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WO2015150337A1 - Inhibiteurs de la lim kinase - Google Patents

Inhibiteurs de la lim kinase Download PDF

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Publication number
WO2015150337A1
WO2015150337A1 PCT/EP2015/056920 EP2015056920W WO2015150337A1 WO 2015150337 A1 WO2015150337 A1 WO 2015150337A1 EP 2015056920 W EP2015056920 W EP 2015056920W WO 2015150337 A1 WO2015150337 A1 WO 2015150337A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
amino
optionally substituted
halo
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.)
Ceased
Application number
PCT/EP2015/056920
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English (en)
Inventor
Arnaud Pierre Jean BOURIN
Sandro Boland
Olivier Defert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amakem NV
Original Assignee
Amakem NV
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
Application filed by Amakem NV filed Critical Amakem NV
Publication of WO2015150337A1 publication Critical patent/WO2015150337A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • LIMK inhibitor application is oncology and ophthalmic applications and only a few different classes of LIMK inhibitors have been described.
  • modulation of LIMK activity is of interest for the treatment of multiple diseases and conditions.
  • LIMKs represent downstream effectors of ROCK, and known selective ROCK inhibitors have been shown to prevent LIMK activation.
  • treatment with Y-27632 prevents the phosphorylation / activation of LIMK2 by ROCK1 , and the subsequent phosphorylation of cofilin in fibroblasts and trabecular meshwork cells.
  • LIMK inhibitors Inhibition of cofilin phosphorylation by LIMK1 prevented actin filament remodeling and neuronal degeneration induced by fibrillar amyloid ⁇ . Consequently, LIMK inhibitors might also be of interest for the treatment of neurodegenerative diseases and disorders including, but not limited to, Alzheimer's disease.
  • Eye diseases or disorders including but not limited to glaucoma and degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy; inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure, dry eye, allergic conjunctivitis, posterior capsule opacification, cataract formation, abnormalities of corneal wound healing, ocular pain and ocular hypertension.
  • degenerative retinal diseases such as macular degeneration, vision loss due to diabetic macular edema, vision loss due to macular edema secondary to retinal vein occlusion proliferative vitreoretinopathy
  • inflammatory eye diseases such as anterior uveitis, panuveitis, intermediate uveitis and posterior uveitis, glaucoma filtration surgery failure,
  • compounds of the invention can be used in the prevention or and/or treatment of several viral diseases, in particular retroviral diseases, including infection by HIV.
  • the compounds of the invention are used for the treatment and/or prevention of sclerosis.
  • C C 6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl , ethyl , n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl.
  • alkyl refers to d- 6 alkyl .
  • optionally substituted alkyl refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3, or 4 substituents or 1 to 2 substituents) at any available point of attachment.
  • substituents for example 1 to 4 substituents, for example 1 , 2, 3, or 4 substituents or 1 to 2 substituents
  • alkynyl as used herein, unless otherwise indicated, means straight-chain or branched- chain hydrocarbon radicals containing at least one carbon-carbon triple bond.
  • alkynyl radicals include ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • An optionally substituted alkynyl refers to an alkynyl having optionally one or more substituents (for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • Non-limiting examples of such heteroaryl include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3- d][1 ,3]thiazolyl, thieno[2,3-d]imidazoly
  • triazolyl as used herein includes 1 H-triazolyl and 4H- 1 ,2,4-triazolyl
  • ⁇ H-triazolyl includes 1 H-1 ,2,3-triazol-1 -yl, 1 H-1 ,2,3-triazol-4-yl, 1 H-1 ,2,3-triazol-5-yl, 1 H-1 ,2,4-triazol-1 -yl, 1 H-1 ,2,4-triazol-3-yl and 1 H-1 ,2,4-triazol-5-yl.
  • “4H-1 ,2,4-triazolyl” includes 4H- 1 ,2,4-triazol-4-yl, and 4H-1 ,2,4-triazol-3-yl.
  • oxadiazolyl as used herein includes 1 ,2,3- oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl, 1 ,2,4-oxadiazol -3-yl, 1 ,2,4-oxadiazol-5-yl, 1 ,2,5-oxadiazol-3-yl and 1 ,3,4-oxadiazol-2-yl.
  • pyrimidyl as used herein includes pyrimid-2-yl, pyrimid-4-yl, pyrimid-5-yl and pyrimid-6-yl.
  • pyrazinyl as used herein includes pyrazin-2-yl and pyrazin-3-yl.
  • pyridazinyl as used herein includes pyridazin-3-yl and pyridazin-4-yl.
  • oxazinyl (also called “1 ,4-oxazinyl”) as used herein includes 1 ,4-oxazin-4-yl and 1 ,4-oxazin-5-yl.
  • indazolyl (also called 1 H-indazolyl or 2- azaindolyl) as used herein includes 1 H-indazol-1 -yl, 1 H-indazol-3-yl, 1 H-indazol-4-yl, 1 H-indazol-5-yl, 1 H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H- indazol-6-yl, and 2H-indazol-7-yl.
  • haloalkoxy alone or in combination refers to a group of Formula -O-alkyI wherein the alkyl group is substituted by 1 , 2, or 3 halogen atoms.
  • haloalkoxy includes -OCF 3 , -OCHF 2 , -OCH 2 F, -O-CF2-CF3, -O-CH2-CF3, -O-CH2-CH F2, and -0-CH 2 -CH 2 F.
  • R 2 and R 3 are joined together so that they form a C 3 . 6 nitrogen-containing heterocycle
  • Cy is a direct bond or an optionally substituted cyclic structure selected from aryl or heteroaryl; wherein the optional substituents are selected from the group consisting of Ci_ 6 alkyl, amino, alkylamino, dialkylamino, hydroxyl, thiol, alkylthio, cyano, nitro, oxo, halo, alkoxyl, and haloalkoxyl;
  • R 6 and R 6 are hydrogen.
  • the present invention provides those compounds of formula I, wherein Cy is a direct bond; in particular wherein Cy and L are a direct bond.
  • the present invention provides those compounds as described herein, wherein L is not a direct bond and wherein Cy is not a direct bond. In a further embodiment, the present invention provides those compounds wherein
  • the present invention provides those compounds of formula I, wherein
  • L 2 is a direct bond or an optionally substituted Ci_ 8 alkylene
  • R 4 is selected from the group consisting of hydrogen, amino, alkylamino, dialkylamino, alkoxy, haloalkoxyl , alkylthio, and halo.
  • n is an integer from 0 to 1 ;
  • n is an integer from 0 to 6;
  • W is selected from the group consisting of
  • the invention provides a method for the prevention and/or treatment of cardiovascular and vascular diseases: including but not limited to pulmonary hypertension and pulmonary vasoconstriction; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
  • the invention provides a method for the prevention and/or treatment of bone diseases: including but not limited to osteoporosis and osteoarthritis; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein.
  • the formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.
  • the compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers.
  • compositions, formulations (and carriers, excipients, diluents, etc. for use therein), routes of administration etc. which are known per se
  • solutions, gels, tablets and the like are often prepared using a physiological saline solution, gel or excipient as a major vehicle.
  • Ophthalmic formulations should preferably be prepared at a comfortable pH with an appropriate buffer system.
  • compositions are of value in the veterinary field, which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for economically important animals such as cattle, pigs, sheep, chicken, fish, etc. - enhancing the growth and/or weight of the animal and/or the amount and/or the quality of the meat or other products obtained from the animal.
  • the invention relates to a composition for veterinary use that contains at least one compound of the invention and at least one suitable carrier (i.e. a carrier suitable for veterinary use).
  • suitable carrier i.e. a carrier suitable for veterinary use.
  • the invention also relates to the use of a compound of the invention in the preparation of such a composition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs d'une kinase, plus spécifiquement des inhibiteurs de la LIM kinase, des compositions, en particulier des produits pharmaceutiques, comprenant de tels inhibiteurs, et des utilisations de tels inhibiteurs dans le traitement et la prophylaxie de maladies. En particulier, la présente invention concerne de nouveaux inhibiteurs de de la LIM kinase, des compositions, en particulier des produits pharmaceutiques, comprenant de tels inhibiteurs, et des utilisations de tels inhibiteurs dans le traitement et la prophylaxie de maladies. De plus, l'invention concerne des méthodes de traitement et l'utilisation desdits composés dans la fabrication d'un médicament destiné à être administré dans le cadre d'un certain nombre d'indications thérapeutiques, notamment les maladies ophtalmiques et intestinales.
PCT/EP2015/056920 2014-04-01 2015-03-30 Inhibiteurs de la lim kinase Ceased WO2015150337A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14163010 2014-04-01
EP14163010.3 2014-04-01

Publications (1)

Publication Number Publication Date
WO2015150337A1 true WO2015150337A1 (fr) 2015-10-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/056920 Ceased WO2015150337A1 (fr) 2014-04-01 2015-03-30 Inhibiteurs de la lim kinase

Country Status (1)

Country Link
WO (1) WO2015150337A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018055097A1 (fr) 2016-09-23 2018-03-29 Cellipse Inhibiteurs de kinase lim, composition pharmaceutique et procédé d'utilisation dans des maladies induites par limk
CN114773256A (zh) * 2022-03-23 2022-07-22 中国农业大学 一种4-氰基哌啶的合成方法
JP2023527055A (ja) * 2020-05-26 2023-06-26 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィック がんの治療に使用するためのｌｉｍｋ及び／又はｒｏｃｋキナーゼ阻害剤としての４－（７ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－３，６－ジヒドロピリジン－１－（２ｈ）－カルボキサミド誘導体
CN116640089A (zh) * 2023-05-05 2023-08-25 深圳市茵诺圣生物科技有限公司 一种n-boc-4-氨基-4-羧酸哌啶的合成方法
EP4034124A4 (fr) * 2019-09-25 2023-11-01 Macquarie University Traitement de la démence
CN117355532A (zh) * 2021-04-27 2024-01-05 山东轩竹医药科技有限公司 三并环类usp1抑制剂及其用途
EP4457230A4 (fr) * 2021-12-30 2025-09-24 Beigene Switzerland Gmbh Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et méthodes d'utilisation

Citations (9)

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Publication number Priority date Publication date Assignee Title
EP0721331A1 (fr) 1993-10-01 1996-07-17 Astra Aktiebolag Procede (i)
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
WO2009021169A2 (fr) 2007-08-08 2009-02-12 Lexicon Pharmaceuticals, Inc. Inhibiteurs de kinase, compositions les contenant et procédés d'utilisation
WO2009131940A1 (fr) 2008-04-21 2009-10-29 Lexicon Pharmaceuticals, Inc. Inhibiteurs de limk2, compositions les comprenant et leurs procédés d'utilisation
WO2012061565A1 (fr) 2010-11-05 2012-05-10 Lexicon Pharmaceuticals, Inc. Formes solides du diméthylcarbamate de 3-(4-(aminométhyl)-1-(5-méthyl-7h-pyrrolo[2,3-d]pyrimidin-4-yl)pipéridine-4-carboxamido)phényle
WO2012125746A1 (fr) * 2011-03-15 2012-09-20 Trius Therapeutics Inc. Inhibiteurs de la gyrase tricyclique

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US6372778B1 (en) 1992-09-08 2002-04-16 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
EP0721331A1 (fr) 1993-10-01 1996-07-17 Astra Aktiebolag Procede (i)
US6372733B1 (en) 1995-11-01 2002-04-16 Merck & Co., Inc. Hexahydro-5-imino-1,4-1,4-thiazepine derivatives as inhibitors of nitric oxide synthases
US6369086B1 (en) 1997-09-05 2002-04-09 Smithkline Beecham Corporation Substituted oxidole derivatives as protein tyrosine and as protein serine/threonine kinase inhibitors
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
WO2009021169A2 (fr) 2007-08-08 2009-02-12 Lexicon Pharmaceuticals, Inc. Inhibiteurs de kinase, compositions les contenant et procédés d'utilisation
WO2009131940A1 (fr) 2008-04-21 2009-10-29 Lexicon Pharmaceuticals, Inc. Inhibiteurs de limk2, compositions les comprenant et leurs procédés d'utilisation
WO2012061565A1 (fr) 2010-11-05 2012-05-10 Lexicon Pharmaceuticals, Inc. Formes solides du diméthylcarbamate de 3-(4-(aminométhyl)-1-(5-méthyl-7h-pyrrolo[2,3-d]pyrimidin-4-yl)pipéridine-4-carboxamido)phényle
WO2012125746A1 (fr) * 2011-03-15 2012-09-20 Trius Therapeutics Inc. Inhibiteurs de la gyrase tricyclique

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018055097A1 (fr) 2016-09-23 2018-03-29 Cellipse Inhibiteurs de kinase lim, composition pharmaceutique et procédé d'utilisation dans des maladies induites par limk
EP4034124A4 (fr) * 2019-09-25 2023-11-01 Macquarie University Traitement de la démence
JP2023527055A (ja) * 2020-05-26 2023-06-26 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィック がんの治療に使用するためのｌｉｍｋ及び／又はｒｏｃｋキナーゼ阻害剤としての４－（７ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－３，６－ジヒドロピリジン－１－（２ｈ）－カルボキサミド誘導体
JP7719803B2 (ja) 2020-05-26 2025-08-06 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィック がんの治療に使用するためのｌｉｍｋ及び／又はｒｏｃｋキナーゼ阻害剤としての４－（７ｈ－ピロロ［２，３－ｄ］ピリミジン－４－イル）－３，６－ジヒドロピリジン－１－（２ｈ）－カルボキサミド誘導体
CN117355532A (zh) * 2021-04-27 2024-01-05 山东轩竹医药科技有限公司 三并环类usp1抑制剂及其用途
EP4457230A4 (fr) * 2021-12-30 2025-09-24 Beigene Switzerland Gmbh Dégradation de la tyrosine kinase de bruton (btk) par conjugaison d'inhibiteurs de btk avec un ligand de ligase e3 et méthodes d'utilisation
CN114773256A (zh) * 2022-03-23 2022-07-22 中国农业大学 一种4-氰基哌啶的合成方法
CN114773256B (zh) * 2022-03-23 2024-05-03 中国农业大学 一种4-氰基哌啶的合成方法
CN116640089A (zh) * 2023-05-05 2023-08-25 深圳市茵诺圣生物科技有限公司 一种n-boc-4-氨基-4-羧酸哌啶的合成方法

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