DOP2010000349A - Heterociclicos que contienen nitrogeno fusionado y composiciones de los mismos como inhibidores de cinasa - Google Patents

Heterociclicos que contienen nitrogeno fusionado y composiciones de los mismos como inhibidores de cinasa

Info

Publication number
DOP2010000349A
DOP2010000349A DO2010000349A DO2010000349A DOP2010000349A DO P2010000349 A DOP2010000349 A DO P2010000349A DO 2010000349 A DO2010000349 A DO 2010000349A DO 2010000349 A DO2010000349 A DO 2010000349A DO P2010000349 A DOP2010000349 A DO P2010000349A
Authority
DO
Dominican Republic
Prior art keywords
compositions
hypercycles
fusionated
nitrogen
same
Prior art date
Application number
DO2010000349A
Other languages
English (en)
Inventor
Pamela A Albaugh
Paul Vincent Rucker
Ha-Soon Choi
Gregory Chopiuk
Yi Fan
Zhicheng Wang
Original Assignee
Irm Llc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41202804&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=DOP2010000349(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Irm Llc filed Critical Irm Llc
Publication of DOP2010000349A publication Critical patent/DOP2010000349A/es

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P37/04—Immunostimulants
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Dermatology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Psychiatry (AREA)
  • AIDS & HIV (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Otolaryngology (AREA)
  • Transplantation (AREA)

Abstract

La invención proporciona compuestos, composiciones farmacéuticas que comprenden estos compuestos, y métodos para utilizar tales compuestos con el fin de tratar o prevenir las enfermedades o los trastornos asociados con una actividad de cinasa anormal o mal regulada, en particular de Ros, KDR, FMS, c-FMS, FLT3, c-Kit, JAK2, JAK3, Aurora, PDGFR, Lck, TrkA, TrkB, TrkC, IGF-1R, ALK4, ALK5 y ALK, o combinaciones de las mismas.
DO2010000349A 2008-05-13 2010-11-12 Heterociclicos que contienen nitrogeno fusionado y composiciones de los mismos como inhibidores de cinasa DOP2010000349A (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5287908P 2008-05-13 2008-05-13
US15287209P 2009-02-16 2009-02-16

Publications (1)

Publication Number Publication Date
DOP2010000349A true DOP2010000349A (es) 2010-11-30

Family

ID=41202804

Family Applications (1)

Application Number Title Priority Date Filing Date
DO2010000349A DOP2010000349A (es) 2008-05-13 2010-11-12 Heterociclicos que contienen nitrogeno fusionado y composiciones de los mismos como inhibidores de cinasa

Country Status (27)

Country Link
US (1) US8507488B2 (es)
EP (1) EP2300469B1 (es)
JP (2) JP5492194B2 (es)
KR (1) KR101324804B1 (es)
CN (1) CN102056927B (es)
AR (1) AR071778A1 (es)
AU (1) AU2009246687B2 (es)
BR (1) BRPI0912668A2 (es)
CA (1) CA2722418C (es)
CL (1) CL2009001160A1 (es)
CO (1) CO6321286A2 (es)
CR (1) CR11797A (es)
DO (1) DOP2010000349A (es)
EA (1) EA019507B1 (es)
EC (1) ECSP10010676A (es)
ES (1) ES2548135T3 (es)
IL (1) IL208993A0 (es)
MA (1) MA32393B1 (es)
MX (1) MX2010012457A (es)
NI (1) NI201000194A (es)
PA (1) PA8826501A1 (es)
PE (1) PE20091849A1 (es)
SV (1) SV2010003733A (es)
TW (1) TW201012820A (es)
UY (1) UY31821A (es)
WO (1) WO2009140128A2 (es)
ZA (1) ZA201008476B (es)

Families Citing this family (121)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7868001B2 (en) 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
JP5503655B2 (ja) 2008-09-22 2014-05-28 アレイ バイオファーマ、インコーポレイテッド Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP5600111B2 (ja) 2008-10-22 2014-10-01 アレイ バイオファーマ、インコーポレイテッド ＴＲＫキナーゼ阻害剤としての置換ピラゾロ［１，５−ａ］ピリミジン化合物
AU2010239396B2 (en) 2009-04-20 2016-06-23 Auspex Pharmaceuticals, Llc Piperidine inhibitors of Janus Kinase 3
US20110053968A1 (en) 2009-06-09 2011-03-03 Auspex Pharmaceuticals, Inc. Aminopyrimidine inhibitors of tyrosine kinase
AR077468A1 (es) 2009-07-09 2011-08-31 Array Biopharma Inc Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
US8415381B2 (en) 2009-07-30 2013-04-09 Novartis Ag Heteroaryl compounds and their uses
WO2011101644A1 (en) 2010-02-18 2011-08-25 Centro Nacional De Investigaciones Oncologicas (Cnio) Triazolo [4, 5 - b] pyridin derivatives
WO2011112666A1 (en) 2010-03-09 2011-09-15 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
GB201004200D0 (en) * 2010-03-15 2010-04-28 Univ Basel Spirocyclic compounds and their use as therapeutic agents and diagnostic probes
TW201144310A (en) * 2010-04-28 2011-12-16 Daiichi Sankyo Co Ltd [5,6] heterocyclic compound
CA2798080C (en) 2010-05-17 2020-08-25 Incozen Therapeutics Pvt. Ltd. 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued -3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases
KR101852169B1 (ko) 2010-05-20 2018-04-26 어레이 바이오파마 인크. Trk 키나제 저해제로서의 매크로시클릭 화합물
WO2012016133A2 (en) * 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
WO2012034095A1 (en) * 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
UY33597A (es) 2010-09-09 2012-04-30 Irm Llc Compuestos y composiciones como inhibidores de la trk
ES2543151T3 (es) * 2010-10-20 2015-08-17 Pfizer Inc Derivados de 2-piridina como moduladores del receptor Smoothened
EP2463289A1 (en) * 2010-11-26 2012-06-13 Almirall, S.A. Imidazo[1,2-b]pyridazine derivatives as JAK inhibitors
WO2012097478A1 (en) * 2011-01-21 2012-07-26 Abbott Laboratories Bicyclic carboxamide inhibitors of kinases
BR112013021638A2 (pt) * 2011-02-25 2016-08-02 Irm Llc "compostos inibidores de trk, seu uso e composições que os compreendem"
WO2012125667A1 (en) * 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
US8673905B2 (en) * 2011-03-17 2014-03-18 Hoffmann-La Roche Inc. Imidazo pyrazines
NZ618795A (en) 2011-05-13 2015-07-31 Array Biopharma Inc Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as trka kinase inhibitors
SG195100A1 (en) * 2011-07-01 2013-12-30 Bayer Ip Gmbh Hydroxymethylaryl-substituted pyrrolotriazines as alk1 inhibitors
US8883819B2 (en) 2011-09-01 2014-11-11 Irm Llc Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
CN103930427B (zh) * 2011-09-30 2016-03-09 昂科迪塞恩股份有限公司 大环flt3激酶抑制剂
AU2012351748B2 (en) 2011-12-12 2016-04-14 Dr. Reddy's Laboratories Ltd. Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (Trk) inhibitors
JP6418950B2 (ja) * 2012-03-09 2018-11-07 レクシコン ファーマシューティカルズ インコーポレイテッド ピラゾロ［１，５−ａ］ピリミジン系化合物、それを含む組成物、及びそれらを使用する方法
CN104220071A (zh) * 2012-03-09 2014-12-17 莱西肯医药有限公司 抑制转接物关联激酶1以治疗疼痛
TWI585088B (zh) 2012-06-04 2017-06-01 第一三共股份有限公司 作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
WO2014009305A1 (en) * 2012-07-09 2014-01-16 Janssen Pharmaceutica Nv Inhibitors of phosphodiesterase 10 enzyme
US9572811B2 (en) 2012-08-03 2017-02-21 Principia Biopharma Inc. Treatment of dry eye
ES2731833T3 (es) 2012-09-10 2019-11-19 Principia Biopharma Inc Compuestos pirazolopirimidínicos comos inhibidores de cinasas
WO2014044025A1 (zh) * 2012-09-20 2014-03-27 山东亨利医药科技有限责任公司 嘧啶胺衍生物及其制备方法和应用
CA2890006C (en) 2012-11-06 2021-11-23 Shanghai Fochon Pharmaceutical Co Ltd Alk kinase inhibitors
WO2014078322A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078325A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9969694B2 (en) 2012-11-13 2018-05-15 Array Biopharma Inc. N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
US9809578B2 (en) 2012-11-13 2017-11-07 Array Biopharma Inc. Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trkA kinase inhibitors
DK2922844T3 (en) * 2012-11-13 2018-03-05 Array Biopharma Inc N-PYRROLIDINYL, N'-PYRAZOLYL-URINE, THIOURINE, GUANIDINE AND CYANOGUANIDE COMPOUNDS AS TRKA-KINASE INHIBITORS
LT2920166T (lt) 2012-11-13 2016-12-12 Array Biopharma, Inc. Bicikliniai karbamido, tiokarbamido, guanidino ir cianoguanidino junginiai, tinkami naudoti skausmo gydymui
WO2014078378A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078408A1 (en) 2012-11-13 2014-05-22 Array Biopharma Inc. Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9546156B2 (en) 2012-11-13 2017-01-17 Array Biopharma Inc. N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors
US9790178B2 (en) 2012-11-13 2017-10-17 Array Biopharma Inc. Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
TWI600654B (zh) 2012-11-19 2017-10-01 艾姆公司 用於治療寄生蟲疾病之化合物及組合物
US9757395B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
US9757529B2 (en) 2012-12-20 2017-09-12 Otitopic Inc. Dry powder inhaler and methods of use
JP2016510000A (ja) * 2013-02-20 2016-04-04 カラ ファーマシューティカルズ インコーポレイテッド 治療用化合物およびその使用
US9073921B2 (en) 2013-03-01 2015-07-07 Novartis Ag Salt forms of bicyclic heterocyclic derivatives
CA2901427A1 (en) 2013-03-07 2014-09-12 Califia Bio, Inc. Mixed lineage kinase inhibitors and method of treatments
RU2015143526A (ru) * 2013-03-13 2017-04-19 Бостон Байомедикал, Инк. Производные 3-(арил или гетероарил)метилениндолин-2-она в качестве ингибиторов киназного пути раковых стволовых клеток для лечения рака
JP2016510797A (ja) * 2013-03-15 2016-04-11 オンコデザイン エス．ア． 大環状塩誘導性キナーゼ阻害剤
JP2016518388A (ja) 2013-04-30 2016-06-23 オティトピック インク． 乾燥粉末配合および使用方法
EP3027655B1 (en) 2013-07-30 2019-08-21 Blueprint Medicines Corporation Ntrk2 fusions
WO2015017528A1 (en) * 2013-07-30 2015-02-05 Blueprint Medicines Corporation Pik3c2g fusions
AR097543A1 (es) * 2013-09-06 2016-03-23 Lexicon Pharmaceuticals Inc COMPUESTOS BASADOS EN IMIDAZO[1,2-b]PIRIDAZINA, COMPOSICIONES QUE LOS COMPRENDEN Y SUS MÉTODOS DE USO
TW201542550A (zh) * 2013-09-06 2015-11-16 Lexicon Pharmaceuticals Inc 吡唑并［１，５－ａ］嘧啶基化合物、包含彼之組合物以及使用彼之方法
JP6504548B2 (ja) 2014-02-21 2019-04-24 プリンシピア バイオファーマ インコーポレイテッド Ｂｔｋ阻害剤の塩および固体形態
BR112016021507B1 (pt) * 2014-03-27 2022-10-18 Janssen Pharmaceutica Nv Derivados de 4,5,6,7-tetra-hidro-pirazolo[1,5-a]pirimidina substituídos e derivados de 2,3-dihidro-1himidazo[1,2-b]pirazol como inibidores do ros1 e composição farmacêutica que os compreende
ES2715676T3 (es) 2014-03-27 2019-06-05 Janssen Pharmaceutica Nv Derivados de 4,5,6,7-tetrahidro-pirazolo[1,5-a]pirazina sustituidos y derivados de 5,6,7,8-tetrahidro-4h-pirazolo[1,5-a][1,4]diazepina como inhibidores de ros1
CN103864800A (zh) * 2014-04-03 2014-06-18 定陶县友帮化工有限公司 6-氯咪唑并[1,2-b]哒嗪的合成方法
LT3154959T (lt) 2014-05-15 2019-09-25 Array Biopharma, Inc. 1-((3s,4r)-4-(3-fluorfenil)-1-(2-metoksietil)pirolidin-3-il)-3-(4-metil-3-(2-metilpirimidin-5-il)-1-fenil-1h-pirazol-5-il)karbamidas kaip trka kinazės inhibitorius
WO2015183836A1 (en) * 2014-05-27 2015-12-03 Brian Haynes Compositions, methods, and uses related to ntrk2-tert fusions
WO2015183837A1 (en) * 2014-05-27 2015-12-03 Brian Haynes Compositions, methods, and uses related to ntrk2-tert fusions
BR112016028000B1 (pt) * 2014-05-30 2022-05-17 Qilu Pharmaceutical Co., Ltd Derivado de alça de di-hidropirimido como um inibidor de hbv
WO2016004048A2 (en) 2014-06-30 2016-01-07 Blend Therapeutics, Inc. Targeted conjugates and particles and formulations thereof
JP6706617B2 (ja) * 2014-11-06 2020-06-10 スカラー ロック インコーポレイテッドＳｃｈｏｌａｒ Ｒｏｃｋ，Ｉｎｃ． 抗プロ／潜在型−ミオスタチン抗体およびその使用
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
CA2971024C (en) * 2014-12-15 2023-09-26 Handok Inc. Fused ring heteroaryl compounds and their use as trk inhibitors
US10485797B2 (en) 2014-12-18 2019-11-26 Principia Biopharma Inc. Treatment of pemphigus
MA42242A (fr) 2015-06-24 2018-05-02 Principia Biopharma Inc Inhibiteurs de la tyrosine kinase
AU2016287581B2 (en) 2015-07-02 2019-06-06 F. Hoffmann-La Roche Ag Bicyclic lactams and methods of use thereof
AU2016344058A1 (en) 2015-10-26 2018-05-17 Array Biopharma Inc. Point mutations in Trk inhibitor-resistant cancer and methods relating to the same
EP3368546A4 (en) 2015-10-28 2019-06-26 Tarveda Therapeutics, Inc. SSTR TARGETED CONJUGATES, AND ITS PARTICLES AND FORMULATIONS
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
TN2018000335A1 (en) 2016-04-04 2020-01-16 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
PL3800189T3 (pl) 2016-05-18 2023-10-23 Loxo Oncology, Inc. Wytwarzanie (s)-n-(5-((r)-2-(2,5-difluorofenylo)pirolidyn-1-ylo)pirazolo[1,5-a]pirymidyn-3-ylo)-3-hydroksypirolidyno-1-karboksyamidu
BR112018077503A2 (pt) 2016-06-29 2019-04-09 Principia Biopharma Inc. formulações de liberação modificada de 2-[3-[4-amino-3-(2-fluoro-4- fenoxi-fenil)pirazolo [3,4-d]pirimidin-1-il]piperidino-1- carbonil]-4-metil-4-[4-(oxetan-3-il)piperazin-1-il] pent-2-enenitrila
TW201813963A (zh) 2016-09-23 2018-04-16 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
TW201825465A (zh) 2016-09-23 2018-07-16 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
TW201815787A (zh) 2016-09-23 2018-05-01 美商基利科學股份有限公司 磷脂醯肌醇3-激酶抑制劑
JP7349359B2 (ja) 2016-10-17 2023-09-22 エフ． ホフマン－ラ ロシュ アーゲー 二環式ピリドンラクタム及びその使用方法。
JOP20190092A1 (ar) 2016-10-26 2019-04-25 Array Biopharma Inc عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
US10829492B2 (en) 2016-10-28 2020-11-10 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor
US11072607B2 (en) 2016-12-16 2021-07-27 Genentech, Inc. Inhibitors of RIP1 kinase and methods of use thereof
JOP20190213A1 (ar) 2017-03-16 2019-09-16 Array Biopharma Inc مركبات حلقية ضخمة كمثبطات لكيناز ros1
US10786456B2 (en) 2017-09-22 2020-09-29 Otitopic Inc. Inhaled aspirin and magnesium to treat inflammation
JP7493449B2 (ja) 2017-09-22 2024-05-31 ヴェクチュラ インコーポレイテッド ステアリン酸マグネシウムを含む乾燥粉末組成物
HRP20220464T1 (hr) * 2017-12-15 2022-05-27 Pyramid Biosciences, Inc. Derivati 5-(2-(2,5-difluorfenil)pirolidin-1-il)-3-(1h-pirazol-1-il)pirazolo[1,5-a]pririmidina i srodni spojevi kao inhibitori trk kinaze za liječenje raka
WO2019142128A1 (en) * 2018-01-18 2019-07-25 Integral Biosciences Private Limited Dual inhibitors of alk5 and p38α map kinase
CN108218754B (zh) * 2018-01-23 2021-05-07 广东赛烽医药科技有限公司 一种2-(2,5-二氟苯基)吡咯烷的制备方法
IL301089A (en) * 2018-01-29 2023-05-01 Vertex Pharma GCN2 inhibitors and their uses
EP3768681A4 (en) * 2018-03-01 2022-02-09 The Johns Hopkins University INHIBITION OF nSMase FOR THE TREATMENT OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION
JP7294677B2 (ja) * 2018-03-14 2023-06-20 フォチョン・ファーマシューティカルズ・リミテッド ＴＲＫキナーゼ阻害剤としての置換（２－アザビシクロ［３．１．０］ヘキサン－２－イル）ピラゾロ［１，５－ａ］ピリミジン化合物及び置換（２－アザビシクロ［３．１．０］ヘキサン－２－イル）イミダゾ［１，２－ｂ］ピリダジン化合物
WO2019204537A1 (en) 2018-04-20 2019-10-24 Genentech, Inc. N-[4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-5,6-dihydro-4h-pyrrolo[1,2-b]pyrazol e-2-carboxamide derivatives and related compounds as rip1 kinase inhibitors for treating e.g. irritable bowel syndrome (ibs)
GB201811825D0 (en) * 2018-07-19 2018-09-05 Benevolentai Bio Ltd Organic compounds
JP7106162B2 (ja) * 2018-08-01 2022-07-26 シャンシー・ミコ・テクノロジー・カンパニー・リミテッド 神経系疾患を治療するための化合物及びその応用
CA3110267A1 (en) 2018-08-22 2020-02-27 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (trk) degradation compounds and methods of use
US11969472B2 (en) 2018-08-22 2024-04-30 Cullgen (Shanghai), Inc. Tropomyosin receptor kinase (TRK) degradation compounds and methods of use
CN111039946A (zh) * 2018-10-15 2020-04-21 上海轶诺药业有限公司 一类咪唑并芳环类化合物的制备和应用
CN111302995A (zh) * 2018-12-12 2020-06-19 上海复星星泰医药科技有限公司 一种2-(2,5-二氟苯基)-吡咯烷消旋体的制备方法
CN109942582B (zh) * 2019-03-15 2020-12-01 上海健康医学院 一种靶向原肌球蛋白激酶trk融合蛋白的pet探针及其合成与应用
US20220289739A1 (en) * 2019-05-09 2022-09-15 Bristol-Myers Squibb Company Substituted benzimidazolone compounds
CN112142731B (zh) * 2019-06-28 2022-07-22 成都赜灵生物医药科技有限公司 一种2，4-二取代嘧啶衍生物及其制备方法和用途
WO2021038419A1 (en) * 2019-08-23 2021-03-04 Insilico Medicine Ip Limited Kinase inhibitors and methods of synthesis and treatment
WO2021047584A1 (en) * 2019-09-11 2021-03-18 Fochon Pharmaceuticals, Ltd. SUBSTITUTED (2-AZABICYCLO [3.1.0] HEXAN-2-YL) PYRAZOLO [1, 5-a] PYRIMIDINE AND IMIDAZO [1, 2-b] PYRIDAZINE COMPOUNDS AS TRK KINASES INHIBITORS
WO2021067749A2 (en) * 2019-10-02 2021-04-08 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for the treatment of osteoarthritis
KR20220131267A (ko) * 2020-01-22 2022-09-27 베네볼런트에이아이 바이오 리미티드 약제학적 조성물 및 이의 용도
CN111393347B (zh) * 2020-04-30 2020-11-17 安徽德信佳生物医药有限公司 一种拉洛替尼中间体的合成方法
CN114315900B (zh) * 2020-09-30 2023-09-05 美迪西普胜医药科技(上海)有限公司 3-芳基吡唑并嘧啶类衍生物及其应用
AU2021403015A1 (en) * 2020-12-15 2023-08-03 Children's Hospital Medical Center Multi-cyclic irak and flt3 inhibiting compounds and uses thereof
CN115043844B (zh) * 2021-06-21 2024-05-17 河南迈英诺医药科技有限公司 Trk激酶抑制剂化合物及其用途
EP4363420A1 (en) * 2021-07-01 2024-05-08 Anheart Therapeutics (Hangzhou) Co., Ltd. Crystalline forms of 3-{4-[(2r)-2-aminopropoxy]phenyl}-n-[(1r)- 1-(3-fluorophenyl) ethyl]imidazo[1,2-b]pyridazin-6-amine and salts thereof
CN113480543B (zh) * 2021-07-07 2022-05-17 无锡市第二人民医院 2,6,8-多取代咪唑并[1,2-a]吡嗪及其合成方法和应用
CN113564121A (zh) * 2021-08-10 2021-10-29 合肥滴碧云生物科技有限公司 一种造血干细胞冻存方法
WO2023205701A1 (en) 2022-04-20 2023-10-26 Kumquat Biosciences Inc. Macrocyclic heterocycles and uses thereof
WO2023245123A2 (en) * 2022-06-15 2023-12-21 Children's Hospital Medical Center Multi-cyclic irak and flt3 inhibiting compounds and uses thereof
WO2024054512A1 (en) * 2022-09-08 2024-03-14 Alterome Therapeutics, Inc. Akt1 modulators
US20240124450A1 (en) * 2022-09-21 2024-04-18 Pfizer Inc. Novel SIK Inhibitors
WO2024112721A1 (en) * 2022-11-21 2024-05-30 Cz Biohub Sf, Llc ALLOSTERIC MODULATORS OF THE μ-OPIOID RECEPTOR AND CANNABINOID RECEPTOR 1

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1194152A4 (en) * 1999-06-30 2002-11-06 Merck & Co Inc SIN KINASE INHIBITOR COMPOUNDS
WO2001000213A1 (en) * 1999-06-30 2001-01-04 Merck & Co., Inc. Src kinase inhibitor compounds
JP2003512467A (ja) * 1999-10-27 2003-04-02 ノバルティス アクチエンゲゼルシャフト チアゾールおよびイミダゾ（４，５−ｂ）ピリジン化合物ならびにそれらの医薬用途
US7306631B2 (en) 2004-03-30 2007-12-11 The Procter & Gamble Company Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof
AU2005301568B2 (en) * 2004-11-08 2011-06-09 Msd K.K. Novel fused imidazole derivative
WO2007013673A1 (en) * 2005-07-29 2007-02-01 Astellas Pharma Inc. Fused heterocycles as lck inhibitors
US20070049591A1 (en) 2005-08-25 2007-03-01 Kalypsys, Inc. Inhibitors of MAPK/Erk Kinase
DE102005042742A1 (de) * 2005-09-02 2007-03-08 Schering Ag Substituierte Imidazo[1,2b]pyridazine als Kinase-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
US7750000B2 (en) 2005-09-02 2010-07-06 Bayer Schering Pharma Ag Substituted imidazo[1,2b]pyridazines as kinase inhibitors, their preparation and use as medicaments
US20070078136A1 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US7723336B2 (en) 2005-09-22 2010-05-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
EP2058309A4 (en) * 2006-08-04 2010-12-22 Takeda Pharmaceutical CONDENSED HETEROCYCLIC COMPOUND
CA2663091A1 (en) * 2006-09-07 2008-03-13 Biogen Idec Ma Inc. Modulators of interleukin-1 receptor-associated kinase
WO2008037477A1 (en) * 2006-09-29 2008-04-03 Novartis Ag Pyrazolopyrimidines as p13k lipid kinase inhibitors
AU2007315234A1 (en) * 2006-10-30 2008-05-08 Novartis Ag Heterocyclic compounds as antiinflammatory agents
AR064420A1 (es) * 2006-12-21 2009-04-01 Alcon Mfg Ltd Composiciones farmaceuticas oftalmicas que comprenden una cantidad efectiva de analogos de 6-aminoimidazo[1,2b]piridazinas, utiles para el tratamiento del glaucoma y/o controlar la presion intraocular normal o elevada(iop).
AR067326A1 (es) 2007-05-11 2009-10-07 Novartis Ag Imidazopiridinas y pirrolo -pirimidinas sustituidas como inhibidores de cinasa de lipido
FR2918061B1 (fr) 2007-06-28 2010-10-22 Sanofi Aventis Derives de 6-cycloamino-3-(pyridin-4-yl)imidazo°1,2-b!- pyridazine,leur preparation et leur application en therapeutique.
JP5503655B2 (ja) 2008-09-22 2014-05-28 アレイ バイオファーマ、インコーポレイテッド Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

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