KR102491994B1 - Rock의 억제제로서의 스피로락탐 - Google Patents
Rock의 억제제로서의 스피로락탐 Download PDFInfo
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- KR102491994B1 KR102491994B1 KR1020197003127A KR20197003127A KR102491994B1 KR 102491994 B1 KR102491994 B1 KR 102491994B1 KR 1020197003127 A KR1020197003127 A KR 1020197003127A KR 20197003127 A KR20197003127 A KR 20197003127A KR 102491994 B1 KR102491994 B1 KR 102491994B1
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- 239000011435 rock Substances 0.000 title abstract description 40
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 150000003839 salts Chemical class 0.000 claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 249
- 229910052739 hydrogen Inorganic materials 0.000 claims description 170
- 229910052799 carbon Inorganic materials 0.000 claims description 161
- 125000000623 heterocyclic group Chemical group 0.000 claims description 82
- -1 1'-(5-(1H-pyrazol-4-yl)pyrazin-2-yl)spiro[indoline-2,3'-pyrrolidin]-2'-one Chemical compound 0.000 claims description 71
- 229910052801 chlorine Inorganic materials 0.000 claims description 71
- 229910052731 fluorine Inorganic materials 0.000 claims description 71
- 229910052757 nitrogen Inorganic materials 0.000 claims description 68
- 229910052794 bromium Inorganic materials 0.000 claims description 53
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 43
- 125000004452 carbocyclyl 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
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 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 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- NZBBDMMHADSGAF-UHFFFAOYSA-N 1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(C2(CC1)NC1=CC=CC=C1C2)=O NZBBDMMHADSGAF-UHFFFAOYSA-N 0.000 claims description 14
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
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- 206010020772 Hypertension Diseases 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
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- YWBFHVWUZQRCIP-UHFFFAOYSA-N 6-(cyclopropylmethoxy)-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound C1(COC2=CC=3NC4(CC=3C=C2)CCN(C4=O)C2=CC=C(C=C2)C=2C=NNC=2)CC1 YWBFHVWUZQRCIP-UHFFFAOYSA-N 0.000 claims description 4
- BVXVOSBBRKWXTM-UHFFFAOYSA-N 6-hydroxy-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1,3-dihydroindole-2,3'-pyrrolidine]-2'-one Chemical compound N1C2=C(CC31CCN(C3=O)C1=CC=C(C=C1)C=1C=NNC=1)C=CC(O)=C2 BVXVOSBBRKWXTM-UHFFFAOYSA-N 0.000 claims description 4
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- AEONZEOWPZGQPC-UHFFFAOYSA-N 3,3-dimethyl-1'-[4-(1H-pyrazol-4-yl)phenyl]spiro[1H-indole-2,3'-pyrrolidine]-2'-one Chemical compound N1=CC(=CN1)C1=CC=C(N2C(=O)C3(CC2)C(C)(C)C2=CC=CC=C2N3)C=C1 AEONZEOWPZGQPC-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- 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
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
- C07D401/14—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 three or more hetero rings
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- 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
- C07D403/10—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 carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| US201662359354P | 2016-07-07 | 2016-07-07 | |
| US62/359,354 | 2016-07-07 | ||
| PCT/US2017/040850 WO2018009625A1 (en) | 2016-07-07 | 2017-07-06 | Spirolactams as inhibitors of rock |
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| KR20190025682A KR20190025682A (ko) | 2019-03-11 |
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| WO2017205709A1 (en) | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
| JP7155102B2 (ja) | 2016-07-07 | 2022-10-18 | 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縮合環尿素 |
| EP3481816B1 (en) | 2016-07-07 | 2020-06-24 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
| EP3548468B1 (en) | 2016-11-30 | 2020-09-16 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
| WO2019014300A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | PHENYLACETAMIDES AS ROCK INHIBITORS |
| US12060341B2 (en) | 2017-07-12 | 2024-08-13 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as ROCK inhibitors |
| 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 |
| CN110914257B (zh) | 2017-07-12 | 2023-05-26 | 百时美施贵宝公司 | 作为rock抑制剂的螺庚基乙内酰脲 |
| JP7234201B2 (ja) | 2017-07-12 | 2023-03-07 | ブリストル－マイヤーズ スクイブ カンパニー | 心不全の治療のためのｒｏｃｋの５員アミノヘテロ環および５，６－または６，６員二環式アミノヘテロ環の阻害剤 |
| ES2937039T3 (es) | 2017-11-03 | 2023-03-23 | Bristol Myers Squibb Co | Inhibidores diazaespiro de ROCK |
| LT3860998T (lt) | 2018-10-05 | 2024-06-25 | Annapurna Bio Inc. | Junginiai ir kompozicijos, skirti gydyti būkles, susijusias su apj receptoriaus aktyvumu |
| DK3877364T3 (da) | 2018-11-06 | 2024-09-23 | Cervello Therapeutics LLC | Rock-kinasehæmmere |
| US11248004B2 (en) | 2018-11-06 | 2022-02-15 | Cervello Therapeutics, Llc. | Substituted isoquinolines as rock kinase inhibitors |
| EP3902805A4 (en) | 2018-12-28 | 2023-03-01 | SPV Therapeutics Inc. | CYCLINE-DEPENDENT KINASE INHIBITORS |
| CA3238227A1 (en) | 2021-11-11 | 2023-05-19 | The Doshisha | Cryopreservation preparation for corneal endothelial cells and method for producing said cryopreservation preparation |
| KR20260019479A (ko) | 2023-05-04 | 2026-02-10 | 레볼루션 메디슨즈, 인크. | Ras 관련 질환 또는 장애를 위한 병용 요법 |
| CN121889155A (zh) | 2023-08-07 | 2026-04-17 | 锐新医药公司 | 用于治疗ras蛋白相关疾病或病症的rmc-6291 |
| AU2024360465A1 (en) | 2023-10-12 | 2026-04-09 | Revolution Medicines, Inc. | Macrocyclic ras inhibitors |
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| WO2026015796A1 (en) | 2024-07-12 | 2026-01-15 | Revolution Medicines, Inc. | Methods of treating a ras related disease or disorder |
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| WO2026072904A2 (en) | 2024-09-26 | 2026-04-02 | Revolution Medicines, Inc. | Compositions and methods for treating lung cancer |
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| WO2026128688A2 (en) | 2024-12-13 | 2026-06-18 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2026161839A1 (en) | 2025-01-27 | 2026-07-30 | Revolution Medicines, Inc. | Ras inhibitors |
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| WO2014134391A1 (en) | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
| WO2016065582A1 (en) | 2014-10-30 | 2016-05-06 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
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| ES2232292B1 (es) | 2003-07-30 | 2006-11-01 | Laboratorios Del Dr. Esteve, S.A. | Compuestos sulfonamidicos derivados de benzoxazinona, su preparacion y uso como medicamentos. |
| JP2007519754A (ja) | 2004-01-30 | 2007-07-19 | スミスクライン ビーチャム コーポレーション | 化合物 |
| WO2008096746A1 (ja) | 2007-02-06 | 2008-08-14 | Takeda Pharmaceutical Company Limited | スピロ化合物およびその用途 |
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| JP6434968B2 (ja) | 2013-07-02 | 2018-12-05 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Ｒｏｃｋ阻害剤としての三環式ピリド−カルボキサミド誘導体 |
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| CN107108581B (zh) | 2014-08-21 | 2020-06-23 | 百时美施贵宝公司 | 作为强效rock抑制剂的回接苯甲酰胺衍生物 |
| JP6779214B2 (ja) | 2015-01-09 | 2020-11-04 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Ｒｏｃｋ阻害剤としての環状ウレア |
| ES2730112T3 (es) * | 2015-03-09 | 2019-11-08 | Bristol Myers Squibb Co | Lactamas como inhibidores de ROCK |
| TWI730032B (zh) | 2016-01-13 | 2021-06-11 | 美商必治妥美雅史谷比公司 | 作為ｒｏｃｋ抑制劑之螺庚烷水楊酸醯胺及相關化合物 |
| WO2017205709A1 (en) | 2016-05-27 | 2017-11-30 | Bristol-Myers Squibb Company | Triazolones and tetrazolones as inhibitors of rock |
| JP7155102B2 (ja) | 2016-07-07 | 2022-10-18 | 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縮合環尿素 |
| EP3481816B1 (en) | 2016-07-07 | 2020-06-24 | Bristol-Myers Squibb Company | Lactam, cyclic urea and carbamate, and triazolone derivatives as potent and selective rock inhibitors |
| EP3548468B1 (en) | 2016-11-30 | 2020-09-16 | Bristol-Myers Squibb Company | Tricyclic rho kinase inhibitors |
| CN110914257B (zh) | 2017-07-12 | 2023-05-26 | 百时美施贵宝公司 | 作为rock抑制剂的螺庚基乙内酰脲 |
| 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 |
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| WO2019014300A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | PHENYLACETAMIDES AS ROCK INHIBITORS |
| ES2937039T3 (es) | 2017-11-03 | 2023-03-23 | Bristol Myers Squibb Co | Inhibidores diazaespiro de ROCK |
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2017
- 2017-07-06 ES ES17740241T patent/ES2821877T3/es active Active
- 2017-07-06 KR KR1020197003127A patent/KR102491994B1/ko active Active
- 2017-07-06 CN CN201780054599.9A patent/CN109689639B/zh active Active
- 2017-07-06 WO PCT/US2017/040850 patent/WO2018009625A1/en not_active Ceased
- 2017-07-06 EP EP17740241.9A patent/EP3481817B1/en active Active
- 2017-07-06 JP JP2019500399A patent/JP7113810B2/ja active Active
- 2017-07-06 US US16/315,678 patent/US10696674B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014134391A1 (en) | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
| WO2016065582A1 (en) | 2014-10-30 | 2016-05-06 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3481817B1 (en) | 2020-08-19 |
| US20190322664A1 (en) | 2019-10-24 |
| ES2821877T3 (es) | 2021-04-28 |
| US10696674B2 (en) | 2020-06-30 |
| JP2019520398A (ja) | 2019-07-18 |
| CN109689639B (zh) | 2022-02-18 |
| CN109689639A (zh) | 2019-04-26 |
| WO2018009625A1 (en) | 2018-01-11 |
| KR20190025682A (ko) | 2019-03-11 |
| JP7113810B2 (ja) | 2022-08-05 |
| EP3481817A1 (en) | 2019-05-15 |
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