ES2626968T3 - Derivados heterocíclicos - Google Patents
Derivados heterocíclicos Download PDFInfo
- Publication number
- ES2626968T3 ES2626968T3 ES14727034.2T ES14727034T ES2626968T3 ES 2626968 T3 ES2626968 T3 ES 2626968T3 ES 14727034 T ES14727034 T ES 14727034T ES 2626968 T3 ES2626968 T3 ES 2626968T3
- Authority
- ES
- Spain
- Prior art keywords
- ylmethyl
- pyrazol
- amide
- amino
- carboxylic acid
- 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.)
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- 125000000623 heterocyclic group Chemical group 0.000 title description 3
- -1 methylenedioxy, ethylenedioxy Chemical group 0.000 claims abstract description 95
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000012453 solvate Substances 0.000 claims abstract description 8
- LWDVTRXNUGVQES-UHFFFAOYSA-N 6-(aminomethyl)isoquinolin-1-amine Chemical compound NC1=NC=CC2=CC(CN)=CC=C21 LWDVTRXNUGVQES-UHFFFAOYSA-N 0.000 claims description 48
- 230000000694 effects Effects 0.000 claims description 13
- 102000003827 Plasma Kallikrein Human genes 0.000 claims description 11
- 108090000113 Plasma Kallikrein Proteins 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 7
- 201000011190 diabetic macular edema Diseases 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 5
- QIPKJJHSPMUFFY-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridin-5-ylmethanamine Chemical compound NCC1=CN=C2NC=CC2=C1 QIPKJJHSPMUFFY-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- CLZJGBDROZBBHL-UHFFFAOYSA-N 1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-N-(1H-pyrrolo[2,3-b]pyridin-5-ylmethyl)-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound N1C=CC=2C1=NC=C(C=2)CNC(=O)C=1C(=NN(C=1)CC1=CC=C(C=C1)CN1N=CC(=C1)C)C(F)(F)F CLZJGBDROZBBHL-UHFFFAOYSA-N 0.000 claims description 3
- YGHPLKICZRUACI-UHFFFAOYSA-N 1h-indazol-4-ylmethanamine Chemical compound NCC1=CC=CC2=C1C=NN2 YGHPLKICZRUACI-UHFFFAOYSA-N 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- KXNHEPBASBKDTB-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(5-chloro-6-ethoxypyridin-3-yl)methyl]-3-cyclopropylpyrazole-4-carboxamide Chemical compound C1=C(Cl)C(OCC)=NC=C1CN1N=C(C2CC2)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 KXNHEPBASBKDTB-UHFFFAOYSA-N 0.000 claims description 3
- AKRGGXIRZBHZIN-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(5-chloro-6-pyrrolidin-1-ylpyridin-3-yl)methyl]-3-cyclopropylpyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=C1Cl)=CN=C1N1CCCC1 AKRGGXIRZBHZIN-UHFFFAOYSA-N 0.000 claims description 3
- NTKGSHJOYRJNMU-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[2-(pyrazol-1-ylmethyl)-1,3-thiazol-4-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(N=1)=CSC=1CN1C=CC=N1 NTKGSHJOYRJNMU-UHFFFAOYSA-N 0.000 claims description 3
- ZSWFNMZXDBXLIE-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[4-[(4-cyanopyrazol-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=C1)=CC=C1CN1C=C(C#N)C=N1 ZSWFNMZXDBXLIE-UHFFFAOYSA-N 0.000 claims description 3
- LBMILRLEZDRJSC-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[6-(pyrazol-1-ylmethyl)pyridin-3-yl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=N1)=CC=C1CN1C=CC=N1 LBMILRLEZDRJSC-UHFFFAOYSA-N 0.000 claims description 3
- DYRPOBCRRDNPMT-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-cyclopropyl-1-[[4-(triazol-1-ylmethyl)phenyl]methyl]pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=C1)=CC=C1CN1C=CN=N1 DYRPOBCRRDNPMT-UHFFFAOYSA-N 0.000 claims description 3
- MJXNVOXGGURCQI-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-cyclopropyl-1-[[6-(diethylamino)-5-fluoropyridin-3-yl]methyl]pyrazole-4-carboxamide Chemical compound C1=C(F)C(N(CC)CC)=NC=C1CN1N=C(C2CC2)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 MJXNVOXGGURCQI-UHFFFAOYSA-N 0.000 claims description 3
- 230000002207 retinal effect Effects 0.000 claims description 3
- 230000008728 vascular permeability Effects 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- PWINZESYUZCYRY-UHFFFAOYSA-N 3-amino-n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(6-ethoxypyridin-3-yl)methyl]pyrazole-4-carboxamide Chemical compound C1=NC(OCC)=CC=C1CN1N=C(N)C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)=C1 PWINZESYUZCYRY-UHFFFAOYSA-N 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 206010019860 Hereditary angioedema Diseases 0.000 claims description 2
- 208000001953 Hypotension Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- GOKGDYJODZLJNF-UHFFFAOYSA-N N-(1H-indol-5-ylmethyl)-1-[[4-[(4-methylpyrazol-1-yl)methyl]phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound N1C=CC2=CC(=CC=C12)CNC(=O)C=1C(=NN(C=1)CC1=CC=C(C=C1)CN1N=CC(=C1)C)C(F)(F)F GOKGDYJODZLJNF-UHFFFAOYSA-N 0.000 claims description 2
- XAOAFFYPRSRGEH-UHFFFAOYSA-N N1N=CC2=C(C=CC=C12)CNC(=O)C=1C(=NN(C1)CC1=CC=C(C=C1)CN1C(C=CC=C1)=O)N Chemical compound N1N=CC2=C(C=CC=C12)CNC(=O)C=1C(=NN(C1)CC1=CC=C(C=C1)CN1C(C=CC=C1)=O)N XAOAFFYPRSRGEH-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 206010033645 Pancreatitis Diseases 0.000 claims description 2
- 206010051077 Post procedural haemorrhage Diseases 0.000 claims description 2
- 208000037486 Postoperative Hemorrhage Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 206010047531 Visual acuity reduced Diseases 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 230000002612 cardiopulmonary effect Effects 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000036543 hypotension Effects 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- VRYHLJFFMXJWLQ-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-1-[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C(F)(F)F)=CN1CC(C=C1)=CC=C1CN1C=CC=N1 VRYHLJFFMXJWLQ-UHFFFAOYSA-N 0.000 claims description 2
- MDTXJNQVRIMIES-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-cyclopropyl-1-[(6-phenoxypyridin-3-yl)methyl]pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=N1)=CC=C1OC1=CC=CC=C1 MDTXJNQVRIMIES-UHFFFAOYSA-N 0.000 claims description 2
- PMJBHWGXJWWQJR-UHFFFAOYSA-N n-[(1-aminoisoquinolin-6-yl)methyl]-3-cyclopropyl-1-[(6-pyrrolidin-1-ylpyridin-3-yl)methyl]pyrazole-4-carboxamide Chemical compound C=1C=C2C(N)=NC=CC2=CC=1CNC(=O)C(C(=N1)C2CC2)=CN1CC(C=N1)=CC=C1N1CCCC1 PMJBHWGXJWWQJR-UHFFFAOYSA-N 0.000 claims description 2
- 201000001119 neuropathy Diseases 0.000 claims description 2
- 230000007823 neuropathy Effects 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- HIYGQPZTBFIDNY-UHFFFAOYSA-N 3-amino-n-[(1-aminoisoquinolin-6-yl)methyl]-1-[(6-pyrrolidin-1-ylpyridin-3-yl)methyl]pyrazole-4-carboxamide Chemical compound C1=C(C(=O)NCC=2C=C3C=CN=C(N)C3=CC=2)C(N)=NN1CC(C=N1)=CC=C1N1CCCC1 HIYGQPZTBFIDNY-UHFFFAOYSA-N 0.000 claims 1
- 102000001399 Kallikrein Human genes 0.000 claims 1
- 108060005987 Kallikrein Proteins 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 75
- 125000001424 substituent group Chemical group 0.000 abstract description 45
- 125000003545 alkoxy group Chemical group 0.000 abstract description 35
- 125000003118 aryl group Chemical group 0.000 abstract description 28
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 22
- 239000000203 mixture Substances 0.000 abstract description 20
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 19
- 125000005843 halogen group Chemical group 0.000 abstract description 17
- 229910052799 carbon Inorganic materials 0.000 abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 abstract description 11
- 229910052717 sulfur Inorganic materials 0.000 abstract description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- 125000005842 heteroatom Chemical group 0.000 abstract description 7
- 125000002757 morpholinyl group Chemical group 0.000 abstract description 7
- 125000004043 oxo group Chemical group O=* 0.000 abstract description 7
- 229920006395 saturated elastomer Polymers 0.000 abstract description 7
- 125000003386 piperidinyl group Chemical group 0.000 abstract description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 5
- 125000001963 4 membered heterocyclic group Chemical group 0.000 abstract description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract description 4
- 125000003341 7 membered heterocyclic group Chemical group 0.000 abstract description 4
- 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 abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 abstract description 4
- 229930195734 saturated hydrocarbon Natural products 0.000 abstract description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 4
- 239000004215 Carbon black (E152) Substances 0.000 abstract 2
- 125000002619 bicyclic group Chemical group 0.000 abstract 2
- 235000010290 biphenyl Nutrition 0.000 abstract 2
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- 125000001153 fluoro group Chemical group F* 0.000 abstract 2
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 abstract 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 23
- 239000002253 acid Substances 0.000 description 14
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Landscapes
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Applications Claiming Priority (5)
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| US201361826596P | 2013-05-23 | ||
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| US201361865756P | 2013-08-14 | ||
| PCT/GB2014/051592 WO2014188211A1 (en) | 2013-05-23 | 2014-05-23 | Heterocyclic derivates |
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| JP6527147B2 (ja) * | 2013-08-14 | 2019-06-05 | カルヴィスタ ファーマシューティカルズ リミテッド | 血漿カリクレインの阻害薬 |
| US9611252B2 (en) | 2013-12-30 | 2017-04-04 | Lifesci Pharmaceuticals, Inc. | Therapeutic inhibitory compounds |
| EA032713B1 (ru) | 2013-12-30 | 2019-07-31 | Лайфсай Фармасьютикалс, Инк. | Терапевтические ингибирующие соединения |
| GB201421085D0 (en) | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
| GB201421088D0 (en) * | 2014-11-27 | 2015-01-14 | Kalvista Pharmaceuticals Ltd | New enzyme inhibitors |
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| CN104530013B (zh) * | 2014-12-04 | 2016-06-29 | 中国农业大学 | 基于吲哚环的吡唑酰胺类化合物作为农用杀菌剂的用途 |
| CN104761491B (zh) * | 2015-03-31 | 2018-08-21 | 山东友帮生化科技有限公司 | 2-氨基-3-碘-5-溴吡啶的合成方法 |
| KR20180030545A (ko) * | 2015-06-22 | 2018-03-23 | 다이닛본 스미토모 세이야꾸 가부시끼가이샤 | 바이사이클릭 헤테로사이클릭 아미드 유도체 |
| US10640486B2 (en) | 2015-10-27 | 2020-05-05 | Boehringer Ingelheim International Gmbh | Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors |
| JP6917988B2 (ja) * | 2015-10-27 | 2021-08-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 血漿カリクレイン阻害薬としてのヘテロアリールカルボキサミド誘導体 |
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| WO2018011628A1 (en) | 2016-07-11 | 2018-01-18 | Lifesci Pharmaceuticals, Inc. | Therapeutic inhibitory compounds |
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| MX2020005168A (es) | 2017-11-29 | 2020-08-20 | Kalvista Pharmaceuticals Ltd | Formas de dosificacion que contienen un inhibidor calicreina de plasma. |
| GB201719881D0 (en) | 2017-11-29 | 2018-01-10 | Kalvista Pharmaceuticals Ltd | Solid forms of plasma kallikrein inhibitor and salts thereof |
| US10695334B2 (en) | 2018-08-16 | 2020-06-30 | Boehringer Ingelheim International Gmbh | Heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors |
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