JP6789941B2 - Tgf−ベータ阻害剤としての縮合イミダゾール誘導体 - Google Patents
Tgf−ベータ阻害剤としての縮合イミダゾール誘導体 Download PDFInfo
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- JP6789941B2 JP6789941B2 JP2017527370A JP2017527370A JP6789941B2 JP 6789941 B2 JP6789941 B2 JP 6789941B2 JP 2017527370 A JP2017527370 A JP 2017527370A JP 2017527370 A JP2017527370 A JP 2017527370A JP 6789941 B2 JP6789941 B2 JP 6789941B2
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- JP
- Japan
- Prior art keywords
- dihydro
- pyrrolo
- imidazol
- imidazole
- pyridine
- 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.)
- Expired - Fee Related
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- 150000002460 imidazoles Chemical class 0.000 title claims description 57
- 102000004887 Transforming Growth Factor beta Human genes 0.000 title claims description 17
- 108090001012 Transforming Growth Factor beta Proteins 0.000 title claims description 17
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 title claims description 16
- 239000003112 inhibitor Substances 0.000 title claims description 10
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- 150000001875 compounds Chemical class 0.000 claims description 473
- 125000000217 alkyl group Chemical group 0.000 claims description 280
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 259
- 229910052736 halogen Inorganic materials 0.000 claims description 131
- 150000002367 halogens Chemical class 0.000 claims description 125
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 105
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 claims description 94
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 239000001257 hydrogen Substances 0.000 claims description 68
- 239000000203 mixture Substances 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 58
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 52
- 239000012453 solvate Substances 0.000 claims description 48
- 150000001204 N-oxides Chemical class 0.000 claims description 47
- 125000001188 haloalkyl group Chemical group 0.000 claims description 43
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 37
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 35
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 34
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 33
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 239000002253 acid Substances 0.000 claims description 23
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- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 19
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
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- 239000002246 antineoplastic agent Substances 0.000 claims description 12
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 12
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 11
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 11
- 229940127089 cytotoxic agent Drugs 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 10
- 125000004262 quinoxalin-2-yl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N=C1* 0.000 claims description 10
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 9
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 8
- 210000000988 bone and bone Anatomy 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 102000004190 Enzymes Human genes 0.000 claims description 7
- 108090000790 Enzymes Proteins 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- YDHIMEXEGOCNHU-UHFFFAOYSA-N 2-pyridin-3-ylacetamide Chemical compound NC(=O)CC1=CC=CN=C1 YDHIMEXEGOCNHU-UHFFFAOYSA-N 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 102100039939 Growth/differentiation factor 8 Human genes 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
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- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 4
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| US62/141,509 | 2015-04-01 | ||
| PCT/US2015/060872 WO2016081364A1 (en) | 2014-11-21 | 2015-11-16 | Fused imidazole derivatives as tgf-beta inhibitors |
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| JP2018501209A JP2018501209A (ja) | 2018-01-18 |
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| JP7300394B2 (ja) | 2017-01-17 | 2023-06-29 | ヘパリジェニックス ゲーエムベーハー | 肝再生の促進又は肝細胞死の低減もしくは予防のためのプロテインキナーゼ阻害 |
| JP2020512400A (ja) | 2017-03-23 | 2020-04-23 | クラヴィウス ファーマシューティカルズ,エルエルシー | TGFβの阻害のための三置換イミダゾールおよび治療方法 |
| JP7147048B2 (ja) * | 2018-08-22 | 2022-10-04 | クラヴィウス ファーマシューティカルズ,エルエルシー | Tgf-ベータを阻害するための置換イミダゾールおよび処置方法 |
| AU2019396360A1 (en) | 2018-12-11 | 2021-05-27 | Theravance Biopharma R&D Ip, Llc | Naphthyridine and quinoline derivatives useful as ALK5 inhibitors |
| CN114728941A (zh) | 2019-11-22 | 2022-07-08 | 施万生物制药研发Ip有限责任公司 | 作为alk5抑制剂的经取代的1,5-萘啶或喹啉 |
| JP7389905B2 (ja) * | 2019-12-04 | 2023-11-30 | 河南知微生物医薬有限公司 | ブルトン型チロシンキナーゼ阻害剤としてのイミダゾールカルボキサミド誘導体 |
| US12441707B2 (en) | 2019-12-30 | 2025-10-14 | Tyra Biosciences, Inc. | Indazole compounds |
| US20250270215A1 (en) | 2022-04-27 | 2025-08-28 | Chiesi Farmaceutici S.P.A. | Imidazole derivatives as alk5 inhibitors |
| MA71237A (fr) | 2022-06-22 | 2025-04-30 | Chiesi Farmaceutici S.P.A. | Dérivés de 5-(4-fluorophényl)-2,3-dihydro-1h-imidazo[1,2-a]imidazole utilisés en tant qu'inhibiteurs d'alk pour traiter la fibrose |
| KR20250051687A (ko) * | 2022-08-08 | 2025-04-17 | 메디노 파마슈티컬 테크놀로지 (주하이) 컴퍼니 리미티드 | TGF-β 억제제 화합물 및 그 사용 |
| PL248267B1 (pl) * | 2023-04-13 | 2025-11-17 | Uniwersytet Medyczny W Lublinie | 1-arylo-6-hydroksyimino-5(1H)okso-2,3-dihydroimidazo[1,2-a] imidazole oraz sposób ich wytwarzania oraz ich zastosowanie |
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| ATE322681T1 (de) | 1999-01-21 | 2006-04-15 | Metamorphix Inc | Inhibitoren für wachstumdifferenzierungsfaktor und ihre anwendungen |
| ATE288915T1 (de) * | 1999-11-10 | 2005-02-15 | Ortho Mcneil Pharm Inc | Substituierte 2-aryl-3-(heteroaryl)-imidazo(1,2- alpha)pyrimidine und ihren verwandten arzneimittel und verfahren |
| US7320789B2 (en) | 2001-09-26 | 2008-01-22 | Wyeth | Antibody inhibitors of GDF-8 and uses thereof |
| DE60309342T2 (de) * | 2002-08-09 | 2007-05-16 | Eli Lilly And Co., Indianapolis | Benzimidazole und benzothiazole als inhibitoren der map-kinase |
| WO2004050659A1 (en) | 2002-11-27 | 2004-06-17 | Eli Lilly And Company | Novel compounds as pharmaceutical agents |
| PA8595001A1 (es) * | 2003-03-04 | 2004-09-28 | Pfizer Prod Inc | Nuevos compuestos heteroaromaticos condensados que son inhibidores del factor de crecimiento transforante (tgf) |
| US20100166819A1 (en) * | 2005-12-22 | 2010-07-01 | Biogen Idec Ma Inc. A Corporation | Transforming Growth Factor Modulators |
| CN101553224A (zh) * | 2006-10-06 | 2009-10-07 | 艾博特公司 | 新型咪唑并噻唑和咪唑并唑 |
| US8188083B2 (en) * | 2007-06-28 | 2012-05-29 | Abbott Laboratories | Triazolopyridazines |
| MX369576B (es) * | 2011-07-13 | 2019-11-13 | Tiumbio Co Ltd | Imidazoles 2-piridilo sustituidos como inhibidores de alk5 y/o alk4. |
| US9556179B2 (en) * | 2012-12-21 | 2017-01-31 | Bristol-Myers Squibb Company | Substituted imidazoles as casein kinase 1 D/E inhibitors |
| US20150159134A1 (en) * | 2013-12-11 | 2015-06-11 | Pfizer Limited | Method for producing retinal pigment epithelial cells |
| CN105814194A (zh) * | 2013-12-11 | 2016-07-27 | 辉瑞有限公司 | 产生视网膜色素上皮细胞的方法 |
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- 2015-11-16 JP JP2017527370A patent/JP6789941B2/ja not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| CN107207531B (zh) | 2021-05-25 |
| EP3221318B1 (en) | 2021-08-25 |
| JP2018501209A (ja) | 2018-01-18 |
| WO2016081364A1 (en) | 2016-05-26 |
| CN107207531A (zh) | 2017-09-26 |
| US20180346487A1 (en) | 2018-12-06 |
| ES2895626T3 (es) | 2022-02-22 |
| EP3221318A1 (en) | 2017-09-27 |
| US10696693B2 (en) | 2020-06-30 |
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