIGHLY SELECTIVE Rho-KINASE INHIBITOR |
US8648069B2 (en) | 2007-06-08 | 2014-02-11 | Abbvie Inc. | 5-substituted indazoles as kinase inhibitors |
CN113637008A (zh) | 2012-10-05 | 2021-11-12 | 卡德门企业有限公司 | Rho激酶抑制剂 |
FR3017868A1 (fr) * | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US10106525B2 (en) | 2015-01-26 | 2018-10-23 | BioAxone BioSciences, Inc. | Rho kinase inhibitor BA-1049 (R) and active metabolites thereof |
US10149856B2 (en) | 2015-01-26 | 2018-12-11 | BioAxone BioSciences, Inc. | Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors |
WO2018009627A1 (en) | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Spiro-fused cyclic ureas as inhibitors of rock |
ES2814325T3 (es) | 2016-07-07 | 2021-03-26 | Bristol Myers Squibb Co | Derivados de lactama, urea cíclica y carbamato y de triazolona como inhibidores potentes y selectivos de ROCK |
WO2018009625A1 (en) | 2016-07-07 | 2018-01-11 | Bristol-Myers Squibb Company | Spirolactams as inhibitors of rock |
KR20200027989A (ko) | 2017-07-12 | 2020-03-13 | 브리스톨-마이어스 스큅 컴퍼니 | 심부전의 치료를 위한 rock의 5원-아미노헤테로사이클 및 5,6- 또는 6,6-원 비시클릭 아미노헤테로시클릭 억제제 |
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 |
WO2019014300A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | PHENYLACETAMIDES AS ROCK INHIBITORS |
JP7313331B2 (ja) | 2017-07-12 | 2023-07-24 | 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ヘプタニルヒダントイン |
-
2019
- 2019-11-06 US US16/676,044 patent/US10745381B2/en active Active
- 2019-11-06 AU AU2019377087A patent/AU2019377087A1/en active Pending
- 2019-11-06 WO PCT/US2019/059992 patent/WO2020097158A1/en unknown
- 2019-11-06 MX MX2021005273A patent/MX2021005273A/es unknown
- 2019-11-06 EA EA202191164A patent/EA202191164A1/ru unknown
- 2019-11-06 KR KR1020217016686A patent/KR20210093269A/ko unknown
- 2019-11-06 EP EP19881800.7A patent/EP3877364A4/en active Pending
- 2019-11-06 BR BR112021008883-0A patent/BR112021008883A2/pt unknown
- 2019-11-06 SG SG11202104446UA patent/SG11202104446UA/en unknown
- 2019-11-06 CA CA3118738A patent/CA3118738A1/en active Pending
- 2019-11-06 JP JP2021523997A patent/JP2022506572A/ja active Pending
- 2019-11-06 CN CN201980085629.1A patent/CN113227054A/zh active Pending
-
2020
- 2020-05-05 WO PCT/US2020/031428 patent/WO2021091593A1/en active Application Filing
-
2021
- 2021-05-05 IL IL282941A patent/IL282941A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030171341A1 (en) * | 2001-11-19 | 2003-09-11 | Dongxu Sun | Modulators of Rho C activity |
JP2017513919A (ja) * | 2014-04-28 | 2017-06-01 | メッドシャイン ディスカバリー インコーポレイテッド | Rhoキナーゼ阻害剤としてのイソキノリンスルホン誘導体 |
WO2017038856A1 (ja) * | 2015-08-31 | 2017-03-09 | 興和株式会社 | 眼圧下降増強剤 |
WO2018118109A1 (en) * | 2016-12-21 | 2018-06-28 | BioAxone BioSciences, Inc. | Rho kinase inhibitor ba-1049 (r) and active metabolites thereof |
Non-Patent Citations (2)
Title |
---|
橘高敦史, 創薬科学・医薬化学, JPN6017043458, 2007, pages 142 - 50, ISSN: 0005180127 * |
野崎正勝 等, 創薬化学, vol. 第1版, JPN6012059719, 1995, pages 98 - 99, ISSN: 0005180128 * |
Also Published As
Publication number | Publication date |
---|---|
IL282941A (en) | 2021-06-30 |
EP3877364A1 (en) | 2021-09-15 |
WO2020097158A1 (en) | 2020-05-14 |
WO2021091593A1 (en) | 2021-05-14 |
MX2021005273A (es) | 2021-09-08 |
SG11202104446UA (en) | 2021-05-28 |
BR112021008883A2 (pt) | 2021-08-10 |
CN113227054A (zh) | 2021-08-06 |
EA202191164A1 (ru) | 2022-01-24 |
CA3118738A1 (en) | 2020-05-14 |
AU2019377087A1 (en) | 2021-06-03 |
US10745381B2 (en) | 2020-08-18 |
US20200140412A1 (en) | 2020-05-07 |
EP3877364A4 (en) | 2022-08-03 |
KR20210093269A (ko) | 2021-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6570001B2 (ja) | Alkキナーゼ阻害剤 | |
CA2971640C (en) | Cot modulators and methods of use thereof | |
ES2855135T3 (es) | Amidas heterocíclicas como inhibidores de quinasa | |
CA2710234C (en) | Polycyclic heteroaryl substituted triazoles useful as axl inhibitors | |
AU2009311756B2 (en) | Modulators of amyloid beta. | |
EA017442B1 (ru) | ПРОИЗВОДНЫЕ 2-АРИЛ-6-ФЕНИЛИМИДАЗО[1,2-a]ПИРИДИНОВ, ИХ ПОЛУЧЕНИЕ И ПРИМЕНЕНИЕ В ТЕРАПИИ | |
JP2006503010A (ja) | 数種の新規なイミダゾピリジンおよびその使用 | |
AU2014249003A1 (en) | Novel compounds and compositions for inhibition of FASN | |
EA025436B1 (ru) | Аминохиназолины в качестве ингибиторов киназ | |
WO2020078362A1 (zh) | 一类咪唑并芳环类化合物的制备和应用 | |
WO2009100536A1 (en) | Inhibitors of kinase activity with 1,2-di-cyclyl substituted alkyne structures | |
AU2008233319A1 (en) | New imidazo[ 4,5-B]pyridine-7-carboxamides 704 | |
EP2809652A1 (en) | Isoquinoline and naphthyridine derivatives | |
WO2016180537A1 (en) | Substituted quinoxaline derivatives | |
CN118055933A (zh) | 选择性parp1抑制剂及其应用 | |
WO2020224626A9 (zh) | 用作激酶抑制剂的化合物及其应用 | |
JP2022506572A (ja) | Rockキナーゼ阻害剤 | |
CN112939982A (zh) | 一种炔类杂环btk抑制剂及其制备方法和用途 | |
US11912719B2 (en) | Substituted isoquinolines as rock kinase inhibitors | |
CN115028633A (zh) | 吡咯并嘧啶类化合物的制备及其应用 | |
CN114539283A (zh) | Usp7抑制剂 | |
EP3749671A1 (en) | [1,2,4]triazolo[4,3-a]pyrazin-8-one derivatives | |
CN114853752B (zh) | Btk抑制剂吡啶并杂环类化合物的制备及其应用 | |
CN117229292A (zh) | Ret抑制剂的制备及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20221104 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20231024 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20231026 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20240118 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20240424 |