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WO2010043866A2 - Inhibiteurs d’histone lysine déméthylase - Google Patents

Inhibiteurs d’histone lysine déméthylase Download PDF

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WO2010043866A2
WO2010043866A2 PCT/GB2009/002465 GB2009002465W WO2010043866A2 WO 2010043866 A2 WO2010043866 A2 WO 2010043866A2 GB 2009002465 W GB2009002465 W GB 2009002465W WO 2010043866 A2 WO2010043866 A2 WO 2010043866A2
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unsubstituted
substituted
dme
alkyl
hydrogen
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WO2010043866A3 (fr
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Christopher Joseph Schofield
Michael Mcdonough
Nathan Rose
Armin Thalhammer
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Oxford University Innovation Ltd
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Oxford University Innovation Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to iV-oxalylglycine derivatives, hydroxamic acid derivatives and heteroaryl derivatives, and to the use of these compounds as inhibitors of 2-oxoglutarate (2- OG) dependent histone lysine demethylases.
  • JmjC domain containing proteins jmjC's
  • Fe(II) and 2-oxoglutarate (2-OG) dependent oxygenases have been shown to be histone demethylases which catalyse the demethylation of methylated lysines of histone proteins (Tsukada et al. (2006) Nature 439(7078):811-6; Whestine J. R., et al. (2006) Cell 125(3)467-481; Shin S. and Jankneckt R. (2007) Biochem. Biophys. Res. Com. (2007) 353:973-977).
  • Methyl marks on histones have long been known to be associated with transcriptional control which is accomplished through modification of chromatin organisation.
  • Blocking or modifying histone demethylation is rapidly gaining interest as a method of treating cancer (Holloway A. F. (2007) Curr. Med. Chem. (14) 2530-2547). Loss of trimethylation at H4 K20 and Kl 6 is a common hallmark of human cancer (Fraga M. F. etal. (2005) Nat. Genet. 37(4);391-400) and loss of the trimethylation status of H3 K27 is a predictor of poor outcome in breast, ovarian, and pancreatic cancer patients (Wei Y. et al. (2008) MoI Carcinog. ISSN:0899-1987).
  • JmjD2A-F histone demethylases
  • JmjD2A-F histone demethylases
  • JmjD2A was shown to interact with retinoblastoma-binding protein and class I histone deacetylases and implied to have an important role in cell proliferation and oncogenesis (Gray S. G. et al (2005) J. Biol. Chem. 280 (31):28597-18).
  • This subfamily has been shown to demethylate histone H3 K9 tri- and di-methyl- lysine and H3 K36 tri- and di- methyl-lysine (Whestine J.
  • H3 K4 histone demethylase inhibitors
  • LSD type histone demethylase histone demethylase inhibitors
  • researchers to find histone demethylase inhibitors are currently ongoing (Lee M. G., et al (2006) Chem. Biol. (13) 563-567; TsankovaN. et al (2007) Nature Neuroscience Reviews (8) 355-367).
  • histone demethylase inhibitors as anti-cancer agents and psychiatric or neurological disorders, the potential to use these inhibitors in the modulation of vernalization in plants is becoming clear (Xu, L. et al (2008) MoI. Cell Biol. 28(4) 1348-1360; Noh, B. et al (2004) Plant Cell 16(10) 2601-2613.
  • the present invention relates to compounds that have been found to inhibit the human 2- oxoglutarate-dependent JMJD2 subfamily of histone demethylases.
  • Such inhibitors are useful in changing the epigenetic state of cells resulting in the inhibition / activation of chromatin remodelling, multiple gene activation / deactivation, and in treating cancer and other conditions characterised by undesirable cellular proliferation.
  • Such inhibitors are also useful in treating psychiatric disorders including depression.
  • the invention provides a compound which is an N-oxalylglycine derivative of formula (I):
  • n 1 or 2;
  • Z 1 is selected from hydrogen and unsubstituted or substituted C 1-4 alkyl
  • Z 2 is -C(O)- or -NR 1 -, wherein R 1 is selected from hydrogen, hydroxyl and unsubstituted or substituted C M alkyl;
  • W is -O-, -NR 19 - or -C(R 19 )(R 20 )-, wherein each of R 19 and R 20 is selected from hydrogen, hydroxyl and unsubstituted or substituted C 1-4 alkyl;
  • Y 1 is -C(O)-, -S(O)- or -S(O) 2 -;
  • Y is -OR or -NR R , wherein R and R are the same or different and are selected from hydrogen and unsubstituted or substituted C 1-4 alkyl;
  • A is a 5- or 6- membered aryl or heteroaryl ring, wherein p is 0 or 1 and A is otherwise unsubstituted or substituted, provided that when n is 1, p is 1;
  • X 1 is alk, -C(O)-, -S(O) 2 -, -alk-C(O)-, -.Jk-S(O) 2 -, -C(O)-alk- or -S(O) 2 -alk-, wherein alk is unsubstituted or substituted Ci -I0 alkylene;
  • X 2 is unsubstituted or substituted C 1-1O alkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, or -C(O)-;
  • m is O or 1 ;
  • R 4 is hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-20 carbocyclyl, unsubstituted or substituted C 3-20 heterocyclyl, an unsubstituted or substituted aryl group, unsubstituted or substituted aryloxy, an unsubstituted or substituted heteroaryl group, cyano, amino, nitro, unsubstituted or substituted C 1-10 alkylamino, unsubstituted or substituted di(C 1-10 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted diarylamino, unsubstituted or substituted arylalkylamino, unsubstituted or
  • B is a 5- or 6- membered aryl or heteroaryl ring
  • R 5 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl
  • R 6 is selected from hydrogen, hydroxyl, unsubstituted or substituted C 1-6 alkoxy, unsubstituted or substituted aryloxy, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6 alkynyl, cyano, amino, nitro, halo, carboxy, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(C 1- 6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, unsubstituted or substituted amido, unsubstituted or substituted acylamido, unsubstituted or substituted ester, unsubstituted or substituted acyl, unsubstituted or substituted acyloxy and -OR 66 ,
  • R 7 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl
  • R 8 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl; wherein B is otherwise substituted or unsubstituted;
  • R 9 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl
  • X 3 is N or CR 13 ;
  • R 10 is selected from hydrogen, carboxy, unsubstituted or substituted ester, hydroxyl, halo, cyano, amino, nitro and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di(C 1-4 )alkylamino;
  • R 12 and R 13 which are the same or different, are independently selected from hydrogen, hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di(C 1-4 )alkylamino, or from a group -X 6 - Y 6 , wherein X 6 is a bond , -O-, -S-, -NR'-, an unsubstituted or substituted moiety selected from -0-(C 1-4 alkylene)- , -S-(C 1-4 alkylene)- and -NR'-(C 1-4 alkylene)- or unsubstituted or substituted, saturated or partially unsaturated C 1-4 alkylene which is optionally interrupted with O, S or NR', and Y 6 is hydrogen, halogen, or unsubstituted or substituted aryl
  • R 11 is selected from hydrogen, hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 , unsubstituted or substituted C 1 ⁇ alkyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 1-4 alkylamino, unsubstituted or substituted di(C 1-4 )alkylamino, a group of formula (Ilia) and a group of formula (FIIb):
  • each R 14 is independently selected from hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di(C 1-4 )alkylamino;
  • X 4 is NR 17 or O, wherein R 17 is hydrogen or unsubstituted or substituted C 1-6 alkyl; v is O or 1 and L 1 is selected from unsubstituted or substituted C 1-1O alkylene, unsubstituted or substituted arylene and unsubstituted or substituted heteroarylene, wherein said
  • C 1-10 alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or Cr 4 alkyl;
  • R 15 is hydrogen, amino, unsubstituted or substituted Cj -10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(C 1-6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, unsubstituted or substituted C 3-10 carbocyclyl, unsubstituted or substituted C 3-10 heterocyclyl, unsubstituted or substituted C 1-I0 alkoxy, unsubstituted or substituted aryloxy, -NHC(O)OR 65 and -OR 66 , wherein R 65 is unsubstituted or substituted C 1-I o alkyl and wherein R 66 is selected from unsubstituted or substituted C 3-10 carbocyclyl
  • X 5 is NR 18 or O, wherein R 18 is hydrogen or unsubstituted or substituted C 1-6 alkyl; w is 0 or 1 and L 2 is selected from unsubstituted or substituted C 1-10 alkylene, unsubstituted or substituted arylene and unsubstituted or substituted heteroarylene, wherein said C 1-1O alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or C ⁇ - A alkyl; R 16 is hydrogen, amino, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(C 1-6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylal
  • the invention further provides:
  • a pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound of the invention as defined above.
  • a compound of the invention as defined herein for use in a method of medical treatment of the human or animal body by therapy.
  • a compound of the invention as defined herein for use in the treatment of a psychiatric disorder is not limited to a psychiatric disorder.
  • a compound of the invention as defined herein in the manufacture of a medicament for use in the treatment of a condition characterised by undesirable cellular proliferation or a psychiatric disorder.
  • a method of treating a condition characterised by undesirable cellular proliferation or a psychiatric disorder which method comprises administering to a patient in need thereof a compound of the invention as defined herein.
  • An agent for the treatment of a condition characterised by undesirable cellular proliferation or a psychiatric disorder comprising a compound of the invention as defined herein.
  • a compound of the invention for use in the above mentioned therapies and methods of medical treatment encompass the compounds of the invention as set out above and or a compound of formula (III) wherein X 3 , R 9 , R 10 and R 11 are as defined above and R 12 is - X 6 - Y 6 wherein X 6 is a bond and Y 6 is hydrogen.
  • Fig. 1 is a flowchart outlining the experimental process used to determine the relative binding ability of the 7V-oxalylglycine derivatives of formula (I), as described in Example 9.
  • Fig. 2 shows the competitive binding ESMS spectrum of NOG and the iV-oxalylglycine derivative of formula (I), compound C3.
  • the peak at the higher m/z value corresponds to JMJD2E bound to C3, whereas the peak at lower m/z corresponds to JMJD2E bound to NOG.
  • the C3 peak has greater intensity, indicating that C3 outcompetes NOG for JMJD2E binding.
  • the competitive binding results described in Example 9 are summarised in the table in Fig. 2.
  • Fig. 1 is a flowchart outlining the experimental process used to determine the relative binding ability of the 7V-oxalylglycine derivatives of formula (I), as described in Example 9.
  • Fig. 2 shows the competitive binding ESMS spectrum of NOG and the i
  • FIG. 3 shows the ESMS spectra of the iV-oxalylglycine derivatives of formula (I), compounds DI l, B12, C3 and C12, for which IC 50 values were determined.
  • the bottom panel shows the spectrum of JMJD2E (lOO ⁇ M) in the presence of lOO ⁇ M Fe(II).
  • the three different peak clusters result from different charge states of the protein caused by the electrospray ionisation method.
  • the top four panels show JMJD2E (lOO ⁇ M) following incubation with lOO ⁇ M Fe(II) and lOO ⁇ M of inhibitor compound at 37°C for 30 minutes. Note the presence of peaks at higher m/z value than that of the JMJD2E in the absence of compound. These peaks correspond to JMJD2E with bound compound.
  • Figures 4a and 4b provide plots of percentage inhibition against JMJD2E for 2,4-pyridine dicarboxylic acids of formula (HIf), determined according to Example 11.
  • a C 1-20 alkyl group is an unsubstituted or substituted, straight or branched chain saturated hydrocarbon radical. Typically it is C 1-10 alkyl, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, or C 1-6 alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl, or C 1-4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl.
  • alkyl group When an alkyl group is substituted it typically bears one or more (e.g. one, two, three or four) substituents selected from substituted or unsubstituted C 1-20 alkyl; substituted or unsubstituted aryl; substituted or unsubstituted aralkyl; cyano; amino; C 1-10 alkylamino; di(C 1-10 )alkylamino; arylamino; diarylamino; arylalkylamino; nitro; amido; acylamido; hydroxyl; keto; oxo; halo; haloalkl (e.g.
  • substituted alkyl groups include haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl and alkaryl groups.
  • alkaryl as used herein, pertains to a C 1-20 alkyl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been replaced with an aryl group.
  • a substituted Ci -20 alkyl group carries 1, 2 or 3 substituents, for instance 1 or 2.
  • a C 2-20 alkenyl group or moiety is a straight or branched group or moiety, which contains from 2 to 20 carbon atoms. One or more double bonds may be present in the alkenyl group or moiety, typically one double bond.
  • a C 2-20 alkenyl group or moiety is typically ethenyl or a C 3-I0 alkenyl group or moiety, i.e. a C 2-10 alkenyl group, more typically a C 2-6 alkenyl group.
  • a C 3-1O alkenyl group or moiety is typically a C 3-6 alkenyl group or moiety, for example allyl, propenyl, butenyl, pentenyl or hexenyl.
  • a C 2-4 alkenyl group or moiety is ethenyl, propenyl or butenyl.
  • An alkenyl group may be unsubstituted or substituted by one to four (e.g. one, two, three or four) substituents, the substituents, unless otherwise specified, being selected from those listed above for Ci -20 alkyl groups. Where two or more substituents are present, these may be the same or different.
  • a C 2-2O alkynyl group or moiety is a straight or branched group or moiety which, unless otherwise specified, contains from 2 to 20 carbon atoms.
  • One or more triple bonds, and optionally one or more double bonds may be present in the alkynyl group or moiety, typically one triple bond.
  • a C 2-20 alkynyl group or moiety is typically ethynyl or a C 3-10 alkynyl group or moiety, i.e. a C 2-10 alkynyl group, more typically a C 2-6 alkynyl group.
  • a C 3-10 alkynyl group or moiety is typically a C 3-6 alkynyl group or moiety, for example propynyl, butynyl, pentynyl or hexynyl.
  • a C 2-4 alkynyl group or moiety is ethynyl, propynyl or butynyl.
  • An alkynyl group may be unsubstituted or substituted by one to four substituents (e.g. one, two, three or four), the substituents, unless otherwise specified, being selected from those listed above for C 1-20 alkyl groups. Where two or more substituents are present, these may be the same or different.
  • An aryl ring is an unsubstituted or substituted aromatic ring of covalently linked carbon atoms.
  • the aryl ring is a 5- or 6- membered aryl ring, examples of which include cyclopentadienyl (C p ) and phenyl.
  • An aryl ring may be unsubstituted or substituted by, typically, one to four substituents (e.g. one, two, three or four), the substituents, unless otherwise specified, being selected from those listed above for C 1-20 alkyl groups. Where two or more substituents are present, these may be the same or different.
  • a heteroaryl ring is an unsubstituted or substituted heteroaromatic ring of covalently linked atoms including one or more heteroatoms.
  • the one or more heteroatoms are typically selected from nitrogen, phosphorus, silicon, oxygen and sulfur (more commonly from nitrogen, oxygen and sulfur).
  • a heteroaryl ring is typically a 5- or 6- membered heteroaryl ring containing at least one heteroatom selected from nitrogen, phosphorus, silicon, oxygen and sulfur (more commonly selected from nitrogen, oxygen and sulfur). It may contain, for example, 1, 2 or 3 heteroatoms.
  • heteroaryl rings examples include pyridine, pyrazine, pyrimidine, pyridazine, furan, thiofuran, pyrazole, pyrrole, oxazole, oxadiazole, isoxazole, thiadiazole, thiazole, isothiazole, imidazole and pyrazole.
  • a heteroaryl ring may be unsubstituted or substituted by, typically, one to four substituents (e.g. one, two, three or four), the substituents, unless otherwise specified, being selected from those listed above for C 1-20 alkyl groups. Where two or more substituents are present, these may be the same or different.
  • a C 3-20 carbocyclyl group is an unsubstituted or substituted monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which moiety has from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms.
  • the carbocyclyl ring may be saturated or unsaturated.
  • the term "carbocyclyl” includes the sub-classes cycloalkyl, cycloalkyenyl and cycloalkynyl.
  • each ring has from 5 to 7 ring atoms.
  • Examples of groups of C 3-20 carbocyclyl groups include C 3-10 carbocyclyl, C 5-7 carbocyclyl and C 5-6 carbocyclyl. When a C 3-20 carbocyclyl group is substituted it typically bears one or more substituents (typically one, two, three or four substituents) selected from those listed above for C 1-20 alkyl groups.
  • Examples OfC 3-10 carbocyclyl groups include, but are not limited to, those derived from saturated monocyclic hydrocarbon compounds: cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane
  • a C 3-10 cycloalkyl group or moiety is a 3- to 10- membered unsubstituted or substituted group or moiety, typically a 3-to 6-membered group or moiety, which may be a monocyclic ring or which may consist of two or more fused rings.
  • C 3-10 cycloalkyl groups or moieties include cyclopropane (C 3 ), cyclobutane (C 4 ), cyclopentane (C 5 ), cyclohexane (C 6 ), cycloheptane (C 7 ), methylcyclopropane (C 4 ), dimethylcyclopropane (C 5 ), methylcyclobutane (C 5 ), dimethylcyclobutane (C 6 ), methylcyclopentane (C 6 ), dimethylcyclopentane (C 7 ), methylcyclohexane (C 7 ), dimethylcyclohexane (C 8 ), menthane (C 10 ), thujane (C 1O ), carane (C 1O ), pinane (C1 0 ), bornane (C 10 ), norcarane (C 7 ), norpinane (C 7 ), norbornane (C 7 ), adamantane (C 1
  • a C 3-20 heterocyclyl group is an unsubstituted or substituted monovalent, monocyclic, bicyclic or tricyclic moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms.
  • each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.
  • C 3-20 heterocyclyl group When a C 3-20 heterocyclyl group is substituted it typically bears one or more substituents selected from C 1-6 alkyl which is unsubstituted, aryl (as defined herein), cyano, amino, C 1-10 alkylamino, di(C 1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxyl, oxo, halo, haloalkyl (e.g. CF 3 ), carboxy, ester, acyl, acyloxy, C 1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e.
  • thiol -SH
  • a substituted C 3-20 heterocyclyl group carries 1, 2 or 3 substituents, for instance 1 or 2.
  • groups of heterocyclyl groups include C 3-20 heterocyclyl, C 5-20 heterocyclyl,
  • Examples of monocyclic C 3-20 heterocyclyl groups include, but are not limited to, those derived from: N 1 : aziridine (C 3 ), azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C 5 ), pyrroline (e.g.,
  • O 1 oxirane (C 3 ), oxetane (C 4 ), oxolane (tetrahydrofuran) (C 5 ), oxole (dihydrofuran) (C 5 ), oxane (tetrahydropyran) (C 6 ), dihydropyran (C 6 ), pyran (C 6 ), oxepin (C 7 ); S 1 : thiirane (C 3 ), thietane (C 4 ), thiolane (tetrahydrothiophene) (C 5 ), thiane
  • N 2 imidazolidine (C 5 ), pyrazolidine (diazolidine) (C 5 ), imidazoline (C 5 ), pyrazoline (dihydropyrazole) (C 5 ), piperazine (C 6 );
  • N 1 O 1 tetrahydrooxazole (C 5 ), dihydrooxazole (C 5 ), tetrahydroisoxazole (C 5 ), dihydroisoxazole (C 5 ), mo ⁇ holine (C 6 ), tetrahydrooxazine (C 6 ), dihydrooxazine (C 6 ), oxazine (C 6 );
  • NiSj thiazoline (C 5 ), thiazolidine (C 5 ), thiomorpholine (C 6 ); N 2 O 1 : oxadiazine (C 6 );
  • O 1 S 1 oxathiole (C 5 ) and oxathiane (thioxane) (C 6 ); and,
  • N 1 OiSi oxathiazine (C 6 ).
  • Examples OfC 3-20 heterocyclyl groups which are also aryl groups are described below as heteroaryl groups.
  • An aryl group is a substituted or unsubstituted, monocyclic or bicyclic aromatic group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. Examples include phenyl, naphthyl, indenyl and indanyl groups. An aryl group is unsubstituted or substituted.
  • aryl group as defined above When an aryl group as defined above is substituted it typically bears one or more substituents selected from unsubstituted or substituted Cr 6 alkyl (to form an aralkyl group), aryl which is unsubstituted, cyano, amino, C 1-I0 alkylamino, di(C 1-1 o)alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxyl, halo, haloalkyl (e.g. CF 3 ), carboxy, ester, acyl, acyloxy, C 1-20 alkoxy, aryloxy, haloalkyl, sulfhydryl (i.e.
  • a substituted aryl group may be substituted in two positions with a single unsubstituted or substituted C 1-6 alkylene group, or with a bidentate group represented by the formula -X-C 1-6 alkylene, or -X-C 1-6 alkylene-X-, wherein X is selected from O, S and NR, and wherein R is H, aryl or C 1-6 alkyl.
  • a substituted aryl group may be an aryl group fused with a cycloalkyl group or with a heterocyclyl group.
  • aralkyl as used herein, pertains to an aryl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been substituted with a C 1-6 alkyl group.
  • groups include, but are not limited to, tolyl (from toluene), xylyl (from xylene), mesityl (from mesitylene), and cumenyl (or cumyl, from cumene), and duryl (from durene).
  • the ring atoms of an aryl group may include one or more heteroatoms, as in a heteroaryl group.
  • Such an aryl group (a heteroaryl group) is a substituted or unsubstituted mono- or bicyclic heteroaromatic group which typically contains from 6 to 10 atoms in the ring portion including one or more heteroatoms. It is generally a 5- or 6-membered ring, or two fused rings each of which is the same or different and typically independently selected from a 5-membered ring and a 6-membered ring, containing at least one heteroatom selected from O, S, N, P, Se and Si. It may contain, for example, 1, 2 or 3 heteroatoms.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, quinolyl and isoquinolyl.
  • a heteroaryl group may be unsubstituted or substituted, for instance, as specified above for aryl. Typically it carries 0, 1, 2 or 3 substituents.
  • a C 1-10 alkylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound having from 1 to 10 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated.
  • alkylene includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below. Typically it is C 1-6 alkylene.
  • alkylene typically it is C 1- 4 alkylene, for example methylene, ethylene, i-propylene, n-propylene, t-butylene, s-butylene or n-butylene. It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof.
  • An alkylene group may be unsubstituted or substituted, for instance, as specified above for alkyl. Typically a substituted alkylene group carries 1, 2 or 3 substituents, for instance 1 or 2.
  • C M alkylene refers to an alkylene group having from 1 to 4 carbon atoms.
  • groups of alkylene groups include Ci -4 alkylene ("lower alkylene”), C 1-7 alkylene and Ci -I0 alkylene.
  • linear saturated C 1-7 alkylene groups include, but are not limited to, -(CH 2 ) n - where n is an integer from 1 to 7, for example, -CH 2 - (methylene), -CH 2 CH 2 - (ethylene), -CH 2 CH 2 CH 2 - (propylene), and -CH 2 CH 2 CH 2 CH 2 - (butylene).
  • Examples of branched saturated C 1-7 alkylene groups include, but are not limited to, -CH(CH 3 )-, -CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, and -CH 2 CH(CH 2 CH 3 )CH 2 -.
  • alicyclic saturated Ci -7 alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-l,3-ylene), and cyclohexylene (e.g., cyclohex-l,4-ylene).
  • Ci -7 alkylene groups examples include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-l,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-l,4-ylene; 3-cyclohexen-l,2-ylene; 2,5-cyclohexadien-l,4-ylene). These are examples of C 5-6 cycloalkylene groups.
  • C 1-10 alkylene and C 1-20 alkyl groups as defined herein are either uninterrupted or interrupted by one or more heteroatoms or heterogroups, such as S, O or N(R") wherein R" is H, C 1-6 alkyl or aryl (typically phenyl), or by one or more arylene (typically phenylene) groups.
  • the phrase "optionally interrupted” as used herein thus refers to a C 1-20 alkyl group or an alkylene group, as defined above, which is uninterrupted or which is interrupted between adjacent carbon atoms by a heteroatom such as oxygen or sulfur, by a heterogroup such as N(R") wherein R" is H, aryl or C 1 -C 6 alkyl, or by an arylene group.
  • a C 1-20 alkyl group such as n-butyl may be interrupted by the heterogroup
  • N(R") as follows: -CH 2 N(R")CH 2 CH 2 CH 3 , -CH 2 CH 2 N(R")CH 2 CH 3 , or -CH 2 CH 2 CH 2 N(R")CH 3 .
  • an alkylene group such as n-butylene may be interrupted by the heterogroup N(R") as follows: -CH 2 N(R")CH 2 CH 2 CH 2 -, -CH 2 CH 2 N(R")CH 2 CH 2 -, or -CH 2 CH 2 CH 2 N(R")CH 2 -.
  • an interrupted group for instance an interrupted C 1-10 alkylene or C 1-20 alkyl group, is interrupted by 1 , 2 or 3 heteroatoms or heterogroups or by 1, 2 or 3 arylene (typically phenylene) groups. More typically, an interrupted group, for instance an interrupted C 1-10 alkylene or C 1-20 alkyl group, is interrupted by 1 or 2 heteroatoms or heterogroups or by 1 or 2 arylene (typically phenylene) groups.
  • a C 1-20 alkyl group such as n-butyl may be interrupted by 2 heterogroups N(R") as follows: -CH 2 N(R")CH 2 N(R")CH 2 CH 3 .
  • An arylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms of an aromatic compound, which moiety has from 5 to 14 ring atoms (unless otherwise specified). Typically, each ring has from 5 to 7 or from 5 to 6 ring atoms.
  • An arylene group may be unsubstituted or substituted, for instance, as specified above for aryl.
  • a substituted heteroarylene group carries 1, 2 or 3 substituents, for instance 1 or 2.
  • the prefixes e.g., C 5-20 , C 6-20 , C 5-14 , C 5-7 , C 5-6 , etc.
  • the term "C 5-6 arylene,” as used herein, pertains to an arylene group having 5 or 6 ring atoms.
  • groups of arylene groups include C 5-20 arylene, C 6-20 arylene, C 5-14 arylene, C 6-14 arylene, C 6-10 arylene, C 5-12 arylene, C 5-10 arylene, C 5-7 arylene, C 5-6 arylene, C 5 arylene, and C 6 arylene.
  • the ring atoms may be all carbon atoms, as in "carboarylene groups” (e.g., C 6-20 carboarylene, C 6-14 carboarylene or C 6-10 carboarylene).
  • Examples OfC 6-20 arylene groups which do not have ring heteroatoms include, but are not limited to, those derived from the compounds discussed above in regard to aryl groups, e.g. phenylene, and also include those derived from aryl groups which are bonded together, e.g. phenylene-phenylene (diphenylene) and phenylene- phenylene-phenylene (triphenylene).
  • the ring atoms may include one or more heteroatoms, as in "heteroarylene groups” (e.g., C 5-1O heteroarylene).
  • a heteroarylene group may be unsubstituted or substituted, for instance, as specified above for aryl.
  • a substituted heteroarylene group carries 1, 2 or 3 substituents, for instance 1 or 2.
  • Examples of heteroarylene groups include, but are not limited to, those derived from the compounds discussed above in regard to heteroaryl groups.
  • heteroarylene groups include bidentate groups derived from pyridine, pyrazine, pyrimidine, pyridazine, furan, thiofuran, pyrazole, pyrrole, oxazole, oxadiazole, isoxazole, thiadiazole, thiazole, isothiazole, imidazole and pyrazole.
  • R is an acyl substituent, for example, a substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 heterocyclyl group, or a substituted or unsubstituted aryl group.
  • R is an acyloxy substituent, for example, substituted or unsubstituted C 1-20 alkyl group, a substituted or unsubstituted C 3-20 heterocyclyl group, or a substituted or unsubstituted aryl group, typically a C 1-6 alkyl group.
  • phosphonic acid represents a group of the formula: -P(O)(OH) 2 .
  • phosphonic acid salt represents a group which is a salt of a phosphonic acid group.
  • X + may be an alkali metal cation.
  • X + may be Na + or K + , for example.
  • phosphoric acid represents a group of the formula: -OP(O)(OH) 2 .
  • phosphate ester groups include, but are not limited to, -0P(O)(0CH 3 ) 2 , -OP(O)(OCH 2 CHa) 2 , -0P(O)(0-t-Bu) 2 , and -OP(O)(OPh) 2 .
  • amino represents a group of formula -NH 2 .
  • Ci-Ci 0 alkylamino represents a group of formula -NHR' wherein R' is a C 1-I0 alkyl group, preferably a C 1-6 alkyl group, as defined previously.
  • di(C 1-10 )alkylamino represents a group of formula -NR 'R" wherein R' and R" are the same or different and represent C 1-10 alkyl groups, preferably Ci -6 alkyl groups, as defined previously.
  • arylamino represents a group of formula -NHR' wherein R' is an aryl group, preferably a phenyl group, as defined previously.
  • diarylamino represents a group of formula -NR 'R" wherein R' and R" are the same or different and represent aryl groups, preferably phenyl groups, as defined previously.
  • arylalkylamino represents a group of formula -NR 'R" wherein R' is a C 1-10 alkyl group, preferably a C 1-6 alkyl group, and R" is an aryl group, preferably a phenyl group.
  • R x is an amide substituent, for example, hydrogen, a C 1-2 oalkyl group, a C 3-20 heterocyclyl group, an aryl group, preferably hydrogen or a C 1-20 alkyl group
  • R y is an acyl substituent, for example, a C 1-20 alkyl group, a C 3-20 heterocyclyl group, or an aryl group, preferably hydrogen or a C 1-20 alkyl group.
  • R x and R y may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:
  • Ci -1O alkylthio group is a said C MO alkyl group, preferably a C 1-6 alkyl group, attached to a thio group.
  • An arylthio group is an aryl group, preferably a phenyl group, attached to a thio group.
  • a Ci -20 alkoxy group is a said substituted or unsubstituted C 1-20 alkyl group attached to an oxygen atom.
  • a C 1-10 alkoxy group is a said substituted or unsubstituted Cj -10 alkyl group attached to an oxygen atom.
  • a C 1-6 alkoxy group is a said substituted or unsubstituted C 1-6 alkyl group attached to an oxygen atom.
  • a C 1-4 alkoxy group is a substituted or unsubstituted C 1-4 alkyl group attached to an oxygen atom.
  • Said C 1-20 , C 1-10 , C 1-6 and C 1-4 alkyl groups are optionally interrupted as defined herein.
  • C 1-4 alkoxy groups include, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -0(nBu) (n-butoxy), - O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy).
  • C 1-20 alkoxy groups are -O(Adamantyl), -O-CH 2 -Adamantyl and -0-CH 2 -CH 2 - Adamantyl.
  • aryloxy group is a substituted or unsubstituted aryl group, as defined herein, attached to an oxygen atom.
  • An example of an aryloxy group is -OPh (phenoxy).
  • halogen or halo typically represents fluorine, chlorine or bromine.
  • a reference to carboxylic acid or carboxyl group also includes the anionic (carboxylate) form (-COO " ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-O " ), a salt or solvate thereof, as well as conventional protected forms.
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho- chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • keto enol enolate (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including O and O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting known methods, in a known manner.
  • a reference to a particular compound also includes ionic, salt, solvate, protected forms and prodrugs thereof.
  • Examples of pharmaceutically acceptable salts of the compounds for use in accordance with the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, isobutyric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid, benzoic acid and glutamic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid and phosphoric acid
  • organic acids such as methanesulfonic acid, benzenesulphonic acid,
  • the salt is a hydrochloride, an acetate, a propionate, a benzoate, a butyrate or an isobutyrate.
  • pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19.
  • a prodrug of a compound for use in accordance with the present invention is a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • esters of the active compound e.g., a physiologically acceptable metabolically labile ester.
  • R is a C 1-4 alkyl group including, but not limited to, methyl, ethyl, propyl, butyl.
  • such esters may be produced by omitting the final de-esterification step that is usually used to produce the parent compound.
  • the compound of the present invention can be in the free form or the salt form.
  • the compound may also be in prodrug form.
  • the prodrug can itself be in the free form or the salt form.
  • the compound is an N-oxalylglycine derivative of formula (I):
  • Z 1 is selected from hydrogen and unsubstituted or substituted C 1-4 alkyl
  • Z 2 is -C(O)- or -NR 1 -, wherein R 1 is selected from hydrogen, hydroxyl and unsubstituted or substituted C 1-4 alkyl;
  • W is -O-, -NR 19 - or -C(R 19 )(R 20 )-, wherein each of R 19 and R 20 is selected from hydrogen, hydroxyl and unsubstituted or substituted C 1-4 alkyl;
  • Y 1 is -C(O)-, -S(O)- or -S(O) 2 -;
  • Y 2 is -OR 2 or -NR 2 R 3 , wherein R 2 and R 3 are the same or different and are selected from hydrogen and unsubstituted or substituted C 1-4 alkyl;
  • A is a 5- or 6- membered aryl or heteroaryl ring, wherein p is 0 or 1 and A is otherwise unsubstituted or substituted, provided that when n is 1, p is 1;
  • X 1 is alk, -C(O)-, -S(O) 2 -, -alk-C(O)-, -alk-S(O) 2 -, -C(O)-alk- or -S(O) 2 -alk-, wherein alk is unsubstituted or substituted C 1-1O alkylene;
  • X 2 is unsubstituted or substituted C 1-10 alkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, or -C(O)-; m is O or 1 ; and
  • R 4 is hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-20 carbocyclyl, unsubstituted or substituted C 3-20 heterocyclyl, an unsubstituted or substituted aryl group, unsubstituted or substituted aryloxy, an unsubstituted or substituted heteroaryl group, cyano, amino, nitro, unsubstituted or substituted C 1-10 alkylamino, unsubstituted or substituted di(Ci-io)alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted diarylamino, unsubstituted or substituted arylalkylamino, unsubstituted
  • n is 1 and p is 1. hi another embodiment, however, n is 2.
  • p is typically O.
  • Z 1 is selected from hydrogen and unsubstituted C 1-4 alkyl, i.e. from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec butyl and tert-butyl. More typically, Z 1 is hydrogen or methyl. Even more typically, Z 1 is hydrogen.
  • Z 2 is -C(O)-.
  • W is typically -N(R 19 )-. More typically, W is -NH-.
  • each of R 19 and R 20 is selected from hydrogen and unsubstituted or substituted C 1-4 alkyl. More typically each of R 19 and R 20 is selected from hydrogen and unsubstituted C 1-4 alkyl. Even more typically each of R 19 and R 20 is hydrogen or methyl.
  • Y 1 is typically -C(O)-.
  • Y 2 is usually -OR 2 , wherein R 2 is selected from hydrogen and unsubstituted or substituted Ci -4 alkyl. Typically, R 2 is hydrogen or unsubstituted C 1-4 alkyl. More typically, R 2 is hydrogen or methyl. Even more typically, R 2 is hydrogen.
  • Z 1 is hydrogen and Y 2 is hydroxyl.
  • Z 1 is methyl and Y 2 is methoxy.
  • A is a 6-membered aryl or heteroaryl ring, wherein p is 0 or 1 and A is otherwise unsubstituted or substituted, provided that when n is 1, p is 1.
  • A is a 6- membered aryl ring, typically a benzene ring.
  • A is unsubstituted. More typically, when p is 0, A is an unsubstituted phenyl group.
  • A is otherwise unsubstituted. More typically, when p is 1, A is an unsubstituted phenylene group.
  • R 4 is other than hydrogen and other than unsubstituted or substituted C 1-10 alkyl. More typically, when X 1 is alk and m is 0, R 4 is selected from unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-I0 alkynyl, unsubstituted or substituted C 3-20 carbocyclyl, unsubstituted or substituted C 3-20 heterocyclyl, an unsubstituted or substituted aryl group, unsubstituted or substituted aryloxy, and an unsubstituted or substituted heteroaryl group.
  • R 4 is other than hydrogen and other than unsubstituted or substituted C 1-10 alkyl. More typically, when X 1 is alk, m is 1 and X 2 is unsubstituted or substituted C 1-10 alkylene, R 4 is selected from unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-20 carbocyclyl, unsubstituted or substituted C 3-20 heterocyclyl, an unsubstituted or substituted aryl group, unsubstituted or substituted aryloxy, and an unsubstituted or substituted heteroaryl group.
  • X 1 is selected from alk 2 , -C(O)-, -S(O) 2 -, -alk 3 -C(O)-, -alk 3 -S(O) 2 -, -C(O)-alk 3 - and -S(O) 2 -alk 3 -, wherein alk 2 and alk 3 are unsubstituted or substituted C 1-6 alkylene groups.
  • X 1 is selected from alk 2 , -C(O)-, -S(O) 2 -, -alk 3 -C(O)- and -C(O)-alk 3 -, wherein alk and alk are unsubstituted or substituted C 1-6 alkylene groups. Even more typically, X is selected from alk 2 , -C(O)- and -S(O) 2 -, wherein alk 2 is an unsubstituted or substituted C 1-6 alkylene group. Typically, alk 2 and alk 3 are unsubstituted or substituted C 1-4 alkylene groups.
  • alk 2 and alk 3 are unsubstituted or substituted C 1-4 alkylene groups. More typically, alk 2 is an unsubstituted or substituted C 1-4 alkylene group, for instance methylene (i.e. -CH 2 -), - CH(CH 3 )- or -C(CH 3 ) 2 -. Usually, alk 3 is an unsubstituted C 1-4 alkylene group, for instance ethylene or methylene, usually methylene.
  • X 1 is selected from -C(O)-, -S(O) 2 -, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 -C(O)- and -C(O)-CH 2 -.
  • X 1 may for instance be selected from -C(O)-, -S(O) 2 -, -CH 2 -, - CH(CH 3 )- and -C(CH 3 ) 2 -.
  • X 1 may be selected from -C(O)-, -S(O) 2 - and -CH 2 -.
  • X 2 is unsubstituted or substituted C 1-10 alkylene, unsubstituted or substituted arylene, unsubstituted or substituted heteroarylene, or -C(O)-. More typically, X 2 is selected from unsubstituted or substituted C 1-6 alkylene (for instance, unsubstituted or substituted C 1-4 alkylene), unsubstituted or substituted phenylene, unsubstituted or substituted heteroarylene, and -C(O)-, wherein the heteroarylene is a monocyclic heteroaromatic group which contains 5 or 6 atoms in the ring portion.
  • the 5 or 6 atoms in the ring portion include one, two or three heteroatoms each of which is independently selected from nitrogen, oxygen and sulfur. More typically the heteroatom(s) are nitrogen.
  • the heteroarylene group may be substituted with a substituted or unsubstituted C 1-4 alkyl group, for instance a halo-substituted C 1-4 alkyl group, e.g. CF 3 .
  • the heteroarylene group is a group of the following structure:
  • X is typically methylene, ethylene, propylene or -
  • X 2 is selected from methylene, ethylene, -CH 2 -CH 2 -CH 2 -, -CH(CH 2 CH 3 )-, -C(O)-, unsubstituted phenylene and a group of the following structure:
  • X 2 is -C(O)-.
  • m is either O or 1.
  • m is O. In another embodiment, however, m is 1.
  • R 4 is unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted C 2-10 alkenyl, unsubstituted or substituted C 2-10 alkynyl, unsubstituted or substituted C 3-20 carbocyclyl, unsubstituted or substituted C 3-20 heterocyclyl, an unsubstituted or substituted aryl group, unsubstituted or substituted aryloxy or an unsubstituted or substituted heteroaryl group.
  • R 4 is an unsubstituted or substituted aryl group
  • R 4 is an unsubstituted or substituted phenyl group.
  • R 4 is a substituted aryl group, for instance a substituted phenyl group
  • the group typically bears one, two or three substituents.
  • each aryl substituent is independently selected from unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted Ci -4 alkoxy, ester, halo, cyano, -NO 2 and -CF 3 .
  • each of the aryl group substituents is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, butyl, -NO 2 , -CF 3 , -OCH 3 and -C(O)OCH 3 .
  • each of the aryl group substituents is independently selected from F, Cl, Br, cyano, methyl, -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -NO 2 , -CF 3 , -OCH 3 and - C(O)OCH 3 .
  • R 4 is unsubstituted or substituted C 1-6 alkyl (for instance unsubstituted or substituted C 1-4 alkyl), unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 2-4 alkenyl, unsubstituted or substituted C 2-4 alkynyl, unsubstituted or substituted C 5-10 carbocyclyl, unsubstituted or substituted C 5-10 heterocyclyl, an unsubstituted or substituted phenyl group, unsubstituted or substituted phenoxy or an unsubstituted or substituted heteroaryl group.
  • C 1-6 alkyl for instance unsubstituted or substituted C 1-4 alkyl
  • C 2-4 alkenyl unsubstituted or substituted C 2-4 alkynyl
  • unsubstituted or substituted C 5-10 carbocyclyl unsubstituted or substituted C 5-10 heterocyclyl
  • the unsubstituted or substituted heteroaryl group is a monocyclic heteroaromatic group which contains 5 or 6 atoms in the ring portion or a fused bicyclic heteroaromatic group which contains 9 or 10 atoms in the ring portions.
  • the 5 or 6 atoms in the ring portion of the monocyclic heteroaromatic group, or the 9 or 10 atoms in the ring portions of the bicyclic heteroaromatic group include one, two or three heteroatoms each of which is independently selected from nitrogen, oxygen and sulfur.
  • R 4 is selected from any one of the following groups:
  • R 4 is selected from cyclohexyl and 5,5,8,8-tetramethyl tetralyl, whose structure is as follows:
  • R 4 is selected from any one of the following groups:
  • R 4 is usually selected from unsubstituted or substituted C 1-4 alkyl; unsubstituted C 1-4 alkoxy; unsubstituted C 2-3 alkenyl; unsubstituted C 2-3 alkynyl; unsubstituted phenoxy; unsubstituted phenyl; phenyl substituted with one, two or three substituents each of which is independently selected from F, Cl, Br, cyano, methyl, ethyl, propyl, butyl, -NO 2 , -CF 3 , -OCH 3 and -C(O)OCH 3 ; and any one of the following groups:
  • R 4 may be selected from methyl, unsubstituted phenyl, mesityl, phenyl substituted with an NO 2 group, phenyl substituted with a bromo group, phenyl substituted with a chloro group, phenyl substituted with a fluoro group, phenyl substituted with a CF 3 group, phenyl substituted with two chloro groups, phenyl substituted with two fluoro groups, phenyl substituted with a cyano group and any one of the following groups:
  • Z 1 is hydrogen or methyl; Z 2 is -C(O)-; W is -NH-; Y 1 is -C(O)-; Y 2 is -OR 2 , wherein R 2 is selected from hydrogen and methyl; A is a 6-membered aryl ring, wherein p is O or 1 and A is otherwise unsubstituted or substituted, provided that when n is 1, p is 1; X 1 is selected from alk 2 , -C(O)-, -S(O) 2 -, -alk 3 - C(O)- and -C(O)-alk 3 -, wherein alk 2 is an unsubstituted or substituted C M alkylene group and alk 3 is a methylene or ethylene group; X 2 is selected from -C(O)-, unsubstituted or substituted C 1-4 alkylene,
  • Z 1 is hydrogen or methyl; Z 2 is -C(O)-; W is -NH-; Y 1 is -C(O)-; Y 2 is -OR 2 , wherein R 2 is selected from hydrogen and methyl; A is a 6-membered aryl ring, wherein p is 0 or 1 and A is otherwise unsubstituted or substituted, provided that when n is 1, p is 1; X 1 is selected from alk 2 , -C(O)- and -S(O) 2 -, wherein alk 2 is an unsubstituted or substituted C 1-4 alkylene group; X 2 is -C(O)-; and R 4 is unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 5-10 heterocyclyl, unsubstituted or substituted phenyl, or an unsubstitute
  • iV-oxalylglycine derivatives of formula (I) include those listed in Table 1 below:
  • 7V-oxalylglycine derivatives of formula (I) include the dimethyl ester (DME) derivatives of the compounds listed in Table 1 above, i.e. the ester analogues of the compounds listed in Table 1 above in which Z 1 is a methyl group and Y 2 is a methoxy group.
  • DME dimethyl ester
  • the N-oxalylglycine derivative is selected from Al, A2, A3, A4, A5, A6, A7, A8, A9, AlO, Al 1, A12, Bl, B2, B3, B4, B5, B6, B7, B8, B9, BlO, Bl 1, B12, Cl, C2, C3, C4, C5, C6, C7, C8, C9, ClO, CI l, C12, Dl, D2, D3, D4, D5, D6, D7, D8, D9, DlO, DI l, D12, El, E2, E3, E4, E5, E6, E7, E8, E9, ElO, El l, E12, Fl, F2, F3, F4, F5, F6, F7, F8, F9, FlO, FIl, F12, Gl, Ic, A1_DME, A2_DME, A3_DME, A4_DME, A5_DME, A6_DME, A7_DME, A8_DME, A
  • the jV-oxalylglycine derivative is selected from Al, B12, C2, C3, C4,
  • the N-oxalylglycine derivative is selected from B12, C2, C3, C4, C5, C12, D2, DIl, D12, F8, Fl 1 and F12.
  • the compound of the invention is a hydroxamic acid derivative of formula (II):
  • B is a 5- or 6- membered aryl or heteroaryl ring
  • R 5 is selected from hydrogen and unsubstituted or substituted Cj -6 alkyl
  • R 6 is selected from hydrogen, hydroxyl, unsubstituted or substituted Ci -6 alkoxy, unsubstituted or substituted aryloxy, unsubstituted or substituted Ci -6 alkyl, unsubstituted or substituted C 2-6 alkenyl, unsubstituted or substituted C 2-6 alkynyl, cyano, amino, nitro, halo, carboxy, unsubstituted or substituted Ci -6 alkylamino, unsubstituted or substituted di(Ci- 6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, unsubstituted or substituted amido, unsubstituted or substituted acylamido, unsubstituted or substituted ester, unsubstituted or substituted acyl, unsubstituted or substituted acyloxy and -OR 66
  • R 7 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl
  • R 8 is selected from hydrogen and unsubstituted or substituted Ci -6 alkyl; wherein B is otherwise substituted or unsubstituted; or a pharmaceutically acceptable salt thereof.
  • B is a 6- membered aryl or heteroaryl ring. More typically, B is a 6- membered aryl ring, i.e. a benzene ring.
  • B is otherwise unsubstituted, i.e. the only non-hydrogen substituents present on the ring B are -R 6 (when R 6 is other than hydrogen), -OR 5 and -C(O)NR 7 OR 8 .
  • R 5 is hydrogen or unsubstituted Ci -4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 5 is hydrogen.
  • R 7 is hydrogen or unsubstituted C M alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 7 is hydrogen.
  • R 8 is hydrogen or unsubstituted Ci -4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 8 is hydrogen.
  • R 6 is selected from hydrogen, unsubstituted or substituted C 1-6 alkoxy and unsubstituted or substituted phenoxy. More typically, R 6 is hydrogen, unsubstituted phenoxy or unsubstituted C 1-4 alkoxy (for instance methoxy, ethoxy, propoxy or butoxy). Even more typically, R is hydrogen, methoxy or unsubstituted phenoxy.
  • B is a benzene ring and the hydroxamic acid derivative is of formula (Ila):
  • R 5 , R 6 , R 7 and R 8 are as defined above.
  • R is selected from hydrogen, unsubstituted or substituted C 1-6 alkoxy and unsubstituted or substituted phenoxy; and R , R and R , which are the same or different, are independently selected from hydrogen and unsubstituted C 1-4 alkyl.
  • the hydroxamic acid derivative is selected from any one of the following compounds 5a, 5b and 5c:
  • the compound of the invention is a heteroaryl derivative of formula
  • R 9 is selected from hydrogen and unsubstituted or substituted C 1-6 alkyl;
  • X 3 is N or CR 13 ;
  • R 10 is selected from hydrogen, carboxy, unsubstituted or substituted ester, hydroxyl, halo, cyano, amino, nitro and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di(C 1-4 )alkylamino;
  • R 12 and R 13 which are the same or different, are independently selected from hydrogen, hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino or di(Q ⁇ alkylamino, or from a group -X ⁇ Y 6 , wherein X 6 is a bond , -O-, -S-, -NR'-, an unsubstituted or substituted moiety selected from -0-(C 1-4 alkylene)- , -S-(C 1-4 alkylene)- and -NR'-(C 1-4 alkylene)- or unsubstituted or substituted, saturated or partially unsaturated C 1-4 alkylene which is optionally interrupted with O, S or NR', and Y 6 is hydrogen, halogen, or unsubstituted or substituted aryl or heteroaryl,
  • R 11 is selected from hydrogen, hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 , unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 1-4 alkylamino, unsubstituted or substituted Ui(C 1 ⁇ alkylamino, a group of formula (Ilia) and a group of formula (IQb):
  • each R 14 is independently selected from hydroxyl, halo, cyano, amino, nitro, carboxy, -C(O)OCH 3 and unsubstituted or substituted C 1-4 alkyl, C 1-4 alkoxy, Cj -4 alkylamino or di(C 1-4 )alkylamino;
  • X 4 is NR 17 or O, wherein R 17 is hydrogen or unsubstituted or substituted C 1-6 alkyl; v is O or 1 and L 1 is selected from unsubstituted or substituted C 1-10 alkylene, unsubstituted or substituted arylene and unsubstituted or substituted heteroarylene, wherein said C 1-I0 alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or Cp 4 alkyl;
  • R 15 is hydrogen, amino, unsubstituted or substituted C 1-I0 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(C 1-6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, unsubstituted or substituted C 3-10 carbocyclyl, unsubstituted or substituted C 3-10 heterocyclyl, unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted aryloxy, -NHC(O)OR 65 and -OR 66 , wherein R 65 is unsubstituted or substituted C 1-10 alkyl and wherein R is selected from unsubstituted or substituted C 3-10 carbocyclyl, unsubstit
  • X 5 is NR 18 or O, wherein R 18 is hydrogen or unsubstituted or substituted C 1-6 alkyl; w is 0 or 1 and L 2 is selected from unsubstituted or substituted C 1-10 alkylene, unsubstituted or substituted arylene and unsubstituted or substituted heteroarylene, wherein said C 1-10 alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or Cr 4 alkyl;
  • R 16 is hydrogen, amino, unsubstituted or substituted C 1-I0 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(C 1-6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, unsubstituted or substituted C 3-10 carbocyclyl, unsubstituted or substituted C 3-10 heterocyclyl, unsubstituted or substituted C 1-10 alkoxy, unsubstituted or substituted aryloxy, -NHC(O)OR 65 and -OR 66 , wherein R 65 is unsubstituted or substituted C 1-I0 alkyl and wherein R 66 is selected from unsubstituted or substituted C 3-I0 carbocyclyl,
  • R 9 is hydrogen or unsubstituted C 1-4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 9 is hydrogen or methyl. Even more typically, R 9 is hydrogen.
  • R 10 is typically hydrogen.
  • R 10 is typically selected from carboxy and unsubstituted or substituted ester. More typically, when X 3 is N, R 10 is selected from carboxy and -C(O)OR 101 wherein R 101 is unsubstituted C 1-4 alkyl.
  • R 10 is selected from carboxy and -C(O)OCH 3 .
  • R 12 is typically hydrogen.
  • R 12 is a group -X 6 - Y 6 .
  • R 11 is typically hydrogen.
  • R 12 is a group -X 6 - Y 6
  • X 3 is typically -CH.
  • R 13 is hydrogen.
  • R 12 is a group -X 6 -Y 6
  • R 10 is typically carboxy or an unsubstituted ester, hi one embodiment, when R 12 and/or R 13 represents -X 6 - Y 6 , when X 6 is a bond, Y 6 is other than hydrogen.
  • X 6 is a a bond, -O-, -NR'-, unsubstituted or substituted -NR'-(C 1-4 alkylene)- or unsubstituted or substituted, saturated or partially unsaturated C 1-4 alkylene.
  • Y 6 is hydrogen, halogen (e.g. bromine), unsubstituted or substituted phenyl or unsubstituted naphthyl. hi one embodiment, Y 6 is unsubstituted or substituted phenyl or unsubstituted naphthyl.
  • substituents include halogen (e.g. fluorine), C 1-4 alkyl, C 1-4 alkoxy, C 1-4 thioalkyl, nitro, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, carboxy and (C 1-4 alkyl) ester. More preferred substituents include fluorine, methyl, ethyl, methoxy, ethoxy, thiomethyl, nitro, amino, carboxy and methyl ester.
  • fluorine e.g. fluorine
  • C 1-4 alkyl C 1-4 alkoxy
  • C 1-4 thioalkyl nitro, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, carboxy and (C 1-4 alkyl) ester.
  • substituents include fluorine, methyl, ethyl, methoxy, ethoxy, thiomethyl, nitro, amino, carboxy and
  • each R 14 is typically selected from hydroxyl, halo, cyano, amino, unsubstituted C 1-4 alkyl, unsubstituted C 1-4 alkoxy, unsubstituted C 1-4 alkylamino and unsubstituted di(Ci- 4 )alkylamino. More typically, each R 14 is selected from hydroxyl, halo, cyano, amino, unsubstituted Ci -4 alkyl and -CF 3 .
  • X 4 is NR 17 or O, wherein R 17 is hydrogen or unsubstituted C M alkyl, for instance methyl, ethyl, propyl or butyl. More typically, X 4 is NH or O.
  • L 1 is typically unsubstituted or substituted Ci -I0 alkylene, which C 1-10 alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or Ci- 4 alkyl. More typically, L 1 is unsubstituted or substituted C 1-10 alkylene which is uninterrupted.
  • L 1 is unsubstituted C 1-I0 alkylene, for instance unsubstituted C 1-6 alkylene or unsubstituted C 1-4 alkylene. L 1 is usually methylene, ethylene or n-propylene.
  • R 15 is typically hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted Ci -I0 alkyl. More typically, when v is 0, R 15 is unsubstituted or substituted aryl, or unsubstituted or substituted Ci-I 0 alkyl.
  • R 15 is unsubstituted or substituted phenyl, or unsubstituted or substituted C 1-6 alkyl. Even more typically, when v is 0, R 15 is unsubstituted phenyl or unsubstituted C 1-4 alkyl.
  • v is 0, X 4 is O and R is hydrogen or unsubstituted or substituted C 1- 6 alkyl. Typically, in this embodiment, R 15 is hydrogen or methyl.
  • R 15 is typically selected from hydrogen, amino, unsubstituted or substituted aryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted Oi(C 1- 6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, and -NHC(O)OR 65 , wherein R 65 is unsubstituted or substituted C 1-10 alkyl.
  • R 15 is selected from hydrogen, amino, unsubstituted or substituted phenyl, unsubstituted or substituted C 1-6 alkylamino and -NHC(O)OR 65 , wherein R 65 is unsubstituted or substituted C 1-6 alkyl.
  • R 15 is selected from hydrogen, amino, unsubstituted or substituted phenyl, and -NHC(O)OR 65 , wherein R 65 is unsubstituted C 1-4 alkyl.
  • R 65 is tert-butyl, sec-butyl, n-butyl, n- propyl, iso-propyl, ethyl and methyl. More typically, R 65 is butyl, for instance tert-butyl.
  • X 5 is NR 18 or O, wherein R 18 is hydrogen or unsubstituted C 1-4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, X 5 is NH or O. Even more typically, X 5 is NH.
  • L 2 is typically unsubstituted or substituted C 1-1O alkylene, which C 1-10 alkylene is optionally interrupted by O, S, N(R") or arylene, wherein R" is H, aryl or Cj- 4 alkyl. More typically, L 2 is unsubstituted or substituted C 1-I0 alkylene which is uninterrupted. Even more typically, L 2 is unsubstituted C 1-10 alkylene, for instance unsubstituted Ci -6 alkylene or unsubstituted Ci -4 alkylene. L 2 is usually methylene, ethylene or n-propylene.
  • R 16 When w is O, R 16 is typically unsubstituted or substituted aryl, or unsubstituted or substituted Ci -I0 alkyl. More typically, when w is O, R 16 is unsubstituted or substituted phenyl, or unsubstituted or substituted Ci -6 alkyl. Even more typically, when w is O, R 16 is unsubstituted phenyl or unsubstituted Ci -4 alkyl.
  • w is 1.
  • R 16 is selected from hydrogen, amino, unsubstituted or substituted aryl, unsubstituted or substituted C 1-6 alkylamino, unsubstituted or substituted di(Ci- 6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, and -NHC(O)OR 65 , wherein R 65 is unsubstituted or substituted C 1-1O alkyl.
  • R 16 is selected from amino, unsubstituted or substituted di(C 1-6 )alkylamino, unsubstituted or substituted arylamino, unsubstituted or substituted arylalkylamino, and -NHC(O)OR 65 , wherein R 65 is unsubstituted or substituted C 1-6 alkyl.
  • the heteroaryl derivative has formula (IIIc):
  • R 9 and R 12 are as defined above and wherein R 10 is selected from carboxy and unsubstituted or substituted ester.
  • R 9 is hydrogen or unsubstituted C 1-4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 9 is hydrogen or methyl. Even more typically, R 9 is hydrogen. Usually, in this embodiment, R 12 is hydrogen. Typically, in this embodiment R 10 is selected from carboxy and -C(O)OR 101 wherein R 101 is unsubstituted Ci -4 alkyl. Even more typically, R 10 is selected from carboxy and -C(O)OCH 3 .
  • the heteroaryl derivative of formula (IIIc) is the following compound 8a:
  • heteroaryl derivative has formula (HId):
  • R 9 , R 10 , R 12 , R 13 , u, R 14 , X 4 , L 1 , v and R 15 are as defined above.
  • each of R 10 , R 12 and R 13 is hydrogen and u is O.
  • the heteroaryl derivative of formula (HId) is any one of the following compounds 7a and 3 to 13 in Table 2:
  • the heteroaryl derivative has formula (HIe): wherein R 9 , R 10 , R 12 , R 13 , X 5 , L 2 , w and R 16 are as defined above.
  • each of R 10 , R 12 and R 13 is hydrogen.
  • the heteroaryl derivative of formula (HIe) is any one of the following compounds 1 and 2:
  • heteroaryl derivative has formula (THf):
  • R is as defined above;
  • R , 10 is selected from carboxy and unsubstituted or substituted ester
  • R 12 is a group -X 6 - Y 6 , wherein X 6 and Y 6 are as defined above.
  • R 9 is hydrogen or unsubstituted C 1-4 alkyl, for instance methyl, ethyl, propyl or butyl. More typically, R 9 is hydrogen or methyl. Even more typically, R 9 is hydrogen.
  • R 10 is selected from carboxy and -C(O)OR 101 wherein R 101 is unsubstituted C 1-4 alkyl. Even more typically, R 10 is selected from carboxy and C(O)OCH 3 .
  • the groups R 10 and -C(O)OR 9 are identical.
  • the heteroaryl derivative of formula (Illf) is a compound of formula (HIf) wherein R 9 is hydrogen and R 10 is carboxy and X 6 and Y 6 are as defined as set out in Table 2a, preferably as set out for compounds Z2 to Z20 in Table 2a.
  • dimethyl esters corresponding to the dicarboxylic acids Zl to Z20 above.
  • N-oxalylglycine derivatives of formula (I) in which n is 2 can be prepared in accordance with the following scheme and as described in Example 2 below:
  • Reagents and conditions a) methyloxalyl chloride, Et 3 N, CH 2 CI 2 , O 0 C, 5 min, then r.t. 1 h, 78 % (12c); b) 1N NaOH, 2 h, r.t, 96 % (1c).
  • 7V-oxalylglycine derivatives of formula (I) can be produced by analogy with the methods shown in the above schemes and described in Examples 1 and 2 below, from starting materials which are commercially available or which may readily be synthesised by known techniques.
  • Hydroxamic acid derivatives of formula (II) can be prepared as described in Example 3 below, with derivatives other than compounds 5a, 5b and 5c being preparable by analogy with those methods, from starting materials that are commercially available or which can be synthesised by known techniques.
  • Heteroaryl derivatives of formula (III) can be produced as described in detail in
  • Heteroaryl derivatives of formula (III) other than the exemplified compounds, 7a, 8a, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13, can be produced by analogy with the relevant methods described in Examples 4 and 5, from starting materials which are commercially available or which may readily be synthesised by known techniques.
  • Heteroaryl derivatives of formula (DIf) can be produced according to the following scheme, with subsequent derivatisation of intermediate 11 as described in Example 6. Derivatisation may be achieved, for example, via a Buchwald-Hartig coupling with a variety of aromatic amines under non-hydrolytic conditions (Cs 2 CO 3 /toluene) and Pd 2 (dibenzyl acetone) 3 /4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene catalysis.
  • Heteroaryl derivatives of formula (IEf) other than the exemplified compounds can be produced by analogy with the relevant methods described in Example 6, from starting materials which are commercially available or which may readily be synthesised by known techniques.
  • Compounds of the invention have been found to inhibit the human 2-oxoglutarate- dependant JMJD2 subfamily of histone demethylases, and in particular JMJD2E and JMJD2A. Such inhibitors are useful in changing the epigenetic state of cells resulting in the inhibition / activation of chromatin remodelling, multiple gene activation / deactivation, and in treating cancer and other conditions characterised by undesirable cellular proliferation, and psychiatric disorders including depression.
  • the compounds of the invention may be useful as therapeutic agents, in particular for use in treating cancers and other conditions characterised by undesirable cellular proliferation, and neurological or psychiatric disorders including depression.
  • Conditions which may be treated by the compounds of the invention include conditions characterised by undesirable cellular proliferation, that is to say, conditions characterised by an unwanted or undesirable proliferation of normal or abnormal cells. Such conditions may involve neoplastic or hyperplastic growth of any type of cell.
  • conditions characterised by undesirable cellular proliferation include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g., histocytoma, glioma, astrocytoma, osteoma), hypoxic tumours, cancers (e.g., lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma) and leukemias.
  • neoplasms and tumours e.g., histocytoma, glioma, astrocytoma, osteoma
  • hypoxic tumours e.g., cancers (e.g., lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer,
  • the condition characterised by undesirable cellular proliferation is cancer, for instance breast cancer, pancreatic cancer or ovarian cancer.
  • Conditions which may be treated by the compounds of the invention also include psychiatric and neurological disorders.
  • the psychiatric or neurological disorder includes but is not limited to depression, schizophrenia, Huntington disease, autism, Alzheimers, obsessive compulsive disorder, post traumatic stress syndrome, bulimia nervosa, tourettes syndrome, bipolar disorder, serotonin syndrome, and anxiety disorder.
  • these diseases include but are not limited to Rubinstein-Taybi syndrome, Fragile-X syndrome, Coffm-Lowry synrome, Rett syndrome, Alpha-thalassemia/mental retardation syndrome X-linked, Immunodeficiency-centromeric instability-facial abnormalities syndrome, myotonic dystrophy, Prader-Willi syndrome, Angleman syndrome, addiction, and learning and memory disorders.
  • the modulation of vernalization in plants by use of the compounds of the invention include uses in commercial farming of plant crops, flowers, trees and shrubs.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention as defined above and a pharmaceutically acceptable carrier or diluent.
  • a compound of the invention is formulated for use as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier or diluent.
  • the compositions are typically prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the compound may be administered in any conventional form, for instance as follows:
  • compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the complex in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulphate.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, maize
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Such preparations may be manufactured in a known manner, for example by means of mixing, granulating, tableting, sugar coating or film coating processes.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the complex is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the complex in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyoxyethylene sorbitan monooleate.
  • the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, such as sucrose or saccharin.
  • preservatives for example, ethyl or n-propyl p-hydroxybenzoate
  • colouring agents such as sucrose or saccharin.
  • Oily suspension may be formulated by suspending the complex in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by this addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occuring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids an hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.
  • a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and coloring agents.
  • sterile injectable aqueous or oleaginous suspensions This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables;
  • Example 1 Synthesis of compounds A1-A12, B1-B12, C1-C12, D1-D12, E1-E12, Fl to F12 and Gl, and the dimethyl esters (DMEs) thereof
  • H-D-Tyrosine methyl ester hydrochloride (5 g, 21.6 mmol) was suspended in dichloromethane (80 ml), to which was added triethylamine (6.6 ml, 47.48 mmol) and N, N- dimethylaminopyridine (264 mg, 2.16 mmol) under a blanket of nitrogen. The mixture was cooled to between 0° and 10° C whilst methyl chlorooxylate (2.067 ml, 5% in dichloromethane) was added dropwise. The mixture was then left to warm to room temperature and stirred for one hour. This left a biphasic mixture composing a yellow lower solution and an upper solid layer. HPLC-MS showed the majority was product plus an impurity.
  • Each reactive building block (see list below in Table 5) was dissolved in dimethylacetamide (1.5 ml) and H-D-tyrosine methyl ester (112.5 mg, 0.4 mmol) was added to each reaction. To these reactions was added triethylamine (55.6 ⁇ l, 0.4 mmol) and dimethylaminopyridine (catalytic quantitiy). The mixtures were then stirred and heated (40° C) for 48 hours. Each reaction was purified by Cl 8 reverse phase chromatography.
  • H-D-Tyrosine t-butyl ester (2.37 g, 10 mmol) was suspended in dichloromethane (50 ml) and N, N'-diisopropylethylamine (3.5 ml, 20 ml) was added. To this mixture was added dropwise over 30 minutes a dichloromethane (10 ml) solution oft-butyl oxalyl chloride (1.81 g, 11 mmol) which produced a white vapour. The reaction was left for 72 hours and the mixture was washed with sodium hydroxide (50 ml, IM), then with water (50 ml).
  • Each acid chloride or sulphonyl chloride (list below in Table 10) was dissolved in dimethylacetamide (1.5 ml), to each reaction was added D-tyrosine bis t-butyl ester (109.6 mg, 0.3 mmol). To these reactions was then added triethylamine (67 ⁇ l, 0.48 mmol) and dimethylaminopyridine (trace, catalytic amount). The reactions were left to stir at 4O 0 C overnight. Each reaction was checked for product and starting material and each showed the reactions to be complete. The solvent was evaporated and dichloromethane added (0.5 ml) followed by trifluoroacetic acid (0.5 ml) were added, the reactions were left stirring for two hours followed by three hours without stirring. The solvent was removed and the compounds purified by reverse phase chromatography (details below).
  • N,5-Dihydroxy-2-methoxybenzamide To a stirred solution of 27 (150 mg, 0.55 mmol) under a nitrogen atmosphere in MeOH (5 mL) was added 10 % Pd-C (29 mg, 0.27 mmol). After 5 min the reaction vessel was evacuated and flushed with hydrogen (3 times) and stirred at 23 0 C for 1 h. The catalyst was removed by filtration and the solvent removed under reduced pressure to afford 89 mg (89 %) of 5b as a white solid.
  • Reagents and conditions a) Phenol, K 2 CO 3 , CuO, pyr, 13 h, reflux, 58 %; b) ITMAH][AI 2 CI 7 ], CH 2 CI 2 , 6 h, reflux, 73 %; c) MEMCI, NaH, THF, 1 h, rt, 88 %; d) NaOH (1 N), MeOH, 3 h, 70 0 C, 99 %; e) EDCI, HOBt, Et 3 N, NH 2 OBn-HQ, CH 2 CI 2 , 7 h, rt, 84 %; f) HQ (1 N), MeOH, 1.5 h, reflux, 74 %; g) 10 % Pd/C, H 2 , MeOH, 1 h, rt, 68 %.
  • Reagents and conditions a) H 2 SO 4 , MeOH, 15 h, reflux, 92 %; b) BzCI, Et 3 N, CH 2 CI 2 , 1 h, rt, 92 %; c) NaOH (1 N), THF/MeOH, 1 h, rt, 76 %; d) MEMCI, NaH, THF, 1.5 h, rt, 99 %; e) MeONa, THF, 1.5 h, 4 0 C, 92 %; f) R 1 I or R 1 Br, K 2 CO 3 , DMF, 2 h at 80 0 C then 14 h at 60 0 C, 66 %; g) NaOH (1 N), MeOH, 3 h, 70 0 C, 81 % ; h) EDCI, HOBt, Et 3 N, NH 2 OBn.HCI, CH 2 CI 2 , 7 h, rt, 85 %; j) H
  • Reagents and conditions a) MEMO, NaH, THF, 1.5 h, rt, 98 %; b) NaOH (1 N), MeOH, 3 h, 70 0 C, 93 %; c) EDCI 1 HOBt, Et 3 N, NH 2 OBn.HCI, CH 2 Q 2 , 12 h, rt, 89 %; d) HCI (1 N), MeOH, 1 h, reflux, 65 %; g) 10 % Pd/C,H 2 , MeOH, 30 min, rt, 99 %.
  • Example 4 Synthesis of compound 8a
  • Reagents and conditions a) NaOH, KMnO 4 , H 2 0, 80 0 C, 3 h; b) MeOH, H 2 SO 4 , reflux, 24 h, 20 %; c) NaOH, MeOH, r.t, 2 h, 86 %.
  • Methyl 4 '-(3-(tert-butoxycarbonylamino)propylcarbamoyl)-2,2 '-bipyridine-4-carboxylate (L) To a solution of 7a (200 mg, 0.95 mmol), G (198 mg, 1.14 mmol), HOBt (140 mg, 1.04 mmol) in DMF (25 mL) was added triethylamine (132 ⁇ L, 0.95 mmol) and EDCI (182 mg, 0.95) in DMF (2 mL). The mixture was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water.
  • Compound 3 can be prepared by an analogous reaction using J as the starting material instead of L.
  • Methyl 4'-(phenylcarbamoyl)-2,2'-bipyridine-4-carboxylate (M) To a solution of 7a (120 mg, 0.47 mmol), aniline (47 ⁇ L, 0.51 mmol), HOBt (69 mg, 0.51 mmol) in DMF (10 mL) was added triethylamine (64 ⁇ L, 0.47 mmol) and EDCI (89 mg, 0.47 mmol) in DMF (2 mL). The mixture was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was partitioned between EtOAc (10 mL) and water (10 mL).
  • Example 6 Synthesis of heteroaryl derivatives Zl to Z20 and corresponding dimethyl esters The synthesis of these compounds was carried out in accordance with the following schemes Zl and Z2. Reference numerals used in this example relate to schemes Zl and Z2.
  • dicarboxylic acids Z3 to Z7, Z9 to ZI l, Zl 3, Z14 and Zl 6 to Zl 9 were produced from their corresponding dimethyl esters by a method analogous to that described above for Z2.
  • JMJD2A, B, C, D and E the recombinant forms of the catalytic domains of 5 of the 6 predicted human JMJD2 demethylase genes (JMJD2A, B, C, D and E) were produced in E. coli and purified to > 95% purity (by SDS-PAGE analyses).
  • JMJD2E was chosen as the most suitable for inhibition work because of its stability, activity levels and substrate selectivity profile.
  • Formaldehyde release by demethylation of the histone peptide substrate was monitored by its oxidation to give formate as catalyzed by FDH, which is carried out concomitantly with the reduction of nicotinamide adenine dinucleotide (NAD + ).
  • NAD + nicotinamide adenine dinucleotide
  • the production of NADH was monitored by fluorescence spectroscopy (Table 1).
  • a construct encoding residues 1-337 was PCR amplified from a synthetic entry clone using the gene sequence from XM_372429 and LIC cloned into the pNIC28Bsa4 vector.
  • the expression plasmid was transformed into a phage-resistant strain E. coli BL21 (D ⁇ 3) containing the pRARE2 plasmid supplying tRNA for rare codons.
  • Culture (5 mL) from an overnight growth was used to inoculate each litre of 12 litres of Terrific Broth containing 50 ⁇ g mL "1 kanamycin and 34 ⁇ g mL "1 of chloramphenicol, grown in 2.5 L baffled Erlenmeyer flasks at 37 °C.
  • the cells were harvested by centrifugation and frozen at -80 °C.
  • the cells were resuspended in 50 mM HEPES pH 7.5, 500 mM NaCl, 20 mM imidazole, 5% glycerol, and were lysed by high pressure homogenisation using an Avestin C3 homogeniser.
  • the lysate was clarified by centrifugation in a Avanti J-20XP (Beckman-Coulter) using a JLA-16.250 rotor at 21,500 rpm for 60 min at 4 0 C. The supernatant was carefully decanted off and applied to a 2 mL bed volume Nickel Sepharose (GE Healthcare) gravity flow column. The column was then washed with 200 ml of 50 mM HEPES pH 7.5, 500 mM NaCl, 40 mM imidazole, 5% glycerol and finally eluted with 50 mM HEPES pH 7.5, 500 mM NaCl, 250 mM imidazole, 5% glycerol, collecting the eluted protein.
  • the protein was then EDTA-treated by addition of 500 mM EDTA pH 8.0 to a final concentration of 0.05 mM, for 1 h.
  • the protein was then concentrated to 5 mL and applied to a 16/60 Superdex 200 gel filtration column equilibrated with 10 mM HEPES pH 7.5, 500 mM NaCl, 5% glycerol and attached to an AKTA Purifier.
  • the protein was pooled based on purity from SDS-PAGE analysis of the collected fractions.
  • the H3K9me 3 peptide [ARK(me 3 )STGGK-NH 2 ] was synthesised using a CS-Bio CS336S automated peptide synthesizer, using PL-AMS resin (Polymer Laboratories) and a Rink amide linker. Fmoc-protected amino acids were activated using diisopropylcarbodiimide/1- hydroxybenzotriazole. Cleavage of the completed peptides from the resin was carried out with trifluoroacetic acid/triethylsilane (97.5/2.5).
  • the peptide was purified by reverse phase HPLC on a C18-silica column (Grace- Vydac) prior to use, and the peptide mass was confirmed by MALDI-TOF-MS.
  • FDH 0.1 unit
  • NAD + 500 ⁇ M
  • ascorbate 100 ⁇ M
  • Fe(II) variant concentrations
  • JMJD2E 2 ⁇ M
  • ARK(me 3 )STGGK-NH 2 peptide variant concentrations
  • 2-OG various concentrations
  • inhibitor variant concentrations
  • Inhibitors were dissolved in DMSO at various concentrations, and added to the assay mixture such that the final DMSO concentration was 5 %.
  • MALDI-TOF-MS Inhibition Assay Methods For compounds which were shown to inhibit FDH, a MALDI-TOF-MS inhibition assay was employed. JMJD2E (2 ⁇ M), Fe(II) (10 ⁇ M), ascorbate (100 ⁇ M), 2-OG (50 ⁇ M) and peptide (10 ⁇ M), in HEPES buffer, 50 mM, pH 7.5, with inhibitor (stock solutions in DMSO, final in- assay concentration varied, but final DMSO concentration was 5 % of assay mix) were incubated for 30 min at 37 0 C, before 1:1 quenching with methanol followed by addition of four volumes of 20 mM triammonium citrate.
  • the protein was mixed with equimolar amounts of Fe(II) and two inhibitors at concentration of 15 ⁇ M and incubated for 30 minutes at 37 0 C prior ESI-MS analysis.
  • the sample cone voltage was typically 80 V with a source temperature of 40 °C and with an acquisition/scan time of 10s/ls.
  • Example 8 Initial Results, including inhibition data for the iV-oxalylglycine derivative Ia, the hydroxamic acid derivatives 5a, 5b and 5c and the heteroaryl derivatives 7a and 8a
  • N-oxalyl glycine, Ia inhibited JMJD2E with an IC50 value of 78 ⁇ M; this value decreased to 24 ⁇ M with 30 min preincubation (Table 14).
  • HDACs histone deacetylases
  • JmjC demethylases employ active site metal co factors, (Zn(II) or Fe(II), respectively, involved in catalysis, hi addition to the active site Fe(II), the JMJD2 demethylases also contain a Zn binding site located close to the active site entrance. Therefore, the known HDAC inhibitors trichostatin A (TSA, 2), 2 suberoylanilide hydroxamic acid (SAHA, 3), and butyrate 4 were tested.
  • TSAHA 2 suberoylanilide hydroxamic acid
  • JMJD2A and JMJD2E have -65% identity over their catalytic domains
  • 9 JMJD2A and JMJD2E have -65% identity over their catalytic domains
  • 5a, 5b and 5c low molecular weight aromatic hydroxamic acids intended to chelate the Fe(II) of JMJD2E in a manner similar to that predicted for 3.
  • Variation in the Fe(II) concentration showed that 5a is a 2-OG competitor, and that inhibition was not predominantly due to Fe(II) chelation in solution.
  • pyridine carboxylates (6a-6f), some of which are known inhibitors of collagen and HEF prolyl hydroxylases.
  • Electrospray ionisation (ESI)-MS analyses under non-denaturing conditions verified binding of the inhibitors to the JMJD2E.Fe(II).Zn(II) complex.
  • Competitive binding experiments were then used to rank the most potent inhibitors qualitatively in terms of binding affinity for JMJD2E (Table 15 below), hi these competitive experiments, the seven inhibitors observed to bind the best in the initial MS analyses, were ranked by experiments in which pairs of inhibitors were mixed with JMJD2E and allowed to compete with each other for the binding.
  • N.A means that formaldehyde dehydrogenase assays were not possible due to partial inhibition of FDH by the inhibitor under pre-incubation conditions. Note that JMJD2E concentration in all assays was relatively high (2 ⁇ M) in order for sufficient NADH to be produced to be detected reliably. The IC 50 value reported for 2 (found to be an FDH inhibitor) was obtained by MALDI-TOF-MS, monitoring turnover of trimethyl peptide, not using the FDH coupled assay. Assays were all carried out in triplicate, and SEMs in log(IC 50 ) values were below 10%. The ranking of inhibitor binding to the JMJD2E.Fe(II). Zn(II) complex was assessed by non-denaturing ESI-MS.
  • Inhibitors that bound the best in the group were first ranked by knock-out experiments, where two inhibitors were mixed with JMJD2E and allowed to compete with each other for the binding in the active site. Results revealed that 6a bound the tightest, followed by 5a, 7a, 3 and 8a (see Table 14). These five inhibitors were also ranked as the most potent in the group in the FDH assays for JMJD2E. Additional ESI-MS competition experiments showed that 8 bound stronger than Ia and Ic. Finally, when Ia and Ic competed for JMJD2E binding, compound of the invention Ic was observed to bind slightly better.
  • the compound number in bold at the intersection between row and column indicates which of the two compounds bound more strongly to the enzyme complex when the two inhibitors were allowed to compete.
  • Table 16 below gives the results (in terms Of IC 50 values) of the FDH coupled inhibition assay on compounds 3 to 11, and the results of the non-denaturing MS binding assay on those compounds.
  • JMJD2 family of enzymes were identified by screening a compound library based upon an NOFD scaffold against recombinant JMJD2E. These inhibitors are the N-oxalylglycine derivatives of formula (I) shown in Table 1 above, compounds Al to A12, Bl to B12, Cl to C12, Dl to D12, El to E12, Fl to F12, Gl and Ic. ESMS was used to determine the relative binding ability of compounds in the library. These preliminary data were then verified using the in vitro JMJD2E activity assay (the FDH coupled inhibition assay), as set out in Figure 1.
  • reaction mix (see Table 17 below) was incubated at 37°C/5% CO2 for 30 minutes in a water bath, in order to facilitate compound binding. 4 ⁇ l of this mixture were then delivered to the electrospray instrument using the robot, sample was then delivered to the TOF MS instrument.
  • the sample cone voltage was varied between 50, 80 and 200V and spectra recorded at each. The delivery voltage was varied between 1.60-1.72kV in order to obtain the optimum spectra with the majority of samples behaving best at the lower end of this range. Not all compounds produced a clean spectrum, probably due to sample contamination (see results).
  • JMJD2E inhibition assay The coupled enzyme assay using recombinant JMJD2E and formaldehyde dehydrogenase (FDH) was employed. 2-OG, Fe(II) and an H3K9me3 peptide were included as substrates for JMJD2E as well as NAD+ for the FDH reaction.
  • the coupled reaction proceeds as illustrated below yielding formaldehyde from the JMJD2E reaction which provides substrate for the FDH, accordingly, NADH is produced and may be monitored spectrophotometrically.
  • the following demethylation reaction is catalyzed by the JMJD2 oxygenases, and is shown for the conversion of the trimethyl lysine state to the dimethyl lysine state:
  • IC50 values were determined for certain compounds selected from the 12 outlined above (see Table 19 below). Not all compounds were available in sufficient quantity for the assay. Time constraints and software problems with the plate reader prevented IC50 data for all compounds being collected.
  • IC 50 values for compounds Zl to Z20 were determined as follows. Compounds were dissolved in DMSO or DMSCVH 2 O (1:1, v/v) at stock concentrations of 10 mM and used at final DMSO concentrations of 1%. Measurements were performed in triplicates in black 384-well microplates with a non-binding surface (Corning Inc., Cat. No.
  • Inhibition was calculated relative to positive control reactions (containing no JMJD2E) and negative control reactions (containing JMJD2E in the absence of inhibitors). Percentage inhibition was plotted again the logarithm of compound concentration and fitted in GraphPad Prism 5.0TM using a sigmoidal dose-response model. FDH and JMJD2E were kindly provided by the Structural Genomics Consortium, Oxford.
  • Table 20 below gives full inhibition data against JMJD2E (200 nM) for compounds Zl to Z20 (8-point serial dilutions from 100 ⁇ M). For compounds that are not sufficiently potent to allow fitting of a sigmoidal dose-response curve, residual activities at the highest dose are reported instead of IC 50 values. Plots of percentage inhibition appear in Figures 4a and 4b.
  • Tablets each weighing 0.15 g and containing 25 mg of a compound of the invention, are manufactured as follows:
  • the active compound, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size.
  • Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium is added, carefully mixed and processed into tablets.
  • the active compound is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).
  • the compound of the invention is dissolved in a mixture of the glycerol and most of the purified water.
  • An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavour.
  • the volume is made up with purified water and mixed well.

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Abstract

Cette invention concerne un composé qui est un dérivé de iV-oxalylglycine de formule (I) : un dérivé d’acide hydroxamique de formule (II) : ou un dérivé hétéroaryle de formule (III) : n, Z1, Z2, Y1, Y2, A, p, X1, X2, m, R4, B, R5, R6, R7, R8, R9, X3, R10, R11 et R12 étant tels que définis dans la description, ou un de leurs sels pharmaceutiquement acceptables. Ces composés sont des inhibiteurs de la sous-famille des JMJD2 humains à 2-oxoglutarate des histone déméthylases, en particulier les JMJD2E. Ces inhibiteurs sont utilisés pour changer l’état épigénétique des cellules entraînant l’inhibition/l’activation de la recomposition de la chromatine, l’activation/la désactivation de multiples gènes, et dans le traitement du cancer et d’autres maladies caractérisées par une prolifération cellulaire indésirable et des troubles psychiatriques y compris la dépression.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012007007A1 (fr) * 2010-07-15 2012-01-19 Epitherapeutics Aps Inhibiteurs de hdme
WO2012052390A1 (fr) * 2010-10-19 2012-04-26 Glaxo Group Limited Dérivés de n-2-(2-pyridinyl)-4-pyrimidinyl-bêta-alanine en tant qu'inhibiteurs d'histone déméthylase jmjd3
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WO2012150042A1 (fr) 2011-05-04 2012-11-08 Cellzome Ag Composés et procédés pour identifier des molécules ayant une interaction avec les histones déméthylases et pour purifier des protéines d'histone déméthylase
EP2592154A1 (fr) 2011-11-09 2013-05-15 Cellzome Ag Produits d'immobilisation et procédés d'identification de molécules d'interaction de déméthylase d'histone et de purification des protéines de déméthylase d'histone
WO2013143597A1 (fr) 2012-03-29 2013-10-03 Glaxo Group Limited Inhibiteurs d'enzymes de déméthylase
US20140024558A1 (en) * 2009-10-27 2014-01-23 Glaxo Group Limited Method of Treatment
WO2014089364A1 (fr) * 2012-12-06 2014-06-12 Quanticel Pharmaceuticals, Inc Inhibiteurs de l'histone déméthylase
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WO2016210292A1 (fr) 2015-06-25 2016-12-29 Children's Medical Center Corporation Procédés et compositions se rapportant à l'expansion, l'enrichissement et la conservation de cellules souches hématopoïétiques
WO2017161001A1 (fr) 2016-03-15 2017-09-21 Children's Medical Center Corporation Procédés et compositions concernant l'expansion de cellules souches hématopoïétiques
WO2017207813A1 (fr) 2016-06-03 2017-12-07 Oryzon Genomics, S.A. Acides hétéroaryl-carboxyliques utilisés en tant qu'inhibiteurs de l'histone déméthylase
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WO2018149986A1 (fr) * 2017-02-16 2018-08-23 Oryzon Genomics, S.A. Dérivés de 2-(bicyclo-hétéroaryl)-isonicotinique en tant qu'inhibiteurs d'histone déméthylase
WO2018219478A1 (fr) 2017-06-02 2018-12-06 Oryzon Genomics, S.A. Hétéroaryl-carboxamides comme inhibiteurs de l'histone déméthylase
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Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4743587A (en) * 1985-09-10 1988-05-10 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
DE3713842A1 (de) * 1987-04-22 1988-11-17 Schering Ag Substituierte cyclische komplexbildner, komplexe und komplexsalze, verfahren zu deren herstellung und diese enthaltende pharmazeutische mittel
HUT61973A (en) * 1990-12-03 1993-03-29 Celltech Ltd Process for producing peptidyl derivatives and pharmaceutical compositions comprising such compounds as active ingredient
UA48121C2 (uk) * 1993-11-04 2002-08-15 Сінтекс (С.Ш.А.) Інк. Інгібітори матричних металопротеаз і фармацетична композиція на їх основі
US5691381A (en) * 1995-04-18 1997-11-25 The Dupont Merck Pharmaceutical Company Hydroxamic and carbocyclic acids as metalloprotease inhibitors
EP0848957A1 (fr) * 1995-09-08 1998-06-24 Kanebo Ltd. INHIBITEUR DE SOLUBILISATION DE LIGAND Fas
JPH0987291A (ja) * 1995-09-26 1997-03-31 Wakamoto Pharmaceut Co Ltd 新規なアラニン誘導体
GB9609794D0 (en) * 1996-05-10 1996-07-17 Smithkline Beecham Plc Novel compounds
KR20000048811A (ko) * 1996-10-02 2000-07-25 한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터 히드록삼산 유도체
GB9804504D0 (en) * 1998-03-03 1998-04-29 Leo Pharm Prod Ltd Matrix metalloproteinase inhibitors
IT1317049B1 (it) * 2000-06-23 2003-05-26 Sigma Tau Ind Farmaceuti Composti utili per la preparazione di medicamenti ad attivita'inibitrice della fosfodiesterasi iv.
WO2005027856A2 (fr) * 2003-03-17 2005-03-31 Cengent Therapeutics Inhibiteurs du facteur letal du charbon
RU2008108632A (ru) * 2005-08-10 2009-09-20 Джонс Хопкинс Юниверсити (Us) Полиамины, используемые при противопаразитарных и противораковых терапиях и в качестве ингибиторов лизин-специфической деметилазы
JP5421238B2 (ja) * 2008-03-13 2014-02-19 株式会社ヤクルト本社 Ｍｍｐ阻害剤

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US20140024558A1 (en) * 2009-10-27 2014-01-23 Glaxo Group Limited Method of Treatment
WO2012007008A1 (fr) * 2010-07-15 2012-01-19 Epitherapeutics Aps Inhibiteurs de hdme
WO2012007007A1 (fr) * 2010-07-15 2012-01-19 Epitherapeutics Aps Inhibiteurs de hdme
EP2595613B1 (fr) * 2010-07-22 2019-01-09 The U.S.A. as represented by the Secretary, Department of Health and Human Services Composés destinés à être utilisés dans une méthode destinée à prévenir ou à traiter une infection virale
WO2012052390A1 (fr) * 2010-10-19 2012-04-26 Glaxo Group Limited Dérivés de n-2-(2-pyridinyl)-4-pyrimidinyl-bêta-alanine en tant qu'inhibiteurs d'histone déméthylase jmjd3
CN102731487B (zh) * 2011-04-01 2015-06-17 季昀 衍生自4,4’-二酸-2,2’-双吡啶的三牙配位子、金属错合物及其应用
CN102731487A (zh) * 2011-04-01 2012-10-17 季昀 衍生自4,4’-二酸-2,2’-双吡啶的三牙配位子、金属错合物及其应用
WO2012150042A1 (fr) 2011-05-04 2012-11-08 Cellzome Ag Composés et procédés pour identifier des molécules ayant une interaction avec les histones déméthylases et pour purifier des protéines d'histone déméthylase
EP2592154A1 (fr) 2011-11-09 2013-05-15 Cellzome Ag Produits d'immobilisation et procédés d'identification de molécules d'interaction de déméthylase d'histone et de purification des protéines de déméthylase d'histone
WO2013143597A1 (fr) 2012-03-29 2013-10-03 Glaxo Group Limited Inhibiteurs d'enzymes de déméthylase
US9604961B2 (en) 2012-12-06 2017-03-28 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US9714230B2 (en) 2012-12-06 2017-07-25 Celgene Quantical Research, Inc. Histone demethylase inhibitors
JP2016501882A (ja) * 2012-12-06 2016-01-21 クオンティセル ファーマシューティカルズ，インク． ヒストンデメチラーゼ阻害剤
WO2014089364A1 (fr) * 2012-12-06 2014-06-12 Quanticel Pharmaceuticals, Inc Inhibiteurs de l'histone déméthylase
US9908865B2 (en) 2012-12-06 2018-03-06 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US10173996B2 (en) 2012-12-06 2019-01-08 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US9458129B2 (en) 2012-12-06 2016-10-04 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
EP3763367A1 (fr) * 2012-12-06 2021-01-13 Celgene Quanticel Research, Inc. Dérivés de pyridine-pyrazole comme inhibiteurs de l'histone déméthylase
US9107916B2 (en) 2012-12-06 2015-08-18 Quanticel Pharmaceuticals, Inc. Histone demethylase inhibitors
US8987461B2 (en) 2012-12-06 2015-03-24 Quanticel Pharmaceuticals, Inc. Histone demethylase inhibitors
EP2969007A4 (fr) * 2013-03-14 2016-07-27 Quanticel Pharmaceuticals Inc Inhibiteurs d'histone déméthylase
US9701657B2 (en) 2013-03-14 2017-07-11 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US9527829B2 (en) 2013-03-14 2016-12-27 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
US10273222B2 (en) 2013-03-14 2019-04-30 Celgene Quantscel Research, Inc. Histone demethylase inhibitors
JP2016514159A (ja) * 2013-03-14 2016-05-19 クオンティセル ファーマシューティカルズ，インク． ヒストンデメチラーゼ阻害剤
US9963441B2 (en) 2013-03-14 2018-05-08 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
CN109574865A (zh) * 2013-08-30 2019-04-05 英属哥伦比亚大学 单胺氧化酶-b选择性抑制剂化合物、其药物组合物及应用
CN105566145A (zh) * 2014-11-03 2016-05-11 广州德汇行医药科技有限公司 氨基酸衍生物及其应用
WO2016210292A1 (fr) 2015-06-25 2016-12-29 Children's Medical Center Corporation Procédés et compositions se rapportant à l'expansion, l'enrichissement et la conservation de cellules souches hématopoïétiques
EP4049665A1 (fr) 2016-03-15 2022-08-31 Children's Medical Center Corporation Procédés et compositions associées à l'expansion de cellules souches hématopoïétiques
WO2017161001A1 (fr) 2016-03-15 2017-09-21 Children's Medical Center Corporation Procédés et compositions concernant l'expansion de cellules souches hématopoïétiques
WO2017207813A1 (fr) 2016-06-03 2017-12-07 Oryzon Genomics, S.A. Acides hétéroaryl-carboxyliques utilisés en tant qu'inhibiteurs de l'histone déméthylase
EP3579834A4 (fr) * 2017-02-10 2021-04-28 Temple Otorongo LLC Traitement du diabète et d'états métaboliques associés au moyen de modulateurs épigénétiques
WO2018149986A1 (fr) * 2017-02-16 2018-08-23 Oryzon Genomics, S.A. Dérivés de 2-(bicyclo-hétéroaryl)-isonicotinique en tant qu'inhibiteurs d'histone déméthylase
WO2018219478A1 (fr) 2017-06-02 2018-12-06 Oryzon Genomics, S.A. Hétéroaryl-carboxamides comme inhibiteurs de l'histone déméthylase
CN107540574B (zh) * 2017-09-19 2021-06-11 成都西岭源药业有限公司 R-联苯丙氨醇的制备方法
CN107540574A (zh) * 2017-09-19 2018-01-05 成都西岭源药业有限公司 R‑联苯丙氨醇的制备方法
WO2019236766A1 (fr) 2018-06-06 2019-12-12 Ideaya Biosciences, Inc. Procédés de culture et/ou d'expansion de cellules souches et/ou de cellules progénitrices engagées dans une lignée à l'aide de composés lactames
CN109456262A (zh) * 2018-12-22 2019-03-12 山东大学 基于抑制组蛋白去甲基化酶化合物及其制备方法与抗胃癌应用
CN109438339A (zh) * 2018-12-22 2019-03-08 山东大学 Rbp2酶抑制剂小分子化合物wxsa-072a及其制备方法与抗胃癌应用
CN114409557A (zh) * 2022-01-19 2022-04-29 中南民族大学 一种具有神经保护活性的炭角酸及其制备方法和应用
CN114409557B (zh) * 2022-01-19 2022-08-30 中南民族大学 一种具有神经保护活性的炭角酸及其制备方法和应用

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