WO2013005157A1 - Dérivés de sulfone et leur utilisation en tant que modulateurs de pkm2 pour le traitement du cancer - Google Patents

Dérivés de sulfone et leur utilisation en tant que modulateurs de pkm2 pour le traitement du cancer Download PDF

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WO2013005157A1
WO2013005157A1 PCT/IB2012/053353 IB2012053353W WO2013005157A1 WO 2013005157 A1 WO2013005157 A1 WO 2013005157A1 IB 2012053353 W IB2012053353 W IB 2012053353W WO 2013005157 A1 WO2013005157 A1 WO 2013005157A1
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alkyl
substituted
unsubstituted
alkynyl
alkenyl
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Gagan Kukreja
Samiron Phukan
Jawahar KODAM
Dattatray Maruti More
Mahesh Vilas URAVANE
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D237/30—Phthalazines
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
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    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is related to novel compound of the general formula (I) ,
  • Tumor cells unlike normal cells, use aerobic glycolysis for glucose metabolism (referred to as the Warburg effect) and this step is essential for tumorigenesis. Additionally, cancer cells show preferential utilization of glucose (aerobic glycolysis) and reduced oxidative phosphorylation (mitochondrial ETC). Cancer cells utilize a very small fraction of glucose for oxidative phosphorylation (and the subsequent generation of CO2). The majority goes towards macromolecular synthesis, a property seen in fetal cells as well. Cancer cells thus show a distinct reprogramming of metabolic pathways as compared to normal cells (Mazurek et al., Semin. Cancer Biol., 2005, 15, p. 300).
  • a key enzyme in the metabolism of glucose is pyruvate kinase. It catalyzes the conversion of phosphoenol pyruvate (PEP) to pyruvate and in the process generates energy in the form of adenosine triphosphate (ATP).
  • PEP phosphoenol pyruvate
  • ATP adenosine triphosphate
  • Humans possess four isoforms of PK L: Liver; R: RBC; Ml : adult tissues; M2: fetal tissues).
  • PKM1 and PKM2 are splice variants and differ in one exon. PKM2 is present in fetal tissues as well as adult tissues (Bluemlein et al., Oncotarget, 2011 , 2(5), p. 393-400).
  • Cancer cells are known to harbour both dimeric as well as the tetrameric forms of PKM2 (Mazurek et al., Semin. Cancer Biol., 2005, 15, p. 300).
  • Dimeric (less active) form allows synthesis of amino acids, macromolecules, etc.
  • Accumulation of fructose- 1 ,6-bisphosphate (FBP) leads to tetramerization which in turn leads to enhanced formation of pyruvate and lactate.
  • FBP fructose- 1 ,6-bisphosphate
  • Phosphorylation of PKM2 by tyrosine kinases e.g.
  • Bcr-Abl, FGFR1 leads to retention of PKM2 in dimeric form and subsequent lack of pyruvate kinase activity (Christofk et al., Nature, 2008, 452(7184), p. 181- 186; Hitosugi et al., Sci Signal, 2009, 2(97), ra73).
  • the tetrameric PKM2 is allosterically activated by fructose- 1 ,6-bis-phosphate (FBP) through binding at the flexible loop region near the dimer-dimer interface of the tetramer.
  • FBP fructose- 1 ,6-bis-phosphate
  • PKM1 although has high affinity for PEP, is not bound by FBP.
  • the glycolytic intermediates are channelized towards macromolecular synthesis by the two activity states of PKM2.
  • PKM2 In the low activity state, PKM2 cannot efficiently catalyze the conversion of PEP to pyruvate and this leads to the accumulation of glycolytic intermediates. These are then utilized for synthesis of amino acids, nucleic acids, etc.
  • concentration of FBP in the cell reaches a certain level
  • the dimeric low activity PKM2 is converted to a tetrameric high activity state. In this conformation, PKM2 rapidly converts PEP to pyruvate and generates energy in the form of ATP.
  • PKM2 In cancer cells, PKM2 is phosphorylated (by tyrosine kinases) and is maintained in its dimeric low activity state. It can oscillate between the low and high activity state depending upon the phosphorylation status and the intracellular concentration of FBP.
  • PKM2 The function of PKM2 is thought to be critical for cancer cell survival and for the sustenance of the Warburg effect. (Vander Heiden et al., Science, 2009, 324, p. 1029; Ferguson and Rathmell, Trends Biochem. Sci., 2008, 33, p. 359). Activating PKM2 would starve cancer cells of building blocks essential for survival. In human lung cancer cells, accumulation of reactive oxygen species (ROS) was shown to lead to inhibition of PKM2 activity by oxidation of Cys358 (Anastasiou et al., Science, 201 1 , 334(6060), p. 1278-83).
  • ROS reactive oxygen species
  • the tumor suppressor protein DAPK (Death Associated Protein Kinase) has been shown to bind to and activate PKM2 function. Binding of DAPK to PKM2 stabilizes the later in the active tetrameric form. Inactivation of DAPK in most cancers allows cancer cells to retain PKM2 in the inactive dimeric form (Mor et al., Oncogene, 2012, 31 (6), p. 683-93; Erol Cell Cycle, 2012, 1 1 (8)).
  • DAPK Death Associated Protein Kinase
  • Nuclear dimeric PKM2 has been shown to regulate the activity of transcription factors such as HIF- la (Luo et al., Cell, 2011 , 145(5), p. 732-44), b-catenin (Yang et al., Nature, 201 1 , 480(7375), p. 118- 122) and STAT3 (Gao et al., Mol. Cell, 2012, 45(5), p. 598-609). This is an additional mechanism by which dimeric PKM2 can promote tumorigenesis.
  • PKM2 modulators can be used for treatment of diseases including but not limited to cancer and other diseases occurring as a result of cell proliferation and/or deregulation of PKM2 activity.
  • 'n' and 'm' are the integers independently selected from 0, 1 , 2 and 3, 'q' is an integer selected from 0, 1 and 2; ring 'A' is selected from
  • D and E are independently selected from CR 5 , S, O and NR 5a ;
  • G and G' are independently selected from N and CH, such that when either of G or G' is selected as CH, being a part of ring, hydrogen of CH may be substituted with Re or R 7 ;
  • R 5 is selected from hydrogen, substituted or unsubstituted alkyl, halogen, and hydroxy
  • R 5a is selected from hydrogen, and substituted or unsubstituted alkyl
  • the present invention provides a pharmaceutical composition containing the compound of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N- oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment of a disease responsive to activation of human PKM2.
  • the present invention provides the compound of general formula (I) for use in treating a disease responsive to activation of human PKM2.
  • 'n' and 'm' are the integers independently selected from 0, 1 , 2 and 3, 'q' is an integer selected from 0, 1 and 2; ring 'A' is selected from
  • D and E are independently selected from CR 5 , S, O and NR 5a ;
  • G and G' are independently selected from N and CH, such that when either of G or G' is selected as CH, being a part of ring, hydrogen of CH may be substituted with R 6 or R 7 ;
  • R 5 is selected from hydrogen, substituted or unsubstituted alkyl, halogen, and hydroxy;
  • R 5a is selected from hydrogen, and substituted or unsubstituted alkyl
  • R 8 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
  • R 8a is selected from alkyl, alkenyl, alkynyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;
  • a 1 is selected from the group consisting of O and S.
  • ring ⁇ is selected from
  • R 5 , R 5a , R 6 , and R 7 are as defined above.
  • ring 'A' is selected from
  • R 5 , R 5a , R 6 , and R 7 are as defined above;
  • alkyl means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms.
  • the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, and n-hexyl.
  • alkenyl' means an alkyl group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one double bond.
  • alkenyl include, but are not limited to, ethylene, propenyl, isopropenyl, n-butenyl, sec-butenyl, isobutenyl, tert-butenyl, pentenyl, isopentenyl, hexenyl, and the like.
  • alkynyl' as used herein means an alkyl group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one triple bond.
  • alkynyl include, but are not limited to propynyl, isopropynyl, n-butynyl, sec-butynyl, isobutynyl, tert-butynyl, pentynyl, isopentynyl, hexynyl, and the like.
  • 'Alkyl', 'alkenyl' or 'alkynyl' as defined hereinabove may be substituted or unsubstituted with one or more substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, cycloalkyl, hereroaryl, R 8 A !
  • the term 'perhaloalkyl' used herein means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl and the like.
  • 'cycloalkyl' as used herein, means a monocyclic, bicyclic, or tricyclic non- aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
  • bicyclic ring systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, and octahydro- lH-indene.
  • Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non- adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 7 ]nonane and tricyclo[3.3.1.1 3 7 ]decane (adamantane) .
  • cycloalkyl also include spiro systems wherein one of the ring is annulated on a single carbon atom such ring systems are exemplified by spiro [2.5] octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2, 1 '-cyclopentane] , hexahydro-2'H- spiro [cyclopropane- 1 , 1 '-pentalene] .
  • cycloalkenyl as used herein, means cycloalkyl group as defined hereinabove containing 3 to 20 carbon atoms and containing at least one double bond.
  • Representative examples of cycloalkenyl include, but are not limited to cyclopentenyl and cyclohexenyl.
  • 'aryl' refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
  • aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene.
  • the said aryl group also includes aryl rings fused with heteroaryl or heterocyclic rings such as 2,3-dihydro-benzo[l ,4]dioxin-6-yl, 2,3- dihydro-benzo[ 1 ,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro- benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3- dihydro- lH-indol-5-yl, 2,3-dihydro- lH-indol-4-yl, 2,3-dihydro- lH-indol-6-yl, 2,3- dihydro- lH-indol-7-yl, benzo[l ,3]dioxol-4-yl, benzo[l ,3]dio
  • heteroaryF refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1. 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include pyridyl, 1 -oxo- pyridyl, furanyl, thienyl, pyrro!yl, oxazolyl, oxadiazolyl, imidazolyl, fhiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, beiizimidazolyl, benzothiazolyl, benzothiadiazolvl.
  • 'heterocycle' or 'heterocyclic' as used herein, means a cycloalkyl group wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2 )-, -S(O)-, - N(R m )-, -Si(R m )R n -, wherein, R m and R n are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl.
  • the heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl; azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3- dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothien
  • bicyclic heterocycle include, but are not limited to 1 ,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro- l ,4- benzodioxinyl, 2,3-dihydro- l -benzofuranyl, 2,3-dihydro- l -benzothienyl, 2,3- dihydro- lH-indolyl and 1 ,2,3,4-tetrahydroquinolinyl.
  • the term heterocycle also include bridged heterocyclic systems such as azabicyclo[3.2. 1 ]octane, azabicyclo[3.3. 1 ]nonane and the like.
  • Heterocyclyl' group may be substituted or unsubstituted on ring carbons with one or more substituents selected independently from the group consisting halogen, nitro, cyano, oxo, alkyl, alkenyl, alkynyl, aryl, heteroaryl, R 8 A !
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • 'halo' or 'halogen' means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.
  • phrases 'pharmaceutically acceptable salt' is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • a range of the number of atoms in a structure is indicated (e.g., a C i to C20 alkyl, C2 to C20 alkenyl, C3 to C20 alkynyl etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1- 6 carbon atoms e.g., C i to Ce
  • 2-6 carbon atoms e.g. , C2 to Ce
  • 3-6 carbon atoms e.g.
  • any chemical group e.g., alkyl, alkenyl, etc.
  • any chemical group e.g., alkyl, alkenyl, etc.
  • referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, and/ or 6 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms as appropriate).
  • a compound its stereoisomers, racemates, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compound of general formula (I) is selected from:
  • the compound of general formula (I) where all the symbols are as defined earlier can be prepared by method given in Scheme 1 or examples. Representative procedures are shown below, however; the disclosure should not be construed to limit the scope of the invention arriving at compound of formula (I) as disclosed hereinabove.
  • the present invention provides a method of preparation of compound of formula (I) by coupling the compound of formula (III), wherein meaning of R 1 , R 2 , n, m and ring 'A' are as defined above and L represents a suitable leaving group such as chloro, bromo, iodo, methanesulfonyloxy and trifluoromethanesulfonyloxy group, with compound of formula (II) and (V) followed by subsequent oxidation of compound of formula (VI).
  • a compound of formula (III) can be conveniently coupled under standard C(aryl)-S bond formation conditions with an appropriate benzenethiol of formula (II) in presence of suitable base, for example, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium tert-butoxide or sodium tert- butoxide, ⁇ , ⁇ -diisopropylethylamine in an appropriate solvent, for example, toluene, 1 ,2-dimethoxyethane, 1 ,4-dioxane and at a temperature in the range, for example, 10 to 150°C, conveniently at or near 100°C in presence of suitable metal catalyst, e.g.
  • suitable base for example, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, potassium tert-butoxide or sodium tert- butoxide, ⁇ , ⁇ -diisopropylethylamine in an appropriate solvent, for example, toluene, 1 ,2-d
  • an appropriate palladium source such as palladium acetate, £rfe(dibenzylideneacetone)dipalladium(0) and appropriate ligand such as bis(2-diphenylphosphinophenyl)ether, l-dicyclohexylphosphino-2-di-tert-butyl phosphino ethylferrocene, l , l'-bis(di-tert-butylphosphino)ferrocene, 9,9-dimethyl- 4,5-bis(diphenylphosphino)xanthene to afford compound of formula (IV).
  • an appropriate palladium source such as palladium acetate, £rfe(dibenzylideneacetone)dipalladium(0)
  • appropriate ligand such as bis(2-diphenylphosphinophenyl)ether, l-dicyclohexylphosphino-2-di-tert-butyl phosphino
  • Oxidizing agents such as hydrogen peroxide /glacial acetic acid, hydrogen peroxide/trifluoroacetic acid, hydrogen peroxide/potassium permanganate, hydrogen peroxide/p-toulenesulfonylimidazole, urea.hydrogen peroxide/trifluoroacetic acid, magnesium monoperoxyphthalate, potassium monopersulfate, m-chloroperbenzoic acid and other organic peracids and the like can be employed for the oxidation.
  • the intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent under vacuum and re- crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloro me thane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichlorome thane, ethyl acetate, hexane, methanol, acetone and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloro me thane, ethyl acetate, acetone or their combinations
  • the purification methods such as column chromatography (e.g. flash
  • Salts of compound of formula (I) are obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences, volume 66, page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H. Einrich Stahland Camille G. wasmuth, Wiley- VCH (2002).
  • a suitable solvent for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, their tautomeric forms, their stereoisomers, their analogs, their prodrugs, their isotopes, their N-oxides, their metabolites, their pharmaceutically acceptable salts, polymorphs, solvates, optical isomers, clathrates, or co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment of a disease responsive to activation of human PKM2.
  • the present invention provides the Modulators of PKM2 described herein can be used for treatment of various cancers.
  • cervical carcinoma hepatocellular carcinoma (Iqbal and Bamezai PLoS One, 2012, 7(5), e36764), glioblastoma (Yang et al., Nature, 201 1 , 480(7375), p. 118-22), squamous cell carcinoma (Wong et al., Int. J. Cancer, 2008, 123, p. 251-257), renal cell carcinoma (Ashrafian et al., Cancer Res., 2010, 70(22) p. 9153-65), colon cancer, ovarian cancer, multiple myeloma, melanoma (Goldberg and Sharp, J. Exp. Med., 2012, 209(2), p. 217-24).
  • the compound of present invention will be useful in the treatment of all types of leukemias, lymphomas, solid tumors such as sarcoma and carcinoma (liposarcoma, fibrosarcoma, myxosarcoma, chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, mesothelioma, rhabdomyosarcoma, pancreatic cancer, cervical cancer, uterine cancer, bladder cancer, glioma, medulloblastoma, astrocytoma, and retinoblastoma).
  • PKM2 is known to be expressed in adipose tissue.
  • PKM2 modulators could be used for the treatment of type II diabetes.
  • Autoimmune disorders that could be treated with PKM2 modulators include but are not limited to Crohn's disease, ulcerative colitis, multiple sclerosis, rheumatoid arthritis, systemic lupun erythematosus, autoimmune liver diseases, autoimmune diabetes, autoimmune neutropenia, pernicious anemia, and Sjorgen's syndrome.
  • Proliferative diseases include but are not limited to cancer, benign prostatic hyperplasia, lymphoproliferative disorders, and psoriasis
  • Step 1 3,6-dibromobenzene- l ,2-diamine (lb) 4,7-dibromobenzo[c]- l ,2,5-thiadiazole (la) was dissolved (2 g, 6.8 mmol) in tetrahydrofuran (20 ml) and ethanol (45 ml) under stirring. C0CI2 (10 mg, 0.07 mmol) was added followed by portion wise addition of sodium borohydride (708 mg, 18.73 mmol), during an interval of 30 min. The reaction was continued at reflux temperature till the consumption of starting material. The reaction mixture was cooled at room temperature and quenched with water (50 ml).
  • Step 2 4,7-dibromo- lH-benzo[d]imidazole (lc) Diamine ( lb) (1 g, 3.76 mmol) was dissolved in methanol (20 ml) under stirring. To the resulting solution triethyl orthoformate (0.748 ml, 4.5 mmol) and sulfamic acid ( 18 mg, 0.18 mmol) was added. The resulting reaction mixture was stirred overnight. Solvent was evaporated from the reaction mass to obtain the residue which was rinsed with ether, dried under air to afford (950 mg, 50% yield for 2 steps) 4,7-dibromo- lH-benzo[d]imidazole ( lc) as a yellow solid.
  • Tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ) (24.88 mg, 0.027 mmol), xantphos (31.41 mg, 0.054 mmol) and 4-methoxybenzenethiol (0.2 ml, 1.63 mmol) were added and the reaction mixture was again degassed twice more. The reaction mixture was heated to reflux for 18 hour. After the completion of reaction, the reaction mixture allowed to reach ambient temperature, filtered and concentrated.
  • Step 4 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazole (1)
  • Step 1 4-bromo-7-((4-methoxyphenyl)thio)benzo[c] [ l ,2,5]thiadiazole (3a)
  • Step 2 4-((2,3-dihydrobenzo[b][ l ,4]dioxln-5-yl)thio)-7-((4- methoxyphenyl)thio)benzo[c] [ l ,2,5]thiadiazole (3b)
  • Step 3 4-((2,3-dihydrobenzo[b] [ l ,4]dioxin-5-yl)sulfonyl)-7-((4- methoxyphenyl)sulfonyl) benzo[c][ l ,2,5]thiadiazole (3)
  • Title compound 4-((2,3-dihydrobenzo[b][ l ,4]dioxin-5-yl)sulfonyl)-7-((4- methoxyphenyl) sulfonyl)benzo[c] [l ,2,5]thiadiazole (3) was prepared by fallowing the oxidation of intermediate (3b) as described for (1).
  • Example 4 Compounds (4) and (5) were prepared in analogous manner as that of example 3 from appropriate intermediates.
  • 3,6-dibromobenzene- l,2-diamine (2) (1.0 g, 3.76 mmol) was dissolved in 12 ml of acetic acid, to which a solution of NaN02 (290 mg, 4.21 mmol) in 10 ml of 3 ⁇ 40 was added. After 20 minutes of stirring at room temperature, the precipitate so obtained was collected by filtration and washed with water to afford 4,7-dibromo- lH-benzo[d] [l ,2,3]triazole (6a) ( 360 mg, 25 %) as a solid.
  • Step 3 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d][ l ,2,3]triazole (6)
  • Step 3 4,7-bis((4-methox ⁇ Dheiiyl)sulfonyl)- lH-mdazole (7)
  • Title compound 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-indazole (7) was prepared by fallowing the oxidation of intermediate (7c) as described for (1).
  • Step 1 (2-nitro- 1 ,4-phenylene)bis((4-methoxyphenyl)sulfane) (9b)
  • Step 2 4,4'-(2-nitro- l,4-phenylenedisulfonyl)bis(methox3 ⁇ benzene) (9c)
  • Urea.hydrogen peroxide (280 mg, 0.30 mmol)
  • trifluoroacetic anhydride (0.3 ml)
  • acetonitrile (5 ml)
  • the solution of (2-nitro- l ,4-phenylene)bis((4-methoxyphenyl)sulfane) (9b) (100 mg, 0.25 mmol) in acetonitrile (5 ml) was added and the reaction mixture was allowed to stir at room temperature for 3 hours.
  • Example 10 Compound (10) was prepared in analogous manner of example (9) from appropriate intermediates
  • Step 2 4,7-bis((4-methoxyphenyl)sulfonyl)- lH-benzo[d]imidazol-2(3H)-one ( 1 1)
  • Step 1 5,8-bis((4-methoxyphenyl)thio)quinoline (12b) Title compound 5,8-bis((4-methoxyphenyI)thio)quinomie (12b) was prepared as described for (I d) starting from 5,8-dibromoquinoline ( 12a) and 4- methoxybenzenethiol.
  • Step 3 5,8-bis((4-methoxyphenyl)sulfonyl)isoquinolme ( 13) 3% KM11O4 (5 ml) solution was added dropwise to a solution of 5,8-bis((4- methoxyphenyl)thio)isoquinoline ( 13c) ( 150 nig, 0.37 mmol) in acetic acid (5 ml) until the purple color of permanganate persisted.
  • the resulting reaction mixture was made alkaline with 20% NaHSOs (25 ml) and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04, filtered and concentrated under vacuum.
  • Example 14 Compounds (14) to (20) were prepared in analogous manner as that of example 13 from appropriate intermediates
  • Example 22 Compound (22) was prepared in analogous manner as that of example 21 from appropriate intermediates (22) 5,8-bis((4-iluorophenyl)sulfonyl)quinoxaline. MS (EI) m/z: 447.45 (M+ l) . i H NMR (400 MHz, DMSO-d 6 ) : 8 9.01 (s, 2H) , 8.89 (s, 2H) , 8. 16-8.20 (m, 4H) , 7.39- 7.44 (m, 4H).
  • Example 23 Preparation of 5,8-bis((4-methoxyphenyl)sulfonyl)-2,3- dimethylquinoxaline
  • Step 1 5,8-dibromo-2,3-dimethylquinoxaline (23a) 3,6-dibromobenzene- l ,2-diamine ( lb) (0.95 g, 3.57 mmol) in ethanol (6 ml) and butanedione (0.49 ml, 5.71 mmol) were mixed together and heated to reflux for 2 hours. The resulting reaction mixture was allowed to cool at room temperature and filtered under vacuum to obtain 5,8-dibromo-2,3-dimethylquinoxaline (23a) (0.7 g, 62 %) as a solid. MS (EI) m/z: 316.8 (M+ l) . i H NMR (400 MHz, DMSO-d 6 ): 8 8.01 (s, 2H) , 2.76 (s, 6H) .
  • Step 2 5,8-bis((4-methoxyphenyl)thio)-2,3-dimethylquinoxaline (23b) Title compound 5,8-bis((4-methoxyphenyl)thio)-2,3-dimethylquinoxaline (23b) was prepared as described for ( Id) starting from 5,8-dibromo-2,3-dimethylquinoxaline (23a) and 4-methoxybenzenethiol.
  • Step 3 5,8-bis((4-methoxyphenyl) sulfonyl)-2,3-dimethylquinoxaline (23)
  • Example 28 Compound (28) was prepared in analogous manner as that of example 27 from appropriate intermediates
  • Step 1 3,6-dibromo-2-nitrobenzaldehyde (30b) H2SO4 (6.87 ml, 129 mmol) and KNO3 (1.64 g, 16.26 mmol) were mixed together under cooling to which 2,5-dibromobenzaldehyde (30a) (1.5 g, 5.68 mmol) was added slowly, while maintaining the temperature below 30°C. The reaction mixture was further stirred at 23°C for 16 hours. The reaction mixture was quenched by careful addition of H 2 0 (100 ml) and extracted with CH 2 C1 2 (3 x 80 ml).
  • Step 3 5,8-dibromoquinazolin-4(3H)-one (30d) 2-amino-3,6-dibromobenzaldehyde (30c) (0.65 g, 2.33 mmol) and urea (1.95 g, 32.6 mmol) were fused at 160°C under inert atmosphere. After 6 hours, the mixture was allowed to cool at room temperature and 5 ml of water was added under stirring in 5 min. The precipitated solid was filtered off and washed with water. The solid residue so obtained was suspended in a solution of 0.5 N NaOH in water. The resulting suspension was heated to boil for 5 min and then cooled at room temperature.
  • Step 2 5,8-bis((4-methoxyphenyl)sulfonyl)quinoxalin-2( lH)-one (31)
  • Step 2 (E) - ( ( (2 , 5-bis ( (4-methoxyphenyl) thio) phenyl) amino) (cyclopropylamino) methylene)ethylcarbamate (32b)
  • Step 3 2-(cyclopropylamino)-5,8-bis((4-methoxyphenyl)thio)quinazolin-4(3H)-one (32c)
  • Step 4 2-(cyclopropylamino)-5,8-bis((4-methoxyphenyl)sulfonyl)quinazolin-4(3H)- one (32)
  • Step 1 (lE,2E)- l ,2-bis(2,5-dibromobeiizylideiie)hydrazine (33a)
  • Step 3 5,8-bis((4 ⁇ mefhox henyl)thio)phthalazi e (33c)
  • Title compound 5,8-bis((4-methoxyphenyl)thio)phthalazine (33c) was prepared as described for ( I d) starting from 5,8-dibromophthalazine (33b) and 4- methoxybenzenethiol.
  • Step 4 5,8-bis((4 ⁇ mefhox henyl)sulfonyl)phthalazi e (33)
  • Step 3 4,7-dibromoisobenzofuran- l ,3-dione (34d) 3,6-dibromophthalic acid (34c) (2.5 g, 7.71 mmol) was refluxed for 1 hour with acetic anhydride (8.33 ml, 81.5 mmol). The reaction mixture was cooled in an ice bath and the resulting precipitate was filtered, washed with cold ether and dried under reduced pressure to afford 4,7-dibromoisobenzofuran- l ,3-dione (34d) (1.6 g , 69 %) as a solid. MS (EI) m/z: 306.9 (M+ l).
  • 4,7-dibromoisoindoline- l ,3-dione (34e) 800 mg, 2.62 mmol was added to a suspension of zinc powder (206 mg, 3.15 mmol) and copper(II) sulfate pentahydrate (3.34 mg, 0.0135 mmol) in aqueous sodium hydroxide (2M, 3.34 ml) at 0°C (ice- bath) in six portions over 30 min. The resulting mixture was stirred at 0°C for an additional 30 min, followed by room temperature for 2.5 hours to complete the reaction.
  • reaction mixture was neutralized to pH 7 with 20% hydrochloric acid, diluted with 5 ml of ethanol, and then extracted with ethyl acetate (2 x 35 ml). The combined organic layer was washed with brine, dried over Na2S04 and concentrated under vacuum to afford (600 mg, 75%) 4,7-dibromo-3- hydroxyisoindolin- 1 -one (34f) as a yellow solid.
  • Step 7 5,8-bis((4-methoxyphenyl)thio)phthalazin- l (2H)-one (34h)
  • Step 8 5,8-bis((4-methoxyphenyl)sulfonyl)phthalazin- l (2H)-one (34)
  • AC50 (nM) Group Compounds with ACsoinM) between 1 - 100 are grouped as A, the compound with ACsoinM) between 101-500 are grouped as B, and the compound with ACsoinM) above 501 are grouped as C. Following table 1 provides AC5o(nM) of the compounds of the present invention.

Abstract

La présente invention concerne un nouveau composé de la formule générale (I), ses formes tautomères, ses stéréoisomères, ses analogues, ses promédicaments, ses isotopes, ses N-oxydes, ses métabolites, ses sels pharmaceutiquement acceptables, ses polymorphes, ses solvates, ses isomères optiques, ses clathrates, ses co-cristaux, ses combinaisons avec un médicament approprié et des compositions pharmaceutiques le comprenant. L'invention concerne également une méthode de traitement d'une maladie sensible à l'activation de PKM2 humain par l'administration dudit composé et son utilisation en tant que modulateur de PKM2 dans divers états pathologiques.
PCT/IB2012/053353 2011-07-05 2012-07-02 Dérivés de sulfone et leur utilisation en tant que modulateurs de pkm2 pour le traitement du cancer WO2013005157A1 (fr)

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CN112839647A (zh) * 2018-06-07 2021-05-25 达萨玛治疗公司 Sarm1抑制剂
US11712433B2 (en) 2019-03-22 2023-08-01 Sumitomo Pharma Oncology, Inc. Compositions comprising PKM2 modulators and methods of treatment using the same
CN116606271A (zh) * 2023-07-21 2023-08-18 北京百力格生物科技有限公司 一种3,6-二氯偏苯三酸酐的合成方法
US11865120B2 (en) 2013-08-23 2024-01-09 Neupharma, Inc. Substituted quinazolines for inhibiting kinase activity

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US10766865B2 (en) 2012-10-16 2020-09-08 Sumitomo Dainippon Pharma Oncology, Inc. PKM2 modulators and methods for their use
US11865120B2 (en) 2013-08-23 2024-01-09 Neupharma, Inc. Substituted quinazolines for inhibiting kinase activity
JP2019526550A (ja) * 2016-08-15 2019-09-19 ニューファーマ， インコーポレイテッド 特定の化学的実体、組成物、および方法
JP2022058912A (ja) * 2016-08-15 2022-04-12 ニューファーマ， インコーポレイテッド 特定の化学的実体、組成物、および方法
JP7101165B2 (ja) 2016-08-15 2022-07-14 ニューファーマ， インコーポレイテッド 特定の化学的実体、組成物、および方法
WO2019075367A1 (fr) 2017-10-13 2019-04-18 Tolero Pharmaceuticals, Inc. Activateurs de pkm2 en combinaison avec des espèces réactives de l'oxygène pour le traitement du cancer
CN112839647A (zh) * 2018-06-07 2021-05-25 达萨玛治疗公司 Sarm1抑制剂
EP3801500A4 (fr) * 2018-06-07 2022-03-02 Disarm Therapeutics, Inc. Inhibiteurs de sarm1
US11712433B2 (en) 2019-03-22 2023-08-01 Sumitomo Pharma Oncology, Inc. Compositions comprising PKM2 modulators and methods of treatment using the same
CN116606271A (zh) * 2023-07-21 2023-08-18 北京百力格生物科技有限公司 一种3,6-二氯偏苯三酸酐的合成方法
CN116606271B (zh) * 2023-07-21 2023-09-29 北京百力格生物科技有限公司 一种3,6-二氯偏苯三酸酐的合成方法

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