CN108137510B - 化合物 - Google Patents
化合物 Download PDFInfo
- Publication number
- CN108137510B CN108137510B CN201680054465.2A CN201680054465A CN108137510B CN 108137510 B CN108137510 B CN 108137510B CN 201680054465 A CN201680054465 A CN 201680054465A CN 108137510 B CN108137510 B CN 108137510B
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- CN
- China
- Prior art keywords
- methyl
- indazol
- cis
- fluoro
- group
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 437
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 60
- 238000011282 treatment Methods 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims description 176
- -1 1,2,3, 6-tetrahydropyridinyl Chemical group 0.000 claims description 59
- 125000001424 substituent group Chemical group 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
- 125000000623 heterocyclic group Chemical group 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 39
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- 229920006395 saturated elastomer Polymers 0.000 claims description 35
- 125000003566 oxetanyl group Chemical group 0.000 claims description 28
- 125000003545 alkoxy group Chemical class 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 15
- 125000003386 piperidinyl group Chemical group 0.000 claims description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
- 125000004193 piperazinyl group Chemical group 0.000 claims description 14
- 125000002757 morpholinyl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 125000002393 azetidinyl group Chemical group 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- ZHAIMJRKJKQNQI-UHFFFAOYSA-N 2-oxa-7-azaspiro[3.4]octane Chemical group C1OCC11CNCC1 ZHAIMJRKJKQNQI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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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
- C07D403/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D471/04—Ortho-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
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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CNPCT/CN2015/084893 | 2015-07-23 | ||
CN2015084893 | 2015-07-23 | ||
PCT/CN2016/090962 WO2017012576A1 (en) | 2015-07-23 | 2016-07-22 | Compounds |
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CN108137510A CN108137510A (zh) | 2018-06-08 |
CN108137510B true CN108137510B (zh) | 2021-07-20 |
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CA3050023A1 (en) * | 2017-01-25 | 2018-08-02 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
WO2018137573A1 (en) * | 2017-01-25 | 2018-08-02 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
BR112019015314A2 (pt) * | 2017-01-25 | 2020-05-19 | Glaxosmithkline Ip Dev Ltd | compostos para inibir a atividade da quinase lrrk2 |
BR112019015278A2 (pt) * | 2017-01-25 | 2020-04-14 | Glaxosmithkline Ip Dev Ltd | compostos |
WO2018137607A1 (en) * | 2017-01-25 | 2018-08-02 | Glaxosmithkline Intellectual Property Development Limited | Compounds |
CN106866547B (zh) * | 2017-03-15 | 2020-11-10 | 江苏省农用激素工程技术研究中心有限公司 | 2-乙氧基-4,6-二氯嘧啶的合成方法 |
WO2019046316A1 (en) * | 2017-08-28 | 2019-03-07 | Acurastem Inc. | PIKFYVE KINASE INHIBITORS |
WO2019222173A1 (en) * | 2018-05-15 | 2019-11-21 | E-Scape Bio, Inc. | Fused tetrazoles as lrrk2 inhibitors |
KR20190131981A (ko) * | 2018-05-18 | 2019-11-27 | 재단법인 대구경북첨단의료산업진흥재단 | 외상성 뇌손상 또는 뇌졸중의 예방 또는 치료용 약학적 조성물 |
TWI833770B (zh) * | 2018-06-27 | 2024-03-01 | 美商Ionis製藥公司 | 用於減少 lrrk2 表現之化合物及方法 |
EP3873471A4 (en) * | 2018-10-31 | 2022-06-15 | Merck Sharp & Dohme Corp. | N-HETEROARYL INDAZOLE DERIVATIVES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND THEIR USES |
US20220259188A1 (en) | 2019-06-06 | 2022-08-18 | Merck Sharp & Dohme Corp. | 1-pyrazolyl, 5-, 6- disubstituted indazole derivatives as lrrk2 inhibitors, pharmaceutical compositions, and uses thereof |
WO2021003161A1 (en) * | 2019-07-01 | 2021-01-07 | Curasen Therapeutics, Inc. | Beta adrenergic agonist and methods of using the same |
CN114450274A (zh) * | 2019-07-11 | 2022-05-06 | 伊斯凯普生物公司 | 作为lrrk2抑制剂的吲唑及氮杂吲唑 |
EP4103281A1 (en) * | 2020-02-11 | 2022-12-21 | Acurastem Inc. | Pikfyve kinase inhibitors |
WO2021178780A1 (en) * | 2020-03-06 | 2021-09-10 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as lrrk2 inhibitors |
CN115916338A (zh) * | 2020-04-24 | 2023-04-04 | 加利福尼亚大学董事会 | Nurr1受体调节剂及其用途 |
WO2022155419A1 (en) * | 2021-01-15 | 2022-07-21 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as lrrk2 inhibitors |
US11780851B2 (en) | 2021-10-27 | 2023-10-10 | H. Lundbeck A/S | LRRK2 inhibitors |
WO2023076404A1 (en) | 2021-10-27 | 2023-05-04 | Aria Pharmaceuticals, Inc. | Methods for treating systemic lupus erythematosus |
US11958865B1 (en) | 2022-09-15 | 2024-04-16 | H. Lundbeck A/S | Leucine-rich repeat kinase 2 (LRRK2) inhibitors |
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WO2014134774A1 (en) * | 2013-03-04 | 2014-09-12 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
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2016
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- 2016-07-22 JP JP2018503191A patent/JP6746679B2/ja not_active Expired - Fee Related
- 2016-07-22 BR BR112018001303A patent/BR112018001303A2/pt not_active IP Right Cessation
- 2016-07-22 WO PCT/CN2016/090962 patent/WO2017012576A1/en active Application Filing
- 2016-07-22 KR KR1020187004848A patent/KR20180030201A/ko not_active Application Discontinuation
- 2016-07-22 CA CA2993269A patent/CA2993269A1/en not_active Abandoned
- 2016-07-22 EP EP16827267.2A patent/EP3325449B1/en active Active
- 2016-07-22 CN CN201680054465.2A patent/CN108137510B/zh not_active Expired - Fee Related
- 2016-07-22 US US15/746,817 patent/US10975081B2/en active Active
- 2016-07-22 AU AU2016295604A patent/AU2016295604B2/en not_active Ceased
- 2016-07-22 ES ES16827267T patent/ES2862188T3/es active Active
Patent Citations (6)
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WO2006047516A2 (en) * | 2004-10-26 | 2006-05-04 | Irm Llc | Compounds and compositions as inhibitors of cannabinoid receptor 1 activity |
WO2011106168A1 (en) * | 2010-02-24 | 2011-09-01 | Dcam Pharma Inc | Purine compounds for treating autoimmune and demyelinating diseases |
WO2012009258A2 (en) * | 2010-07-13 | 2012-01-19 | Edward Roberts | Peptidomimetic galanin receptor modulators |
CN104428299A (zh) * | 2012-06-27 | 2015-03-18 | 霍夫曼-拉罗奇有限公司 | 5-氮杂吲唑化合物及其使用方法 |
WO2015099196A1 (en) * | 2013-12-26 | 2015-07-02 | Takeda Pharmaceutical Company Limited | 4-(piperrazin-1-yl)-pyrrolidin-2-one compounds as monoacylglycerol lipase (magl) inhibitors |
WO2016036586A1 (en) * | 2014-09-03 | 2016-03-10 | Merck Sharp & Dohme Corp. | Compounds inhibiting leucine-rich repeat kinase enzyme activity |
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JP2018524390A (ja) | 2018-08-30 |
US20200079777A1 (en) | 2020-03-12 |
ES2862188T3 (es) | 2021-10-07 |
RU2018106453A (ru) | 2019-08-26 |
EP3325449A1 (en) | 2018-05-30 |
AU2016295604B2 (en) | 2019-08-01 |
JP6746679B2 (ja) | 2020-08-26 |
EP3325449B1 (en) | 2021-01-13 |
WO2017012576A1 (en) | 2017-01-26 |
AU2016295604A1 (en) | 2018-02-01 |
EP3325449A4 (en) | 2019-01-09 |
CN108137510A (zh) | 2018-06-08 |
RU2725616C2 (ru) | 2020-07-03 |
RU2018106453A3 (US06894165-20050517-C00155.png) | 2019-12-05 |
CA2993269A1 (en) | 2017-01-26 |
BR112018001303A2 (pt) | 2018-09-11 |
KR20180030201A (ko) | 2018-03-21 |
US10975081B2 (en) | 2021-04-13 |
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