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WO2016041618A1 - Indazoles substitués et hétérocycles associés - Google Patents

Indazoles substitués et hétérocycles associés Download PDF

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Publication number
WO2016041618A1
WO2016041618A1 PCT/EP2015/001732 EP2015001732W WO2016041618A1 WO 2016041618 A1 WO2016041618 A1 WO 2016041618A1 EP 2015001732 W EP2015001732 W EP 2015001732W WO 2016041618 A1 WO2016041618 A1 WO 2016041618A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
indazol
benzyl
denotes
pyrazol
Prior art date
Application number
PCT/EP2015/001732
Other languages
English (en)
Inventor
Kai Schiemann
Original Assignee
Merck Patent Gmbh
Cancer Research Technology Ltd.
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 Merck Patent Gmbh, Cancer Research Technology Ltd. filed Critical Merck Patent Gmbh
Publication of WO2016041618A1 publication Critical patent/WO2016041618A1/fr

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Classifications

    • 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
    • C07D403/10—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 carbon chain containing aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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

Definitions

  • Ar 4 denotes a mono- or bicyclic aromatic ring system with 6, 7, 8, 9, 10 ring carbon atoms wherein that aromatic ring system may be unsubstituted or mono-, di- or tri-substituted with substituents that are independently from each other selected from R 4a , R 4b , R 4c ;
  • R 1a , R 1 b denote independently from each other H, straight-chain or branched Ci-e-alkyl, or
  • R a and R 1 b form together with the nitrogen atom to which they are
  • R 4a , R 4b , R 4c form together a divalent alkylene chain with 2, 3, 4,
  • LA 5 , LA 7a , LA 7b denote independently from each other a straight- chain or branched Ci-8-alkyl which may be unsubstituted or substituted with 1 , 2 or 3 substituents selected independently from each other from Hal;
  • Hetcyc 8 , Hetcyc 4a , Hetcyc b each denote independently from each other saturated or partially unsaturated heterocycle with 3, 4, 5,
  • aromatic ring system may be unsubstituted or mono-, di- or tri-substituted with substituents that are independently from each other selected from R 6b1 , R 6 2 , R 6b3 ;
  • Ci-8-alkyl straight-chain or branched Ci-8-alkyl
  • Z 3 denotes CH or N
  • Ar 4 denotes phenyl that may be unsubstituted or mono-, di- substituted with substituents that are independently from each other selected from R 4a , R 4b ;
  • Hetar 4 denotes a mono- or bi-cyclic aromatic ring system with 5, 6, 9, 10 ring atoms wherein 1 of said ring atoms is a nitrogen atom or 2 of said ring atoms are two nitrogen atoms wherein that aromatic ring system may be unsubstituted or mono-substituted with a substituent R d ;
  • R 1a , R 1b denote H
  • 1 of said ring atoms is a nitrogen atom or 2 of said ring atoms are either one nitrogen and one oxygen atom or two nitrogen atoms wherein that heterocycle may be unsubstituted or mono- or di-substituted with substituents that are independently from each other selected from straight-chain or branched Ci-4- alkyl, straight-chain or branched -O-Ci-4-alkyl, F, CI, OH, Ar 613 ;
  • Particularly preferred embodiments of the present invention is a compound, or derivatives, prodrugs, solvates, tautomers or stereoisomers thereof as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, that is selected from the group consisting of: 1 ) 3-(3,4-Dimethoxy-benzyl)-1 H-indazole-5-carboxylic acid methylamide
  • aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C7 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Ci-6-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, 2-hexyl, n-septyl, 2-septyl, n-octyl, 2-octyl, 2,2,4- trimethylpentyl.
  • C 3 -5-cycloalkyl refers to a cycloaliphatic hydrocarbon, as defined above, with 3, 4 or 5 ring carbon atoms.
  • C 3 -5-cycloalkyl groups may be unsubstituted or substituted with - unless specified differently elsewhere in this specification - 1, 2 or 3 substituents that may be the same of different and are - unless specified differently elsewhere in this specification - selected from the group comprising Ci-6-alkyl, O- Ci-6-alkyl, halogen, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino.
  • Exemplary C 3 -5-cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9- or 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably 1 , 2, 3 or 4, heteroatoms, as defined herein.
  • nitrogen includes a substituted nitrogen.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group is optionally mono- or bicyclic.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically acceptable salts.
  • the compounds of the present invention which contain acidic groups can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts.
  • crizotinib such as crizotinib, dasatinib, eriotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib;
  • zanolimumab matuzumab, dalotuzumab 1 - 2 3 , onartuzumab 1 3 , racotumomab 1 , tabalumab 1 3 , EMD-525797 4 , nivolumab 1 3 ;
  • aldesleukin interferon alfa 2 , interferon alfa2a 3 , interferon alfa2b 23 ;
  • trastuzumab emtansine prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept;
  • cintredekin besudotox edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab 1 - 3 , vintafolide 1 ' 3 ;
  • sipuleucel 3 vitespen 3 , emepepimut-S 3 , oncoVAX 4 , rindopepimut 3 , troVax 4 , MGN-1601 4 , MGN-1703 4 ;
  • a compound of the invention administered in combination with a compound of the invention, and either administered separately or in the same pharmaceutical composition and are useful for the treatment of diseases other than cancer, include, but are not limited to the compound classes and specific compounds listed in the
  • MS Multiple sclerosis
  • RA Rheumatoid arthritis
  • methotrexate methotrexate, leflunomide, sulfasalazine, chloroquine, hydroxychloroquine, cyclosporine A, azathioprine, auranofin, adalimumab, certilizumab, etanercept, golimumab, infliximab, anakinra, rituximab, abatacept, tocilizumab, cortisone;
  • SLE Systemic lupus erythematodes
  • NSAIDs chloroquine, cortisone, azathioprine, cyclophosphamide, cyclosporine, mycophenolate-motefil (MMF), methotrexate, thalidomide
  • MMF mycophenolate-motefil
  • Alzheimer's disease memantine, galantamine, rivastigmine, donepezil.
  • compositions of the present invention characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and
  • pharmaceutically active agents other than the compounds according to the invention are converted in a suitable dosage form.
  • compositions of the present invention may be any pharmaceutical compositions of the present invention.
  • administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes.
  • administration may be by the oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.
  • Tablets mixing of active ingredient s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mixture before compression.
  • Capsules mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
  • Aerosols dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer.
  • non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds of the invention into a dosage form suitable for administration to a patient in need of such a treatment.
  • the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention.
  • Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compressing the respective active and non- active ingredients.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • suspensions of the active include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic bases, e.g. quaternary ammonium salts.
  • a preferred means is to measure the physiological potency of a given compound.
  • the specific dose for the individual patient depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates.
  • the specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
  • PG may also be replaced by a hydrogen atom, H.
  • Suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons). They may be selected, for instance, from benzyl or oxan-2-yl (tetrahydropyran-2-yl). (It is to be noted that the terms "protecting group(s)” and “protective group(s)” are used interchangeably throughout this specification and the claims.)
  • Suitable reduction means for performing process step (a), i.e., means for reducing the carbonyl group to which R 4 is attached to into a CH2 moiety are well-known to the person skilled in the art of chemical synthesis.
  • suitable reduction means are strong bases like potassium tert.-butylate in an appropriate solvent, e.g., DMSO; metal halides like sodium borohydride (NaBhUythfluoroacetic acid or UAIH4; or alkylsilanes like triethylsilane.
  • C-N coupling reactions are, among others, the Hartwig- Buchwald reaction, the Ullmann coupling reaction, reactions similar to Suzuki or Heck reaction and coupling reactions utilizing organo cuprates. Depending on the specific method applied reagents, solvents and reaction conditions are selected accordingly.
  • the suitable catalyst may be a palladium(ll) complex, e.g., bis(diphenylphosphino)ferrocene)-palladium(ll) chloride dichloromethane complex; the reaction may be performed by applying potassium acetate under CO(g) (carbon monoxide) atmosphere in methanol and DMF in the presence of the suitable catalyst.
  • suitable reduction means are, for instance, NaBhU or triethylsilane in trifluoroacetic acid.
  • the choice of a suitable base and a suitable catalyst for performing the final reaction step (e) depends on the chemical nature of compound (VII) to be reacted with the product of reaction step (d).
  • R 4 denotes Ar 4 being substituted with a substituent R 4a which in turn denotes Hetar 43 (i.e., R 4 being Ai ⁇ -Hetar 43 )
  • the skilled person will recognize that the same methodology may be applied for introducing other complex substituents like, for instance, Hetai ⁇ -Ar 41 ', Hetar 4 -Hetar 4b or Hetar 4 - Hetcyc 4b .
  • Solvent A water + 0, 1 % TFA
  • Solvent B water +0.1% formic acid
  • Compounds 43-50 can be prepared by utilizing the the procedures described in Synthetic Examples 1 and 2 hereinbefore in an analogous manner starting either with 5-bromo-1 H-pyrazolo[3,4-b]pyridine-3-carboxylic acid or with 5- bromo-1 H-pyrazolo[4,3-b]pyridine-3-carboxylic acid, as the case may be, as the starting material and applying synthetic steps 2.1. , 2.2. 1.2., 1.3., 1.4., 1.5., 1.6.. Synthetic Example 3:

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Cette invention concerne des indazoles substitués et des hétérocycles associés. Ces composés sont utiles pour prévenir et/ou traiter les troubles et les maladies d'ordre hyperprolifératif, inflammatoire et dégénératif. Par conséquent, cette invention concerne également l'utilisation des composés selon l'invention pour prévenir et/ou traiter les troubles et les maladies d'ordre hyperprolifératif, inflammatoire et dégénératif ainsi qu'une composition pharmaceutique, des médicaments et des kits comprenant les indazoles substitués et autres hétérocycles associés selon l'invention et des procédés pour les fabriquer.
PCT/EP2015/001732 2014-09-15 2015-08-25 Indazoles substitués et hétérocycles associés WO2016041618A1 (fr)

Applications Claiming Priority (2)

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EP14003182.4 2014-09-15
EP14003182 2014-09-15

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WO2016041618A1 true WO2016041618A1 (fr) 2016-03-24

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Cited By (16)

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US10266530B2 (en) 2016-09-09 2019-04-23 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US10280164B2 (en) 2016-09-09 2019-05-07 Incyte Corporation Pyrazolopyridone compounds and uses thereof
KR20200051626A (ko) * 2017-08-07 2020-05-13 조인트 스탁 컴퍼니 "바이오케드" Cdk8/19 저해제로서 새로운 헤테로사이클릭 화합물
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US10752635B2 (en) 2018-02-20 2020-08-25 Incyte Corporation Indazole compounds and uses thereof
US10800761B2 (en) 2018-02-20 2020-10-13 Incyte Corporation Carboxamide compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
US11014929B2 (en) 2016-09-09 2021-05-25 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
CN113677341A (zh) * 2019-02-01 2021-11-19 南卡罗莱纳大学 双环吡啶组合物及其用于癌症治疗的方法
US11242343B2 (en) 2016-09-09 2022-02-08 Incyte Corporation Pyrazolopyridine compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US11406624B2 (en) 2017-02-15 2022-08-09 Incyte Corporation Pyrazolopyridine compounds and uses thereof
WO2023078337A1 (fr) * 2021-11-04 2023-05-11 Insilico Medicine Ip Limited Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation

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EP3666770A4 (fr) * 2017-08-07 2021-04-07 Joint Stock Company "Biocad" Nouveaux composés hétérocycliques comme inhibiteurs de cdk8/19
KR102700664B1 (ko) 2017-08-07 2024-08-29 조인트 스탁 컴퍼니 “바이오케드” Cdk8/19 저해제로서 새로운 헤테로사이클릭 화합물
JP7365332B2 (ja) 2017-08-07 2023-10-19 ジョイント・ストック・カンパニー “バイオキャド” Ｃｄｋ８／１９阻害薬としての新規ヘテロ環式化合物
AU2018312836B2 (en) * 2017-08-07 2022-12-08 Joint Stock Company "Biocad" Novel heterocyclic compounds as CDK8/19 inhibitors
KR20200051626A (ko) * 2017-08-07 2020-05-13 조인트 스탁 컴퍼니 "바이오케드" Cdk8/19 저해제로서 새로운 헤테로사이클릭 화합물
US10722495B2 (en) 2017-09-08 2020-07-28 Incyte Corporation Cyanoindazole compounds and uses thereof
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US10745388B2 (en) 2018-02-20 2020-08-18 Incyte Corporation Indazole compounds and uses thereof
US11299473B2 (en) 2018-04-13 2022-04-12 Incyte Corporation Benzimidazole and indole compounds and uses thereof
US10899755B2 (en) 2018-08-08 2021-01-26 Incyte Corporation Benzothiazole compounds and uses thereof
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US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
CN113677341A (zh) * 2019-02-01 2021-11-19 南卡罗莱纳大学 双环吡啶组合物及其用于癌症治疗的方法
US11787784B2 (en) 2019-08-06 2023-10-17 Incyte Corporation Solid forms of an HPK1 inhibitor
US11066394B2 (en) 2019-08-06 2021-07-20 Incyte Corporation Solid forms of an HPK1 inhibitor
WO2023078337A1 (fr) * 2021-11-04 2023-05-11 Insilico Medicine Ip Limited Inhibiteurs doubles de cdk8/19 et leurs procédés d'utilisation

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