RU2730552C2 - Спироконденсированные пирролидиновые производные в качестве ингибиторов деубиквитилирующих ферментов (DUB) - Google Patents
Спироконденсированные пирролидиновые производные в качестве ингибиторов деубиквитилирующих ферментов (DUB) Download PDFInfo
- Publication number
- RU2730552C2 RU2730552C2 RU2018133279A RU2018133279A RU2730552C2 RU 2730552 C2 RU2730552 C2 RU 2730552C2 RU 2018133279 A RU2018133279 A RU 2018133279A RU 2018133279 A RU2018133279 A RU 2018133279A RU 2730552 C2 RU2730552 C2 RU 2730552C2
- Authority
- RU
- Russia
- Prior art keywords
- oxo
- pyrrolidine
- carbonitrile
- dihydro
- spiro
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 10
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 title 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 title 1
- 150000003235 pyrrolidines Chemical class 0.000 title 1
- 125000003003 spiro group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 146
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 63
- 239000001257 hydrogen Substances 0.000 claims abstract description 62
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 125000003118 aryl group Chemical group 0.000 claims abstract description 53
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 52
- 150000002367 halogens Chemical class 0.000 claims abstract description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 35
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 239000000460 chlorine Substances 0.000 claims abstract description 23
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 20
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract description 18
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 18
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 10
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 8
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims abstract description 6
- 150000001408 amides Chemical class 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract 5
- -1 CF 3 Chemical group 0.000 claims description 173
- 125000001424 substituent group Chemical group 0.000 claims description 59
- 125000001153 fluoro group Chemical group F* 0.000 claims description 25
- 125000002619 bicyclic group Chemical group 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- QJSGPSYFYHOZNH-UHFFFAOYSA-N CC1NC(C2(CCN(C2)C#N)C1)=O Chemical compound CC1NC(C2(CCN(C2)C#N)C1)=O QJSGPSYFYHOZNH-UHFFFAOYSA-N 0.000 claims description 6
- FYLPWNSSPLONCB-UHFFFAOYSA-N O=C1NC2=C(NCC11CN(CC1)C#N)N=CC=C2 Chemical compound O=C1NC2=C(NCC11CN(CC1)C#N)N=CC=C2 FYLPWNSSPLONCB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 230000004065 mitochondrial dysfunction Effects 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- AJLXUHSMNZNGBR-UHFFFAOYSA-N 1,2,3,5-tetrahydropyrido[2,3-b][1,4]diazepin-4-one Chemical class N1C(=O)CCNC2=CC=CN=C21 AJLXUHSMNZNGBR-UHFFFAOYSA-N 0.000 claims description 5
- PBQINQSJWPGZAX-UHFFFAOYSA-N 1,5-dihydro-4,1-benzoxazepin-2-one Chemical class N1C(=O)COCC2=CC=CC=C21 PBQINQSJWPGZAX-UHFFFAOYSA-N 0.000 claims description 5
- ORNSLMJWQDGQFF-UHFFFAOYSA-N 1h-pyrido[2,3-b][1,4]oxazin-2-one Chemical class C1=CC=C2NC(=O)COC2=N1 ORNSLMJWQDGQFF-UHFFFAOYSA-N 0.000 claims description 5
- HIGOCZJARKJCGG-UHFFFAOYSA-N 3,4-dihydro-1h-pyrido[2,3-b]pyrazin-2-one Chemical class C1=CC=C2NC(=O)CNC2=N1 HIGOCZJARKJCGG-UHFFFAOYSA-N 0.000 claims description 5
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical class C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 5
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- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
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- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
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| US11059809B2 (en) | 2017-06-20 | 2021-07-13 | Mission Therapeutics Limited | Substituted cyanopyrrolidines with activity as DUB inhibitors |
| US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
| IL278291B2 (en) | 2018-05-17 | 2023-10-01 | Forma Therapeutics Inc | Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors |
| US11572374B2 (en) | 2018-08-14 | 2023-02-07 | Amgen Inc. | N-cyano-7-azanorbornane derivatives and uses thereof |
| LT3860989T (lt) | 2018-10-05 | 2023-06-12 | Forma Therapeutics, Inc. | Sulieti pirolinai, kurie veikia kaip ubikvitinui specifinės proteazės 30 (ups30) inhibitoriai |
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| CN115461340A (zh) | 2020-04-08 | 2022-12-09 | 特殊治疗有限公司 | 具有作为usp30抑制剂活性的n-氰基吡咯烷类化合物 |
| WO2021239863A1 (en) | 2020-05-28 | 2021-12-02 | Mission Therapeutics Limited | N-(1-cyano-pyrrolidin-3-yl)-5-(3-(trifluoromethyl)phenyl)oxazole-2-carboxamide derivatives and the corresponding oxadiazole derivatives as usp30 inhibitors for the treatment of mitochondrial dysfunction |
| CN115698001A (zh) | 2020-06-04 | 2023-02-03 | 特殊治疗有限公司 | 具有作为usp30抑制剂活性的n-氰基吡咯烷类化合物 |
| FI4161929T3 (fi) | 2020-06-08 | 2025-07-30 | Mission Therapeutics Ltd | 1-(5-(2-syaanipyridin-4-yyli)oksatsoli-2-karbonyyli)-4-metyyliheksahydropyrrolo[3,4-b]pyrroli-5(1h)-karbonitriili usp30-inhibiittorina käytettäväksi mitokondrioiden toimintahäiriön, syövän ja fibroosin hoitamisessa |
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| CN116143782B (zh) * | 2021-11-22 | 2024-04-12 | 西南大学 | 一类螺[吡咯烷-2,3'-喹啉]-2'-酮类衍生物的设计合成与应用 |
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| WO2024151847A1 (en) * | 2023-01-13 | 2024-07-18 | The University Of North Carolina At Chapel Hill | Identification of otud7b inhibitor 7bi and its application in reducing growth of nsclc and leukemia cells |
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| WO2008036168A2 (en) * | 2006-08-30 | 2008-03-27 | The Regents Of The University Of Michigan | New small molecule inhibitors of mdm2 and the uses thereof |
| WO2009026197A1 (en) * | 2007-08-20 | 2009-02-26 | Glaxo Group Limited | Novel cathepsin c inhibitors and their use |
| US20120264738A1 (en) * | 2011-03-10 | 2012-10-18 | Yuuichi Sugimoto | Dispiropyrrolidine derivatives |
| RU2571100C2 (ru) * | 2009-12-02 | 2015-12-20 | Ф. Хоффманн-Ля Рош Аг | Спироиндолинонпирролидины, полезные при лечении злокачественных новообразований |
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| AU2001256981A1 (en) | 2000-04-06 | 2001-10-23 | Axys Pharmaceuticals, Inc. | Cathepsin cysteine protease inhibitors |
| SG176463A1 (en) | 2005-02-22 | 2011-12-29 | Univ Michigan | Small molecule inhibitors of mdm2 and uses thereof |
| WO2008144507A2 (en) | 2007-05-16 | 2008-11-27 | President And Fellows Of Harvard College | Spirooxindole inhibitors of aurora kinase |
| GB0922589D0 (en) | 2009-12-23 | 2010-02-10 | Almac Discovery Ltd | Pharmaceutical compounds |
| EP2752191A1 (en) | 2013-01-07 | 2014-07-09 | Sanofi | Compositions and methods using hdm2 antagonist and mek inhibitor |
| GB201416754D0 (en) * | 2014-09-23 | 2014-11-05 | Mission Therapeutics Ltd | Novel compounds |
| EP3277677B9 (en) | 2015-03-30 | 2021-07-14 | Mission Therapeutics Limited | 1-cyano-pyrrolidine compounds as usp30 inhibitors |
| EP3322702B1 (en) * | 2015-07-14 | 2019-11-20 | Mission Therapeutics Limited | Cyanopyrrolidines as dub inhibitors for the treatment of cancer |
| GB201521109D0 (en) | 2015-11-30 | 2016-01-13 | Mission Therapeutics Ltd | Novel compounds |
| GB201522267D0 (en) | 2015-12-17 | 2016-02-03 | Mission Therapeutics Ltd | Novel compounds |
| GB201522768D0 (en) | 2015-12-23 | 2016-02-03 | Mission Therapeutics Ltd | Novel compounds |
| GB201602854D0 (en) * | 2016-02-18 | 2016-04-06 | Mission Therapeutics Ltd | Novel compounds |
| GB201603779D0 (en) * | 2016-03-04 | 2016-04-20 | Mission Therapeutics Ltd | Novel compounds |
| GB201604638D0 (en) | 2016-03-18 | 2016-05-04 | Mission Therapeutics Ltd | Novel compounds |
| GB201604647D0 (en) | 2016-03-18 | 2016-05-04 | Mission Therapeutics Ltd | Novel compounds |
| WO2017163078A1 (en) | 2016-03-24 | 2017-09-28 | Mission Therapeutics Limited | 1-cyano-pyrrolidine derivatives as dbu inhibitors |
| EP3519385B1 (en) | 2016-09-27 | 2020-11-18 | Mission Therapeutics Limited | Cyanopyrrolidine derivatives with activity as inhibitors of usp30 |
| GB201616511D0 (en) | 2016-09-29 | 2016-11-16 | Mission Therapeutics Limited | Novel compounds |
| GB201616627D0 (en) | 2016-09-30 | 2016-11-16 | Mission Therapeutics Limited | Novel compounds |
| TWI771327B (zh) | 2016-10-05 | 2022-07-21 | 英商使命醫療公司 | 新穎化合物 |
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