WO2014147586A1 - 1-(2-(éthylamino)pyrimidin-4-yl)pyrrolidin-2-ones en tant qu'inhibiteurs du mutant idh - Google Patents

1-(2-(éthylamino)pyrimidin-4-yl)pyrrolidin-2-ones en tant qu'inhibiteurs du mutant idh Download PDF

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WO2014147586A1
WO2014147586A1 PCT/IB2014/060007 IB2014060007W WO2014147586A1 WO 2014147586 A1 WO2014147586 A1 WO 2014147586A1 IB 2014060007 W IB2014060007 W IB 2014060007W WO 2014147586 A1 WO2014147586 A1 WO 2014147586A1
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optionally substituted
alkyl
ethyl
pharmaceutically acceptable
mmol
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Young Shin Cho
Julian Roy LEVELL
Cynthia Shafer
Michael David SHULTZ
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention is directed to novel 1-(2-(ethylamino)pyrimidin-4-yl)pyrrolidin-2- one compounds, compositions containing these compounds, the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity and in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
  • Isocitrate dehydrogenase is a key family of enzymes found in cellular metabolism. They are NADP + / NAD + and metal dependent oxidoreductases of the enzyme class EC 1.1.1.42.
  • the wild type proteins catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate generating carbon dioxide and NADPH / NADH in the process. They are also known to convert oxalosuccinate into alpha-ketoglutarate.
  • IDH1 cytosolic
  • IDH2 mitochondrial
  • glioma glioblastoma multiforme
  • paraganglioma supratentorial primordial neuroectodermal tumors
  • acute myeloid leukemia (AML) prostate cancer
  • thyroid cancer colon cancer
  • chondrosarcoma cholangiocarcinoma
  • peripheral T-cell lymphoma peripheral T-cell lymphoma
  • melanoma See L. Deng et al., Trends Mol. Med., 2010, 16, 387; T. Shibata et al., Am. J. Pathol., 201 1 , 178(3), 1395; Gaal et al., J.
  • Mutant IDH2 is also associated with the rare neurometabolic disorder D-2- hydroxyglutaric aciduria type II (D-2-HGA type II). Germline mutations were found at R140 in IDH2 in 15 pateints having D-2-HGA type II. Patients having this disorder also have consistently increased levels of D-2-HG in their urine, plasma and cerebrospinal fluid. (See Kranendijk, M. et al., Science, 2010, 330, 336). Finally, patients with Oilier Disease and Mafucci Syndrome (two rare disorders that predispose to cartilaginous tumors) have been shown to be somatically mosaic for IDH1 and 2 mutations and exhibit high levels of D-2-HG. (See Amary et al., Nature Genetics , 2011 and Pansuriya et al., Nature Genetics, 2011).
  • this invention provides for a compound of formula (I):
  • this invention provides for a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of a mutant IDH protein having a neomorphic activity such as reducing alpha-ketoglutarate to 2-hydroxyglutarate (2-HG neomorphic activity).
  • this invention provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of mutant IDH1 having a neomorphic activity, such as 2-HG neomorphic activity, and/or mutant IDH2 having a neomorphic activity, such as 2-HG neomorphic activity.
  • This invention further provides for the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof as an inhibitor of IDH1 having a mutation at residue 97, 100 or 132, for example G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V; and/or an inhibitor of IDH2 having a mutation at residue 140 or 172, for example R172K, R172M, R172S, R172G, and R172W.
  • this invention provides for a method of treating a disease or disorder associated with a mutant I DH protein having a neomorphic activity comprising administration of an effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the disease or disorder is a cell proliferation disorder, such as cancer.
  • the cancer is brain cancer, 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, including melanoma; prostate cancer; thyroid cancer; colon cancer; lung cancer; sarcoma, including central chondrosarcoma, central and periosteal chondroma; and fibrosarcoma.
  • the disease or disorder is D-2-hydroxyglutaric aciduria.
  • the invention provides for a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent.
  • the present invention is directed to a compound of formula (I)
  • Rl a is H, methyl, or ethyl
  • R " " 3 is H, cyano, -COOC-1.4 alkyl, C 3.6 cycloalkyi, C-1.3 haloalkyi, optionally substituted C-1.3 alkyl, optionally substituted aryl or optionally substituted heteroaryl, wherein said C-1.3 alkyl is optionally substituted with one substituent selected from the group consisting of: OH, N H2, C-1.3 alkoxy, and optionally substituted phenyl, and said aryl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, C-1.3 alkyl, C-1.3 haloalkyi,
  • R1° is H, methyl or ethyl
  • R d is H, OH, C-1.3 alkoxy, C 3.6 cycloalkyl, NH2, -NHCOO-t-butyl, or C-1.3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, NH2, and C-1.3 alkoxy; or
  • R1 c and R ⁇ are joined together forming a C 3.6 cycloalkyl or a 4 to 6 membered heterocyclic ring;
  • R ⁇ e is H, methyl or ethyl and R f is H, OH, NH 2 , -NHCOO-t-butyl or C-
  • R " “ 3 and Rlf are joined together forming a methylene or ethylene bridge; provided that R ⁇ a and R “ “ “ 3 and/or R ⁇ c and R ⁇ and/or R “ “ 3 and are not joined together at the same time;
  • R2 and R3 are each independently H, deuterium, halo, C-1.3 alkyl or C-1.3 haloalkyi;
  • R 4 is:
  • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms
  • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
  • X is N or CH; each is independently hydrogen, halo, C-1.3 alkyl or C-1.3 haloalkyi; n is 1 , 2 or 3;
  • R R is H, halo, C-1.3 haloalkyi, optionally substituted C-
  • R Ra is optionally substituted C-
  • _6 alkyl is optionally substituted with one C3.6 cycloalkyi
  • said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C-1.5 alkyl, C-1.5 haloalkyi, C-1.3 alkoxy, and C-1.3 haloalkoxy
  • said C3.7 cycloalkyi and 5 or 6 membered heterocyclic are optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, -NRR, cyano, C-1.3 alkyl,
  • R R k is optionally substituted C3.6 cycloalkyi, optionally substituted phenyl or optionally substituted 5 or 6 membered heterocyclic, said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C-1.5 alkyl, C-1.5 haloalkyi, C-1.3 alkoxy, and C-1.3 haloalkoxy, and said C3.5 cycloalkyi and 5 or 6 membered heterocyclic are optionally substituted with one to three substituents each independently selected from the group consisting of: hydroxyl, CH2OH, -NRR, cyano, halo, C-1.3 alkyl, C-1.3 haloalkyi, and C-1.3 alkoxy; and each R is independently selected from the group consisting of H and C-1.3 alkyl; provided the compound is not (S)-1-[6-Chloro-2-[[1-(4-fluoropheny
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of carbon atoms.
  • C-1.5 alkyl refers to an alkyl group having from 1 to 6 carbon atoms.
  • Alkyl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • Alkoxy refers to any alkyl moiety attached through an oxygen bridge (i.e. a -O-C-1.3 alkyl group wherein C-1.3 alkyl is as defined herein). Examples of such groups include, but are not limited to, methoxy, ethoxy, and propoxy.
  • Aryl refers to a hydrocarbon ring system having an aromatic ring. Aryl groups are monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl. Bicyclic aryl rings refer to naphthyl and to rings wherein phenyl is fused to a C5.7 cycloalkyi or
  • Aryl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Cycloalkyi refers to a saturated hydrocarbon ring system having the specified number of carbon atoms. Cycloalkyi groups are monocyclic or bicyclic ring systems. For example, C3.
  • cycloalkyi refers to a cycloalkyi group having from 3 to 6 carbon atoms. Cycloalkyi groups may be optionally substituted with one or more substituents as defined in formula (I). Examples of cycloalkyi groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Cycloalkenyl refers to an unsaturated hydrocarbon ring system having the specified number of carbon atoms and having a carbon-carbon double bond within the ring.
  • C5.7 cycloalkenyl refers to a cycloalkenyl group having from 5 to 7 carbon atoms.
  • cycloalkenyl groups have one carbon-carbon double bond within the ring.
  • cycloalkeneyl groups have more than one carbon-carbon double bond within the ring.
  • Cycloalkenyl rings are not aromatic. Cycloalkenyl groups may be optionally substituted with one or more substituents as defined in formula (I).
  • Halo refers to the halogen radicals fluoro, chloro, bromo, and iodo.
  • Haloalkyl refers to an alkyl group wherein at least one hydrogen atom attached to a carbon atom within the alkyl group is replaced with halo.
  • the number of halo substituents includes, but is not limited to, 1 , 2, 3, 4, 5, or 6 substituents.
  • Haloalkyi includes, but is not limited to, monofluoromethyl, difluoroethyl, and trifluoromethyl.
  • Haloalkoxy refers to a haloalkyi moiety attached through an oxygen bridge (i.e. a -O- C-
  • An example of a haloalkoxy group is trifluoromethoxy.
  • Heteroaryl refers to an aromatic ring system containing from 1 to 5 heteroatoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined in formula (I). Heteroaryl groups are monocyclic ring systems or are fused bicyclic ring systems. Monocyclic heteroaryl rings have from 5 to 6 ring atoms. Bicyclic heteroaryl rings have from 8 to 10 member atoms. Bicyclic heteroaryl rings include those ring systems wherein a heteroaryl ring is fused to a phenyl ring.
  • Heteroaryl includes, but is not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl (including 1 ,3,4-oxadiazolyl and 1 ,2,4-oxadiazolyl), thiazolyl, isothiazolyl, thiadiazolyl, furanyl, furanzanyl, thienyl, triazolyl, pyridinyl (including 2-, 3-, and 4-pyridinyl), pyrimidinyl, pyridazinyl, pyrazinyl, trazinyl, tetrazinyl, tetrzolyl, indonyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl,
  • Heteroatom refers to a nitrogen, oxygen, or sulfur atom.
  • Heterocyclic refers to a 3 to 1 1 membered saturated or unsaturated monocyclic or bicyclic ring containing from 1 to 4 heteroatoms. Heterocyclic ring systems are not aromatic. Heterocyclic groups containing more than one heteroatom may contain different heteroatoms. Heterocyclic includes ring systems wherein a sulfur atom is oxidized to form SO or S02- Heterocyclic groups may be optionally substituted with one or more substituents as defined in formula (I). Heterocyclic groups are monocyclic, spiro, or fused or bridged bicyclic ring systems. Monocyclic heterocyclic rings have 3 to 7 ring atoms.
  • Examples of monocyclic heterocyclic groups include oxtanyl, tetrahydrofuranyl, dihydrofuranyl, 1 ,4-dioxanyl, morpholinyl, 1 ,4-dithianyl, piperazinyl, piperidinyl, 1 ,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl, 1 ,3-dioxanyl, 1 ,3-dithianyl, oxathianyl, thiomorpholinyl, tetrahydro-thiopyran 1 , 1 -dioxide, 1 ,4-diazepanyl, and the like.
  • Fused heterocyclic ring systems have from 8 to 1 1 ring atoms and include groups wherein a heterocyclic ring is fused to a phenyl ring, a heteroaryl ring or another heterocyclic ring.
  • fused heterocyclic rings include 2,3-dihydrobenzo[b][1 ,4]dioxinyl, octahydro- pyrrolo[1 ,2-a]pyrazinyl, octahydro-pyrido[1 ,2-a]pyrazinyl, octahydro-pyrrolo[3,4-c]pyrrolyl, 5,6,7,8-tetrahydro-[1 ,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydro-imidazo[1 ,2-a]pyrazinyl and the like.
  • bridged heterocyclic groups examples include 3,8-diaza-bicyclo[3.2.1]octanyl, 3,8- diaza-bicyclo[4.2.0]octanyl and the like.
  • spiro heterocyclic groups examples include 4,7- diaza-spiro[2.5]octanyl and the like.
  • 4-6 membered heterocyclic refers to a heterocyclic group as defined above, having from 4 to 6 ring atoms and containing from 1 to 4 heteroatoms.
  • 5-6 membered heterocylic refers to a heterocyclic group as defined above, having 5 or 6 ring atoms and containing from 1 to 4 heteroatoms.
  • Optionally substituted indicates that a group, such as an alkyl, cycloalkyl, heteroaryl, heterocyclic, phenyl, and benzyl may be unsubstitued or the group may be substituted with one or more substituents as defined in formula (I).
  • “Pharmaceutically acceptable” means a compound which is suitable for pharmaceutical use.
  • Salts and solvates (e.g. hydrates and hydrates of salts) of compounds of the invention which are suitable for use in medicine are those where in the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • Substituted in reference to a group such as alkyl, phenyl, benzyl, heteroaryl, and heterocyclic, indicates that one or more hydrogen atoms attached to an atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation, for example, by hydrolysis, rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture).
  • a group may contain one or more substituents, one or more (as appropriate) atoms within the group may be substituted.
  • a single atom within the group may be substituted with more than one substituent as long as such substitution is accordance with the permitted valence of the atom.
  • Suitable substituents are defined for each substituted or optionally substituted group.
  • salts including pharmaceutically acceptable salts, of the compounds according to formula (I) may be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Solvates, including pharmaceutically acceptable solvates, of the compounds of formula (I) may also be prepared.
  • “Solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the compounds of formula (I), including salts and solvates thereof, may exist in crystalline forms, non-crystalline forms, or mixtures thereof.
  • the compound or salt or solvate thereof may also exhibit polymorphism, i.e. the capacity of occurring in different crystalline forms. These different crystalline forms are typically known as "polymorphs". Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, all of which may be used for identification.
  • different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing a compound of formula (I).
  • the invention also includes various isomers of the compounds of formula (I).
  • “Isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereosiomers). With regard to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of a compound of formula (I) can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (£)- form.
  • a compound of formula (I) can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • the invention includes unlabeled forms as well as isotopically labeled forms of compounds of formula (I).
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, C, 3 C, 4 C, 5 N, 8 F 3 P, 32 P, 35 S, 36 CI, 2 5 l respectively.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H and 4 C, or those into which non-radioactive isotopes, such as 2 H and 3 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 4 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 8 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • R a is H
  • R b is H, methyl, CH 2 OH, CH 2 -phenyl, COOCH 2 CH 3 , COOCH 3 , CH 2 NH 2 ,
  • R c , R d , R e and R f are all H.
  • R ⁇ c is H or methyl
  • R ⁇ d is H, OH, NH 2 or C-
  • R a , R b , R e and R f are all H.
  • R c is H or methyl
  • R d is H, OH, NH 2 , CH 2 OH or methyl; and R a , R b , R e and R f are all H.
  • R c is
  • R d is H, OH, or NH 2 ; and R a , R b , R e and R f are all H.
  • R ⁇ e is H
  • R ⁇ is H, OH or NH 2 ;
  • R a , R b , R c , R d and R e are all H.
  • R ⁇ a is H or methyl
  • R " " 3 is H or methyl
  • R c , R d , R e and R f are all H.
  • R ⁇ a and R " " 3 , R ⁇ c , Rl d , R ⁇ and R ⁇ are all H.
  • R ⁇ 3 is H; R " " 3 is -CH 2 -phenyl; R ⁇ c is H; R d is OH; R e is H; and R f is H.
  • R " " 3 and R ⁇ are joined together forming an ethylene bridge and R ⁇ 3 , R ⁇ c , R ⁇ and R ⁇ e are all H.
  • R ⁇ c and R ⁇ are joined together forming a C 3.6 cycloalkyl or a 4 to 6 membered heterocyclic ring and R ⁇ 3 , R " " 3 , R ⁇ e and R ' are all H.
  • R ⁇ c and R ⁇ are joined together forming a 4 to 6 membered heterocyclic ring and R ⁇ a , R " " 3 le anc
  • Rlf are A
  • More suitably R ⁇ c and R ⁇ are joined together forming an oxetanyl ring and R ⁇ 3 , R “ “ 3 , R ⁇ e and R ⁇ are all H.
  • R2 and R ⁇ are each independently hydrogen or halo.
  • R2 and R3 are each independently hydrogen, fluoro or chloro.
  • R2 is H and R ⁇ is H, fluoro or chloro.
  • R2 is H, fluoro or chloro and R ⁇ is H.
  • R2 and R3 are both H.
  • R5 is hydrogen or halo and n is 1.
  • R ⁇ is hydrogen, chloro or fluoro and n is 1.
  • R ⁇ is hydrogen and n is 1.
  • R ⁇ is hydrogen, halo, C-1.3 haloalkyi or optionally substituted C-i_6 alkyl.
  • R ⁇ is optionally substituted phenyl.
  • R ⁇ is phenyl optionally substituted with one halo.
  • R ⁇ is phenyl optionally substituted with one fluoro or chloro group.
  • R ⁇ is optionally substituted heteroaryl.
  • R ⁇ is optionally substituted pyrazolyl.
  • pyrazolyl optionally substituted with one or two C-
  • R ⁇ a is C-
  • R ⁇ is -OR ⁇ a wherein R ⁇ a is CH2CF3, C-
  • R ⁇ is -C(0)NHR6a wherein R a is optionally substituted C3.5 cycloalkyl.
  • R ⁇ is -C(0)NHR6a wherein R a is C3.7 cycloalkyl optionally substituted with one OH.
  • R ⁇ is -C(0)NHR6a wherein R a is cyclohexyl or cycloheptyl optionally substituted with one OH.
  • R ⁇ is -C ⁇ R ⁇ b wherein R ⁇ b js optionally substituted
  • R ⁇ is -C ⁇ R ⁇ b wherein R ⁇ b js optionally substituted piperidinyl or piperazinyl.
  • R ⁇ is -C ⁇ R ⁇ ' 3 wherein R ⁇ b js piperidinyl or piperazinyl each of which is optionally substituted with one or two substituents each independently selected from the group consisting of: methyl, NH2, and -C(0)CH3.
  • the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of formula (I).
  • the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • Conditions (a) may include the following: NaH, DMF; KH, THF; CS2CO3, Pd2(dba)3, xantphos, dioxane; or CS2CO3, Pd(OAc)2, xantphos, THF.
  • Intermediate (iii) may be further manipulated to exchange, remove, or add a protecting group (as appropriate) or to convert a sidechain into an alternative moiety.
  • Conditions (b) may include the following: Hunig's base (N,N- diisopropylethylamine) or triethylamine with solvents of either NMP, DMSO, or n-butanol; with either conventional heating or microwave heating.
  • conditions (b) may also include a stepwise conversion of the chloropyrimidine intermediate into the fluoro intermediate in-situ with KF, DMSO prior to the final coupling with amine (iv) using Hunig's base and heating in DMSO.
  • Compound (I) may be further manipulated to exchange, remove, or add a protecting group (as appropriate) or to convert a sidechain into an alternative moiety.
  • the compounds of the present invention are inhibitors of a mutant IDH protein having a neomorphic activity and are therefore useful in the treatment of diseases or disorders associated with such proteins including, but not limited to, cell proliferation disorders, such as cancer.
  • mutant IDH protein having a neomorphic activity examples include mutant IDH1 and mutant IDH2.
  • a neomorphic activity associated with mutant IDH1 and mutant IDH2 is the ability to produce 2-hydroxyglutarate (2-HG neomorphic activity), specifically R-2-HG (R-2-HG neomorphic activity).
  • Mutations in IDH1 associated with 2-HG neomorphic activity, specifically R-2-HG neomorphic activity include mutations at residues 97, 100, and 132, e.g. G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • Mutations in IDH2 associated with 2-HG neoactivity, specifically R-2-HG neomorphic activity, include mutations at residues 140 and 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • Cell-proliferation disorders associated with a mutant IDH protein having a neomorphic activity include, but are not limited to, cancer.
  • cancers include Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS- Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocyto
  • the cancer associated with a mutant IDH protein having a neomorphic acitvity is brain cancer, such as astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma); oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma); oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma); ependymoma (e.g., myxop
  • the cancer associated with a mutant IDH protein having a neomorphic acitvity is leukemia, such as acute myeloid leukemia (AML), myelodysplasia syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), M DS.MPN including chronic myelomonocytic leukemia, post MDS AML, post MPN AML, post M DS/MPN AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma and acute lymphoblastic leukemia.
  • AML acute myeloid leukemia
  • MDS myelodysplasia syndrome
  • CML chronic myelogenous leukemia
  • MPN myeloproliferative neoplasm
  • M DS.MPN including chronic myelomonocytic leukemia,
  • the cancer associated with a mutant I DH protein having a neomorphic activity is skin cancer, including melanoma.
  • the cancer associated with a mutant I DH protein having a neomorphic activity is prostate cancer, thyroid cancer, colon cancer, or lung cancer.
  • the cancer associated with a mutant I DH protein having a neomorphic activity is sarcoma, including central chondrosarcoma, central and periosteal chondroma, and fibrosarcoma.
  • the cancer associated with a mutant I DH protein having a neomorphic activity is cholangiocarcinoma.
  • Another disease or disorder associated with a mutant I DH protein having R-2-HG neomorphic activity is D-2-hydroxyglutaric aciduria.
  • Another disease or disorder associated with a mutant I DH protein having R-2-HG neomorphic activity is Diller disease and Mafucci syndrome.
  • neomorphic activity refers to a gain of novel activity of a protein that the wild-type protein does not have or does not exhibit to a significant degree.
  • a neomorphic activity associated with a mutant form of I DH 1 and I DH2 is the ability to reduce alpha-ketoglutarate to 2-hydroxyglutarate (i.e. 2-HG, specifically R-2-HG).
  • the wild type form of I DH 1 and I DH2 does not have the ability to reduce alpha-ketoglutarate to 2- hydroxyglutarate (i.e. 2-HG, specifically R-2-HG) or if it does have this ability, it does not produce significant (i.e. harmful or disease causing) amounts of 2-HG.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • the term "therapeutically effective amount" in reference to a compound of the invention means an amount of the compound sufficient to treat the subject's disease or condition, but low enough to avoid serious sides effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a therapeutically effective amount of a compound will vary with the particular compound chosen (e.g. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of the concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e. , slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the compounds of the present invention may be administered by any suitable route including oral and parenteral administration.
  • Parenteral administration is typically by injection or infusion and includes intravenous, intramuscular, and subcontaneous injection or infusion.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution and half life which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the disease or condition being treated, the severity of the disease or condition, the age and physical condition of the subject being treated, the medical history of the subject being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual subject's response to the dosing regimen or over time as the individual subject needs change. Typical daily dosages may vary depending upon the particular route of administration chosen. Typical daily dosages for oral administration, to a human weighing approximately 70kg would range from about 5mg to about 500mg of a compound of formula (I).
  • One embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of I DH having a neomorphic activity comprising administration of a therapeutically effective amount of a compound of formula (I) to a subject in need of treatment thereof.
  • the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder.
  • the cell proliferation disorder is cancer.
  • the cancer is a cancer associated with mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplasia syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for a method of treating a disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity comprising administration of a therapeutically effective amount of a compound according to formula (I) to a subject in need thereof wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.
  • the therapy is a disease or disorder associated with a mutant form of IDH having a neomorphic activity.
  • the therapy is a cell proliferation disorder associated with a mutant form of IDH having a neomorphic activity.
  • the therapy is cancer.
  • the therapy is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R-2-HG neomorphic activity having a mutation at residue at residues R140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplasia syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound of formula (I) in therapy wherein the therapy is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having a neomorphic activity.
  • the disease or disorder associated with a mutant form of IDH having a neomorphic activity is a cell proliferation disorder.
  • the cell proliferation disorder is cancer.
  • the cancer is a cancer associated with a mutant IDH protein having a neomorphic activity, such as mutant IDH1 having 2-HG neomorphic activity or mutant IDH2 having 2-HG neomorphic activity.
  • the neomorphic activity is R-2-HG neomorphic activity.
  • the cancer is associated with mutant IDH1 having 2-HG or R-2-HG neomorphic activity having a mutation at residues 97, 100, or 132, such as G97D, R100Q, R132H, R132C, R132S, R132G, R132L, and R132V.
  • the cancer is associated with mutant IDH2 having 2-HG or R- 2-HG neomorphic activity having a mutation at residue at residues 140 or 172, e.g. R140Q, R140G, R172K, R172M, R172S, R172G, and R172W.
  • the cancer is brain cancer, leukemia, skin cancer, prostate cancer, thyroid cancer, colon cancer, lung cancer or sarcoma.
  • the cancer is glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia, myelodysplasia syndrome, chronic myelogenous leukemia, melanoma, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
  • Another embodiment of the present invention provides for the use of a compound according to formula (I) in the manufacture of a medicament for the treatment of disease or disorder associated with a mutant form of IDH having R-2-HG neomorphic activity wherein the disease or disorder is D-2-hydroxyglutaric aciduria, Oilier Disease, or Mafucci Syndrome.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to a subject, such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 5mg to 500mg of a compound of formula (I).
  • pharmaceutically acceptable carrier or excipient means a pharmaceutically acceptable material, composition or vehicle that, for example, are involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a subject and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must, of course, be of sufficiently high purity to render it pharmaceutically acceptable.
  • the compound of the invention and the pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to the subject by the desired route of administration.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution.
  • suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable carriers and excipients in appropriate amounts for the use in the invention.
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a therapeutically effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives, (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the composition can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • the compounds of the invention may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of the invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanacrylates and cross- linked or amphipathic block copolymers of hydrogels.
  • the invention is directed to a liquid oral dosage form.
  • Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of the invention.
  • Syrups can be prepared by dissolving the compound of the invention in a suitably flavored aqueous solution; while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or other natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.
  • compositions adapted for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the compound of the present invention may be administered either simultaneously with, or before or after, one or more other therapeutic agent(s).
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or disorder associated with a mutant form of IDH.
  • Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I).
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic agent may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of I DH, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of I DH, wherein the medicament is administered with a compound of formula (I).
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of IDH, wherein the compound of formula (I) is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of IDH , wherein the other therapeutic agent is prepared for administration with a compound of formula (I).
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or disorder associated with a mutant form of I DH, wherein the compound of formula (I) is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or disorder associated with a mutant form of I DH, wherein the other therapeutic agent is administered with a compound of formula (I).
  • the invention also provides the use of a compound of formula (I) for treating a disease or disorder associated with a mutant form of I DH, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or disorder associated with a mutant form of I DH, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I).
  • the other therapeutic agent is selected from: vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and other cytotoxic agents.
  • VEGF vascular endothelial growth factor
  • vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark Avastin® by Genentech/Roche), axitinib, (A/-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1/-/-indazol-6-yl]sulfanyl]benzamide, also known as AG013736, and described in PCT Publication No.
  • topoisomerase II inhibitors include but are not limited to, etoposide (also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), and teniposide (also known as VM-26, sold under the tradename Vumon®).
  • etoposide also known as VP-16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®
  • teniposide also known as VM-26, sold under the tradename Vumon®
  • alkylating agents include but are not limited to, temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames P
  • anti-tumor antibiotics include, but are not limited to, doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename EllenceTM), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), and mitomycin C (sold under the tradename Mutamycin®).
  • doxorubicin sold under the tradenames Adriamycin® and Rubex®
  • bleomycin sold under the trade
  • anti-metabolites include, but are not limited to, claribine (2- chlorodeoxyadenosine, sold under the tradename leustatin®), 5-fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCytTM), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, DroxiaTM and MylocelTM), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-ch
  • retinoids examples include, but are not limited to, alitretinoin (sold under the tradename Panretin®), tretinoin (a ⁇ -trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-c/s-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), and bexarotene (sold under the tradename Targretin®).
  • Panretin® tretinoin (a ⁇ -trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®)
  • Isotretinoin 13-c/s-retinoic acid
  • cytotoxic agents include, but are not limited to, arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®).
  • Trisenox® arsenic trioxide
  • asparaginase also known as L-asparaginase, and Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®.
  • LCMS data (also reported herein as simply MS) were recorded using a Waters System (Acuity UPLC and a Micromass ZQ mass spectrometer; Column: Acuity HSS C18 1.8-micron, 2.1 x 50 mm; gradient: 5-95 % acetonitrile in water with 0.05 % TFA over a 1.8 min period; flow rate 1.2 mL/min; molecular weight range 200-1500; cone Voltage 20 V; column temperature 50 °C). All masses reported are those of the protonated parent ions unless recorded otherwise.
  • HRMS methods A, B and C are referred to throughout as HRMS(A), HRMS(B), or HRMS(C), respectively.
  • Eluent A Water + 0.1 % formic acid.
  • Eluent B ACN + 0.04% formic acid.
  • Column: Acquity CSH 1.7 ⁇ 2.1x50mm. T 50°C.
  • Xantphos (0.1588 g, 0.269 mmol) was then added, followed by Pd 2 (dba) 3 (0.1212 g, 0.132 mmol).
  • the glass vessel was capped and immersed in a pre-heated oil bath. The mixture was heated at 92°C for 19 h. The mixture was filtered through 1 ⁇ PTFE filter, eluting with excess EtOAc, and the organics removed. The crude product was purified by silica gel chromatography (0-100% EtOAc/heptanes) to give 1-(2-chloropyrimidin-4-yl)-4,4- dimethylpyrrolidin-2-one (1.21 g, 80 % yield) as yellow solid.
  • Step 1 In a 25ml_ round-bottomed flask was added 2,4-dichloro-5-fluoropyrimidine (1.01 g, 6.05 mmol) and (S)-(+)-5-(trityloxymethyl)-2-pyrrolidinone (0.79 g, 2.21 mmol) in DMF (12 mL) to give an off white solution. The solution was cooled with an ice bath, and 95% NaH (252.4 mg, 10.52 mmol) was added in 1 portion (bubbling occurred). The reaction was stirred for 10 min, and then the ice bath was removed. The reaction stirred for 2 days at room temperature. The reaction was quenched slowly with water. The reaction mixture was poured into water and EtOAc.
  • Step 2 (S)-1-(2-Chloro-5-fluoropyrimidin-4-yl)-5-((trityloxy)methyl)pyrrolidin-2-one was dissolved in DCM (4 ml) and TFA (1 ml) and stirred overnight at room temperature. The reaction was concentrated to dryness to give (S)-1-(2-chloro-5-fluoropyrimidin-4-yl)-5- (hydroxymethyl)pyrrolidin-2-one (65.8 mg) which was taken on crude.
  • Step 1 To a 25 °C solution of (R)-5-(hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) in DCM (20 mL) was added imidazole (443 mg, 6.51 mmol) followed by TBSCI (851 mg, 5.65 mmol). Reaction was stirred at 25°C for 12 hr. Reaction was diluted with DCM and washed with sat. aq. NaHC0 3 .
  • Step 2 To a 25 °C suspension of NaH (126 mg, 3.14 mmol) in DMF (6.5 mL) was added a solution of (R)-5-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (600 mg, 2.62 mmol) in DMF (6.5 mL) followed by stirring at RT for 20 min. After this time, 2,4,5-trifluoropyrimidine (386 mg, 2.88 mmol) was added dropwise and reaction was stirred at 25 °C for 2 hr. The reaction was quenched with NH 4 CI (sat. aq.), diluted with EtOAc and washed with water.
  • NH 4 CI sat. aq.
  • Step 1 To a 25 °C solution of 4-(hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) in DCM (20 ml_) was added imidazole (443 mg, 6.51 mmol) followed by TBSCI (851 mg, 5.65 mmol). Reaction was stirred at 25 °C for 12 hr. LC/MS indicated reaction complete with only product noted. Reaction was diluted with DCM and washed with sat. aq. NaHC0 3 .
  • Step 2 To a 25°C suspension of NaH (73.2 mg, 1.831 mmol) in DMF (25 ml_) was added a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidin-2-one (350 mg, 1.526 mmol) in DMF (1 ml_) followed by stirring at RT for 20 min. After this time, 2,4,5-trifluoropyrimidine (195 mg, 1.678 mmol) was added dropwise, and reaction was stirred at 25 °C for 2 hr. The reaction was quenched with NH4CI (sat. aq.), diluted with EtOAc and washed with water.
  • NH4CI sat. aq.
  • Step 1 (S)-4-(1-(tert-butoxycarbonylamino)ethyl)-2-fluorobenzoic acid
  • the basic aqueous solution was extracted with 2 x 50 ml of (15% ethyl acetate in heptane) solution. Then to the basic aqueous solution was added 150 ml of ethyl acetate and with stirring acidified with 2M HCI solution to about pH 3. Then the ethyl acetate was extracted, and the acidic water extracted again with 100 ml of ethyl acetate.
  • Step 2 (S)-tert-butyl 1-(4-(cycloheptylcarbamoyl)-3-fluorophenyl)ethylcarbamate
  • Step 1 Preparation of ethyl 5-chloro-6-(2,2,2-trifluoroethoxy)nicotinate
  • Step 1 To a oven dried round bottom flask with stir bar was added 2-fluoro-4-(trifluoromethyl) benzaldehyde (5 g, 26.0 mmol), (R)-2-methylpropane-2-sulfinamide (3.47 g, 28.6 mmol) and DCE (52 mL). To this mixture was then added copper (II) sulfate (6.23 g, 39.0 mmol). The reaction mixture was heated in a preheated oil bath at 55 °C for 18 hours. The reaction mixture was filtered through a pad celite, washing the solids with DCE.
  • Step 2 To a solution of (R,E)-N-(2-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2- sulfinamide (7.3 g, 24.7 mmol) in CH2CI2 (247 mL) cooled to 0°C (water/ice bath) under nitrogen, was added 3M methyl magnesium bromide (33 mL, 99 mmol) in Et 2 0. Reaction mixture allowed to stir for 30 min at 0°C, then gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. Reaction mixture was cooled to 0°C then quenched with the slow addition of a saturated solution of NH 4 CI. Aqueous mixture extracted with EtOAc.
  • Step 1 To a mixture of 1 H-imidazole-4-carbaldehyde (3.71 g, 38.6 mmol), 1-chloro-4- iodobenzene (13.81 g, 57.9 mmol), (1 R,2R)-N1 ,N2-dimethylcyclohexane-1 ,2-diamine (1.10 g, 7.72 mmol), copper(l) iodide (0.368 g, 1.93 mmol) and cesium carbonate (25.2 g, 77 mmol) was added DMF (50 ml_). The reaction was sealed and heated to 110 °C for 18 hours.
  • Step 2 To a suspension of (S)-(-)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and 1-(4- chlorophenyl)-1 H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE (39 ml_) was added CuS0 4 (4.63 g, 29.0 mmol). The reaction mixture was heated at 60 °C for 18 hours in a oil bath. A dark brown suspension resulted. The reaction mixture was then cooled to RT, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated onto silica gel.
  • Step 3 To a solution of (S,E)-N-((1-(4-chlorophenyl)-1 H-imidazol-4-yl)methylene)-2- methylpropane-2-sulfinamide (1.69 g, 5.45 mmol) in DCM (27 ml_), cooled to -40°C (acetone/dry ice) under N 2 , was added 3M MeMgBr (7.27 ml, 21.8 mmol) in diethyl ether. Reaction mixture allowed to stir for 1 hr at -40 °C. Reaction mixture was quenched with the slow addition of a saturated solution of NH 4 CI and diluted with EtOAc.
  • Step 1 To a oven dried round bottom flask with stir bar was added 4-iodobenzaldehyde (3 g, 12.9 mmol), (R)-2-methylpropane-2-sulfinamide (1.72 g, 14.2 mmol) and DCE (26 mL). To this mixture was then added CuS0 4 (3.10 g, 19.4 mmol). Reaction mixture heated in a preheated oil bath to 55 °C for 18 hr. Filtered the slurry through a 0.45 ⁇ syringe filter washing solids with DCM. Combined filtrate was concentrated onto silica gel.
  • Step 2 To a solution of (R,E)-N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (2.54 g, 7.58 mmol) in DCM (76 mL), cooled to 0°C (water/icebath) under N2, was added 3M MeMgBr (10.1 mL, 30.3 mmol) in diethyl ether. Reaction mixture allowed to stir for 30 min at 0 °C. Then gradually allowed to warm to RT and stirred for 1 hr at RT. Reaction mixture was then quenched with the slow addition of a saturated solution of NH 4 CI and diluted with EtOAc.
  • Step 3 To a microwave vial with stir bar was added (R)-N-((S)-1-(4-iodophenyl)ethyl)-2- methylpropane-2-sulfinamide (400 mg, 1.139 mmol), 1-Methyl-4-1 H-pyrazoleboronic acid, pincacol ester (711 mg, 3.42 mmol), DME (6 mL), Na 2 C0 3 (5.69 ml, 11.4 mmol) (2.0 M aq) and PdCl 2 (dppf).CH 2 Cl 2 adduct (47 mg, 0.06 mmol). Vessel was capped and heated by microwave irradiation for 20 min at 100 °C.
  • Step 1 To a round bottom flask with stir bar was added 4-((S)-1 aminoethyl-2-chlorobenzoic acid HCI salt (1.05 g, 4.45 mmol) followed by the addition of THF (40 mL). To this solution was added DIEA (1.86 ml, 10.7 mmol). The reaction mixture becomes cloudy white followed by the addition of di-tert-butyl dicarbonate (1.07 g, 4.89 mmol). Resulting reaction mixture allowed to stir for 18 hours at room temperature. At which time the reaction mixture was then heated to 60 °C for 2 hours in an oil bath.
  • Step 2 To a round bottom flask with stir bar was added (S)-4-(1-(tert- butoxycarbonylamino)ethyl)-2-chlorobenzoic acid (450 mg, 1.20 mmol), (1 r,4r)-4- aminocyclohexanol (415 mg, 3.60 mmol), EDC HCI (460 mg, 2.40 mmol), 1 -hydroxy- 7-aza- benzotriazole (229 mg, 1.68 mmol) and DMF (6 ml_). To this mixture was then added DIEA (629 ⁇ _, 3.60 mmol). Reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with water and extracted with EtOAc.
  • Step 3 To a round bottom flask containing tert-butyl (S)-1-(3-chloro-4-((1 r,4S)-4- hydroxycyclohexyl carbamoyl)phenyl)ethylcarbamate (330 mg, 0.83 mmol) was added dioxane (6 ml_). To this mixture was then added HCI in dioxane (2.08 ml_, 8.31 mmol, 4 M). Resulting homogenous reaction mixture allowed to stir at RT for 1 hr whereupon a biphasic mixture resulted. To this mixtuew was added MeOH (2 ml_) and solution becomes homogenous again. Allowed mixture to stir 15 min at RT.
  • HRMS(A) m/z 395.1993 (M + H) + ; Rt 1.76 min.
  • HRMS(A) m/z 395.1997 (M + H) + ; Rt 1.82 min.
  • HRMS(A) m/z 409.2144 (M + H) + ; Rt 1.82 min.
  • HRMS(A) m/z 409.2151 (M + H) + ; Rt 1.88 min.
  • Example 29 Example 29
  • HRMS(A) m/z 416.1284 (M + H) + ; Rt 2.26 min.
  • HRMS(A) m/z 416.1293 (M + H) + ; Rt 2.27 min.
  • Peak 2 73.1 mg.
  • Retention time on analytical chiral column 4.652 min (8 min run time).
  • Peak 1 carried on in a method similar to those described for the preparation of Example 29 (reaction temperature 85°C).
  • the resulting regioisomers were separated via chiral HPLC on an AD column (20 ml/min, 21 x 250 mm) eluting 60/40 heptane/EtOH (v/v) to give product as a single diastereomer (Example 47).
  • Step 1 (S)-4-(1-Aminoethyl)-2-fluorobenzoic acid (2.08 g, 9.47 mmol) was dissolved in toluene (40 ml_) and methanol (20 ml_). Trimethylsilyl diazomethane in hexanes (2M, 7.10 ml_, 14.21 mmol) was added to the reaction mixture which immediately turned white. After 4 h, an additional 8 ml_ of trimethylsilyldiazomethane in hexanes was added, and the material stirred overnight. Then an additional 40 ml_ of toluene and 20 ml_ of methanol were added to the reaction to solubilize the reaction mixture.
  • Step 2 To a cooled (0°C) suspension of (S)-methyl 4-(1-aminoethyl)-2-fluorobenzoate hydrochloride (1.1556 g, 4.01 mmol) in THF (50 ml_) was added a solution of LAH in THF (2.0 M in THF, 6.0 ml_, 12.00 mmol), and the resulting white cloudy mixture was stirred at 0 °C for 1 h and then at room temperature for 2.5 h. The reaction mixture was cooled with an ice bath and quenched by addition of Na 2 S0 4 decahydrate/Celite (1 :1 by weight) until gas evolution ceased.
  • Step 3 1-(2,5-Dichloropyrimidin-4-yl)pyrrolidin-2-one (176.5 mg, 0.76 mmol), (S)-(4-(1- aminoethyl)-2-fluorophenyl)methanol (156.2 mg, 0.92 mmol), Hunig's base (0.8 ml_, 4.58 mmol) were combined in DMSO (3 ml) and heated in the microwave at 190°C for 25 min. Reaction mixture wet loaded to silica gel cartridge and purified by silica gel chromatography (0-100% EtOAc: heptane). DMSO still present so material lyophilized to a yellow gum (0.14 g).
  • Step 4 To a solution of (S)-1-(5-chloro-2-((1-(3-fluoro-4- (hydroxymethyl)phenyl)ethyl)amino)pyrimidin-4-yl)pyrrolidin-2-one (64.3 mg, 0.18 mmol) in DCM (5 ml_) was added Mn0 2 (690 mg, 7.94 mmol). The reaction was stirred at room temperature for 3 h. Reaction mixture filtered and rinsed with DCM.
  • Step 5 To a solution of (S)-4-(1-((5-chloro-4-(2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)ethyl)-2- fluorobenzaldehyde (assume theoretical yield from previous experiment, 32.2 mg, 0.09 mmol) and 1 -acetyl piperazine (44.7 mg, 0.35 mmol) in MeOH (2 mL) was added acetic acid (13 uL, 0.22 mmol). The mixture was shaken at room temperature for 40 minutes.
  • Example 53 Prepared using methods similar to those described for the preparation of Example 53.
  • the diastereomers were separated using CFC (Supercritical Fluid Chromatography) chiral purification, IC column (21 x 250 mm, 100ml/min), eluting with 35% EtOH in C0 2 isocratic, to obtain tert-butyl ((S)-1-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5- yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate and tert-butyl ((R)-1-(2-(((S)-1-(2- (4-chlorophenyl)thiazol-5-yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate.
  • CFC Supercritical Fluid Chromatography
  • Example 53 Prepared using methods similar to those described for the preparation of Example 53.
  • the diastereomers were separated using Reverse Phase Chromatography, to obtain tert-butyl ((S)-1-(2-(((S)-1-(5-(4-chlorophenyl)isoxazol-3- yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate and tert-butyl ((R)-1-(2-(((S)-1-(5- (4-chlorophenyl)isoxazol-3-yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate.
  • Example 53 Prepared using methods similar to those described for the preparation of Example 53.
  • the diastereomers were separated using CFC (Supercritical Fluid Chromatography) chiral purification, AD column (21 x 250 mm, 100ml/min), eluting with 40% EtOH in C0 2 isocratic, to obtain tert-butyl ((S)-1-(2-(((S)-1-(1-(4-chlorophenyl)-1 H-imidazol-4- yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate and tert-butyl ((R)-1-(2-(((S)-1-(1- (4-chlorophenyl)-1 H-imidazol-4-yl)ethyl)amino)pyrimidin-4-yl)-5-oxopyrrolidin-3-yl)carbamate.
  • CFC Supercritical Fluid Chromatography
  • Peak 1 was carried on in a method similar to that described for the preparation of Example 74 to prepare Example 81.
  • Example 85 Peak 1 : 17.7 mg.
  • RP- HPLC Rt 2.28 min (Gradient: 2 to 98% B in 4.4 min - flow 1 mL/min.
  • Example 86 Peak 2: 19.6 mg.
  • Example 87 Peak 1: 23 mg (off-white foam).
  • Example 88 Peak 2: 23 mg (off-white foam).
  • Example 92 Peak 4: 5 mg.
  • H NMR 400 MHz, CD 3 OD
  • ⁇ 8.22 - 8.00 m, 1H
  • 7.98-7.83 m, 2H
  • 7.47 - 7.36 m, 2H
  • 5.32 - 5.17 m, 1H
  • 4.69 - 4.57 m, 1H
  • Example 96 Peak 1 : 12.8 mg.
  • Example 97 Peak 2: 21.9 mg.
  • Eluent A Water + 3.75 mM ammonium acetate + 0.1 % formic acid.
  • Eluent B ACN + 0.08% formic acid.
  • Column: Acquity CSH 1.7 ⁇ 2.1x50mm. T 50°C).
  • HRMS(B or C) m/z 446.0905 (M + H) + .
  • Step 1 To a RBF with stir bar was added (R)-1-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5- yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)pyrrolidin-2-one (30 mg, 0.067 mmol) followed by the addition of DCM (1 mL) under nitrogen. To this cold solution was added DIEA (0.047 mL, 0.268 mmol) followed by the addition of MsCI (0.016 mL, 0.208 mmol). Reaction mixture stirred for 1 hr at 25°C. Reaction was washed with sat. aq. NaHC0 3 .
  • Step 2 To a 2.5 ml microwave vial containing ((R)-1-(2-(((S)-1-(2-(4-chlorophenyl)thiazol-5- yl)ethyl)amino)-5-fluoropyrimidin-4-yl)-5-oxopyrrolidin-2-yl)methyl methanesulfonate (20 mg, 0.038 mmol) in DMF (600 ⁇ _) was added sodium azide (25 mg, 0.385 mmol). Resulting reaction was sealed and mixture was allowed to stir at 80°C for 3 hr. Reaction was diluted with EtOAc and washed with water.
  • Step 3 To a round bottom flask containing (R)-5-(azidomethyl)-1-(2-(((S)-1-(2-(4- chlorophenyl)thiazol-5-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)pyrrolidin-2-one (14 mg, 0.030 mmol) was added THF (1 ml_) and trimethylphosphine (in THF) (0.059 ml_, 0.059 mmol). Resulting reaction mixture allowed to stir 2 hr at RT. Reaction was quenched with sat. aq. NaHC0 3 , and extracted with EtOAc 3 times.
  • Mutant IDH1 biochemical assay LC-MS detection of 2-HG.
  • Mutant IDH1 R132H catalytic activity was monitored using the quantitative liquid chromatography/mass spectrometry (LC-MS) detection of 2-HG, a product of the NADPH-dependent alpha-KG reduction reaction.
  • LC-MS quantitative liquid chromatography/mass spectrometry
  • biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Costar, Cat. No. 781201) using a final reaction volume of 30 ⁇ _ and the following assay buffer conditions: 50 mM HEPES pH 7.4, 10 mM MgCI 2 , 50 mM KCI, 1 mM DTT, 0.02% BSA, 5 uM NADPH and 100 uM alpha-KG.
  • the final reaction mixture contained 3.3% DMSO and inhibitors with concentrations ranging 0.02 - 50 ⁇ .
  • the IDH1 enzyme was used at a final concentration of 0.25 nM.
  • the reaction mixtures were quenched by the addition of 10 ⁇ _ of 16% formic acid containing 800 nM of 5-carbon labeled 3 C-2-HG).
  • the protein was then precipitated by the addition of 2.5 volumes of acetonitrile followed by centrifugation (3000 x g, 20 minutes). The concentration of 2-HG in the resulting supernatants was measured by LC- MS (see below).
  • Nicotinamide was eluted at 1 ml/min using a 85-5% B gradient over 0.9 minutes (Agilent 1200SL LC system, Thermofisher LX-4 autosampler) and analyzed by multiple reaction monitoring (MRM) on a API4000 QTrap mass spectrometer (ABSciex, Framingham, MA) in the positive electrospray ionization (ESI+) mode.
  • MRM multiple reaction monitoring
  • API4000 QTrap mass spectrometer API4000 QTrap mass spectrometer
  • the mass transition for 2-HG and 3 C-2-HG were 147 ⁇ 129 and 152 ⁇ 134, respectively.
  • the relative responses (2-HG/ 3 C-2-HG) were measured at varied inhibitor concentrations and used to calculate inhibitory IC50 values (normalized IC50 regression curves).
  • IDH1 R132H was cloned into the pET47b vector using the restriction sites Xmal/Xhol which yields an in frame, N-terminal His 6 site cleavable with Prescission protease.
  • This plasmid was transformed into RosettaTM 2(DE3) (Novagen) cells.
  • 8L of cells were grown in Terrific Broth (Teknova) (plus kanamycin 50 ⁇ g/mL and chloramphenicol 34 ⁇ g/mL) at 37°C to an OD 6 oo of 0.8 and protein expression was induced by addition of IPTG to a concentration of 0.20mM. The cells were subsequently grown for 18 hours at 18°C.
  • IDH1 (R132H) Prescission Cut Protein (N-term gpg is cloning artifact)
  • the cells were homogenized in Lysis Buffer with protease inhibitors (complete EDTA- free protease inhibitor tablets (Roche), 1 tablet per 50mL of buffer), DNAse, and to 200 ⁇ PMSF and lysed in a Microfluidizer. After lysis, Triton X-100 was added to 0.1 % and stirred at 4°C for 30 minutes.
  • the cleared lysate was loaded onto 2 x 5mL HisTrap FF crude columns (GE), washed extensively with Lysis Buffer until the A 2 so stabilized and eluted with Ni Elution Buffer. Peak eluted fractions were concentrated to 30ml_, EDTA was added to 1 mM and GST-Prescission protease was added to ⁇ / ⁇ of protein.
  • the sample was dialyzed against 2L Dialysis Buffer I (MWCO 50kDa) for 6 hours at 4°C then dialyzed against 2L of Dialysis Buffer II for at least 6 more hours.
  • GST-Prescission cleaved sample was rocked with Glutathione Agarose Beads, spun down and then the supernatant was loaded through a 5ml_ HisTrap HP column and the flow through was collected.
  • the IDH1 (R132H) mutant catalyzes the reduced form of NADP+ (NADPH) and a- ketoglutarate (a-KG) to form nicotinamide adenine dinucleotide phosphate (NADP+) and R (-)- 2-hydroxyglutarate (2HG).
  • the reaction can be monitored kinetically by following the oxidation of NADPH to NADP+ which is measured using fluorescence, excitation at 355 nm and emission at 530 nm. Reactions were monitored using the Perkin-Elmer Envision, Model 2101. More specifically, the biochemical reactions were performed at room temperature in 384-well Greiner flat-bottom plates (Cat. No.
  • Embodiment 1 A compound according to formula (I):
  • Rl a is H, methyl, or ethyl
  • R 1 D is H, cyano, -COOC-1.4 a 'M > C 3.6 cycloalkyi, C-1.3 haloalkyi, optionally substituted C-1.3 alkyl, optionally substituted aryl or optionally substituted heteroaryl, wherein said C-1.3 alkyl is optionally substituted with one substituent selected from the group consisting of: OH, N H2, C-1.3 alkoxy, and optionally substituted phenyl, and said aryl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, C-1.3 alkyl, C-1.3 haloalkyi,
  • R1 a and R " " 3 are joined together forming a C 3.6 cycloalkyi or a 4 to 6 membered heterocyclic ring;
  • R1° is H, methyl or ethyl and R D is H, OH, C ⁇
  • R ⁇ E is H, methyl or ethyl
  • R F is H, OH, NH 2 , -NHCOO-t-butyl or C ⁇
  • R2 and R ⁇ are each independently H, deuterium, halo, C-1.3 alkyl or C-1.3 haloalkyi;
  • R4 is:
  • ring A is a 6 membered heteroaryl ring having one to three nitrogen atoms
  • ring B is a 5 membered heteroaryl ring having one to four heteroatoms each independently selected from the group consisting of N, O and S;
  • X is N or CH; each is independently hydrogen, halo, C-1.3 alkyl or C-1.3 haloalkyi; n is 1 , 2 or 3;
  • R R is H, halo, C-1.3 haloalkyi, optionally substituted C-
  • R 6 is hydrogen, ⁇ .3 haloalkyi, optionally substituted C ⁇ _Q alkyl, optionally substituted C3.5 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -SC>2R Ra or -C(0)NHR Ra , said C-
  • R ⁇ b is optionally substituted C3.6 cycloalkyi, optionally substituted phenyl or optionally substituted 5 or 6 membered heterocyclic, said phenyl is optionally substituted with one to three substituents each independently selected from the group consisting of: halo, hydroxyl, cyano, C-
  • each R is independently selected from the group consisting of H and C-1.3 alkyl; provided the compound is not (S)-1-[6-Chloro-2-[[1-(4-fluorophenyl)ethyl]amino]pyrimidin-4-yl]pyrrolidin-2- one; or a pharmaceutically acceptable salt thereof.
  • Embodiment 2 The compound according to embodiment 1 wherein: R a is H, methyl, or ethyl;
  • R " " 3 is H, cyano, -COOC-1.4 alkyl, C 3.5 cycloalkyi, C-1.3 haloalkyi, optionally substituted C-1.3 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
  • R1 c is H, methyl or ethyl
  • Rid is H, OH, C-1.3 alkoxy, C 3.5 cycloalkyi, NH2 or C-1.3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, NH2, and C-1.3 alkoxy; and
  • R ⁇ e is H, methyl or ethyl and R f is H, OH, NH 2 or C-
  • Embodiment 3 The compound according to embodiment 2 wherein R ⁇ a is H or methyl; R " " 3 is H, cyano or C-1.3 alkyl optionally substituted with one substituent selected from the group consisting of: OH, NH2, C ⁇
  • R ⁇ e and R ⁇ are all H; or a pharmaceutically acceptable salt thereof.
  • Embodiment 4 The compound according to embodiment 3 wherein R " " 3 is H or methyl; or a pharmaceutically acceptable salt thereof.
  • Embodiment 5 The compound according to embodiment 2 wherein R ⁇ c is H or methyl; Rld is H, OH, NH2 or C-
  • Embodiment 6 The compound according to embodiment 2 wherein R ⁇ is H, OH or NH2 and R ⁇ a , Rib R1 c , R ⁇ d and R ⁇ e are all H; or a pharmaceutically acceptable salt thereof.
  • Embodiment 7. The compound according to embodiment 2 wherein R ⁇ a is H; R " " 3 is -CH2- phenyl; R ⁇ c is H; R ⁇ d is OH; R ⁇ e is H; and R ⁇ is H; or a pharmaceutically acceptable salt thereof.
  • Embodiment s The compound according to embodiment 2 wherein R " " 3 and R ⁇ are joined together forming an ethylene bridge and R ⁇ 3 , R ⁇ c , Rid and R ⁇ e are all H; or a
  • Embodiment 9 The compound according to any one of embodiments 1-8 wherein R2 and R3 are each independently hydrogen or halo; or a pharmaceutically acceptable salt thereof.
  • Embodiment 10 The compound according to any one of embodiments 1-9 wherein R2 is H and R3 is H, fluoro or chloro; or a pharmaceutically acceptable salt thereof.
  • Embodiment 11 The compound according to any one of embodiments 1-9 wherein R ⁇ is H, fluoro or chloro and R3 is H; or a pharmaceutically acceptable salt thereof.

Abstract

L'invention concerne une formule (I) : (I) ou un sel pharmaceutiquement acceptable de celle-ci, où R1a-R1f, R2, R3 et R4 sont décrits ici. L'invention concerne également des compositions contenant un composé de formule (I) et l'utilisation de tels composés dans l'inhibition de protéines IDH mutantes ayant une activité néomorphique. L'invention concerne en outre l'utilisation d'un composé de formule (I) dans le traitement de maladies ou de troubles associés à de telles protéines IDH mutantes comprenant, mais sans y être limitées, des troubles de la prolifération cellulaire, tels que le cancer.
PCT/IB2014/060007 2013-03-22 2014-03-20 1-(2-(éthylamino)pyrimidin-4-yl)pyrrolidin-2-ones en tant qu'inhibiteurs du mutant idh WO2014147586A1 (fr)

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US9187453B2 (en) * 2012-03-28 2015-11-17 Takeda Pharmaceutical Company Limited Heterocyclic compound
US11512060B2 (en) 2013-09-06 2022-11-29 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10590093B2 (en) 2013-09-06 2020-03-17 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10961205B2 (en) 2013-09-06 2021-03-30 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US10173989B2 (en) 2013-09-06 2019-01-08 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole derivatives as immunomodulators
US11465976B2 (en) 2015-03-10 2022-10-11 Aurigene Discovery Technologies Limited 1,2,4-oxadiazole and thiadiazole compounds as immunomodulators
US10781189B2 (en) 2015-03-10 2020-09-22 Aurigene Discovery Technologies Limited 1,2,4-Oxadiazole and thiadiazole compounds as immunomodulators
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US10253041B2 (en) 2015-07-27 2019-04-09 Eli Lilly And Company 7-phenylethylamino-4H-pyrimido[4,5-d][1,3]oxazin-2-one compounds and their use as mutant IDH1 inhibitors
WO2017140758A1 (fr) 2016-02-19 2017-08-24 Debiopharm International S.A. 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
AU2017239295B2 (en) * 2016-03-22 2020-01-02 Shanghai Haihe Pharmaceutical Co., Ltd. Compound having mutant IDH inhibitory activity, preparation method and use thereof
EA037974B1 (ru) * 2016-03-22 2021-06-18 Шанхай Хайхэ Фармасьютикал Ко., Лтд. Соединение, имеющее мутантную idh ингибирующую активность, способ его получения и применения
US10682352B2 (en) 2016-03-22 2020-06-16 Shanghai Haihe Pharmaceutical Co., Ltd. Compound having mutant IDH inhibitory activity, preparation method and use thereof
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CN107216312A (zh) * 2016-03-22 2017-09-29 上海海和药物研究开发有限公司 一种具有突变型idh抑制活性的化合物、其制备方法及用途
WO2017162133A1 (fr) * 2016-03-22 2017-09-28 上海海和药物研究开发有限公司 Composé ayant une activité inhibitrice de l'idh mutée, son procédé de préparation et son utilisation
US10696665B2 (en) 2016-06-06 2020-06-30 Eli Lilly And Company Mutant IDH1 inhibitors
CN107556366A (zh) * 2016-06-30 2018-01-09 上海海和药物研究开发有限公司 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途
WO2018001332A1 (fr) * 2016-06-30 2018-01-04 上海海和药物研究开发有限公司 Composé ayant une activité inhibitrice contre l'isocitrate déshydrogénase mutante, son procédé de préparation et son utilisation
WO2018095344A1 (fr) * 2016-11-24 2018-05-31 Shanghai Meton Pharmaceutical Co., Ltd Inhibiteur de l'isocitrate déshydrogénase (idh)
US11939306B2 (en) 2017-09-29 2024-03-26 Curis, Inc. Crystal forms of immunomodulators
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US11013733B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mlDH-1)
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