CN108137510B - 化合物 - Google Patents

化合物 Download PDF

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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
mmol
Prior art date
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Expired - Fee Related
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CN201680054465.2A
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English (en)
Chinese (zh)
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CN108137510A (zh
Inventor
丁晓
金赟
刘谦
任峰
桑迎霞
L.P.斯塔西
万泽红
王海龙
邢唯强
湛洋
赵保卫
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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Publication of CN108137510A publication Critical patent/CN108137510A/zh
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Expired - Fee Related legal-status Critical Current
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Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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 & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • 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)
  • Plural Heterocyclic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
CN201680054465.2A 2015-07-23 2016-07-22 化合物 Expired - Fee Related CN108137510B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2015084893 2015-07-23
CNPCT/CN2015/084893 2015-07-23
PCT/CN2016/090962 WO2017012576A1 (en) 2015-07-23 2016-07-22 Compounds

Publications (2)

Publication Number Publication Date
CN108137510A CN108137510A (zh) 2018-06-08
CN108137510B true CN108137510B (zh) 2021-07-20

Family

ID=57833742

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201680054465.2A Expired - Fee Related CN108137510B (zh) 2015-07-23 2016-07-22 化合物

Country Status (11)

Country Link
US (1) US10975081B2 (enExample)
EP (1) EP3325449B1 (enExample)
JP (1) JP6746679B2 (enExample)
KR (1) KR20180030201A (enExample)
CN (1) CN108137510B (enExample)
AU (1) AU2016295604B2 (enExample)
BR (1) BR112018001303A2 (enExample)
CA (1) CA2993269A1 (enExample)
ES (1) ES2862188T3 (enExample)
RU (1) RU2725616C2 (enExample)
WO (1) WO2017012576A1 (enExample)

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CA3050152A1 (en) * 2017-01-25 2018-08-02 Glaxosmithkline Intellectual Property Development Limited Compounds
JP2020505398A (ja) * 2017-01-25 2020-02-20 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 化合物
BR112019015269A2 (pt) * 2017-01-25 2020-04-14 Glaxosmithkline Ip Dev Ltd compostos
CN110248936A (zh) * 2017-01-25 2019-09-17 葛兰素史密斯克莱知识产权发展有限公司 化合物
CA3049820A1 (en) 2017-01-25 2018-08-02 Glaxosmithkline Intellectual Property Development Limited Compounds for inhibiting lrrk2 kinase activity
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
US20210261553A1 (en) * 2018-05-15 2021-08-26 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
US12030872B2 (en) * 2018-10-31 2024-07-09 Merck Sharp & Dohme Llc N-heteroaryl indazole derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
US12448352B2 (en) 2019-03-27 2025-10-21 Curasen Therapeutics, Inc. Beta adrenergic agonist and methods of using the same
US12319671B2 (en) * 2019-06-06 2025-06-03 Merck Sharp & Dohme Llc 1-pyrazolyl, 5-, 6-disubstituted indazole derivatives as LRRK2 inhibitors, pharmaceutical compositions, and uses thereof
TWI877182B (zh) * 2019-07-01 2025-03-21 美商古拉森療法公司 β腎上腺素激動劑及其使用方法
CA3145305A1 (en) 2019-07-11 2021-01-14 ESCAPE Bio, Inc. Indazoles and azaindazoles as lrrk2 inhibitors
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
WO2023073013A1 (en) 2021-10-27 2023-05-04 H. Lundbeck A/S Lrrk2 inhibitors
WO2023076404A1 (en) 2021-10-27 2023-05-04 Aria Pharmaceuticals, Inc. Methods for treating systemic lupus erythematosus
TW202412777A (zh) 2022-09-15 2024-04-01 丹麥商Ｈ 朗德貝克公司 富白胺酸重複激酶2（lrrk2）抑制劑
WO2025201511A1 (zh) * 2024-03-29 2025-10-02 上海京新生物医药有限公司 吲唑衍生物及其制备方法与应用

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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CA2584317A1 (en) * 2004-10-15 2006-04-27 Memory Pharmaceuticals Corporation Pyrazole derivatives as phosphodiesterase 4 inhibitors
JPWO2009157196A1 (ja) 2008-06-25 2011-12-08 武田薬品工業株式会社 アミド化合物
GB201008134D0 (en) * 2010-05-14 2010-06-30 Medical Res Council Technology Compounds
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WO2014134772A1 (en) 2013-03-04 2014-09-12 Merck Sharp & Dohme Corp. Compounds inhibiting leucine-rich repeat kinase enzyme activity
WO2014134774A1 (en) * 2013-03-04 2014-09-12 Merck Sharp & Dohme Corp. Compounds inhibiting leucine-rich repeat kinase enzyme activity

Patent Citations (6)

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Publication number Priority date Publication date Assignee Title
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

Also Published As

Publication number Publication date
RU2018106453A3 (enExample) 2019-12-05
AU2016295604A1 (en) 2018-02-01
KR20180030201A (ko) 2018-03-21
RU2725616C2 (ru) 2020-07-03
BR112018001303A2 (pt) 2018-09-11
WO2017012576A1 (en) 2017-01-26
EP3325449A1 (en) 2018-05-30
US10975081B2 (en) 2021-04-13
JP2018524390A (ja) 2018-08-30
CN108137510A (zh) 2018-06-08
US20200079777A1 (en) 2020-03-12
AU2016295604B2 (en) 2019-08-01
RU2018106453A (ru) 2019-08-26
ES2862188T3 (es) 2021-10-07
CA2993269A1 (en) 2017-01-26
EP3325449A4 (en) 2019-01-09
EP3325449B1 (en) 2021-01-13
JP6746679B2 (ja) 2020-08-26

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