WO2017140758A1 - Dérivés de 2-amino-4-(2-oxazolidinone-3-yl)-pyrimidine fusionnés avec un noyau hétéroaromatique à cinq chaînons en position 5,6 qui sont utiles dans le traitement de divers cancers - Google Patents

Dérivés de 2-amino-4-(2-oxazolidinone-3-yl)-pyrimidine fusionnés avec un noyau hétéroaromatique à cinq chaînons en position 5,6 qui sont utiles dans le traitement de divers cancers Download PDF

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WO2017140758A1
WO2017140758A1 PCT/EP2017/053464 EP2017053464W WO2017140758A1 WO 2017140758 A1 WO2017140758 A1 WO 2017140758A1 EP 2017053464 W EP2017053464 W EP 2017053464W WO 2017140758 A1 WO2017140758 A1 WO 2017140758A1
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salt
group
solvate
compound according
compound
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PCT/EP2017/053464
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English (en)
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Duncan HAY
Clive Mccarthy
Rose CHAPPELL
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Debiopharm International S.A.
Evotec International Gmbh
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Publication of WO2017140758A1 publication Critical patent/WO2017140758A1/fr

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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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Isocitrate dehydrogenases represent a family of Isocitrate dehydrogenases
  • IDH1 Human IDHs exist in several forms; the isoforms IDH1
  • IDH cytosolic and peroxisomal
  • IDH2 mitochondrial
  • Mutant forms of IDH often exhibit a neomorphic activity as a result of a "gain of function" mutation, whereby ⁇ -ketoglutarate is reduced to 2- hydroxyglutarate (2-HG)
  • 2-HG 2- hydroxyglutarate
  • Regular cells have 2-HG levels, while cells and tumors with mutated IDH1 or IDH2 (referred herein as mIDHI and mIDH2) show increased 2-HG levels (See S. Gross et al . , J. Exp. Med.
  • the dysregulation caused by the altered levels of 2-HG and ⁇ -ketoglutarate in cells bearing mIDHI and/or mIDH2 may contribute to an alteration in a number of cellular activities, e.g. signaling and gene expression, and give raise to increased angiogenesis in human cancers. Accordingly, elevated levels of 2-HG are highly associated with tumorigenesis (J.R. Prensner et al . , Nature Med. 2011, 17, 291-293) .
  • Malignant gliomas including primary and secondary
  • glioblastomas are among the most lethal and also the most prevalent of brain tumors.
  • Genomic analyses of glioma genomes have revealed recurrent mutations of IDH in up to 70% of grade II-IV gliomas, in about 10% of acute myeloid leukemia (AML) cases, and in several other cancer types.
  • IDH1 R132 and IDH2 R172 mutations have been shown to have neomorphic activity (reducing -ketoglutarate to 2- HG) , as disclosed by L. Dang et al . , Nature 2009, 462 and in WO 2011/123618 Al and WO 2015/003641 Al .
  • IDH1 and IDH2 have been further identified in multiple cancer types, in particular brain cancers, such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET) ; leukemia, such as acute myeloid leukemia (AML) , myelodysplasia syndrome, and chronic myelogenous leukemia (CML) , skin cancer such as melanoma, prostate cancer, thyroid cancer, colon cancer, lung cancer, sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.
  • brain cancers such as glioma, glioblastoma multiforme, paraganglioma, and supratentorial primordial neuroectodermal tumors (pNET) ; leukemia, such as acute myeloid leukemia (AML) , myelodysplasia syndrome, and chronic mye
  • WO 2015/003355 A2 and WO 2015/003641 Al disclose compounds based on a 2, 4-diamino-l, 3, 5-triazine core as inhibitors of the neomorphic activity of mIDH2 R140Q and IDH2 R172K.
  • WO 2012/171506 Al discloses compounds based on a pyridine or a pyrimidine core fused to a saturated 6-membered ring as inhibitors of the neomorphic activity of mlDHl R132H.
  • WO 2013/046136 Al, WO 2014/141104 Al, WO 2014/141153 Al and WO 2014/147586 Al disclose inhibitors of the neomorphic activity of mlDHl R132H.
  • IDH related compounds are also described in WO 2015/017821 A2, WO 2015/003640 Al, WO 2015/003360 A2 , WO 2015/006591 Al, WO 2015/006592 Al, WO 2012/171337 Al, WO 2012/171506 Al, WO 2014/062511 Al, WO 2013/107291 Al, WO 2013/107405 Al and WO 2013/102431 Al .
  • the present invention relates to a compound of general
  • n 0 or 1 ;
  • R 1 is N (R 11 ) or CH;
  • R 2 is N or C (R 12 ) ;
  • R 3 is S or C (R 13 ) ;
  • R 1 is CH and R 2 is CR 12 when R 3 is S;
  • R 1 is N(R 1X ) when R 3 is C(R 13 );
  • R 11 is a hydrogen atom or C3 ⁇ 4;
  • R 12 is a hydrogen atom, a cyano group or C3 ⁇ 4;
  • R 13 is a hydrogen atom or a halogen atom
  • R 4 , R 5 are independently selected from a hydrogen atom; C3 ⁇ 4OH; CH 2 OCH 3 ; a Ci-6 alkyl group, wherein the Ci-6 alkyl group is unsubstituted or substituted with at least one halogen atom; or
  • R 4 , R 5 may be joined together to form a C3-6 cycloalkyl group;
  • R is an aromatic group, a heteroaromatic group or a C3-6 cycloalkyl group, wherein R 6 is unsubstituted or substituted with one or two R 6a , which are the same or different;
  • R 6a is a halogen atom, a Ci-6 alkyl group, a Ci-6 alkoxy group, a S(0) 2 -Ci-6 alkyl group, or R 6aa ;
  • R 6aa is an aromatic group, a heteroaromatic group, or a heteroalicyclylalkyl group, wherein R 6aa is unsubstituted or substituted with one or two R 6b , which are the same or different ;
  • R 6b is a halogen atom; a Ci-6 alkyl group, which is
  • R 7 , R 8 are independently selected from a hydrogen atom, or R 7a , or R 7 and R 8 may be joined together to form a C3-6 cycloalkyl group or a heteroalicyclic group;
  • R 7a is a Ci-6 alkyl group, an aromatic group, a heteroaromatic group, or a heteroalicyclic group, wherein R 7a is
  • R 9 , R 10 are independently selected from a hydrogen atom, or R 9a , or R 9 and R 10 may be joined together to form a C3-6 cycloalkyl group or a heteroalicyclic group;
  • R 9a is a Ci-6 alkyl group, an aromatic group, a heteroaromatic group, or a heteroalicyclic group, wherein R 9a is
  • a further aspect of the present invention relates to the compound of general Formula (I) or a salt or solvate thereof as a medicament and may be used in the treatment of a human or animal body.
  • the present invention relates to the compound of the general Formula (I) or a salt or a solvate thereof for use in the treatment or prophylaxis of a disease or disorder associated with a mutant isocitrate dehydrogenase having a neomorphic activity, preferably a cell proliferation disorder.
  • compositions comprising a therapeutically effective amount of the compound of general Formula (I), or a salt or solvate thereof as active ingredient.
  • said pharmaceutical composition may be an oral dosage form.
  • Yet a further aspect of the present invention relates to the use of a compound of the general Formula (I) or a salt or a solvate thereof for the preparation of a medicament for the treatment or prophylaxis of a disease or disorder associated with a mutant isocitrate dehydrogenase having a neomorphic activity, preferably a cell proliferation disorder.
  • Yet a further aspect of the present invention is a method of treating, controlling, delaying or preventing in a mammalian patient in need of the treatment of one or more diseases or disorders associated with a mutant isocitrate dehydrogenase having a neomorphic activity, preferably a cell proliferation disorder, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound of the present invention or a salt or a solvate thereof.
  • substituted means that one or more hydrogen atoms of a molecule or residue are replaced by a substituent.
  • substituents are further described herein. Generally -but not limited to-, "one or more substituents” means one, two or three, preferably one or two substituents and more preferably one substituent unless specifically defined herein. Generally these substituents can be the same or different .
  • alkyl or "alkyl group” means a straight-chain or branched hydrocarbon chain.
  • C 1 -4 alkyl or "C 1 -4 alkyl group” means an alkyl chain having 1 - 4 carbon atoms, e.g. if present at the end of a molecule: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or e.g. -CH 2 -, -CH 2 -CH 2 -, - CH(CH 3 )-, -CH2-CH2-CH2-, -CH(C 2 H 5 )-, -C(CH 3 ) 2 -, when two moieties of a molecule are linked by the alkyl group.
  • Ci-6 alkyl or "Ci-6 alkyl group” means an alkyl chain having 1 - 6 carbon atoms, e.g. if present at the end of a molecule: C 1 -4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl; tert-butyl, n-pentyl, n-hexyl, or e.g.
  • Ci_6 alkoxy group (O-Ci-6 alkyl) means a Ci-6 alkyl group, which is attached to the rest of the molecule via oxygen atom. Examples are OCH 3 and OCH 2 CH 3 .
  • aromatic group means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aromatic group embraces aromatic substituents such as phenyl, naphthyl, and biphenyl .
  • aromatic group refers to a phenyl group.
  • C3-6 cycloalkyl or “C3-6 cycloalkyl ring” or “C3-6 cycloalkyl group” means a cyclic alkyl chain having 3 - 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl .
  • cyloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • Examples for a 3 to 7 membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazoline, thiadiazole,
  • heterocyclyl or "4 to 7 membered heterocycle” is defined accordingly.
  • the term “5 to 6 membered heterocyclyl” or “5 to 6 membered heterocycle” is defined accordingly.
  • “Saturated 4 to 7 membered heterocyclyl” or “saturated 4 to 7 membered heterocycle” means fully saturated “4 to 7 membered heterocyclyl” or "4 to 7 membered heterocycle”.
  • 5 to 6 membered aromatic heterocyclyl or “5 to 6 membered aromatic heterocycle” means a heterocycle derived from cyclopentadienyl or benzene, where at least one carbon atom is replaced by a heteroatom selected from the group
  • heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine .
  • heteromatic group means a 5 to 6 membered aromatic heterocyclyl or 5 to 6 membered aromatic
  • heteroalicyclic group means a 4 to 7 membered at least partly saturated heterocyclyl or 4 to 7 membered at least partly saturated heterocycle or a saturated 4 to 7 membered heterocyclyl or saturated 4 to 7 membered
  • heteroalicyclic group means a saturated 4 to 7 membered heterocyclyl or saturated 4 to 7 membered heterocycle.
  • heteroalicyclylalkyl group means a heteroalicyclyl group, which is attached to the rest of the molecule via a Ci-6 alkyl group.
  • halogen or "halogen atom” means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.
  • cyano group means -CN.
  • benzyl means Ph-C3 ⁇ 4- (phenylmethyl ) , wherein "Ph” means phenyl .
  • the compounds of the present invention may also exist as several tautomeric forms.
  • R 9a is a pyridyl group substituted with a hydroxyl group
  • R 9a and the corresponding compound of the Formula (I) may exist in a corresponding pyridone form.
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein
  • R 1 is NH, R 2 is CH, R 3 is CH; or (ii) R is NH, IT is N, R J is CH; or
  • R 1 is CH, R 2 is CH, R 3 is S ;
  • R 1 is NH, R 2 is CH, R 3 is CF; or
  • R 1 is NH, R 2 is CCN, R 3 is CH; or
  • R 1 is NH, R 2 is CCH 3 , R 3 is CH; or
  • R 1 is NCH 3 , R 2 is CH, R 3 is CH.
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein one of R 4 , R 5 is a hydrogen atom or CH 3 and the other is a hydrogen atom, CH 3 , CH 2 CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 F or CF 3 ; or R 4 , R 5 are joined together to form a cyclopropyl group .
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 6 is an aromatic group or a heteroaromatic group and wherein R 6 is unsubstituted or substituted with one or two R 6a , which are the same or different.
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 6 is imidazolyl, pyridyl, thiazolyl, pyrazolyl, phenyl, oxadiazolyl, oxazolyl, cyclohexyl, thiophenyl or furanyl and wherein R 6 is unsubstituted or substituted with one or two R 6a , which are the same or different .
  • R 6 is imidazolyl, pyridyl, thiazolyl, pyrazolyl, phenyl, oxadiazolyl, oxazolyl, cyclohexyl, thiophenyl or furanyl and wherein R 6 is unsubstituted or substituted with one or two R 6a , which are the same or different .
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 6a is CH 3 , OCH 3 , F, CI, S(0) 2 CH 3 or R 6aa .
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 6aa is phenyl, pyridyl, thiophenyl or piperazinylmethyl and wherein R 6aa is unsubstituted or
  • R 6b substituted with one or two R 6b , which are the same or different .
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 6b is CI, F, CF 3 , cyclopropyl or
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein one of R 7 , R 8 is a hydrogen atom or CH 3 and the other is C3 ⁇ 4F, a fluoroethyl, methyl, ethyl, isopropyl, tert. -butyl, 1-methyl-propyl, a hydroxyethyl , phenyl, pyridyl or methylimidazolyl ; or R 7 and R 8 are joined together to form a cyclopropyl, tetrahydrofuranyl or tetrahydropyranyl group.
  • R 7 , R 8 is a hydrogen atom or CH 3 and the other is C3 ⁇ 4F, a fluoroethyl, methyl, ethyl, isopropyl, tert. -butyl, 1-methyl-propy
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein R 9 and R 10 are hydrogen atoms, and at least one of R 7 and R 8 is other than a hydrogen atom.
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein n is 1.
  • the compound of the present invention or a salt or solvate thereof is preferably the compound of general Formula (I) as defined in the summary of the invention or a salt or solvate thereof, wherein n is 1, R 4 is a hydrogen atom and R 5 is other than a hydro en atom to give Formula (la)
  • the compound of the present invention or a salt or solvate thereof is preferably selected from Table 1 herein or more preferably one of the following:
  • a further aspect of the present invention is a solvent or salt of a compound of formula (I) .
  • the invention also comprises their corresponding salt, preferably
  • alkaline earth metal salts or as ammonium salts More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine,
  • acids examples include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines ( zwitterions ) .
  • a compound of general Formula (I) according to the present invention or a salt or solvate thereof can be used in the treatment or prophylaxis of a human or animal body.
  • the use may be in the treatment or prophylaxis of a disorder associated with a mutant isocitrate dehydrogenase having a neomorphic activity.
  • the disorder associated with a mutant isocitrate dehydrogenase having a neomorphic activity may be a cell proliferation disorder.
  • the disorder may be one of the following: brain cancer, such as glioma, glioblastoma
  • pNET primordial neuroectodermal tumors
  • leukemia such as acute myeloid leukemia (AML) , myelodysplasia syndrome, and chronic myelogenous leukemia (CML)
  • skin cancer such as melanoma, prostate cancer, thyroid cancer, colon cancer, lung cancer, sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.
  • the present invention also provides pharmaceutical
  • compositions comprising the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, as active ingredient, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salt includes an ammonium salt, a calcium salt, a magnesium salt, a potassium salt or a sodium salt of compound of Formula (I) .
  • compositions of the present invention may comprise the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof in form of one or several polymorphs .
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active
  • pharmaceutically acceptable excipients that make up the pharmaceutically acceptable carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the
  • ingredients or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the
  • compositions made by admixing the compound of Formula (I) and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a patient, with an effective dosage of a compound of the present invention, including without limitation oral and parenteral (such as intravenous bolus or infusion, injection, intraperitoneal, subcutaneous or intramuscular administration) .
  • parenteral such as intravenous bolus or infusion, injection, intraperitoneal, subcutaneous or intramuscular administration
  • suitable solid oral dosage forms include discrete units such as capsules, pills,
  • Suitable liquid oral dosage forms include solutions or suspensions in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including
  • compositions of the present invention elixirs, tinctures, solutions, suspensions, syrups and emulsions.
  • inventions may also be in the form of sustained release formulations .
  • any inert ingredient that is commonly used as a carrier or diluent may be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic material, an acrylate, or mixtures thereof.
  • a preferred diluent is microcrystalline cellulose.
  • compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e.g.,
  • magnesium stearate may additionally comprise one or more additives selected from a binder, a buffer, a protease inhibitor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a stabilizing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof .
  • compositions of the present invention may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet, cachet or capsule contains from about 0.1 to 1,000 mg, particularly 0.1, 0.2, 0.5, 1.0, 5, 10, 25, 50, 75, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 175, 180, 200, 225, 250, 300, 350, 400, 450, 500, 750 and 1,000 milligrams of the active ingredient, for the
  • Formula (I) might be synthesised by several processes using both solid and/or solution phase chemistry protocols. Examples of synthetic pathways for the preparation of compounds of general Formula (I) are described here below. Optimal reaction conditions may vary with particular
  • Triethylamine (8.5 ml, 60.96 mmol) in dichloromethane (10 ml) was then added slowly and the reaction was allowed to warm to ambient temperature overnight.
  • the reaction was diluted with water (75.0 ml) and aHC03 (sat aq) (50.0 ml) along with further DCM (50.0 ml) and the organic layer was separated, dried over Na2SOz [ , filtered and concentrated in vacuo. The residue was retreated in a similar manner.
  • Oxalyl chloride (1.62 ml, 19.4 mmol) was dissolved in
  • Titanium tetraethoxide (3.11 ml, 14.84 mmol) was added to a solution of 5- (4-chlorophenyl) -l-methyl-lH-pyrazole-3- carbaldehyde (1.64 g, 7.42 mmol) and (R) -2-methylpropane-2- sulfinamide (0.99 g, 8.16 mmol) in tetrahydrofuran (25 ml) and the reaction heated to 55 °C under nitrogen for 4 hours. The reaction was cooled, diluted with EtOAc (50.0 ml) and water (30.0 ml) then stirred for 10 minutes. The biphasic suspension was filtered through celite, washing with further EtOAc then the organic layer was separated, dried over
  • reaction was cooled then purified by column chromatography to give 480mg of the required product as a brown oil containing -50% residual DMSO.
  • Trifluoroacetic acid (20 ml) was added to a solution of (4R) 4- [ (1R) -1- ( tert-butoxy) ethyl] -3- [ (4-methoxyphenyl) methyl] - 1, 3-oxazolidin-2-one (2.75 g, 8.95 mmol) in DCM (20 ml). The reaction was stirred for 10 min. The reaction mixture was concentrated in vacuo then partitioned between saturated aq. NaHC03 (20 ml) and EtOAc (20 ml) .
  • PBSF PBSF (4.71 ml, 26.3 mmol) was added drop-wise to a cooled (0 °C, ice bath) solution of (4R) -4- [ (1R) -1-hydroxyethyl] -3- [ (4- methoxyphenyl) methyl] -1, 3-oxazolidin-2-one (2.18 g, 8.69 mmol) and triethylamine (11 ml, 79 mmol) in MeCN (50 ml) .
  • the reaction solution was stirred at 0 °C for 5 min then TREAT-HF (4.3 ml, 27 mmol) was added drop-wise.
  • TREAT-HF 4.3 ml, 27 mmol
  • the reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml) .
  • the phases were separated and the organic phase washed with brine (100 ml), dried over Na2SC>4 and evaporated.
  • the crude material was pre-adsorbed onto silica then purified by flash column chromatography on a silica column (50 g) .
  • the column was eluted with EtOAc : heptane, increasing the gradient linearly from 10:90 to 50:50 over 10 column volumes then isocratic at 50:50 for 2 CVs to afford the required product as colourless oil which solidified on standing to an off- white solid.
  • Trifluoroacetic acid (0.5 ml) was added to a solution of (4R) -4- [ (1R) -1- (tert-butoxy) ethyl] -3- (2- ⁇ [ (IS) -1- ⁇ -methyl-5- [2- (trifluoromethyl ) pyridin-4 -yl ] pyridin-2 -yl ⁇ ethyl ] amino ⁇ - 7H-pyrrolo [2, 3-d] pyrimidin-4-yl )-l,3-oxazolidin-2-one (94%, 46 mg, 0.074 mmol) in DCM (0.5 ml) . The reaction solution was left to stir at RT for 1 h.
  • the mixture was then heated at 80 °C for 16 h.
  • the reaction mixture was cooled to room temperature, then partitioned between DCM (10 ml) and water (10 ml) .
  • the aqueous phase was further extracted with DCM (10 x 2ml) and the combined organic layers dried (Na2SOz [ ) and concentrated.
  • the crude material was purified by Biotage Isolera flash column chromatography (S1O2; 25 g) eluting with
  • the IDH1 R132H mutant residues M1-L414 was directionally cloned via restriction sites Ndel and BamHI into pET9a vector to yield the full length protein carrying a non-cleavable C- terminal Hisg-tag.
  • the protein was expressed from Escherichia coli Rosetta 2 (DE3) cells transformed with the plasmid in the presence of 50 yg/ml kanamycin and after induction by 1 mM IPTG.
  • the IDH protein was isolated by affinity chromatography, desalting and size exclusion chromatography. Protein was loaded onto a 5 ml HisTrap Crude FF column. The column was washed with 100 ml of wash buffer (20 mM Tris/HCl pH 7.4, 500 mM NaCl, 5 mM ⁇ mercaptoethanol , 10% glycerol). The protein was eluted in a linear gradient from wash buffer to elution buffer (20 mM Tris/HCl pH 7.4, 500 mM NaCl, 5 mM ⁇ mercaptoethanol, 10% glycerol, 500 mM imidazol pH 8.0) over 20 column volumes.
  • Positive elution fractions were buffer exchanged using a PD- 10 column to 50 mM Tris/HCl pH 7.5, 200 mM NaCl, 10%
  • glycerol 5 mM ⁇ mercaptoethanol, 2 mM MnS04.
  • the protein was concentrated using 30 K Amicon Ultra centrifugal filters and then subjected to size exclusion chromatography on Superdex S200 16/60pg columns equilibrated in 50 mM Tris/HCl pH 7.5, 200 mM NaCl, 10% glycerol, 5 mM ⁇ mercaptoethanol, 2 mM
  • the IDH2 R172K mutant residues M1-L414 was directionally cloned via restriction sites BamHI and Xhol into pTrilJ-HV vector to yield the full length protein carrying a non- cleavable C-terminal Hisg-tag.
  • This plasmid was used to produce baculovirus for infecting Sf21 insect cells. These cells were stored as BIICs
  • Sf21 cells were prepared at a cell density of -0.5 xlO ⁇ cell/mL 24 hours prior to infection. Cell parameters were measured using a Cell Countess (Invitrogen) at time of infection and prior to harvest. Ideal cell density at time of infection (0 hours) is -1.2x10 ⁇ cell/mL, cell viability -99%. Set cell parameters for harvest are viability -80-90% and cell size increase >2.5ym. Usually at harvest, cell density has reached -2 xlO ⁇ cell/mL.
  • lysis buffer 25 mM HEPES/NaOH pH 7.5, 200 mM NaCl, 5% glycerol
  • 1 Roche Complete protease inhibitor cocktail tablet added per 50 ml.
  • Cells were lysed by sonication (40% amplitude, 2 min 30 sec of sonication time, 30 sec on/off cycles) in batches of 120 ml. The lysate was cleared by centrifugation for 60 min at 16500g.
  • the protein was purified by affinity chromatography,
  • Protein was loaded onto a 5 ml HisTrap Crude FF column equilibrated in lysis buffer (25 mM HEPES pH 7.5, 200 mM NaCl, 5% glycerol) .
  • the column was washed with 10 column volumes of lysis buffer.
  • the protein was eluted in a linear gradient from 0% to 100% elution buffer (25 mM HEPES pH 7.5, 200 mM NaCl, 5% glycerol, 250 mM imidazole pH 8.0) over 10 column volumes.
  • the protein was then loaded onto a 5 ml HiTrap Butyl
  • HIC loading buffer 25 mM HEPES/NaOH pH 7.5, 2 M Ammonium Sulfate, 1 mM DTT, 5%
  • HIC loading buffer 25 mM HEPES/NaOH pH 7.5, 1 mM DTT, 5% Glycerol
  • the protein in the positive elution fractions was pooled and concentrated using 30 K Amicon ultra centrifugal filters and then subjected to size exclusion chromatography on Superdex S75 26/60pg columns equilibrated in 25 mM HEPES/NaOH pH 7.5, 100 mM NaCl, 1 mM DTT, 10% glycerol.
  • the enzymatic reaction was performed at room temperature in 384-well plates using a final reaction volume of 16 ]i containing 20 mM Tris pH 7.5, 150 mM NaCI, 10 mM MgCI 2 and 0.03% BSA.
  • a final concentration 0.5yg/mL IDH1 (R132H) was pre-incubated with compound for 90 minutes, followed by addition of substrate solution (20 ⁇ NADPH and ImM - ketoglutarate) .
  • substrate solution (20 ⁇ NADPH and ImM - ketoglutarate
  • IDH1 (R132H) catalytic activity was measured using the
  • RapidFireTM mass spectrometry (RF/MS) platform was analysed on the Agilent RF300 integrated autosampler/solid- phase extraction (SPE) system coupled to an Agilent QQQ 6460 mass spectrometer for the conversion of substrate (a- ketoglutarate) to product (2-hydroxyglutarate) .
  • Solvent A was water containing 0.1% (v/v) acetic acid.
  • Solvent B was methanol/0.1% ammonium acetate (9:1, v/v) . More specifically, plates were centrifuged at 4350 rpm for 10 min, samples were aspirated under vacuum for 600 ms, then loaded onto a
  • the relative responses 2-HG/ (2-HG+a-KG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC5Q values (normalized IC5Q regression curves) .
  • the enzymatic reaction was performed at room temperature in 384-well plates using a final reaction volume of 16 ]i containing 20 mM Tris pH 7.5, 150 mM NaCI, 10 mM MgCI 2 and 0.03% BSA.
  • a final concentration 0.5yg/mL IDH2 (R172K) was pre-incubated with compound for 90 minutes, followed by addition of substrate solution (20 ⁇ NADPH and ImM - ketoglutarate) .
  • substrate solution (20 ⁇ NADPH and ImM - ketoglutarate
  • RapidFireTM mass spectrometry (RF/MS) platform was analysed on the Agilent RF300 integrated autosampler/solid- phase extraction (SPE) system coupled to an Agilent QQQ 6460 mass spectrometer for the conversion of substrate ( - ketoglutarate) to product (2-hydroxyglutarate) .
  • Solvent A was water containing 0.1% (v/v) acetic acid.
  • Solvent B was methanol/0.1% ammonium acetate (9:1, v/v) .
  • the relative responses 2-HG/ (2-HG+a-KG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC5Q values (normalized IC5Q regression curves) .
  • the compounds according to the present invention were active inhibitors in the employed assays.
  • Compounds 1 and 4 of the present invention are particularly efficient dual mIDHl/mIDH2 inhibitors, whereas compounds 2, 3, 5-10 of the present invention are specific mIDHI inhibitors with considerable mIDH2 inhibitory activity.

Abstract

La présente invention concerne des composés de Formule générale (I), les utilisations du composé de Formule générale (I) dans le traitement prophylactique ou thérapeutique d'un trouble du corps humain ou animal, et des compositions pharmaceutiques comprenant une quantité thérapeutiquement active des composés de Formule générale (I) en tant que principes actifs.
PCT/EP2017/053464 2016-02-19 2017-02-16 Dérivés de 2-amino-4-(2-oxazolidinone-3-yl)-pyrimidine fusionnés avec un noyau hétéroaromatique à cinq chaînons en position 5,6 qui sont utiles dans le traitement de divers cancers WO2017140758A1 (fr)

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EP3555079A4 (fr) * 2016-12-19 2020-08-19 Isocure Biosciences Inc. Inhibiteurs d'isocitrate déshydrogénases mutantes, compositions et procédés correspondants
CN114127063A (zh) * 2019-04-22 2022-03-01 上海仕谱生物科技有限公司 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途

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EP3555079A4 (fr) * 2016-12-19 2020-08-19 Isocure Biosciences Inc. Inhibiteurs d'isocitrate déshydrogénases mutantes, compositions et procédés correspondants
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WO2019206237A1 (fr) * 2018-04-26 2019-10-31 上海嗣新生物科技有限公司 Dérivé de 2-aminopyrimidine, son procédé de préparation et son utilisation
CN114127063A (zh) * 2019-04-22 2022-03-01 上海仕谱生物科技有限公司 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途
EP3967691A4 (fr) * 2019-04-22 2022-12-28 Epitas Biosciences (Shanghai) Co., Ltd. Composé hétérocyclique à cinq chaînons à base de pyrimido et son utilisation en tant qu'inhibiteur d'idh2 mutant
CN114127063B (zh) * 2019-04-22 2023-12-01 上海仕谱生物科技有限公司 嘧啶并五元杂环类化合物及其作为突变型idh2抑制剂的用途

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