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WO2016001077A1 - Composés inhibant l'enzyme kinase de fuseau monopolaire 1, compositions pharmaceutiques et leurs utilisations - Google Patents

Composés inhibant l'enzyme kinase de fuseau monopolaire 1, compositions pharmaceutiques et leurs utilisations Download PDF

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Publication number
WO2016001077A1
WO2016001077A1 PCT/EP2015/064498 EP2015064498W WO2016001077A1 WO 2016001077 A1 WO2016001077 A1 WO 2016001077A1 EP 2015064498 W EP2015064498 W EP 2015064498W WO 2016001077 A1 WO2016001077 A1 WO 2016001077A1
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Prior art keywords
diazepin
methyl
methoxy
anilino
formula
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English (en)
Inventor
Mario Varasi
Anna Cappa
Daniele Fancelli
Alessia Romussi
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IEO ISTITUTO EUROPEO DI ONCOLOGIA Srl
Istituto Europeo di Oncologia SRL IEO
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IEO ISTITUTO EUROPEO DI ONCOLOGIA Srl
Istituto Europeo di Oncologia SRL IEO
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    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present invention relates to compounds able to inhibit the Monopolar Spindle 1 kinase (Mps-1 or TTK), to a process for their preparation, pharmaceutical compositions comprising them, and to their use as therapeutic agents, in particular for the treatment of cancer.
  • Mps-1 or TTK Monopolar Spindle 1 kinase
  • Mps-1 Monopolar Spindle 1 kinase
  • TTK Tyrosine Threonine kinase
  • SAC Spindle Assembly Checkpoint
  • SAC Suppression of multipolarity requires the SAC [Kwon, M. et al. Genes Dev. 22, 2189-203 (2008)]. Inhibition of the SAC has been shown to be synthetically lethal with the presence of supernumerary centrosomes [Kwon, M. et al. Genes Dev. 22, 2189-203 (2008)]. Hence SAC kinases may be considered novel drug targets for anti-cancer therapies.
  • inhibitors of Mps-1 represent valuable compounds that should be useful either as single agents or in combination with other drugs for the treatment of proliferative diseases such as cancer.
  • WO2012032031 discloses imidazopiperazine derivatives
  • WO2014009219, WO2012136531 and WO2012123745 disclose various fused pyridines
  • WO2012101032, WO2009067547, WO20101 1 1406, WO2012013557, WO2014037750 and WO2014037751 disclose different fused pyrimidine compounds.
  • R 1 is a phenyl, optionally substituted by 1 to 3 groups selected from: Ci -3
  • R 2 is hydrogen, Ci -3 alkyl optionally substituted by cyano or methoxy;
  • R 3 is hydrogen, Ci -3 alkyl, C 3-6 cycloalkyl, heterocycloalkyl, indanyl,
  • R 4 , R 5 are, independently, hydrogen; Ci -3 alkyl, phenyl, CH 2 R 8 ; or R 4 and R 5
  • R 4 and R 3 together with the carbon and nitrogen atoms to which they are respectively bound, form a pyrrolidine or piperidine ring;
  • R 6 and R 7 are, independently, hydrogen; heterocycloalkyl; or R 6 and R 7 together with the nitrogen atom to which they are bound form a heterocycloalkyl ring;
  • R 8 is phenyl; or heteroaryl optionally substituted by one to three substituents, selected from Ci -3 alkyl, Ci -3 alkoxy, halogen, Ci -3 haloalkyl, cyano; or R 8 is 1 ,3-benzodioxolyl or 2,2-difluoro-1 ,3- benzodioxolyl;
  • R 4 , R 5 and R 8 may be optionally substituted by one to three substituents, selected from Ci -3 alkyl, Ci -3 alkoxy, or halogen;
  • heterocycloalkyl in R 1 and R 6 or the heterocycloalkyl ring formed by R 6 and R 7 together with the nitrogen atom to which they are bound, is optionally substituted with one to three substituents, selected from Ci -3 alkyl, Ci -3 alkoxy, halogen, hydroxy group, pyrrolidinyl, morpholinyl, piperidinyl or 2-oxo-2-heterocycloalkyl-ethyl;
  • halogen refers to fluoro, chloro, bromo, or iodo.
  • halogen is preferably fluoro or chloro.
  • Ci -3 alkyl refers to methyl, ethyl, n-propyl and /so-propyl.
  • C 3- 6 cycloalkyl refers to a saturated monocyclic hydrocarbon ring system having three to six carbon atoms and zero heteroatoms. Suitable examples of C 3- 6- cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • d-3 alkoxy refers to methoxy, ethoxy, n-propoxy and /so-propoxy.
  • d-3 haloalkyl refers to a straight or branched hydrocarbon chain radical, which is substituted by one or more halogen atoms and having from one to three carbon atoms.
  • C 1 -C3 haloalkyl examples include fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoroethyl, trifluoromethyl and trifluoroethyl.
  • the "d-3 haloalkyl" group is preferably trifluoromethyl.
  • d-3 haloalkoxy refers to a straight or branched O-d-3 haloalkyl, where haloalkyl is defined herein.
  • Suitable examples of "d-6 haloalkoxy” groups are OCF 3 , OCHF 2 or OCH 2 F.
  • heteroaryl means a monocyclic- or bycyclic 5-10 membered aromatic ring comprising carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl rings have less aromatic character than their all-carbon counter parts.
  • a heteroaryl group need only have some degree of aromatic character.
  • heteroaryl groups include, but are not limited to pyridinyl, pyrazolyl, imidazolyl, (1 ,2,3)- and (1 ,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, indazolyl, indolyl, benzoimidazolyl, 1 ,3-benzodioxolyl, and the like.
  • heterocycloalkyi or “heterocyclic ring” represents a mono or bicyclic saturated or partially saturated non-aromatic ring system of, respectively, 5 to 10 members, which contains one or more heteroatoms selected from nitrogen, oxygen, and sulphur Examples of such heterocycles include, but are not limited to: pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl.
  • a heterocycloalkyi can be unsubstituted or substituted with one to three suitable substituents, selected from d-3 alkyl, d-3 alkoxy, halogen, hydroxy group, pyrrolidinyl, morpholinyl, piperidinyl.
  • a phenyl can be optionally substituted by one to three suitable substituents, selected from d -3 alkyl, d -3 alkoxy, halogen.
  • R 2 is methyl
  • R 3 is selected from the group consisting of: Cs-6 cycloalkyl, 5-6 membered heterocycloalkyi, indanyl, or CH2R 8 wherein R 8 is as defined herein above.
  • R 2 is methyl;
  • R 3 is C-5-6 cycloalkyl, 5-6 membered heterocycloalkyl, indanyl, or CH 2 R 8 wherein R 8 is as defined herein above.
  • C-5-6 cycloalkyl refers to a saturated monocyclic hydrocarbon ring system having five to six carbon atoms and zero heteroatoms. Suitable examples of C5-6- cycloalkyl groups include cyclopentyl and cyclohexyl.
  • heterocycloalkyl represents a mono saturated or partially saturated non-aromatic ring system of, respectively, 5 to 6 members, which contains one or more heteroatoms selected from nitrogen, oxygen, and sulphur.
  • heterocycles include, but are not limited to: pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl.
  • R 4 and R 3 together with the carbon and nitrogen atoms to which they are respectively bound, form a pyrrolidine or piperidine ring originating a compound of formula (la), wherein R 1 , R 2 and R 5 are as described herein above, and n is 1 or 2;
  • the compound of formula (I) is selected from:
  • the compounds of the invention are for use as Monopolar Spindle 1 kinase (Mps-1 or TTK) inhibitor.
  • the compounds of the invention are for use as medicament.
  • the compounds of the invention are for use in the treatment and/or prevention of proliferative diseases and/or conditions.
  • the compounds of the invention are for use in the treatment and/or prevention of cancer.
  • the compounds of the invention are for use in the treatment and/or prevention of lymphoma, hepatocellular carcinoma, pancreatic cancer, brain tumour, breast cancer, lung cancer, colon cancer, cervical cancer, prostate cancer, kidney cancer, osteosarcoma, nasopharyngeal cancer, oral cancer, melanoma and ovarian cancer.
  • “Pharmaceutically acceptable salt” comprise a conventional non-toxic salt obtained by salification of a compound of formula (I) with inorganic acids (e.g. hydrochloric, hydrobromic, sulphuric or phosphoric acids), or with organic acids (e.g. acetic, propionic, succinic, benzoic, sulfanilic, 2-acetoxy-benzoic, cinnamic, mandelic, salicylic, glycolic, lactic, oxalic, malic, maleic, malonic, fumaric, tartaric, citric, p-toluenesulfonic, methanesulfonic, ethanesulfonic, or naphthalensulfonic acids).
  • inorganic acids e.g. hydrochloric, hydrobromic, sulphuric or phosphoric acids
  • organic acids e.g. acetic, propionic, succinic, benzoic, sulfanilic, 2-ace
  • salts which are not pharmaceutically acceptable, for example the trifluoroacetate salt, may be useful in the preparation of compounds of this invention and these form a further aspect of the invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • the compounds of the present invention can exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like and these forms are also included within the scope of the present invention.
  • the compounds of formula (I) of the invention have asymmetric carbon atoms and may therefore exist as individual optical isomers, as racemic mixtures or as any other mixture comprising a majority of one of the two optical isomers, which are all to be intended as within the scope of the present invention.
  • the invention also includes all suitable isotopic variations of a compound of formula (I) of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated 3 H, and carbon-14 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • composition comprising at least one compound as defined herein above or stereoisomers, a hydrate, solvate, or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient and/or diluent, and optionally a further therapeutic agent.
  • Non-exhaustive examples of a suitable further therapeutic agent include: antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example platin derivatives like cis-platin, carboplatin, oxaliplatin, lobaplatin, satraplatin, nedaplatin, heptaplatin; nitrogen mustard such as chlorambucil, melphalan, chlormethine, cyclophosphamide, ifosfamide, trofosfamide, uramustine, bendamustine, estramustine; busulphan, temozolomide or nitrosoureas); antimetabolites (for example antifolates such as aminopterin, methotrexate, pemetrexed, raltitrexed); purines such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine; pyr
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, liarozole or cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha- reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifen
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function for example growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibody figitumumab), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example enzastaurin, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib, regorafenib, everolimus, sirolimus or temsirolimus;
  • growth factor antibodies for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibody figitumum
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], lenalidomide or thalidomide;
  • cell cycle inhibitors including for example CDK inhibitors (for example flavopiridol, roscovitine) and other inhibitors of cell cycle checkpoints; inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation;
  • proteasome inhibitors for example lactacystin, bortezomib, epoxomicin
  • HSP90 inhibitors for example 17-AAG, AT-13387, KOS-953, KOS-1022, CNF-1010, CNF-2024, IPI-504, IPI-926, SNX 5422, STA-9090, VER-52296, PU-H17 or XL-888
  • histone deacetylase inhibitors for example SAHA, PXD101 , JNJ-16241 199, JNJ- 26481585, SB939, ITF-2357, LBH589, PCI-24781 , valproic acid, butyric acid, MS-275, MGCD0103 or FK-228)
  • selective COX-2 inhibitors for example celecoxib
  • non selective NSAIDs for example diclofenac, flurbiprofen, ibuprofen, ketoprofen, or naproxen.
  • a compound of general formula (I) can be used in combination with radiation therapy.
  • a compound of general formula (I) may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5- fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5- fluorouracil and prednisone).
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • CAF cyclophosphamide, doxorubicin and 5-fluorouracil
  • AC doxorubicin and cyclophosphamide
  • FEC fluorouraci
  • the pharmaceutical composition as defined above is in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid solutions, suspensions, emulsions, suppositories, ointments, creams, lotions, gels, pastes, transdermal delivery devices.
  • the compounds of formula (I) can be pharmaceutically formulated according to known methods.
  • the pharmaceutical compositions can be chosen on the basis of the treatment requirements.
  • Such compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable, or infusible liquid solutions, suspensions, or suppositories.
  • Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • excipients such as binders, fillers (including cellulose, mannitol, lactose), diluents, tableting agents, lubricants (including magnesium stearate), detergents, disintegrants (e.g. polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch), coloring agents, flavoring agents, and wetting agents (for example sodium lauryl sulfate).
  • the oral solid compositions can be prepared by conventional methods of blending, filling or tableting.
  • the blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers. Such operations are conventional.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p- hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents.
  • Oral formulations also include conventional slow-release formulations such as enterically coated tablets or granules.
  • composition for administration by inhalation can be delivered from an insufflator or a nebulizer pressurized pack.
  • parenteral administration fluid unit dosages can be prepared, containing the compound and a sterile vehicle.
  • the compound can be either suspended or dissolved, depending on the vehicle and concentration.
  • the parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilising by filtration, filling suitable vials and sealing.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle.
  • the composition can be frozen after having filled the vials and removed the water under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the invention.
  • the compositions may be tablets, lozenges, pastilles, or gel.
  • the compounds can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • suppositories or retention enemas e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres.
  • ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights.
  • Creams are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol.
  • Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • transdermal delivery comprises conventional aqueous and nonaqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches.
  • the compounds of the present invention may be employed alone as a sole therapy or in combination with other therapeutic agents for the treatment of the above-mentioned conditions.
  • the combination can be administered as separate compositions (simultaneous, sequential) of the individual components of the treatment or as a single dosage form containing both agents.
  • the active ingredients may be separately formulated into single- ingredient preparations of one of the above-described forms and then provided as combined preparations, which are given at the same time or different times, or may be formulated together into a two- or more- ingredient preparation.
  • Compounds of general formula (I) may be administered to a patient in a total daily dose of, for example, from 0.001 to 1000 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The determination of optimum dosages for a particular patient is well known to one skilled in the art.
  • compositions are normally accompanied by written or printed instructions for use in the treatment in question.
  • kits comprising a compound as defined above and at least one therapeutic agent, preferably selected from the group consisting of: Mps1 inhibitors, antiproliferative/antineoplastic agents, cytostatic agents, agents which inhibit cancer cell invasion, inhibitors of growth factor function, antiangiogenic agents, cell cycle inhibitors, proteasome inhibitors, HSP90 inhibitors, selective COX-2 inhibitors histone deacetylase inhibitors, non selective NSAIDs or a chemotherapeutic agent for use in the treatment and/or prevention of cancer.
  • the compound of the invention and the at least one therapeutic agent are in separated containers.
  • step (a) of the process the 2-[(2,4- dichloropyrimidin-5-yl)methyl]isoindoline-1 ,3-dione A2 is prepared by reaction of commercially available 2,4-dichloro-5-(iodomethyl)pyrimidine A1 and potassium phthalimide in a suitable solvent, such as tetrahydrofuran or 1 ,4-dioxane at a temperature ranging from about 22°C to the reflux temperature of the reaction mixture.
  • a suitable solvent such as tetrahydrofuran or 1 ,4-dioxane
  • step (b) of the process A2 is then reacted with any suitable amino-ester of formula A3 as to yield a compound of formula A4.
  • the reaction is carried out in a suitable solvent, such as, for instance, tetrahydrofuran, 1 ,4-dioxane, dimethylformamide or N- methylpyrrolidinone in the presence of an opportune base such as triethylamine, N,N- diisopropylethylamine or pyridine at a temperature ranging from about 22°C and the reflux temperature of the reaction mixture.
  • a suitable solvent such as, for instance, tetrahydrofuran, 1 ,4-dioxane, dimethylformamide or N- methylpyrrolidinone
  • an opportune base such as triethylamine, N,N- diisopropylethylamine or pyridine
  • the reaction is carried out in tetrahydrofuran in the presence of ⁇ , ⁇
  • step (b) of the process may produce an admixture of regio-isomers; their separation to isolate the single isomer of formula A4, carried out according to conventional techniques, is still within the scope of the present invention.
  • step (c) of the process the phthalimido group of compounds of formula A4 is removed by treatment with a suitable alkaline agent such as methylamine, ethylamine, hydrazine, methylhydrazine, or phenylhydrazine in a solvent such as methanol, ethanol, tetrahydrofyrane, water, or a mixture thereof at a temperature ranging from about 22°C to the reflux temperature of the reaction mixture.
  • a suitable alkaline agent such as methylamine, ethylamine, hydrazine, methylhydrazine, or phenylhydrazine in a solvent such as methanol, ethanol, tetrahydrofyrane, water, or a mixture thereof at a temperature ranging from about
  • step (c) is carried out by treating a compound of formula A4 with aqueous hydrazine in ethanol, tetrahydrofuran, or a mixture thereof at a temperature from about 22°C to the reflux temperature of the reaction mixture.
  • Intra-molecular cyclization at step (d) may spontaneously occur in the reaction conditions above described for step (c), thus directly providing compounds of formula A6.
  • an amino derivative of formula A5 may be cyclized by treatment with a base such as, for instance, sodium methylate, sodium ethylate or potassium tert-butylate in a suitable solvent such as methanol, ethanol or tert-butanol at a temperature ranging from about 22°C and the reflux temperature of the reaction mixture.
  • a base such as, for instance, sodium methylate, sodium ethylate or potassium tert-butylate
  • a suitable solvent such as methanol, ethanol or tert-butanol
  • step (d) is carried out by treating a compound of formula A5 with sodium methylate in methanol, at a temperature from about 40°C to the reflux temperature of the reaction mixture.
  • the lactamic nitrogen of a compound of formula A6 may be alkylated to provide a compound of formula A8 by reaction with a base such as, for instance, sodium hydride, potassium tert-butylate, lithium diisopropylamide and an opportune alkyl halide A7 of formula R 2 -X wherein R 2 is as defined above for compounds of formula (I) and X is halogen, preferably bromine or iodine.
  • a base such as, for instance, sodium hydride, potassium tert-butylate, lithium diisopropylamide and an opportune alkyl halide A7 of formula R 2 -X wherein R 2 is as defined above for compounds of formula (I) and X is halogen, preferably bromine or iodine.
  • step (e) is carried out by reaction of a compound of formula A6, sodium hydride, and a compound of formula A7 in ⁇ , ⁇ '-dimethylacetamide at a temperature ranging from about -20°C to about 5°C.
  • a 2-chloro-5,6,8,9-tetrahydropyrimido[4,5- e][1 ,4]diazepin-7-one of formulae A8 or A6 may be coupled with an aniline A9 of formula R 1 -NH 2 wherein R 1 is as defined above to provide a compound of formula (I).
  • the coupling reaction at step (f) may be carried out in a suitable solvent such as ⁇ , ⁇ '- dimethylformamide, dimethoxyethane, tert-butanol, 1 ,4-dioxane or acetonitrile in the presence of a catalyst such as, for example, palladium acetate or tris(dibenzylideneacetone)dipalladium, a base such as, for instance, potassium carbonate, potassium phosphate, or cesium carbonate and an organophosphorus ligand such as, for instance, 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP) or 4,5- Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) at a temperature ranging from about 22°C to about 180°C, optionally under microwave irradiation.
  • a catalyst such as, for example, palladium acetate or
  • step (f) is carried out by reaction of a compound of formulae A8 or A6 with an aniline of formula R 1 - NH 2 in the presence of potassium carbonate or cesium carbonate and catalytic amounts of tris(dibenzylideneacetone)dipalladium and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene in tert-butanol or 1 ,4-dioxane at a temperature ranging from about 140°C to about 170°C, in sealed tube under microwave irradiation.
  • step (f) of the process may be conveniently carried out by reaction of a compound of formulae A8 or A6 with an aniline A9 of formula R 1 -NH 2 in isopropyl alcohol at a temperature of about 160°C in sealed tube under microwave irradiation.
  • step (g) of the process outlined in Scheme A2 a compound of formula A4 obtained as described in Scheme A1 may be coupled with an aniline A9 of formula R 1 -NH 2 wherein R 1 is as defined above to provide a compound of formula A10.
  • the coupling reaction at step (g) may be carried out in a suitable solvent such as ⁇ , ⁇ '- dimethylformamide, dimethoxyethane, tert-butanol, 1 ,4-dioxane or acetonitrile in the presence of a catalyst such as, for example, palladium acetate or tris(dibenzylideneacetone)dipalladium, a base such as, for instance, potassium carbonate, potassium phosphate, or cesium carbonate and an organophosphorus ligand such as, for instance, 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP) or 4,5-
  • a catalyst such as, for example, palladium acetate or tris(dibenzylideneacetone)dipalladium
  • a base such as, for instance, potassium carbonate, potassium phosphate, or cesium carbonate
  • an organophosphorus ligand such as,
  • step (g) is carried out by reaction of a compound of formulae A4 with an aniline of formula R 1 -NH 2 in the presence of potassium carbonate or cesium carbonate and catalytic amounts of tris(dibenzylideneacetone)dipalladium and 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene in tert-butanol or 1 ,4-dioxane at a temperature ranging from about 140°C to about 170°C, in sealed tube under microwave irradiation.
  • step (g) of the process may be conveniently carried out by reaction of a compound of formula A4 with an aniline A9 in isopropyl alcohol at a temperature of about 160°C in sealed tube under microwave ir
  • step (h) of the process outlined in Scheme A2 the phthalimido group of compounds of formula A10 is removed by treatment with a suitable alkaline agent such as methylamine, ethylamine, hydrazine, methylhydrazine, or phenylhydrazine in a solvent such as methanol, ethanol, tetrahydrofyrane, water, or a mixture thereof at a temperature ranging from about 22°C to the reflux temperature of the reaction mixture.
  • step (h) is carried out by treating a compound of formula A10 with aqueous hydrazine in ethanol, tetrahydrofuran, or a mixture thereof at a temperature from about 22°C to the reflux temperature of the reaction mixture.
  • Intra-molecular cyclization at step (i) may spontaneously occur in the reaction conditions above described for step (h), thus directly providing compounds of formula (I).
  • an amino derivative of formula A11 may be cyclized by treatment with a base such as, for instance, sodium methylate, sodium ethylate or potassium tert-butylate in a suitable solvent such as methanol, ethanol or tert-butanol at a temperature ranging from about 22°C and the reflux temperature of the reaction mixture.
  • step (i) is carried out by treating a compound of formula A11 with sodium methylate in methanol, at a temperature from about 40°C to the reflux temperature of the reaction mixture.
  • amino-esters of formula A3 can be easily obtained by reaction between an amine of formula R 3 NH 2 , wherein R 3 is as defined above for compounds of formula (I) and an opportune a-halogen acetate of formula XCH 2 COOR 9 wherein R 9 is as defined above for compounds of formula A3 and X is halogen, preferably bromine.
  • reaction between an amine of formula R 3 NH 2 and an opportune a-halogen acetate of formula XCH 2 COOR 9 is carried out according to well-known operative conditions, in a suitable solvent, such as, for instance, tetrahydrofuran, 1 ,4-dioxane, or acetonitrile in the presence of an opportune proton scavenger such as triethylamine or ⁇ , ⁇ -diisopropylethylamine at a temperature ranging from about -5°C to about 22°C.
  • a suitable solvent such as, for instance, tetrahydrofuran, 1 ,4-dioxane, or acetonitrile
  • an opportune proton scavenger such as triethylamine or ⁇ , ⁇ -diisopropylethylamine at a temperature ranging from about -5°C to about 22°C.
  • amino-esters of formula A3 wherein R 3 is CH 2 R 8 and R 8 is as defined above for formula (I) can be easily obtained by reaction between an opportune aldehyde of formula R 8 CHO and a glycine ester of formula NH2-CH2-COOR 9 wherein R 9 is as defined above for compounds of formula A3.
  • the reaction between an aldehyde R 8 CHO and a glycine ester of formula NH 2 -CH 2 - COOR 9 is carried out according to well-known operative conditions, in a suitable solvent, such as, for instance, methyl alcohol, ethyl alcohol, or 2,2,2-trifluoroethanol in the presence of an opportune reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature ranging from about 10°C to the reflux temperature of the reaction mixture.
  • a suitable solvent such as, for instance, methyl alcohol, ethyl alcohol, or 2,2,2-trifluoroethanol
  • an opportune reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature ranging from about 10°C to the reflux temperature of the reaction mixture.
  • compounds of formula (I), wherein the R 1 substituent is phenyl substituted by CONR 6 R 7 or compound 52 can be conveniently prepared by coupling the opportune carboxylic acid and amine according to standard procedures well known in the art.
  • HPLC Waters Acquity UPLC
  • MS Waters SQD Single quadrupole (Waters).
  • UV detection wavelength 254 nm.
  • TMS tetramethylsilane
  • xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
  • THF tetrahydrofuran
  • DCM dichloromethane
  • AcOEt ethyl acetate
  • EDC N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • HOBT 1 -
  • reaction mixture was concentrated under vacuum and the crude was taken up with DCM, filtered, and the resulting solution was concentrated and purified by flash chromatography (eluent DCM/MeOH/NH 3 aq 95:5:0.5) to yield about 20 mg of the title compound.
  • N-methylpiperidine 56 mg, 0.49 mmol
  • EDC 126 mg, 0.66 mmol
  • HOBT 44 mg, 0.33 mmol
  • 4-[[4-[cyclopentyl-(2-ethoxy-2-oxo-ethyl)amino]-5- [(1 ,3-dioxoisoindolin-2-yl)methyl]-pyrimidin-2-yl]amino]-3-(trifluoromethoxy)benzoic acid (intermediate 58) (206 mg, 0.33 mmol) in THF(8 ml_)/DMF(0.4 ml_).
  • ethyl 1 -aminocyclopropanecarboxylate hydrochloride (0.278 g, 1 .68 mmol) was added to a solution of 2-[(2,4-dichloropyrimidin-5-yl)methyl]isoindoline-1 ,3-dione (intermediate 1 15) (0.493 g, 1.6 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.62 g, 4.8 mmol) in dry THF (6 mL) at room temperature and the mixture was stirred at the reflux temperature for 45 h. Then a second aliquot of ethyl 1 -aminocyclopropanecarboxylate hydrochloride (1 .6 mmol) was added and the mixture was refluxed under stirring for additional 24 h.
  • ethyl 2-(benzylamino)acetate 0.335 g, 1.68 mmol was added to a solution of 2-[(2,4- diiodopyrimidin-5-yl)methyl]isoindoline-1 ,3-dione (intermediate 125) (0.786 g, 1.6 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.62 g, 4.8 mmol) in dry THF (6 ml_) at room temperature and the mixture was stirred at the reflux temperature for 24 h. Then a second aliquot of ethyl 2-(benzylamino)acetate (1.6 mmol) was added and the mixture was refluxed under stirring for additional 24 h.
  • reaction mixture was then carefully neutralized with K 2 CO 3 and washed with aqueous sodium metabisulfite.
  • the organic layer was separated and the aqueous layer was extracted with DCM.
  • the combined organic layers were dried over sodium sulphate and the solvent was removed in vacuo to give 700 mg of off white solid that was used in the following synthetic step without further purification.
  • the inhibiting activity of putative Mps-1 inhibitors and the potency of selected compounds were determined through an assay based on the use of the ADP-Glo KinaseTM Assay technology (V9102 ,Promega, Madison Wl 5371 1 USA).
  • N-terminal His-tagged human Mps-1 kinase domain (corresponding to residues 519-808 of the full length sequence GenBank accession number: NP_003309.2) was expressed in E.Coli and purified using standard affinity purification techniques. To get a fully activated enzyme, the protein was then subjected to auto-phosphorylation in presence of 1 mM ATP at 25°C for 1 hour in kinase buffer (HEPES 50 mM pH 7.5, MgCI 2 5 mM, MnCI 2 1 mM, DTT 1 mM, orthovanadate 100 ⁇ ); ATP was then removed with a desalting column.
  • kinase buffer HEPS 50 mM pH 7.5, MgCI 2 5 mM, MnCI 2 1 mM, DTT 1 mM, orthovanadate 100 ⁇
  • a fragment of human Mad1 protein (corresponding to residues 485-584 of the full length sequence (GenBank accession number: NP_001013859.1 ), His tagged expressed in E.Coli and purified using affinity chromatography techniques were used.
  • This method measures kinase activity by quantifying the amount of ADP produced during a kinase reaction.
  • the assay is performed in two steps: first, after the kinase reaction, an equal volume of ADP-Glo Reagent is added to terminate the kinase reaction and deplete the remaining ATP; second, the Kinase Detection Reagent is added to simultaneously convert ADP to ATP and allow the newly synthesized ATP to be measured using luciferase/luciferin reaction.
  • the light generated is measured using a luminometer (Infinite® F200, Tecan, 8708
  • Kinase Assay conditions 200 ⁇ Mad1 protein substrate (equal to the Km app Mad1 ), 5nM Mps-1 -Kinase Domain, and test compound in 100% DMSO were added in a final volume of 40 ⁇ kinase buffer (HEPES 50 mM pH 7.5, MgCI 2 5 mM, MnCI2 1 mM, DTT 1 mM, orthovanadate 100 ⁇ ) to each well of a 96 half area flat bottom white well plate.
  • the mixture was incubated for 15 minutes at room temperature to allow pre-binding of the test compounds to Mps-Kinase Domain before to start kinase reaction by the addition of 20 ⁇ ATP (equal to 2Km app ATP) (purchased from Sigma). After a reaction time of 30 minutes at room temperature, an half volume of reaction was transferred from the original plate into a new 96 well plate to be stopped by adding 20 ⁇ of ADP-Glo Reagent. The resulting mixture was incubated 40minut.es at room temperature. Then 40 ⁇ of Kinase Detection Reagent was added to each well and let stand 30 minutes before luminescence was read by a luminometer (Infinite ® F200, Tecan).
  • IC-50 determination inhibitors diluted in DMSO were tested at different concentrations ranging from 0.005 to 100 ⁇ (serial 1 :3 dilutions). Control wells that produced a maximum signal corresponding to maximum enzyme activity were created by adding 2.5% DMSO instead of test compound. Control wells that produced a minimum signal corresponding to fully inhibited enzyme were created by not adding enzyme to the reaction.
  • x is the logarithm of the inhibitor concentration
  • y is the response; y starts at bottom and goes to top with a sigmoid shape.

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Abstract

La présente invention concerne des composés capables d'inhiber la kinase dz fuseau mpolaire (Mps-1 ou TTK), répondant à la formule générale (I), dans laquelle R1, R2, R3, R4 , et R5 sont tels que définis dans la description. La présente invention concerne également un procédé pour leur préparation, des compositions pharmaceutiques les comprenant, et leur utilisation en tant qu'agents thérapeutiques, en particulier dans le traitement du cancer.
PCT/EP2015/064498 2014-06-30 2015-06-26 Composés inhibant l'enzyme kinase de fuseau monopolaire 1, compositions pharmaceutiques et leurs utilisations Ceased WO2016001077A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10603319B2 (en) 2016-08-04 2020-03-31 ReViral Limited Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection
CN111808080A (zh) * 2019-04-12 2020-10-23 四川科伦博泰生物医药股份有限公司 取代的吡啶或嘧啶化合物、其制备方法及其在医药上的应用
WO2023030295A1 (fr) * 2021-09-01 2023-03-09 先声再明医药有限公司 Inhibiteur de protéase 1 spécifique de l'ubiquitine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120040961A1 (en) * 2009-01-06 2012-02-16 Dana-Farber Cancer Institute Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders
US20120149898A1 (en) * 2006-02-14 2012-06-14 Vertex Pharmaceuticals Incorporated Dihydrodiazepines useful as inhibitors of protein kinases
US20120309747A1 (en) * 2008-06-23 2012-12-06 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120149898A1 (en) * 2006-02-14 2012-06-14 Vertex Pharmaceuticals Incorporated Dihydrodiazepines useful as inhibitors of protein kinases
US20120309747A1 (en) * 2008-06-23 2012-12-06 Vertex Pharmaceuticals Incorporated Protein kinase inhibitors
US20120040961A1 (en) * 2009-01-06 2012-02-16 Dana-Farber Cancer Institute Pyrimido-diazepinone kinase scaffold compounds and methods of treating disorders

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10603319B2 (en) 2016-08-04 2020-03-31 ReViral Limited Pyrimidine derivatives and their use in treating or preventing a respiratory syncytial virus infection
CN111808080A (zh) * 2019-04-12 2020-10-23 四川科伦博泰生物医药股份有限公司 取代的吡啶或嘧啶化合物、其制备方法及其在医药上的应用
CN111808080B (zh) * 2019-04-12 2024-03-08 四川科伦博泰生物医药股份有限公司 取代的吡啶或嘧啶化合物、其制备方法及其在医药上的应用
WO2023030295A1 (fr) * 2021-09-01 2023-03-09 先声再明医药有限公司 Inhibiteur de protéase 1 spécifique de l'ubiquitine

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