AU2014289762B2 - Protein tyrosine kinase modulators and methods of use - Google Patents

Protein tyrosine kinase modulators and methods of use Download PDF

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Publication number
AU2014289762B2
AU2014289762B2 AU2014289762A AU2014289762A AU2014289762B2 AU 2014289762 B2 AU2014289762 B2 AU 2014289762B2 AU 2014289762 A AU2014289762 A AU 2014289762A AU 2014289762 A AU2014289762 A AU 2014289762A AU 2014289762 B2 AU2014289762 B2 AU 2014289762B2
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chloro
phenyl
pyrimidin
dimethylamino
ylamino
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AU2014289762A
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AU2014289762A1 (en
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Jinlong Bai
Shaojing Hu
Xiangyong LIU
Wei LONG
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
AU2014289762A 2013-07-11 2014-07-11 Protein tyrosine kinase modulators and methods of use Ceased AU2014289762B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CNPCT/CN2013/079232 2013-07-11
CN2013079232 2013-07-11
PCT/CN2014/082084 WO2015003658A1 (en) 2013-07-11 2014-07-11 Protein tyrosine kinase modulators and methods of use

Publications (2)

Publication Number Publication Date
AU2014289762A1 AU2014289762A1 (en) 2016-02-18
AU2014289762B2 true AU2014289762B2 (en) 2017-02-16

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AU2014289762A Ceased AU2014289762B2 (en) 2013-07-11 2014-07-11 Protein tyrosine kinase modulators and methods of use

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US (2) US9783524B2 (enExample)
EP (1) EP3019489A4 (enExample)
JP (1) JP6510510B2 (enExample)
AU (1) AU2014289762B2 (enExample)
CA (1) CA2917735C (enExample)
RU (1) RU2656591C2 (enExample)
SG (1) SG11201600055PA (enExample)
TW (1) TWI610923B (enExample)
WO (1) WO2015003658A1 (enExample)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RS53350B (sr) 2008-09-22 2014-10-31 Array Biopharma, Inc. Supstituisana jedinjenja imidazo[1,2-b]piridazina kao inhibitori trk kinaze
HRP20140309T1 (hr) 2008-10-22 2014-05-09 Array Biopharma, Inc. SUPSTITUIRANI SPOJEVI PIRAZOLO[1,5-a]PIRIMIDINA KAO INHIBITORI TRK KINAZE
AR077468A1 (es) 2009-07-09 2011-08-31 Array Biopharma Inc Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
KR102015402B1 (ko) 2010-05-20 2019-08-28 어레이 바이오파마 인크. Trk 키나제 저해제로서의 매크로시클릭 화합물
JP6914834B2 (ja) 2014-11-16 2021-08-04 アレイ バイオファーマ インコーポレイテッド （Ｓ）−Ｎ−（５−（（Ｒ）−２−（２，５−ジフルオロフェニル）−ピロリジン−１−イル）−ピラゾロ［１，５−ａ］ピリミジン−３−イル）−３−ヒドロキシピロリジン−１−カルボキサミド硫酸水素塩の結晶形
CN106146525B (zh) * 2015-04-10 2018-11-02 山东轩竹医药科技有限公司 三并环类间变性淋巴瘤激酶抑制剂
CN104803925B (zh) * 2015-04-16 2018-01-12 温州医科大学 一类以fgfr为靶点的2，4，5‑三取代嘧啶类化合物及其制备方法和用途
US10494373B2 (en) * 2015-04-29 2019-12-03 Guangdong Zhongsheng Pharmaceutical Co., Ltd Fused-ring or tricyclic aryl pyrimidine compound used as kinase inhibitor
CN106187915A (zh) * 2015-05-27 2016-12-07 上海翰森生物医药科技有限公司 具有alk与egfr双重活性的抑制剂及其制备方法和应用
CN105017160B (zh) * 2015-06-24 2017-12-29 温州医科大学 一种嘧啶类egfrt790m抑制剂及其合成方法和应用
TN2018000138A1 (en) 2015-10-26 2019-10-04 Array Biopharma Inc Point mutations in trk inhibitor-resistant cancer and methods relating to the same
CN106749267B (zh) * 2015-11-23 2020-08-21 南京圣和药业股份有限公司 新的表皮生长因子受体抑制剂及其应用
CN106883213B (zh) * 2015-12-15 2021-04-20 合肥中科普瑞昇生物医药科技有限公司 一种egfr和alk激酶的双重抑制剂
CN106928150B (zh) * 2015-12-31 2020-07-31 恩瑞生物医药科技（上海）有限公司 丙烯酰胺苯胺衍生物及其药学上的应用
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
AU2017246554B2 (en) 2016-04-04 2022-08-18 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
KR102566858B1 (ko) 2016-05-18 2023-08-11 어레이 바이오파마 인크. (s)-n-(5-((r)-2-(2,5-디플루오로페닐)피롤리딘-1-일)-피라졸로[1,5-a]피리미딘-3-일)-3-히드록시피롤리딘-1-카르복사미드의 제조 방법
WO2018019252A1 (en) * 2016-07-26 2018-02-01 Jacobio Pharmaceuticals Co., Ltd. Novel fused pyridine derivatives useful as fak/aurora kinase inhibitors
JOP20190092A1 (ar) 2016-10-26 2019-04-25 Array Biopharma Inc عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
JOP20190213A1 (ar) 2017-03-16 2019-09-16 Array Biopharma Inc مركبات حلقية ضخمة كمثبطات لكيناز ros1
TWI798334B (zh) * 2018-01-31 2023-04-11 大陸商迪哲（江蘇）醫藥股份有限公司 Ｅｒｂｂ／ｂｔｋ抑制劑
CN110372664A (zh) * 2018-04-13 2019-10-25 华东理工大学 选择性jak2抑制剂及其应用
US10644385B1 (en) * 2019-03-14 2020-05-05 L3Harris Technologies, Inc. Wideband antenna system components in rotary aircraft rotors
CN113544130B (zh) * 2019-05-31 2024-01-09 西藏海思科制药有限公司 一种btk抑制剂环衍生物及其制备方法和药学上的应用
KR102168179B1 (ko) 2019-10-31 2020-10-20 주식회사 온코빅스 암세포 성장 억제 효과를 나타내는 신규한 헤테로 고리 치환 피리미딘 유도체 및 그를 포함하는 약제학적 조성물
WO2021142408A1 (en) 2020-01-11 2021-07-15 Institute For Cancer Research D/B/A The Research Institute Of Fox Chase Cancer Center Estrogen metabolite levels and cancer driver gene mutations in lung cancer risk stratification and treatment
WO2022042755A1 (zh) * 2020-08-28 2022-03-03 华东理工大学 抑制突变型egfr的化合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016894A1 (en) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
WO2008118823A2 (en) * 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2011140338A1 (en) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0305929D0 (en) * 2003-03-14 2003-04-23 Novartis Ag Organic compounds
WO2008073687A2 (en) * 2006-12-08 2008-06-19 Irm Llc Compounds and compositions as protein kinase inhibitors
US7989465B2 (en) * 2007-10-19 2011-08-02 Avila Therapeutics, Inc. 4,6-disubstituted pyrimidines useful as kinase inhibitors
NZ603525A (en) * 2008-06-27 2015-02-27 Celgene Avilomics Res Inc Pyrimidine based compound and uses thereof
TW201024281A (en) * 2008-11-24 2010-07-01 Boehringer Ingelheim Int New compounds
HUE025395T2 (en) 2011-02-02 2016-02-29 Novartis Ag Methods using ALK inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005016894A1 (en) * 2003-08-15 2005-02-24 Novartis Ag 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders
WO2008118823A2 (en) * 2007-03-26 2008-10-02 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
WO2011140338A1 (en) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Compounds that modulate egfr activity and methods for treating or preventing conditions therewith

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Publication number Publication date
US10059688B2 (en) 2018-08-28
WO2015003658A1 (en) 2015-01-15
JP2016525509A (ja) 2016-08-25
EP3019489A1 (en) 2016-05-18
EP3019489A4 (en) 2016-12-28
US20160145237A1 (en) 2016-05-26
CA2917735C (en) 2017-04-18
TWI610923B (zh) 2018-01-11
HK1221953A1 (zh) 2017-06-16
AU2014289762A1 (en) 2016-02-18
RU2656591C2 (ru) 2018-06-06
US20180009782A1 (en) 2018-01-11
CA2917735A1 (en) 2015-01-15
US9783524B2 (en) 2017-10-10
TW201512176A (zh) 2015-04-01
SG11201600055PA (en) 2016-02-26
RU2016103938A (ru) 2017-08-16
JP6510510B2 (ja) 2019-05-08

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