AU2007338406B2 - Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase - Google Patents
Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase Download PDFInfo
- Publication number
- AU2007338406B2 AU2007338406B2 AU2007338406A AU2007338406A AU2007338406B2 AU 2007338406 B2 AU2007338406 B2 AU 2007338406B2 AU 2007338406 A AU2007338406 A AU 2007338406A AU 2007338406 A AU2007338406 A AU 2007338406A AU 2007338406 B2 AU2007338406 B2 AU 2007338406B2
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- Prior art keywords
- alkyl
- alkylene
- aryl
- heterocyclyl
- halogen
- Prior art date
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- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title abstract description 21
- 102000000568 rho-Associated Kinases Human genes 0.000 title abstract description 17
- 108010041788 rho-Associated Kinases Proteins 0.000 title abstract description 17
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title description 12
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000002537 isoquinolines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- -1 6-substituted isoquinoline Chemical class 0.000 claims abstract description 40
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 200
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 151
- 125000000623 heterocyclic group Chemical group 0.000 claims description 110
- 125000003118 aryl group Chemical group 0.000 claims description 107
- 229910052736 halogen Inorganic materials 0.000 claims description 95
- 150000002367 halogens Chemical class 0.000 claims description 95
- 238000000034 method Methods 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000002947 alkylene group Chemical group 0.000 claims description 28
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 22
- 230000026731 phosphorylation Effects 0.000 abstract description 6
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- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 abstract description 4
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- 230000006806 disease prevention Effects 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 44
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
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- 125000001424 substituent group Chemical group 0.000 description 19
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 14
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- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 229940113088 dimethylacetamide Drugs 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
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- TYKCTIFMODKQPO-UHFFFAOYSA-N 1,7-dichloro-6-fluoroisoquinoline Chemical compound C1=NC(Cl)=C2C=C(Cl)C(F)=CC2=C1 TYKCTIFMODKQPO-UHFFFAOYSA-N 0.000 description 9
- OQMBJKGORSBEHX-UHFFFAOYSA-N 7-chloro-6-fluoro-2-oxidoisoquinolin-2-ium Chemical compound C1=C(F)C(Cl)=CC2=C[N+]([O-])=CC=C21 OQMBJKGORSBEHX-UHFFFAOYSA-N 0.000 description 9
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- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 9
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Landscapes
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| WO2007008926A1 (en) | 2005-07-11 | 2007-01-18 | Aerie Pharmaceuticals, Inc. | Isoquinoline compounds |
| EP2068878B1 (en) | 2006-09-20 | 2019-04-10 | Aerie Pharmaceuticals, Inc. | Rho kinase inhibitors |
| US8455513B2 (en) | 2007-01-10 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-aminoisoquinoline compounds |
| US8455514B2 (en) | 2008-01-17 | 2013-06-04 | Aerie Pharmaceuticals, Inc. | 6-and 7-amino isoquinoline compounds and methods for making and using the same |
| CA2726588C (en) | 2008-06-03 | 2019-04-16 | Karl Kossen | Compounds and methods for treating inflammatory and fibrotic disorders |
| CA2728123C (en) * | 2008-06-24 | 2017-02-21 | Sanofi-Aventis | Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives |
| CA2728128C (en) * | 2008-06-24 | 2016-06-07 | Sanofi-Aventis | 6-substituted isoquinolines and isoquinolinones |
| CA2728137C (en) * | 2008-06-24 | 2016-10-18 | Sanofi-Aventis | Substituted isoquinolines and isoquinolinones as rho kinase inhibitors |
| US8450344B2 (en) | 2008-07-25 | 2013-05-28 | Aerie Pharmaceuticals, Inc. | Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds |
| EP2424842B1 (en) | 2009-05-01 | 2015-10-28 | Aerie Pharmaceuticals, Inc. | Dual mechanism inhibitors for the treatment of disease |
| CN103781778B (zh) * | 2011-07-08 | 2015-10-07 | 赛诺菲 | 6-(哌啶-4-基氧基)-2h-异喹啉-1-酮盐酸盐的结晶性溶剂化物 |
| EP2729461B1 (en) * | 2011-07-08 | 2016-01-20 | Sanofi | Polymorphs of 6-(piperidin-4-yloxy)-2h-isoquinolin-1-one hydrochloride |
| KR101959711B1 (ko) | 2011-07-08 | 2019-03-19 | 사노피 | 치환된 페닐 화합물 |
| CN103160571A (zh) * | 2011-12-09 | 2013-06-19 | 彩虹天健康科技研究(北京)有限责任公司 | 磷酸化肌球蛋白和驱动蛋白的激酶的发现 |
| AR092742A1 (es) | 2012-10-02 | 2015-04-29 | Intermune Inc | Piridinonas antifibroticas |
| EP3141235A1 (en) | 2012-12-06 | 2017-03-15 | IP Gesellschaft für Management mbH | N-(6-((2r,3s)-3,4-dihydroxybutan-2-yloxy)-2-(4-fluorobenzylthio)pyrimidin-4-yl)-3-methylazetidine-l -sulfonamide |
| PL3811943T3 (pl) | 2013-03-15 | 2023-06-12 | Aerie Pharmaceuticals, Inc. | Związek do stosowania w leczeniu zaburzeń oczu |
| LT3057586T (lt) | 2013-10-18 | 2020-03-10 | Celgene Quanticel Research, Inc. | Bromodomeno inhibitoriai |
| FR3017868A1 (fr) | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| CA2943363A1 (en) | 2014-04-02 | 2015-10-08 | Intermune, Inc. | Anti-fibrotic pyridinones |
| AU2015371255B2 (en) | 2014-12-24 | 2018-09-27 | Gilead Sciences, Inc. | Fused pyrimidine compounds for the treatment of HIV |
| TW202237569A (zh) | 2014-12-24 | 2022-10-01 | 美商基利科學股份有限公司 | 喹唑啉化合物 |
| EP3237397B1 (en) | 2014-12-24 | 2018-11-21 | Gilead Sciences, Inc. | Isoquinoline compounds for the treatment of hiv |
| AR104259A1 (es) | 2015-04-15 | 2017-07-05 | Celgene Quanticel Res Inc | Inhibidores de bromodominio |
| JP6832946B2 (ja) | 2015-11-17 | 2021-02-24 | アエリエ ファーマシューティカルズ インコーポレイテッド | キナーゼ阻害剤およびその中間体の調製方法 |
| US9643927B1 (en) | 2015-11-17 | 2017-05-09 | Aerie Pharmaceuticals, Inc. | Process for the preparation of kinase inhibitors and intermediates thereof |
| AU2017252276A1 (en) | 2016-04-18 | 2018-11-15 | Celgene Quanticel Research, Inc. | Therapeutic compounds |
| US10150754B2 (en) | 2016-04-19 | 2018-12-11 | Celgene Quanticel Research, Inc. | Histone demethylase inhibitors |
| WO2018045091A1 (en) | 2016-08-31 | 2018-03-08 | Aerie Pharmaceuticals, Inc. | Ophthalmic compositions |
| EP3509587B1 (en) | 2016-09-12 | 2023-12-06 | Valo Health, Inc. | Monocyclic compounds useful as gpr120 modulators |
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