WO2008127734A2 - Lysine-specific demethylase inhibitors - Google Patents

Lysine-specific demethylase inhibitors Download PDF

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Publication number
WO2008127734A2
WO2008127734A2 PCT/US2008/004874 US2008004874W WO2008127734A2 WO 2008127734 A2 WO2008127734 A2 WO 2008127734A2 US 2008004874 W US2008004874 W US 2008004874W WO 2008127734 A2 WO2008127734 A2 WO 2008127734A2
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Prior art keywords
alkyl
substituted
aralkyl
independently
unsubstituted
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PCT/US2008/004874
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French (fr)
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WO2008127734A3 (en
Inventor
Patrick M. Woster
Robert A. Casero
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The Johns Hopkins University
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Priority to US12/595,955 priority Critical patent/US20110092601A1/en
Priority to EP08742925A priority patent/EP2142287A4/en
Priority to JP2010503095A priority patent/JP2010523685A/en
Publication of WO2008127734A2 publication Critical patent/WO2008127734A2/en
Publication of WO2008127734A3 publication Critical patent/WO2008127734A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • This invention pertains to polyamine compounds, polyamine/guanidine compounds, and polyamine/biguanide compounds, which bear allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, or other reactive moieties and which are useful for inhibition of lysine-specific demethylase.
  • the compounds are useful in treatment of cancer.
  • Polyamines are found in both eukaryotic and prokaryotic cells and figure prominently in regulation of the cell cycle and cell division.
  • Agents specifically targeting polyamine biosynthesis such as polyamine analogs, have been shown to have therapeutic effect in treatment of cancer, parasitic diseases, and other indications.
  • These antiproliferatvie effects have been demonstrated to be, in part, a result of agent-induced decreases in the natural intracellular polyamines resulting from inhibition, down- regulation of polyamine biosynthesis and/or up regulation of polyamine catabolism. See, e.g., Wang and Casero, J, Biochem. 139: 17 (2006); Casero et al., Proc. West. Pharmacol. Soc.
  • LSDl lysine-specific demethylase 1
  • the recently discovered enzyme lysine-specific demethylase 1 has been shown to play a significant role in epigenetic control of gene expression (see Shi et al., Cell 1 19:941 (2004) and International Patent Application No. WO 2006/071608).
  • the LSDl enzyme appears to be up-regulated in some forms of human cancer (see Huang, Y.; Greene, E.; Murray-Stewart, T.; Goodwin, A.C.; Baylin, S.B.; Woster, P.M.; Casero, R.A.: Inhibition of the lysine specific demethylase, LSDl, by novel polyamine analogues results in re-expression of aberrantly silenced genes. Proc.
  • Dimethyl lysine 4 histone H3 (H3K4me2) is a transcription activating chromatin mark at gene promoters, and demethylation of this mark by LSDl, a homologue of polyamine oxidases, may broadly repress gene expression.
  • specific inhibitors for LSDl have the potential to act as antitumor agents by limiting the demethylation of dimethyl lysine 4 histone H3 (H3K4me2), thus promoting the reexpression of multiple, aberrantly silenced genes.
  • LSDl inhibitors that bear allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, or other moieties that will form covalent bonds in the LSDl active site, and thus provides a novel set of irreversible inhibitors of LSDl .
  • the invention embraces polyamine, polyamine/guanidine, and polyamine/biguanide compounds having at least one functional group selected from allene
  • the compounds are derivable from lysine and have the functional groups - NR-CH(-COOH)-(CH 2 ) 4 NR-, -NR-CH(-COOR)-(CH 2 ) 4 NR-, or -NR-CH(-CONHR)-(CH 2 ) 4 NR- where each R is independently H, CpC 8 alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl .
  • the invention also embraces uses of those compounds for inhibition of lysine-specific demethylase-1 , and treatment of diseases involving lysine-specific demethylase-1.
  • the invention embraces compounds of the formula
  • each R is independently H, alkyl, or aralkyl
  • each A is independently a Ci-C 8 n-alkyl
  • B is independently selected from Ci-Ci 2 n-alkyl or C 3 -C 8 cycloalkyl
  • B is independently selected from CpC 8 n-alkyl. In another embodiment, B is -(CH 2 ) ? -.
  • At least one E is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one E that is Ci -C 8 alkyl-C ⁇ CH is C r C 8 n-alkyl-C ⁇ CH
  • the at least one E that is Ci-C 8 alkyl-C ⁇ CH is propargyl (-CH 2 -
  • At least one E is Ci-C 8 alkyl-cyclopropane. In one embodiment, the at least one E that is Ci-C 8 alkyl-cyclopropane is Ci-C 8 n-alkyl- cyclopropane. In another variation, the at least one E that is Ci-C 8 alkyl-cyclopropane is
  • the at least one E that is cyc!opropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, C]-C 8 alkyl, which may be a CpC 8 n-alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl, which may be a CpC 8 n- alkyl.
  • the at least one E that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
  • the at least one E that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is ⁇ -N,N- dimethylaminocycloprop-2-yl.
  • -C 8 alkyl-C ⁇ CH, -C,-C 8 alkyl-cyclopropane, -C( O)C,- C 8 alkyl substituted with at least one halo group and -cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl, such as a polyaminobisguanidine or polyaminobiguanide or N-alkylated variation thereof .
  • N-alkylated polyaminoguanidine intends a polyaminoguanidine wherein the imine nitrogen of the guanidine is alkylated, such as in a 2-methylguanadine derivative.
  • each A is -(CH 2 )3- and B is -(CH 2 J 4 -.
  • each A is -(CH 2 ) 3 - and B is -(CH 2 ) 7 -.
  • the compound is a polyaminoguanidine of the formula
  • each Ri is independently selected from the group consisting Of Ci-C 8 substituted or unsubstituted alkyl, C 4 -C 15 substituted or unsubstituted cycloalkyl, C3-C 1 5 substituted or unsubstituted branched alkyl, C 6 -C 2O substituted or unsubstituted aryl, C 6 -C 2O substituted or unsubstituted heteroaryl, C 7 -C 24 substituted or unsubstituted aralkyl, C 7 -C 24 substituted or unsubstituted heteroaralkyl or
  • At least one Ri is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one Ri that is Ci-C 8 alkyl-C ⁇ CH is Ci-C 8 n-alkyl-C ⁇ CH
  • the at least one R 1 that is Cj-C 8 alkyl-C ⁇ CH is propargyl (CH 2 -
  • At least one Ri is C 1 -C 8 alkyl-cyclopropane.
  • the at least one R 1 that is C 1 -C 8 alkyl-cyclopropane is C 1 -C 8 n-alkyl- cyclopropane.
  • the at least one Ri that is Ci-C 8 alkyl-cyclopropane is
  • the at least one of Ri that is C(O)C i-Cgalkyl substituted with at least one halo group is C(O)(CH 2 ) n CH 2 Cl where n is 1-7.
  • the at least one of Ri that is C(O)C i-C 8 alkyl substituted with at least one halo group is chloromethylcarbonyl (C(O)CH 2 Cl).
  • at least one of Ri is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one Ri that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a Ci-C 8 n-alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl, which may be a Ci-C 8 n- alkyl.
  • the at least one Ri that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl wnere R is C
  • the at least one Ri that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is ⁇ -N,N- dimethylaminocycloprop-2-yl.
  • the compound is of the formula (I) wherein one Ri is a
  • C O -C 20 substituted or unsubstituted aryl such as a single ring substituted or unsubstituted aryl, including without limitation, substituted or unsubstituted phenyl.
  • the compound is of the formula (I) and each Ri is phenyl.
  • q is 1, m and p are 3, and n is 4.
  • q is 1, m and p are 3, and n is 7.
  • the compound is of the formula (I) wherein one R
  • Ri may be a Ci-C 8 substituted or unsubstituted linear alkyl, such as methyl or ethyl. In one embodiment, Ri is methyl. Ri may comprise or be a C 4 -Ci 5 cycloalkyl group, such as a cycloalkyl group containing a linear alkyl group, where the cycloalkyl group is connected to the molecule either via its alkyl or cycloalkyl moiety. For instance, Ri may be cyclopropylmethyl or cyclohexylmethyl.
  • Ri is a C3-Q5 branched alkyl group such as isopropyl.
  • the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine.
  • Ri is a CpC 8 alkyl group substituted with an amine such that Ri may be e.g., alkyl-NH 2 or an alkyl-amine-alkyl moiety such as -(CH 2 ) y NH(CH 2 )zCH 3 where y and z are independently an integer from 1 to 8.
  • Ri is -(CH 2 ) B NH 2 .
  • the compound is of the formula (I) where one Ri is a
  • CyC 24 substituted or unsubstituted aralkyl which in one embodiment is an aralkyl connected to the molecule via its alkyl moiety (e.g., benzyl).
  • each Ri is an aralkyl moiety wherein the alkyl portion of the moiety is substituted with two aryl groups and the moiety is connected to the molecule via its alkyl group.
  • at least one or both Ri is a C 7 -C 24 aralkyl wherein the alkyl portion is substituted with two phenyl groups, such as when R] is 2,2-diphenylethyl or 2,2- dibenzylethyl.
  • each Ri of formula (I) is 2,2-diphenylethyl and n is 1, 2 or 5. In one embodiment, each Ri of formula (I) is 2,2-diphenylethyl, n is 1, 2 or 5 and m and p are each 1.
  • At least one Ri is hydrogen.
  • the other Ri may be any moiety listed above for R] , including an aryl group such as benzyl.
  • any of the compounds of formula (I) listed above include compounds where at least one or both of R 2 is hydrogen or a Ci-C 8 substituted or unsubstituted alkyl.
  • each R 2 is an unsubstituted alkyl such as methyl.
  • each R 2 is hydrogen.
  • any of the compounds of formula (I) listed above may be compounds where q is 1 and m and p are the same. Accordingly, the polyaminoguanidines of formula (1) may be symmetric with reference to the polyaminoguanidine core (e.g., excluding Ri). Alternatively, the compounds of formula (I) may be asymmetric, e.g., when q is 0. In one embodiment, m and p are 1. In one embodiment, q is 0. In one embodiment, n is an integer from 1 to 5.
  • each R], R 2 , m, n, p and q disclosed in reference to formula (I) intends and includes all combinations thereof the same as if each and every combination of Ri, R 2 , m, n, p and q were specifically and individually listed.
  • the compound is a polyaminobiguanide or N-alkylated polyaminobiguanide.
  • An N-alkylated polyaminobiguanide intends a polyaminobiguanide wherein at least one imine nitrogen of at least one biguanide is alkylated.
  • the compound is a polyaminobiguanide of the formula (II):
  • one of Ri is a Ci-C 8 substituted or unsubstituted alkyl, such as those listed above in reference to formula (I).
  • R is a C 1 -C 8 substituted alkyl
  • the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine.
  • R 1 is a C 1 -C 8 alkyl group substituted with an amine such that R 1 may be e.g., alkyl-NH 2 or an alkyl-amine-alkyl moiety such as -(CH 2 ) y NH(CH 2 )zCH 3 where y and z are independently an integer from 1 to 8
  • R 1 is -(CH 2 ) 3 NH 2 .
  • R 1 may also be a C 4 -Ci 5 substituted or unsubstituted cycloalkyl or a C 3 -C 15 substituted or unsubstituted branched alkyl, such as described for formula (I) above.
  • one of Ri is a C 6 -C 2O substituted or unsubstituted aryl, such as those listed above in reference to formula (I).
  • q is 1, m and p are 3, and n is 4.
  • q is 1, m and p are 3, and n is 7.
  • At least one Ri is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one Ri that is CpC 8 alkyl-C ⁇ CH is Ci-C 8 n-alkyl-C ⁇ CH
  • the at least one Ri that is Ci-C 8 alkyl-C ⁇ CH is propargyl (CH 2 -
  • At least one Ri is Ci-C 8 alkyl-cyclopropane.
  • the at least one Rj that is C)-C 8 alkyl-cyclopropane is Ci-C 8 n-alkyl- cyclopropane.
  • the at least one Ri that is Ci-C 8 alkyl-cyclopropane is
  • the at least one of Ri that is C( O)C
  • at least one of Ri is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one Ri that is eye lopropy 1-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a CpC 8 n-alkyl, or aralkyl where the alkyl moiety
  • the compound is of the formula (II) where at least one or both Ri is a C 7 -C 24 substituted or unsubstituted aralkyl, which in one embodiment is an aralkyl connected to the molecule via its alkyl moiety.
  • is an aralkyl moiety wherein the alkyl portion of the moiety is substituted with one or two aryl groups and the moiety is connected to the molecule via its alkyl moiety.
  • At least one or both Ri is an aralkyl wherein the alkyl portion is substituted with two phenyl or benzyl groups, such as when Ri is 2,2-diphenylethyl or 2,2- dibenzylethyl.
  • each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5.
  • each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5 and m and p are each 1.
  • any of the compounds of formula (II) listed above include compounds where at least one or both Of R 2 is hydrogen or a Ci-C 8 substituted or unsubstituted alkyl. In one embodiment, each R 2 is an unsubstituted alkyl, such as methyl. In another embodiment, each R 2 is a hydrogen.
  • any of the compounds of formula (II) listed above include compounds where q is 1 and m and p are the same. Accordingly, the polyaminobiguanides of formula (II) may be symmetric with reference to the polyaminobiguanide core (e.g., excluding R
  • each Ri, R 2 , m, n, p and q disclosed in reference to formula (II) intends and includes all combinations thereof the same as if each and every combination of R], R 2 , m, n, p and q were specifically and individually listed.
  • the compound is a polyamine.
  • the polyamine is of the formula (III):
  • R 9 is a Ci-C 8 substituted or unsubstituted alkyl.
  • R9 is a Ci-C 8 substituted alkyl, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, R9 is a Ci-C 8 alkyl group substituted with an amine such that R 9 may be e.g., alkyl-NH 2 or an alkyl-amine-alkyl moiety such as — (CH 2 ) y NH(CH 2 )zCH 3 where y and z are independently an integer from 1 to 8 In one embodiment, R 9 is - (CH 2 ) 3 NHCH 2 CH 3 .
  • one of R 3 and R 4 is hydrogen.
  • one of R 3 and R 4 is a CpC 8 substituted or unsubstituted alkyl, including without limitation a substituted or unsubstituted n-alkyl (such as n-pentyl), substituted or unsubstituted branched (C 3 -C 8 ) alkyl (such as 2- methylbutyl) or substituted or unsubstituted (C 3 -C 8 ) cycloalkyl (such as cyclohexylmethyl). Larger chain alkyl (linear, branched and cyclic) are also considered, such as a C9-C 1 5 substituted or unsubstituted alkyl.
  • R 3 and R 4 is a Ci-C 8 substituted or unsubstituted n-alkyl
  • the moiety may be any n-alkyl, such as methyl or ethyl.
  • the alkyl may be substituted with one or more substituents such as those listed under "Substituted alkyl” and includes alkyl substituted with any halogen, such as a monohaloalkyl, dihaloalkyl, trihaloalkyl or multihaloalkyl, including a perhalooalkyl, for example, perfluoroalkyl and percholoralkyl, such as trifluoromethyl or pentachloroethyl.
  • one of R 3 and R 4 is a C 6 -C 20 substituted or unsubstituted aryl.
  • one Of R 3 and R 4 is a Ce-C 20 substituted aryl, which aryl groups may be substituted with one or more substituents such as those listed under "Substituted aryl.”
  • one of R 3 and R 4 is a C 6 -C 20 substituted aryl, which aryl groups may be substituted with one or more alkyoxy (such as -OCH3), alkyl (including a branched alkyl such as ter/-butyl), or halo groups (such as fluoro).
  • one of R 3 and R 4 is a halo-substituted aryl or a halo-substituted aralkyl, such as 2,4,5-trifluorophenyl or 2,4,5-trifluorobenzyl.
  • one Of R 3 and R 4 is a di-alkyl-monoalkoxy-substituted aryl or aralkyl, such as 4,5-di-ter/-butyl-2- methoxybenzyl or 4,5-di-teA-/-butyl-2-methoxyphenyl.
  • one of R 3 and R 4 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl such as an aralkyl or heteroaralkyl connected to the molecule via its alkyl moiety. In one embodiment, one of R 3 and R 4 is a substituted aralkyl or heteroaralkyl connected to the molecule via its alkyl moiety.
  • a substituted aralkyl may be substituted with one or more substituents such as those listed under "Substituted aralkyl” and a substituted heteroaralkyl may be substituted with one or more substituents such as those listed under "Substituted heteroaralkyl.”
  • one of R 3 and R 4 is a substituted heteroaralkyl having at least one nitrogen atom.
  • one of R 3 and R 4 is a single ring heteroaralkyl having at least one nitrogen atom.
  • one or both of R 3 and R 4 is l-(2-N-methylpyrrolyl)-methyl.
  • at least one of R 3 and R 4 is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one of R 3 and R 4 that is Ci-C 8 alkyl-C ⁇ CH is Ci-C 8 n-alkyl- C ⁇ CH
  • At least one of R 3 and R 4 is Ci-C 8 alkyl- cyclopropane. In one embodiment, the at least one of R 3 and R 4 that is C]-C 8 alkyl- cyclopropane is C)-C 8 n-alkyl-cyclopropane. In another variation, the at least one of R 3
  • R 4 that is CpC 8 alkyl-cyclopropane is cyciopropylmethyl ( ).
  • the at least one of R 3 and R 4 that is C( O)C
  • At least one of R 3 and R 4 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one Of R 3 and R 4 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a Ci-C 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl, which may be a Ci-C 8 n-alkyl.
  • the at least one Of R 3 and R 4 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is 1-N-
  • the at least one of R 3 and R 4 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
  • R 8 is a Ci-C 8 substituted or unsubstituted alkyl.
  • Rs 1 R 9 , R 6, R 7 and R 8 may be a Ci-C 8 substituted or unsubstituted alkyl.
  • at least 1 or at least 2 or at least 3 of R5, R9, R 6 , R7 is a Ci-C 8 unsubstituted n-alkyl, such as methyl or ethyl.
  • both R 6 and R 5 are methyl or ethyl.
  • at least one R 7 and R 8 is methyl or ethyl.
  • R 7 is methyl.
  • R5, R9, R 6 , R 7 , R 8 , m, n, y, z and p disclosed in reference to formula (III) intends and includes all combinations thereof the same as if each and every combination of R 3 , R 4 , R 5 , R9, R 6 , R?, R 8 , m, n, y, z and p were specifically and individually listed.
  • the polyamine is of the formula (IV):
  • At least one of A 1 Rio, Rn 1 Rn and Ri 3 comprises an alkenyl moiety.
  • the alkene portion branches off the direct chain connecting the nitrogen atoms; that is, no more than one sp 2 -hybridized carbon occurs in the carbon nodes along the shortest path from one nitrogen flanking A, Rio, and/or Rn to the other flanking nitrogen.
  • A is (CH 2 ) n and n is 1. In one embodiment, A is ethene- 1 ,1 -diyl. In one embodiment, A is (CH 2 ) n and one or both of R] 2 and Ri 3 comprises an alkenyl moiety, such as propen-2-yl.
  • at least one of Ri 2 and R n is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one of R] 2 and Rj 3 that is Ci-C 8 alkyl-C ⁇ CH is Q-C 8 n- alkyl-C ⁇ CH
  • the at least one of R ]2 and R] 3 that is Ci-C 8 alkyl- C ⁇ CH is propargyl (CH 2 -C ⁇ CH).
  • At least one of Ri 2 and Ri 3 is Ci-C 8 alkyl- cyclopropane.
  • the at least one of Ri 2 and R ]3 that is Ci-C 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane.
  • Rn that is Ci-C 8 alkyl-cyclopropane is cyclopropylmethyl ( ).
  • At least one of Ri 2 and R] 3 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one of Ri 2 and R) 3 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a Ci-C 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl, which may be a C]-C 8 n-alkyl.
  • the at least one of Ri 2 and Ri 3 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is 1-N-
  • the at least one of R )2 and Ri 3 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
  • Rn 1 Ri 2 and R )3 disclosed in reference to formula (IV) intends and includes all combinations thereof the same as if each and every combination of A, n, Ri 0 Rn R !2 and
  • the polyamine is of the formula (V):
  • At least one of Ri 5 and Ri 4 is hydrogen.
  • at least one of R 15 and R] 4 is a Ci-C 8 substituted or unsubstituted n-alkyl or (C 3 -C 8 ) branched alkyl, such as methyl, ethyl, 3-methyl-butyl, 2-ethyl-butyl, 5-NH 2 -pent- 1 -yl, prop-l-yl-methyl(phenyl)phosphinate and the like or any Q-C 8 substituted or unsubstituted n-alkyl or (C 3 -C 8 ) branched alkyl listed above in reference to formulae (I)- (IV).
  • At least one of R 15 and Rj 4 is a Ci-C 8 substituted or unsubstituted n-alkyl, such as an n-alkyl substituted with a methyl(phenyl)phosphinate moiety or a NH 2 -substitued n-alkyl.
  • one of R 15 and Ri 4 is Ci-C 8 substituted or unsubstituted n-alkyl or (C 3 -C 8 ) branched alkyl moieties, such as when one of Ri5 and R ]4 is 3-methyl-butyl or when one of R 15 and R) 4 is 2-ethyl-butyl.
  • At least one of Ris and Ri 4 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl.
  • at least one of Ri 5 and R14 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl having two rings, such as 2- phenylbenzyl, 4-phenylbenzyl, 2-benzylbenzyl, 3-benzylbenzyl, 3,3,-diphenylpropryl, 3- (benzoimidazolyl)-propyl and the like.
  • At least one of Ri 5 and R )4 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl having one ring, such as 4- isopropylbenzyl, 4-fluorobenzyl, 4-rer/-butylbenzyl, 3-imidazolyl-propyl, 2-phenylethyl and the like.
  • one of R 15 and R )4 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl, such as any of the specific substituted or unsubstituted aralkyl or heteroaralkyl moieties listed for any other formula.
  • at least one of R 15 and R 14 is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one of R] 5 and Ri 4 that is Ci-C 8 alkyl-C ⁇ CH is Ci-C 8 n- alkyl-C ⁇ CH
  • At least one of Ri 5 and Ri 4 is Ci-C 8 alkyl- cyclopropane.
  • the at least one of Rj 5 and Ri 4 that is Ci-C 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane.
  • the at least one of Ri 5 is Ci-C 8 alkyl- cyclopropane.
  • R) 4 that is Ci-C 8 alkyl-cyclopropane is cyclopropylmethyl ).
  • the at least one of Ri 5 and R )4 that is C( O)C
  • at least one of Ri 5 and R ]4 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • 4 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a Ci-C 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC 8 alkyl, which may be a Ci-C 8 n-alkyl.
  • the at least one Ri that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
  • N(CH 3 )R wnere R is c,-C 8 alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl).
  • the at least one of R 15 and R )4 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is dimethylaminocycloprop-2-yl.
  • m and n may be the same or different.
  • n does not equal n, such as when m is 1 and n is 2.
  • n is 2.
  • all possible combinations of m, n, R 15 and Ri 4 are intended.
  • 6 and Ri 7 is hydrogen.
  • at least one or both of R 1 6 and Ri 7 is a Ci-C 8 substituted or unsubstituted alkyl, such as a methyl, ethyl and a Ci-C 8 alkyl substituted with e.g., an -NH-Cj-C 8 alkyl such as when at least one or both of R) 6 and Rn is -(CH 2 ) S NHCH 2 CH 3 .
  • R 1 6, Ri7, m, and n disclosed in reference to formula (V) intends and includes all combinations thereof the same as if each and every combination Of Ri 4 , R 1 5, Ri6, Rn, m, and n were specifically and individually listed.
  • the polyamine is of the formula (VI):
  • At least one of R 18 and R 19 is a C 1 -C 8 n-alkyl substituted with a cycloalkyl group comprising at least two rings.
  • the cycloalkyl group comprising at least two rings may be a spiro, fused or bridged cycloalkyl group.
  • Representative examples of a C 1 -C 8 n-alkyl substituted with a cycloalkyl group comprising two rings include moieties such as 2-(6,6-dimethylbicyclo[3.1.1]heptyl)ethyl and 2-(decahydronaphthyl)ethyl.
  • At least one Of R 18 and Ri 9 is 2-(6,6- dimethylbicyclo[3.1.1]heptyl)ethyl. In one embodiment, at least one of R 18 and Ri 9 are 2- (decahydronaphthyl)ethyl.
  • R 18 and R 19 is a C 7 -C 24 substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings, which rings may be but are not required to be fused.
  • the alkyl portion of the aralkyl or heteroaralkyl moiety is connected to the molecule via its alkyl moiety.
  • R 18 and R 19 may be an aralkyl moiety such as 2-phenylbenzyl, 4-phenylbenzyl, 3,3,-diphenylpropyl, 2-(2- phenylethyl)benzyl, 2-methyl-3-phenylbenzyl, 2-napthylethyl, 4-(pyrenyl)butyl, 2-(3- methylnapthyl)ethyl, 2-(l ,2-dihydroacenaphth-4-yl)ethyl and the like.
  • At least one of R 18 and R] 9 may be a heteroaralkyl moiety such as 3- (benzoimidazolyl)propanoyl, l-(benzoimidazolyl)methanoyl, 2- (benzoimidazolyl)ethanoyl, 2-(benzoimidazolyl)ethyl and the like.
  • at least one Of Ri 8 and Ri 9 is Q-C 8 alkyl-C ⁇ CH.
  • the at least one of R ) 8 and Ri 9 that is Ci-C 8 alkyl-C ⁇ CH is C)-C 8 n- alkyl-C ⁇ CH
  • the at least one of R )8 and R 19 that is Ci-C 8 alkyl- C ⁇ CH is propargyl (CH 2 -C ⁇ CH).
  • At least one of R ) 8 and R 19 is CpC 8 alkyl- cyclopropane. In one embodiment, the at least one of R )8 and R 19 that is C)-C 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane. In another variation, the at least one of Ri 8
  • Ci-C 8 alkyl-cyclopropane is cyclopropylmethyl ).
  • the at least one OfRi 8 and R 1 9 that is C(O)Ci -Qalkyl substituted with at least one halo group is C(O)C 1 -C 4 n-alkyl substituted with at least one chloro group.
  • the at least one of Ri 8 and R 1 9 that is C(O)C i-Cgalkyl substituted with at least one halo group is C(O)(CH 2 ) n CH 2 Cl where n is 1 -7. In another embodiment, the at least one Of Ri 8 and R 1 9 that is C(O)C i-C 8 alkyl substituted with at least one halo group is chloromethylcarbonyl (C(O)CH 2 Cl).
  • At least one of Ri 8 and R 19 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one of Ri 8 and R] 9 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, C r C 8 alkyl, which may be a CpC 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a C]-C 8 alkyl, which may be a CpC 8 n-alkyl.
  • the at least one of Ri 8 and R 19 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is 1 -N-
  • the at least one of R ) 8 and R 19 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l -N,N-dimethylaminocycloprop-2-yl.
  • each of m, n and p is the same, such as when m, n and p are each 1.
  • 9 , m, n and p disclosed in reference to formula (VI) intends and includes all combinations thereof the same as if each and every combination of Ri 8 , R 1 9, m, n and p were specifically and individually listed.
  • the polyamine is of the formula (VII):
  • the compound also comprises at least one moiety selected from the group consisting of /-butyl, isopropyl, 2-ethylbutyl, 1 -methylpropyl, 1-methylbutyl, 3-butenyl, isopent-2-enyl, 2-methylpropan- 3-olyl, ethylthiyl, phenylthiyl, propynoyl, 1 -methyl- lH-pyrrole-2-yl, trifluoromethyl, cyclopropanecarbaldehyde, halo-substituted phenyl, nitro-substituted phenyl, alkyl- substituted phenyl, 2,4,6-trimethylbenzyl, halo-S- substituted phenyl (such as para-(F 3 S)- phenyl, azido and 2-methylbutyl.
  • /-butyl isopropyl, 2-ethylbutyl, 1 -methylpropyl,
  • q is 1. In one embodiment, q is 1 and n is 1.
  • one Of R 20 and R 2 i is hydrogen. In one embodiment one Of R 20 and R 2 ] is Ci-C 8 substituted or unsubstituted alkyl, such as any of the substituted or unsubstituted alkyl moieties mentioned above for formulas (I)-(VI). In one embodiment one of R 20 and R 2 ) is a C 7 -C 24 substituted or unsubstituted aralkyl, such as any of the C 7 -C 24 substituted or unsubstituted aralkyl mentioned above for formulas (I)-
  • at least one of R 20 and R 2) is Ci-C 8 alkyl-C ⁇ CH.
  • the at least one of R 20 and R 2 ] that is Ci-C 8 alkyl-C ⁇ CH is Ci-C 8 n- alkyl-C ⁇ CH
  • At least one of R 20 and R 2) is CpC 8 alkyl- cyclopropane.
  • the at least one of R 20 and R 2 ) that is CpC 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane.
  • R 2 i that is Q-C 8 alkyl-cyclopropane is cyclopropylmethyl ( ).
  • At least one Of R 20 and R 2 ] is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one of R 20 and R 2 ] that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, CpC 8 alkyl, which may be a CpC 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC 8 alkyl, which may be a CpC 8 n-alkyl.
  • the at least one of R 20 and R 2 ) that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is 1-N- where R is Ci-Cgalkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl).
  • the at least one of R 20 and R 2 i that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
  • each R 20 , R 2 i, m, n, q and p disclosed in reference to formula (VII) intends and includes all combinations thereof the same as if each and every combination of R 20 , R 2 i, m, n, q and p were specifically and individually listed.
  • the polyamine is of the formula (VIII):
  • m and p are independently an integer from 1 to 5;
  • X is-(CH 2 )n- or cyclohex-l,3-diyl;
  • n is an integer from 1 to 5;
  • n is 5, and at least one Of R 22 and R 23 is hydrogen.
  • R 22 and R 23 are not both benzyl or cyclopropylmethyl.
  • X is-(CH 2 )n (e.g., CH 2 where n is 1 ).
  • X is CH 2 and m and p are both 1.
  • X is cyclohex-1 ,3- diyl.
  • X is cyclohex-l,3-diyl and m and p are both 1.
  • m and p are not the same, e.g., when m is 3 and p is 4.
  • at least one of R 22 and R 23 is CpC 8 alkyl-C ⁇ CH.
  • the at least one of R 22 and R 23 that is Ci-C 8 alkyl-C ⁇ CH is CpC 8 n- alkyl-C ⁇ CH In another embodiment, the at least one Of R 22 and R 23 that is Ci-C 8 alkyl- C ⁇ CH is propargyl (CH 2 -C ⁇ CH).
  • At least one Of R 22 and R 23 is Ci-C 8 alkyl- cyclopropane. In one embodiment, the at least one of R 22 and R 23 that is CpC 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane. In another variation, the at least one Of R 22
  • R 23 that is CpC 8 alkyl-cyclopropane is cyclopropylmethyl ).
  • At least one of R 22 and R 23 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one of R 22 and R 23 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, Ci-C 8 alkyl, which may be a Ci-C 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC 8 alkyl, which may be a Ci-C 8 n-alkyl.
  • the at least one of R 22 and R 23 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is 1-N-
  • the at least one Of R 22 and R 23 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l -N,N-dimethylaminocycloprop-2-yl.
  • each R 22 , R 23 , m, n and p disclosed in reference to formula (VIII) intends and includes all combinations thereof the same as if each and every combination Of R 22 , R 23 , m, n and p were specifically and individually listed.
  • the polyamine is of the formula (IX):
  • R 24 is an amino-substituted C 3 -C 24 cycloalkyl, such as
  • R 25 is a Ci-C 8 substituted or unsubstituted alkyl, which includes an n-alkyl group substituted with a cycloalkyl, such as in cyclopropylmethyl. In one embodiment, R 25 is cyclopropylmethyl or ethyl. In one embodiment, R 24 is 5-NH 2 -cycloheptyl or 3-NH 2 -cyclopentyl.
  • R 24 is a C 2 -C 8 substituted or unsubstituted alkanoyl or R 24 is a C 7 -C 24 substituted or unsubstituted aralkyl, such as 4-phenylbenzyl.
  • At least one Of R 24 and R 25 is Ci-C 8 alkyl-C ⁇ CH. In one embodiment, the at least one of R 24 and R 25 that is Ci-C 8 alkyl-C ⁇ CH is Ci-C 8 n-alkyl-
  • the at least one of R 24 and R 25 that is Ci-C 8 alkyl-C ⁇ CH is propargyl (CH 2 -C ⁇ CH).
  • At least one Of R 24 and R 25 is Ci -C 8 alkyl- cyclopropane. In one embodiment, the at least one of R 24 and R 25 that is Ci-C 8 alkyl- cyclopropane is Ci-C 8 n-alkyl-cyclopropane. In another variation, the at least one of R 24
  • R 25 that is CpC 8 alkyl-cyclopropane is cyclopropylmethyl ).
  • At least one of R 24 and R 25 is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl.
  • the at least one of R 24 and R 25 that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR 2 where each R is independently H, CpC 8 alkyl, which may be a Ci-C 8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C 8 alkyl, which may be a CpC 8 n-alkyl.
  • the at least one Ri that is cyclopropyl-NR 2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
  • the at least one of R 24 and R 25 that is cyclopropyl-N ⁇ where each R is independently H, alkyl, or aralkyl is 1 -N 5 N- dimethylaminocycloprop-2-yl.
  • each R 24 , R 25 and p disclosed in reference to formula (IX) intends and includes all combinations thereof the same as if each and every combination Of R 24 , R 25 and p were specifically and individually listed.
  • the compound is of the formula (X):
  • alkyl moiety of the aryl group is a Ci-C 8 alkyl
  • W is -NH-, guanidino ( H H ) or
  • X is -O-Ci-C 8 alkyl, OH or NHR 28 , where R 28 is hydrogen, Ci-C 8 alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C 8 alkyl; R 27 is is hydrogen, C r C 8 alkyl or aralkyl where the alkyl moiety of the aryl group is a C
  • X is -OCH 3 .
  • q is 3.
  • q is 4.
  • q is 5.
  • the compound is of the formula (XI):
  • the compound is of the formula (XII):
  • R 26 , W, p, n, t, s, X, q and R 27 are as defined for formula (X) and R 29 is Ci-C 8 alkyl-C ⁇ CH, d-C 8 cyclopropane or C(O)Ci -C 8 alkyl substituted with at least one halo group.
  • R 29 is propargyl, cyclopropylmethyl or chloromethylcarbonyl.
  • the compound is of the formula (XIII):
  • the compound is of the formula (XV):
  • the compound is of the formula (XVI):
  • the alkyl moiety of the aryl group is a Ci-C 8 alkyl
  • W is -NH-, guanidino biguanido ( H H H );
  • p and n are independently an integer from 1 to 5; integer from 1 to 6;
  • q is an integer from 1 to 10;
  • s is 0 or 1 ;
  • X is -O-Ci-C 8 alkyl, OH or NHR 28 , where R 28 is hydrogen, C
  • R 27 is is hydrogen, Ci-C 8 alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C 8 alkyl; and
  • R 2 9 is propargyl, cyclopropylmethyl or chloromethylcarbonyl.
  • X is -OCH 3 .
  • q is 3.
  • q is 4.
  • q is 5.
  • any substituent mentioned in one formula is intended to describe the same substituent in any other formula to the extent that the description conforms to the structural characterization of the formula described.
  • Ri in formula I is intended to describe any other Ri found in any other formula to the extent that the description conforms to the structural characterization of the formula described.
  • any description of, e.g., C)-C 8 substituted or unsubstituted alkyl is intended to describe any other Ci-C 8 substituted or unsubstituted alkyl found in any other formula to the extent that the description conforms to the structural characterization of the formula described.
  • any compounds listed as a particular salt thereof is not intended to limit the compound to such salt or form thereof.
  • the structure may or may not explicitly indicate positive or negative charges or the location thereof, and all possibilities thereof are intended.
  • a compound listed as a 4HBr salt does not limit the compound to only the HBr salt and the compound may or may not show the + or - charges of the HBr salt, but rather all possibilities are intended.
  • (IX) may be in a protected form, such as when any one or more amine (e.g., -NH-) is protected by a protecting group (Pg), such as in (-NPg-).
  • Pg may be any protecting group, such as mesityl (e.g., NMes), Boc (e.g., -NBoc) or any other protecting group such as those described in, e.g. T. W. Green, P. G. M. Wuts, Protective Groups in Organic
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (M).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (I).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (II).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (III).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (IV).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (V).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VI).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VII).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VIII).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (IX).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (X).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XI).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XII).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XIII).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XIV).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XV).
  • the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XVI).
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more compounds, where the compound has an allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, and also at least one guanidine moiety or at least one biguanide moiety, in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (M) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (I) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (II) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (III) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (IV) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (V) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VI) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VII) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VIII) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (IX) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (X) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XI) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XII) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XIII) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XIV) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XV) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XVI) in an amount sufficient to inhibit the enzyme.
  • the enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
  • the disclosure includes all salts of the compounds described herein.
  • the invention also includes all non-salt compounds of any salt of a compound named herein, as well as other salts of any salt of a compound named herein.
  • the salts of the compounds comprise pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are those salts which retain the biological activity of the free compounds and which can be administered as drugs or pharmaceuticals to humans and/or animals.
  • the desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts can also be prepared.
  • the desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.
  • the disclosure includes all solvates of the compounds described herein, such as hydrates (in any ratios, e.g. monohydrates, dihydrates, hemihydrates, sesquihydrates), methanolates, ethanolates, etc.
  • any compound described herein may occur in a combined salt and solvate form, for example the hyclate (monohydrochloride hemiethanolate hemihydrate) form.
  • the disclosure includes all stereoisomers of the compounds described herein, including diastereomers and enantiomers in optically pure or substantially optically pure form, as well as mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers of the compound depicted. For cyclopropyl groups, the structures are intended to embrace all stereoisomers of both cis- and trans-substituted cyclopropyl groups.
  • the disclosure includes all crystal and non-crystalline forms of the compounds described herein, including all polymorphs, polycrystalline, and amorphous forms and any mixtures thereof.
  • alkyl refers to saturated aliphatic and alicyclic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • “Straight-chain alkyl” or “linear alkyl” groups refers to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
  • Ci-C 8 n-alkyl consists of the following groups: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec- butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.
  • groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec- butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, non
  • Cycloalkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple bridged or fused rings, including, but not limited to, groups such as adamantyl or norbornyl groups. Cycloalkyl groups can also contain alkyl groups in addition to the cyclic portion, e.g., 2,6,6-trimethylbicyclo[3.1.1]heptane, 2-methyldecalin (2- methyldecahydronaphthalene), cyclopropylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.
  • Substituted alkyl refers to alkyl groups substituted with one or more substituents including, but not limited to, groups such as halogen (including fluoro, chloro, bromo, and/or iodo-substituted alkyl such as a monohaloalkyl, dihaloalkyl, trihaloalkyl or multihaloalkyl, including a perhalooalkyl, for example, perfluoroalkyl, percholoralkyl, trifluoromethyl or pentachloroethyl), alkoxy, acyloxy, amino (including NH 2 , NHalkyl and N(alkyl) 2 ), hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, acyl, acylamino, amidino, alkyl amidino, thioamidino, aminoacyl, aryl, substituted ary
  • substituted alkyl groups include, but are not limited to, CF 3 , CF 2 CF 3 , and other perfluoro and perhalo groups; -CH 2 -OH; -CH 2 CH 2 CH(NH 2 )CH 3 , etc.
  • Alkyl groups can be substituted with other alkyl groups, e.g., C 3 -C 24 cycloalkyl groups.
  • alkynyl refers to unsaturated aliphatic and alicyclic groups including straight-chain (linear), branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, which contain at least one triple bond (-C ⁇ C-).
  • Hydrocarbon chain or “hydrocarbyl” refers to any combination of straight-chain, branched-chain, or cyclic alkyl, alkenyl, or alkynyl groups, and any combination thereof.
  • Substituted alkenyl “substituted alkynyl,” and “substituted hydrocarbon chain” or “substituted hydrocarbyl” refer to the respective group substituted with one or more substituents, including, but not limited to, groups such as halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl,” or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • Aryl or “Ar” refers to an aromatic carbocyclic group having a single ring
  • Aryls include from 6 to 20 carbon atoms in the ring portion.
  • a preferred range for aryls contains 6 to 12 carbon atoms in the ring portion.
  • Substituted aryls refers to aryls substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl," or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
  • Alkyl designates an alkyl-substituted aryl group, where any aryl can be attached to the alkyl; the alkyl portion can comprise one, two, or three straight chains of 1 to 6 carbon atoms each or one, two, or three branched chains of 3 to 6 carbon atoms each or any combination thereof.
  • Aralkyl groups can consist of two aryl groups connected by an alkyl group, such as diphenylmethane or 2-methyl-l-(phenethyl)benzene.
  • the aralkyl group can be connected to the remainder of the molecule at any available valence on either its alkyl moiety or aryl moiety; e.g., the tolyl aralkyl group can be connected to the remainder of the molecule by replacing any of the five hydrogens on the aromatic ring moiety with the remainder of the molecule, or by replacing one of the alpha-hydrogens on the methyl moiety with the remainder of the molecule.
  • the aralkyl group is connected to the remainder of the molecule via the alkyl moiety.
  • a preferred aryl group is phenyl, which can be substituted or unsubstituted.
  • Substituents for substituted phenyl groups include lower alkyl (-C 1 -C 4 alkyl), or a halogen (chlorine ( Cl), bromine ( Br), iodine ( 1), or fluorine ( F); hydroxy (-OH), or lower alkoxy (-C 1 -C4 alkoxy), such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i- propoxy), and butoxy (either n-butoxy, i-butoxy, sec-butoxy, or tert-butoxy); a preferred alkoxy substituent is methoxy.
  • Substituted phenyl groups preferably have one or two substituents; more preferably, one substituent.
  • a preferred group for the aryl portion is phenyl, which can be unsubstituted or substituted as described immediately above.
  • Heteroalkyl refers to alkyl, alkenyl, and alkynyl groups, respectively, that contain the number of carbon atoms specified (or if no number is specified, having up to 12 carbon atoms) which contain one or more heteroatoms as part of the main, branched, or cyclic chains in the group. Heteroatoms include, but are not limited to, N, S, O, and P; N and O are preferred.
  • Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule at any valence where a hydrogen can be removed, for example, at a heteroatom or at a carbon atom (if a valence is available at such an atom by removing a hydrogen).
  • heteroalkyl groups include, but are not limited to, groups such as -O-CH3, -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -S-CH 2 -CH 2 -CH 3 , -CH 2 -CH(CH 3 )-S-CH 3 , -CH 2 -CH 2 -NH-CH 2 -CH 2 -, l-ethyl-6-propylpiperidino, and morpholino.
  • Heteroaryl or “HetAr” refers to an aromatic carbocyclic group having a single ring (including, but not limited to, examples such as pyridyl, imidazolyl, thiophene, or furyl) or two or more condensed rings (including, but not limited to, examples such as indolizinyl, indole, benzimidazole, benzotriazole, or benzothienyl) and having at least one hetero atom, including, but not limited to, heteroatoms such as N, O, P, or S, within the ring.
  • heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups have between one and five heteroatoms and between one and twelve carbon atoms.
  • “Substituted heteroalkyl,” “substituted heteroalkenyl,” “substituted heteroalkynyl,” and “substituted heteroaryl” groups refer to heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted benzyl, substituted or unsubstituted hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano,
  • the heteroatom(s) and/or the carbon atoms of the group can be substituted.
  • a "heteroaralkyl” group is a heteroaryl group substituted with at least one alkyl group. The heteroatom(s) can also be in oxidized form, if chemically possible.
  • alkoxy refers to an alkyl, alkenyl, alkynyl, or hydrocarbon chain linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i-propoxy), and butoxy (either n-butoxy, i-butoxy, sec- butoxy, or tert-butoxy).
  • halo and halogen as used herein refer to the Group Vila elements (Group 17 elements in the 2005 IUPAC Periodic Table, IUPAC Nomenclature of Inorganic Chemistry) and include Cl, Br, F and I substituents.
  • Protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1999) Protective Groups in Organic Synthesis, (Wiley-Interscience., New York).
  • Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t-butyloxycarbonyl (Boc), t- butyldimethylsilyl (TBS or TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6- nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5 bromo 7-nitroindolinyl, and the like.
  • Mts mesitylenesulfonyl
  • CBz or Z benzyloxycarbonyl
  • Boc t-butyloxycarbonyl
  • TBDMS t-
  • Hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4 nitrophenethyloxymethyloxycarbonyl). Synthetic methods — synthesis of alkylpolyamines
  • Scheme 1 illustrates a useful pathway to various polyamine analogs.
  • the tetramesitylated intermediate 8 can be readily alkylated at both terminal nitrogens, since the hydrogens on these nitrogens are rendered acidic by the adjacent mesityl protecting group.
  • Alkylation in the presence of 1.2 to 1.4 equivalents of alkyl halide or tosylate affords primarily the monosubstituted product 9, and disubstituted materials and unreacted starting material can then be separated and recycled (Bellevue et al., Bioorg. Med. Chem. Lett. 6:2765 (1996); Zou et al., Bioorg. Med. Chem. Lett. 1 1 : 1613 (2001)).
  • the resulting monoalkylated derivative 9 can then be deprotected (30% HBr in AcOH), or realkylated with a different alkyl halide to provide the asymmetrically substituted intermediate 11.
  • Deprotection of 11 then provides the desired asymmetrically substituted alkylpolyamine.
  • Treatment of 8 with 2.2 equivalents of alkyl halide in the presence of NaH and DMF affords the bis-substituted intermediate 10, which upon deprotection yields the corresponding symmetrically substituted alkylpolyamine.
  • R protected alkylamino chain
  • R 2 allylic alkyl group B 2 7 H ⁇ ,6
  • Aminopropyl (or other aminoalkyl) moieties can be added to selectively protected primary amines such as 12 by standard peptide coupling techniques (Method A, Woster et al., J. Med. Chem. 32: 1300 (1989)).
  • Method A Woster et al., J. Med. Chem. 32: 1300 (1989)
  • DCC beta-aminopropionate 13
  • HoBt N-methylmorpholine
  • Compound 16 may be synthesized directly by reductive amination (Method B), in which the appropriate aldehyde 15 is added to 12 in the presence of sodium cyanoborohydride.
  • Alkyl substituents that contain an allylic acetate functionality can also be appended to 12 using a palladium catalyzed coupling reaction that proceeds with retention of configuration (Method C, Sirisoma et al., Tetrahedron Lett. 39: 1489 (1998)).
  • This method can also be used to introduce phthalimide or benzylamine to an allylic acetate site as a synthetic equivalent for nitrogen. These nitrogens can then be deprotected and functionalized.
  • the requisite amine 19 (produced when necessary from the corresponding alkyl or aralkylcyanide) is reacted with cyanogen bromide (Goldin et al., U.S. Patent No. 6,288,123 (2001)) to afford the corresponding aminocyanogen 20.
  • cyanogen bromide Goldin et al., U.S. Patent No. 6,288,123 (2001)
  • the desired amine can be prepared from the appropriate cyano compound by catalytic reduction (Bellevue et al., 1996, Zou et al., 2001).
  • the ⁇ -amino group can be alkylated, e.g., with a Ci-C 8 alkyl group or Ci-C 8 alkyl-C ⁇ -Cio aryl group, using an alkyl chloride, aralkyl chloride or other alkyl or aralkyl derivative reactive towards the amino group.
  • aralkyl chloride or other alkyl or aralkyl derivative reactive towards the amino group.
  • transesterification can be readily performed to replace the -OMe group with the desired ester, e.g., -O-Ci-C 8 alkyl.
  • the ester can be easily converted to the -COOH group, which in turn can be reacted with an amine to form an amide group.
  • Compound 116 can then be appended to a variety of aldehydes, amines, guanidines and guanides by nucleophilic substitution (see Casero, Jr. R.A. et al., J. Med. Chem, 44: 1-26 (2001), Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996), Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993), and Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005)).
  • the ester functionality of 121a is hydrolyzed (LiOH) (see Bellevue, Saab, and Varghese references) to produce carboxylate 121b, and this intermediate is in turn converted to substituted amide 121c (using DCC, HOBT, DMF; see Bellevue, Saab, and Varghese references).
  • Synthon 112 is coupled to polyaminocarboxylate of general structure 120 (Casero, Jr. R.A. et al., J. Med. Chem, 44: 1-26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem.
  • R H, alkyl, aralkyl
  • R 2 H, alkyl, aralkyl
  • W NH, guanidino, guanido
  • R H, alkyl, aralkyl
  • R 2 H, alkyl, aralkyl
  • W NH, guanidino, guanido
  • W 2 NH, guanidino, guanido
  • Chloromethyl ketone derivatives act as irreversible, active site-directed inhibitors of proteases and other enzymes, and would also be expected to inactivate LSDl .
  • Intermediates of general structure 130 are commercially available or readily synthesized (Shaw, E.; Glover, G., Arch. Bioch. Bioph., 139:298-305 (1970); Biaas, A. et al., J. Med. Chem., 49: 1744-1753 (2006)), and can be coupled to the appropriate polyamine precursor via peptide coupling, as described above and previously reported (Biaas, A. et al., J. Med. Chem., 49: 1744-1753 (2006)).
  • R, R 4 alkyl, H
  • Compound 133 is then appended to a suitable polyamine precursor (Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.) and elaborated as described above to yield target compounds of formula (XIII).
  • a suitable polyamine precursor Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.
  • R H, alkyl, aralkyl
  • R 2 H, alkyl, aralkyl
  • Formula (XIV) and formula (XV) contain a cyclopropylamine moiety.
  • the synthesis of these analogues proceeds via the production of substituted cyclopropanes 120, 122 and 124, which are accessed from terminal olefins 134, 136 and 138, respectively by cyclopropanation/amination (Raju, B. et al., Bioorg. Med. Chem. Lett., 14:3103-3107 (2004)), followed by alkylation (Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.) of the resulting terminal amine as described above.
  • R H, alkyl, aralkyl
  • R 2 H, alkyl, aralkyl
  • R 3 H, alkyl, aralkyl
  • R H, alkyl, aralkyl
  • R 2 H, alkyl, aralkyl
  • Biological applications lysine-specific demethylase- 1 (LSDl) inhibitors
  • Histories are proteins found in eukaryotic cells which act as support scaffolds for DNA (sometimes compared to a protein spool supporting the DNA thread). Histones, together with other proteins and DNA, form the chromatin of the cell nucleus. Because of their close association with DNA, histones play a role in gene regulation. The tails of histone proteins are a frequent site for covalent modifications which affect gene expression.
  • LSDl lysine-specific demethylase- 1
  • BHCl 10 and KIAA0601 The enzyme lysine-specific demethylase- 1
  • lysine-specific histone demethylase- 1 is an enzyme that affects the covalent modification of histone tails, by demethylating lysine 4 of the histone H3.
  • Shi et al. (Cell, 1 19:941 (2004)) showed that RNAi inhibition of LSDl led to an increase in H3 lysine 4 methylation, followed by de-repression of the target genes.
  • LSDl apparently represses transcription by demethylating histone H3.
  • inhibition of LSDl allows transcription by preventing demethylation.
  • International Patent Application No. WO 2006/071608 is directed to a method for monitoring eukaryotic histone demethylase activity, methods for up-regulating and down-regulating methylated histone-activated genes, and a method for treating or preventing a disease (e.g., a hyperproliferative disease such as cancer) by modulating the level of protein or the activity of a histone demethylase.
  • a disease e.g., a hyperproliferative disease such as cancer
  • inhibitors of the enzyme may have significant therapeutic potential; Bi, X. et al., Bioorg. Med. Chem. Lett. 16:3229-3232 (2006) and International Patent Application No.
  • Lysine-specific demethylase- 1 -inhibiting compounds of the current inventions can inhibit LSDl by at least about 25%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; by at least about 50%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 75%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 90%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about
  • Treating" or “to treat” a disease using the methods of the invention is defined as administering one or more polyamines or polyamine analogs, with or without additional therapeutic agents, in order to palliate, ameliorate, stabilize, reverse, slow, delay, prevent, reduce, or eliminate either the disease or the symptoms of the disease, or to retard or stop the progression of the disease or of symptoms of the disease.
  • “Therapeutic use” of the polyamines and polyamine analogs is defined as using one or more polyamines or polyamine analogs to treat a disease (including to prevent a disease), as defined above.
  • a "therapeutically effective amount” is an amount sufficient to treat (including to prevent) a disease, as defined above. Prevention or suppression can be partial or total.
  • the compounds disclosed herein have anticancer activity, which has been demonstrated in a variety of human tumor cell types representing the major forms of lung, breast, prostate, and colon cancers.
  • the compounds disclosed herein can be used to treat cancer, including lung cancer (including, but not limited to, small cell lung cancer or SCLC, non-small cell lung cancer or NSCLC, alveolar epithelial cell cancer, bronchial epithelial cell cancer, and squamous cell carcinoma), breast cancer, prostate cancer, and colon cancer, or to prevent cancer, including prevention of lung cancer (including, but not limited to, small cell lung cancer or SCLC, non-small cell lung cancer or NSCLC, alveolar epithelial cell cancer, bronchial epithelial cell cancer, and squamous cell carcinoma), breast cancer, prostate cancer, and colon cancer.
  • lung cancer including, but not limited to, small cell lung cancer or SCLC, non-small cell lung cancer or NSCLC, alveolar epithelial cell cancer, bronchial epithelial cell cancer, and
  • MTS dose response experiments in H 157, H82, A549, and/or Beas2B cells cells following a 96hr exposure with compounds of the invention are performed.
  • MTS is a standard colorimetric assay used for measuring metabolic activity in cells.
  • MTS experiments are performed by CellTiter 96® AQ ueUos One Solution Cell Proliferation Assay from Promega Corporation. Cells are seeded at 3000 cells/well on a 96 well tissue culture plate containing lOOul of medium/well and are allowed to attach overnight. The medium is aspirated and replaced with l OOul of fresh medium containing the appropriate concentration of the compound being tested; the cells are then incubated for 96 hrs at 37°C and 5% CO 2 .
  • Hl 57, H82, and A549 cells following exposure to compounds of the invention are performed.
  • a detailed protocol for determining SSAT activity is described in Casero et al., Cancer Research, 49:3829 (1989). Briefly, the SSAT activity is measured by harvesting the treated cells at the exposure time. The cells are then lysed and treated with spermidine, and l-[ 14 C]acetyl coenzyme A for 5 minutes. Enzyme activity is measured in term of picomoles of [ 14 C]acetylspermidine formed per mg of cell protein per min (pmol/mgP/min).
  • SMO Semoxide
  • ODC Organic Decarboxylase

Abstract

Polyamine, polyamine/guanidino, and polyamine/biguanide compounds bearing allene, propargyl, cyclopropyl, and other reactive moieties are disclosed. The compounds are useful as irreversible inhibitors of the enzyme lysine-specific demethylase-1 and for the treatment of cancer.

Description

LYSINE-SPECIFIC DEMETHYLASE INHIBITORS
The present application claims the benefit of U.S. provisional application number 60/911,692 filed April 13, 2007, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0001] This invention pertains to polyamine compounds, polyamine/guanidine compounds, and polyamine/biguanide compounds, which bear allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, or other reactive moieties and which are useful for inhibition of lysine-specific demethylase. The compounds are useful in treatment of cancer.
BACKGROUND
[0002] Polyamines are found in both eukaryotic and prokaryotic cells and figure prominently in regulation of the cell cycle and cell division. Agents specifically targeting polyamine biosynthesis, such as polyamine analogs, have been shown to have therapeutic effect in treatment of cancer, parasitic diseases, and other indications. These antiproliferatvie effects have been demonstrated to be, in part, a result of agent-induced decreases in the natural intracellular polyamines resulting from inhibition, down- regulation of polyamine biosynthesis and/or up regulation of polyamine catabolism. See, e.g., Wang and Casero, J, Biochem. 139: 17 (2006); Casero et al., Proc. West. Pharmacol. Soc. 48:24 (2005); Casero et al., J. Med. Chem. 44: 1 (2001); U.S Patent Nos. 5,889,061, 6,392,098, and 6,794,545; U.S. Patent Application Publication Nos. 2003/0072715, 2003/0195377, and International Patent Applications Nos. WO 98/17624, WO 00/66587, WO 02/10142, and WO 03/050072. Bi et al., Bioorgan. Med. Chem. Letters 16:3229 (2006) discuss novel alkylpolyaminoguanidines and alkylpolyaminobiguanides with potent antitrypanosomal activity.
[0003] The recently discovered enzyme lysine-specific demethylase 1 (LSDl) has been shown to play a significant role in epigenetic control of gene expression (see Shi et al., Cell 1 19:941 (2004) and International Patent Application No. WO 2006/071608). The LSDl enzyme appears to be up-regulated in some forms of human cancer (see Huang, Y.; Greene, E.; Murray-Stewart, T.; Goodwin, A.C.; Baylin, S.B.; Woster, P.M.; Casero, R.A.: Inhibition of the lysine specific demethylase, LSDl, by novel polyamine analogues results in re-expression of aberrantly silenced genes. Proc. Natl. Acad. Sci. U.S.A., 2007, not yet published). Dimethyl lysine 4 histone H3 (H3K4me2) is a transcription activating chromatin mark at gene promoters, and demethylation of this mark by LSDl, a homologue of polyamine oxidases, may broadly repress gene expression. As such, specific inhibitors for LSDl have the potential to act as antitumor agents by limiting the demethylation of dimethyl lysine 4 histone H3 (H3K4me2), thus promoting the reexpression of multiple, aberrantly silenced genes. A novel series of polyaminoguanidines and polyaminobiguanides that are non-competitive inhibitors of LSDl has been described (see International Patent Application No. WO 2007/0218392 and Bi et al., Bioorg. Med. Chem. Lett. 16:3229 (2006)), and that promote the reexpression of secreted frizzle-related proteins (SFRPs) and the GATA-family of transcription factors, which are important in the development of colon cancer. These events are concurrent with increased H3K4me2, decreased H3K9mel and H3K9me2 repressive marks, and for some genes, reduced CpG island DNA methylation at the promoter of these genes. These agents provide an important new class of antitumor therapy.
[0004] The current application discloses LSDl inhibitors that bear allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, or other moieties that will form covalent bonds in the LSDl active site, and thus provides a novel set of irreversible inhibitors of LSDl .
DISCLOSURE OF THE INVENTION
[0005] The invention embraces polyamine, polyamine/guanidine, and polyamine/biguanide compounds having at least one functional group selected from -Ci- C8 alkyl-CH=C=CH2, -CrC8 alkyl-C≡CH, -d-Cs alkyl-cyclopropane, -C(=O)C,-C8 alkyl substituted with at least one halo group and -cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, and uses of those compounds for treatment and prevention of cancer. In one embodiment, the invention embraces polyamine, polyamine/guanidine, and polyamine/biguanide compounds having at least one functional group selected from -N(CH3)(C, -C8 alkyl-CH=C=CH2), -N(CH3)(C1-C8 alkyl-C≡CH), - N(CH3)(Ci-C8 alkyl-cyclopropane), -N(CH3)(C(=O)C,-C8 alkyl substituted with at least one halo group) and -Ci-C8alkyl-cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, and uses of those compounds for treatment and prevention of cancer. In one embodiment, the invention embraces polyamine, polyamine/guanidine, and polyamine/biguanide compounds having at least one functional group selected from allene
(-CH=C=CH2), propargyl (-CH2-C=CH), cyclopropylmethyl
Figure imgf000004_0001
chloromethylcarbonyl (-Q=O)CH2Cl) and l-N-methylaminecycloprop-2-yl
( N(CH3)R where R js crcgalkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl), and uses of those compounds for treatment and prevention of cancer. In another embodiment, the invention embraces polyamine, polyamine/guanidine, and polyamine/biguanide compounds having at least one functional group selected from -N(CH3)(CH2-CH=C=CH2), -N(CH3)(CH2-C=CH), -N(CH3)(
Figure imgf000004_0003
), -N(CH3)(C(=O)CH2C1) and
Figure imgf000004_0002
where R is d-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl), and uses of those compounds for treatment and prevention of cancer. In one embodiment, the compounds are derivable from lysine and have the functional groups - NR-CH(-COOH)-(CH2)4NR-, -NR-CH(-COOR)-(CH2)4NR-, or -NR-CH(-CONHR)-(CH2)4NR- where each R is independently H, CpC8 alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl . The invention also embraces uses of those compounds for inhibition of lysine-specific demethylase-1 , and treatment of diseases involving lysine-specific demethylase-1.
[0006] In one embodiment, the invention embraces compounds of the formula
(M):
E-X-A-NH-B-NH-A-X-E (M) where each E is independently selected from hydrogen, C)-C8 substituted or unsubstituted alkyl, C4-CiS substituted or unsubstituted cycloalkyl, C3-C15 substituted or unsubstituted branched alkyl, C6-C2O substituted or unsubstituted aryl or heteroaryl, C7-C24 substituted or unsubstituted aralkyl or heteroalkyl or heteroaralkyl, C3-C24 substituted or unsubstituted heteroaryl, or CrC8 alkyl-CH=C=CH2 or Ci-C8 alkyl-C≡CH or CrC8 alkyl-cyclopropane or C(=O)Ci-C8alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one E is
C i -C8 alkyl-CH=C=CH2 or C i -C8 alky 1-C≡CH or C i -C8 alkyl-cyclopropane or C(=O)C i -C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; each A is independently a Ci-C8 n-alkyl; B is independently selected from Ci-Ci2 n-alkyl or C3-C8 cycloalkyl; and each X is independently selected from -NH-, -N(CH3)-, -NH-C(=NH)-NH-, and
-NH-C(=NH)-NH-C(=NH)-NH-; and all salts, solvates, hydrates, and stereoisomers thereof.
[0007] In another embodiment, B is independently selected from CpC8 n-alkyl. In another embodiment, B is -(CH2)?-.
[0008] In another embodiment, at least one E is Ci -C8 alkyl-CH=C=CH2. In one embodiment, the at least one E that is Ci-C8 alkyl-CH=C=CH2 is C, -C8 n- alkyl-CH=C=CH2. In another embodiment, the at least one E that is
Ci-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2.
[0009] In another embodiment, at least one E is Ci-C8 alkyl-C≡CH. In one embodiment, the at least one E that is Ci -C8 alkyl-C≡CH is CrC8 n-alkyl-C≡CH In another embodiment, the at least one E that is Ci-C8 alkyl-C≡CH is propargyl (-CH2-
C≡CH).
[0010] In another embodiment, at least one E is Ci-C8 alkyl-cyclopropane. In one embodiment, the at least one E that is Ci-C8 alkyl-cyclopropane is Ci-C8 n-alkyl- cyclopropane. In another variation, the at least one E that is Ci-C8 alkyl-cyclopropane is
cyclopropylmethyl
Figure imgf000005_0001
).
[0011] In another embodiment, at least one of E is C(=O)C]-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of E that is C(=O)Ci- C8alkyl substituted with at least one halo group is C(=O)Ci -C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of E that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)Ci-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of E that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1 -7. In another embodiment, the at least one of E that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1). [0012] In another embodiment, at least one of E is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one E that is cyc!opropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, C]-C8 alkyl, which may be a CpC8 n-alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl, which may be a CpC8 n- alkyl. In another embodiment, the at least one E that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
( N(CH3)R where R is c,-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one E that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is \-N,N- dimethylaminocycloprop-2-yl.
[0013] In another embodiment, at least one X is selected from -NH-C(=NH)-NH- and -NH-C(=NH)-NH-C(=NH)-NH-. In another embodiment, at least one X is -NH-C(=NH)-NH-. In another embodiment, at least one X is -NH-C(=NH)-NH-C(=NH)-NH-. In another embodiment, each X is independently selected from -NH-C(=NH)-NH- and -NH-C(=NH)-NH-C(=NH)-NH-. In another embodiment, both X groups are -NH-C(=NH)-NH-. In another embodiment, both X groups are -NH-C(=NH)-NH-C(=NH)-NH-. In another embodiment, one X is -NH-C(=NH)-NH- and another X is -NH-C(=NH)-NH-C(=NH)-NH-. [0014] In one embodiment, the invention embraces polyamine/guanidine or N- alkylated polyamine/guanidine compounds having at least one functional group selected from -Ci-C8 alkyl-CH=C=CH2, -C|-C8 alkyl-C≡CH, -C,-C8 alkyl-cyclopropane, -C(=O)C,- C8 alkyl substituted with at least one halo group and -cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, such as a polyaminobisguanidine or polyaminobiguanide or N-alkylated variation thereof . An N-alkylated polyaminoguanidine intends a polyaminoguanidine wherein the imine nitrogen of the guanidine is alkylated, such as in a 2-methylguanadine derivative. In one embodiment, each A is -(CH2)3- and B is -(CH2J4-. In another embodiment, each A is -(CH2)3- and B is -(CH2)7-.
[0015] In one embodiment, the compound is a polyaminoguanidine of the formula
(I):
Figure imgf000007_0001
or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1, each Ri is independently selected from the group consisting Of Ci-C8 substituted or unsubstituted alkyl, C4-C15 substituted or unsubstituted cycloalkyl, C3-C15 substituted or unsubstituted branched alkyl, C6-C2O substituted or unsubstituted aryl, C6-C2O substituted or unsubstituted heteroaryl, C7-C24 substituted or unsubstituted aralkyl, C7-C24 substituted or unsubstituted heteroaralkyl or
C1-C8 alkyl-CH=C=CH2 or CrC8 alkyl-C≡CH or C-C8 alkyl-cyclopropane or C(=O)Cr
Qalkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Ri is
Ci-C8 alkyl-CH=C=CH2, Ci -C8 alkyl-C≡CH, Q-C8 alkyl-cyclopropane, or C(=O)CrC8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently selected from hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
[0016] In another embodiment, at least one Ri is Ci-C8 alkyl-CH=C=CH2. In one embodiment, the at least one Ri that is Ci -C8 alkyl-CH=C=CH2 is CrC8 n- alkyl-CH=C=CH2. In another embodiment, the at least one Ri that is
C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2.
[0017] In another embodiment, at least one Ri is Ci-C8 alkyl-C≡CH. In one embodiment, the at least one Ri that is Ci-C8 alkyl-C≡CH is Ci-C8 n-alkyl-C≡CH In another embodiment, the at least one R1 that is Cj-C8 alkyl-C≡CH is propargyl (CH2-
C≡CH).
[0018] In another embodiment, at least one Ri is C1-C8 alkyl-cyclopropane. In one embodiment, the at least one R1 that is C1-C8 alkyl-cyclopropane is C1-C8 n-alkyl- cyclopropane. In another variation, the at least one Ri that is Ci-C8 alkyl-cyclopropane is
cyclopropylmethyl
Figure imgf000007_0002
[0019] In another embodiment, at least one of Ri is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of R| that is C(O)Ci- C8alkyl substituted with at least one halo group is C(=O)C|-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of R1 that is C(O)Ci -Cgalkyl substituted with at least one halo group is C(=O)Ci-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of Ri that is C(O)C i-Cgalkyl substituted with at least one halo group is C(O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of Ri that is C(O)C i-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(O)CH2Cl). [0020] In another embodiment, at least one of Ri is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one Ri that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a Ci-C8 n-alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl, which may be a Ci-C8 n- alkyl. In another embodiment, the at least one Ri that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
Figure imgf000008_0001
wnere R is C|-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one Ri that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is \-N,N- dimethylaminocycloprop-2-yl.
[0021] In one embodiment, the compound is of the formula (I) wherein one Ri is a
CO-C20 substituted or unsubstituted aryl, such as a single ring substituted or unsubstituted aryl, including without limitation, substituted or unsubstituted phenyl. In one embodiment, the compound is of the formula (I) and each Ri is phenyl. In one embodiment, q is 1, m and p are 3, and n is 4. In another embodiment, q is 1, m and p are 3, and n is 7.
[0022] In one embodiment, the compound is of the formula (I) wherein one R| is a
C8-Ci2 or a Ci-C8 substituted or unsubstituted alkyl, such as a linear alkyl. Ri may be a Ci-C8 substituted or unsubstituted linear alkyl, such as methyl or ethyl. In one embodiment, Ri is methyl. Ri may comprise or be a C4-Ci5 cycloalkyl group, such as a cycloalkyl group containing a linear alkyl group, where the cycloalkyl group is connected to the molecule either via its alkyl or cycloalkyl moiety. For instance, Ri may be cyclopropylmethyl or cyclohexylmethyl. In one embodiment, Ri is a C3-Q5 branched alkyl group such as isopropyl. When Ri is a C]-C8 substituted alkyl, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, Ri is a CpC8 alkyl group substituted with an amine such that Ri may be e.g., alkyl-NH2 or an alkyl-amine-alkyl moiety such as -(CH2)yNH(CH2)zCH3 where y and z are independently an integer from 1 to 8. In one embodiment, Ri is -(CH2)BNH2.
[0023] In one embodiment, the compound is of the formula (I) where one Ri is a
CyC24 substituted or unsubstituted aralkyl, which in one embodiment is an aralkyl connected to the molecule via its alkyl moiety (e.g., benzyl). In one embodiment, each Ri is an aralkyl moiety wherein the alkyl portion of the moiety is substituted with two aryl groups and the moiety is connected to the molecule via its alkyl group. For instance, in one embodiment at least one or both Ri is a C7-C24 aralkyl wherein the alkyl portion is substituted with two phenyl groups, such as when R] is 2,2-diphenylethyl or 2,2- dibenzylethyl. In one embodiment, each Ri of formula (I) is 2,2-diphenylethyl and n is 1, 2 or 5. In one embodiment, each Ri of formula (I) is 2,2-diphenylethyl, n is 1, 2 or 5 and m and p are each 1.
[0024] In one embodiment, at least one Ri is hydrogen. When at least one Ri is hydrogen, the other Ri may be any moiety listed above for R] , including an aryl group such as benzyl.
[0025] Any of the compounds of formula (I) listed above include compounds where at least one or both of R2 is hydrogen or a Ci-C8 substituted or unsubstituted alkyl. In one embodiment, each R2 is an unsubstituted alkyl such as methyl. In another embodiment, each R2 is hydrogen.
[0026] Any of the compounds of formula (I) listed above may be compounds where q is 1 and m and p are the same. Accordingly, the polyaminoguanidines of formula (1) may be symmetric with reference to the polyaminoguanidine core (e.g., excluding Ri). Alternatively, the compounds of formula (I) may be asymmetric, e.g., when q is 0. In one embodiment, m and p are 1. In one embodiment, q is 0. In one embodiment, n is an integer from 1 to 5.
[0027] It is understood and clearly conveyed by this disclosure that each R], R2, m, n, p and q disclosed in reference to formula (I) intends and includes all combinations thereof the same as if each and every combination of Ri, R2, m, n, p and q were specifically and individually listed. [0028] In one embodiment, the compound is a polyaminobiguanide or N-alkylated polyaminobiguanide. An N-alkylated polyaminobiguanide intends a polyaminobiguanide wherein at least one imine nitrogen of at least one biguanide is alkylated. In one embodiment, the compound is a polyaminobiguanide of the formula (II):
Figure imgf000010_0001
(ii) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1 , each Rj is independently selected from the group consisting of Ci-C8 substituted or unsubstituted alkyl, C6-C20 substituted or unsubstituted aryl, C6-C20 substituted or unsubstituted heteroaryl, C7-C24 substituted or unsubstituted aralkyl, C7-C24 substituted or unsubstituted heteroaralkyl, Ci-C8 alkyl-CH=C=CH2, Cj-C8 alky 1-C≡CH, C1-C8 alkyl-cyclopropane, Q=O)C1 -C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Ri is C,-C8 alkyl-CH=C=CH2 or C ,-C8 alkyl-G≡CH or C, -C8 alkyl-cyclopropane or C(K))C1-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a CpC8 substituted or unsubstituted alkyl.
[0029] In one embodiment, one of Ri is a Ci-C8 substituted or unsubstituted alkyl, such as those listed above in reference to formula (I). For instance, when R) is a C1-C8 substituted alkyl, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, R1 is a C1-C8 alkyl group substituted with an amine such that R1 may be e.g., alkyl-NH2 or an alkyl-amine-alkyl moiety such as -(CH2)yNH(CH2)zCH3 where y and z are independently an integer from 1 to 8 In one embodiment, R1 is -(CH2)3NH2. R1 may also be a C4-Ci5 substituted or unsubstituted cycloalkyl or a C3-C15 substituted or unsubstituted branched alkyl, such as described for formula (I) above. In one embodiment, one of Ri is a C6-C2O substituted or unsubstituted aryl, such as those listed above in reference to formula (I). In one embodiment, q is 1, m and p are 3, and n is 4. In another embodiment, q is 1, m and p are 3, and n is 7.
[0030] In another embodiment, at least one Ri is Ci -C8 alkyl-CH=C=CH2. In one embodiment, the at least one Ri that is Ci-C8 alkyl-CH=C=CH2 is Ci-C8 n- alkyl-CH=C=CH2. In another embodiment, the at least one Ri that is
C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2.
[0031] In another embodiment, at least one Ri is Ci-C8 alkyl-C≡CH. In one embodiment, the at least one Ri that is CpC8 alkyl-C≡CH is Ci-C8 n-alkyl-C≡CH In another embodiment, the at least one Ri that is Ci-C8 alkyl-C≡CH is propargyl (CH2-
C≡CH).
[0032] In another embodiment, at least one Ri is Ci-C8 alkyl-cyclopropane. In one embodiment, the at least one Rj that is C)-C8 alkyl-cyclopropane is Ci-C8 n-alkyl- cyclopropane. In another variation, the at least one Ri that is Ci-C8 alkyl-cyclopropane is
cyclopropylmethyl
Figure imgf000011_0001
).
[0033] In another embodiment, at least one of Ri is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of Ri that is C(=O)Ci- C8alkyl substituted with at least one halo group is C(=O)C]-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of Ri that is C(=O)C|-C8alkyl substituted with at least one halo group is C(=O)Ci-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of Ri that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of Rj that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1). [0034] In another embodiment, at least one of Ri is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one Ri that is eye lopropy 1-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a CpC8 n-alkyl, or aralkyl where the alkyl moiety
[0035] In one embodiment, the compound is of the formula (II) where at least one or both Ri is a C7-C24 substituted or unsubstituted aralkyl, which in one embodiment is an aralkyl connected to the molecule via its alkyl moiety. In one embodiment, each R| is an aralkyl moiety wherein the alkyl portion of the moiety is substituted with one or two aryl groups and the moiety is connected to the molecule via its alkyl moiety. For instance, in one embodiment at least one or both Ri is an aralkyl wherein the alkyl portion is substituted with two phenyl or benzyl groups, such as when Ri is 2,2-diphenylethyl or 2,2- dibenzylethyl. In one embodiment, each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5. In one embodiment, each Ri of formula (II) is 2,2-diphenylethyl and n is 1, 2 or 5 and m and p are each 1.
[0036] Any of the compounds of formula (II) listed above include compounds where at least one or both Of R2 is hydrogen or a Ci-C8 substituted or unsubstituted alkyl. In one embodiment, each R2 is an unsubstituted alkyl, such as methyl. In another embodiment, each R2 is a hydrogen.
[0037] Any of the compounds of formula (II) listed above include compounds where q is 1 and m and p are the same. Accordingly, the polyaminobiguanides of formula (II) may be symmetric with reference to the polyaminobiguanide core (e.g., excluding R|). Alternatively, the compounds of formula (II) may be asymmetric, e.g., when q is 0. In one embodiment, m and p are 1. In one embodiment, q is 0. In one embodiment, n is an integer from 1 to 5. In one embodiment, q, m and p are each 1 and n is 1, 2 or 5. [0038] It is understood and clearly conveyed by this disclosure that each Ri, R2, m, n, p and q disclosed in reference to formula (II) intends and includes all combinations thereof the same as if each and every combination of R], R2, m, n, p and q were specifically and individually listed.
[0039] In one embodiment, the compound is a polyamine. In one embodiment, the polyamine is of the formula (III):
Figure imgf000012_0001
(III) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R3 and R4 are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted alkyl, Ce-C20 substituted or unsubstituted aryl, C7-C24 substituted or unsubstituted aralkyl, Ci-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of R3 and R4 is Ci-C8 alkyl-CH=C=CH2 or Ci-C8 alkyl- C≡CH or C)-C8 alkyl-cyclopropane or C(=O)C1-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; R5; R9, R6, R7 and R8 are independently selected from the group consisting of hydrogen and Ci-C8 substituted or unsubstituted alkyl; and wherein either m and p are not the same integer or at least one of Rs1 R9, R6, R7 and R8 is a Ci-C8 substituted or unsubstituted alkyl.
[0040] In one embodiment, R9 is a Ci-C8 substituted or unsubstituted alkyl. When
R9 is a Ci-C8 substituted alkyl, the substituted alkyl may be substituted with any substituent, including a primary, secondary, tertiary or quaternary amine. Accordingly, in one embodiment, R9 is a Ci-C8 alkyl group substituted with an amine such that R9 may be e.g., alkyl-NH2 or an alkyl-amine-alkyl moiety such as — (CH2)yNH(CH2)zCH3 where y and z are independently an integer from 1 to 8 In one embodiment, R9 is - (CH2)3NHCH2CH3.
[0041] In one embodiment, one of R3 and R4 is hydrogen.
[0042] In one embodiment, one of R3 and R4 is a CpC8 substituted or unsubstituted alkyl, including without limitation a substituted or unsubstituted n-alkyl (such as n-pentyl), substituted or unsubstituted branched (C3-C8) alkyl (such as 2- methylbutyl) or substituted or unsubstituted (C3-C8) cycloalkyl (such as cyclohexylmethyl). Larger chain alkyl (linear, branched and cyclic) are also considered, such as a C9-C15 substituted or unsubstituted alkyl. Where one Of R3 and R4 is a Ci-C8 substituted or unsubstituted n-alkyl, the moiety may be any n-alkyl, such as methyl or ethyl. When one of R3 and R4 is a substituted alkyl, whether linear, branched or cyclic, the alkyl may be substituted with one or more substituents such as those listed under "Substituted alkyl" and includes alkyl substituted with any halogen, such as a monohaloalkyl, dihaloalkyl, trihaloalkyl or multihaloalkyl, including a perhalooalkyl, for example, perfluoroalkyl and percholoralkyl, such as trifluoromethyl or pentachloroethyl. [0043] In one embodiment, one of R3 and R4 is a C6-C20 substituted or unsubstituted aryl. In one embodiment, one Of R3 and R4 is a Ce-C20 substituted aryl, which aryl groups may be substituted with one or more substituents such as those listed under "Substituted aryl." In one embodiment, one of R3 and R4 is a C6-C20 substituted aryl, which aryl groups may be substituted with one or more alkyoxy (such as -OCH3), alkyl (including a branched alkyl such as ter/-butyl), or halo groups (such as fluoro). In one embodiment, one of R3 and R4 is a halo-substituted aryl or a halo-substituted aralkyl, such as 2,4,5-trifluorophenyl or 2,4,5-trifluorobenzyl. In one embodiment, one Of R3 and R4 is a di-alkyl-monoalkoxy-substituted aryl or aralkyl, such as 4,5-di-ter/-butyl-2- methoxybenzyl or 4,5-di-teA-/-butyl-2-methoxyphenyl.
[0044] In one embodiment, one of R3 and R4 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl such as an aralkyl or heteroaralkyl connected to the molecule via its alkyl moiety. In one embodiment, one of R3 and R4 is a substituted aralkyl or heteroaralkyl connected to the molecule via its alkyl moiety. A substituted aralkyl may be substituted with one or more substituents such as those listed under "Substituted aralkyl" and a substituted heteroaralkyl may be substituted with one or more substituents such as those listed under "Substituted heteroaralkyl." In one embodiment, one of R3 and R4 is a substituted heteroaralkyl having at least one nitrogen atom. In one embodiment, one of R3 and R4 is a single ring heteroaralkyl having at least one nitrogen atom. In one embodiment, one or both of R3 and R4 is l-(2-N-methylpyrrolyl)-methyl. [0045] In another embodiment, at least one of R3 and R4 is Ci-C8 alkyl-CH=C=CH2. In one embodiment, the at least one of R3 and R4 that is Ci-C8 alkyl-CH=C=CH2 is CpC8 n-alkyl-CH=C=CH2. In another embodiment, the at least one Of R3 and R4 that is C-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0046] In another embodiment, at least one of R3 and R4 is Ci-C8 alkyl-C≡CH. In one embodiment, the at least one of R3 and R4 that is Ci-C8 alkyl-C≡CH is Ci-C8 n-alkyl- C≡CH In another embodiment, the at least one of R3 and R4 that is Ci-C8 alkyl-C≡CH is propargyl (CH2-C=CH).
[0047] In another embodiment, at least one of R3 and R4 is Ci-C8 alkyl- cyclopropane. In one embodiment, the at least one of R3 and R4 that is C]-C8 alkyl- cyclopropane is C)-C8 n-alkyl-cyclopropane. In another variation, the at least one of R3
and R4 that is CpC8 alkyl-cyclopropane is cyciopropylmethyl (
Figure imgf000014_0001
).
[0048] In another embodiment, at least one of R3 and R4 is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of R3 and R4 that is C(=O)C|-C8alkyl substituted with at least one halo group is C(=O)Ci-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one Of R3 and R4 that is C(=O)Ci-Cgalkyl substituted with at least one halo group is C(=O)C]-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of R3 and R4 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of R3 and R4 that is C(=O)CrC8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1).
[0049] In another embodiment, at least one of R3 and R4 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one Of R3 and R4 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a Ci-C8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl, which may be a Ci-C8 n-alkyl. In another embodiment, the at least one Of R3 and R4 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is 1-N-
methylaminecycloprop-2-yl ( N(CH3 )R wnere R JS d-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R3 and R4 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
[0050] In one embodiment, at least 1 or at least 2 or at least 3 of Rs; R9, R6, R7 and
R8 is a Ci-C8 substituted or unsubstituted alkyl. Rs1 R9, R6, R7 and R8 may be a Ci-C8 substituted or unsubstituted alkyl. In one embodiment at least 1 or at least 2 or at least 3 of R5, R9, R6, R7 is a Ci-C8 unsubstituted n-alkyl, such as methyl or ethyl. In one embodiment, both R6 and R5 are methyl or ethyl. In one embodiment, at least one R7 and R8 is methyl or ethyl. In one embodiment, R7 is methyl.
[0051] It is understood and clearly conveyed by this disclosure that each R3, R4,
R5, R9, R6, R7, R8, m, n, y, z and p disclosed in reference to formula (III) intends and includes all combinations thereof the same as if each and every combination of R3, R4, R5, R9, R6, R?, R8, m, n, y, z and p were specifically and individually listed. [0052] In one embodiment, the polyamine is of the formula (IV):
Figure imgf000015_0001
(IV) or a salt, solvate, or hydrate thereof, wherein A, Rj0 and Rn are independently (CH2)n or ethene-1, 1 -diyl; n is an integer from 1 to 5; Ri2 and Rn are independently selected from the group consisting of hydrogen, C2-C8 substituted or unsubstituted alkenyl, Ci-C8 substituted or unsubstituted alkyl, C-C8 alkyl-CH=C=CH2, C)-C8 alkyl-C≡CH, CpC8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of Ri2 and R)3 is C-C8 alkyl-CH=C=CH2 or CrC8 alkyl-C≡CH or CrC8 alkyl- cyclopropane or Q=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl. In one embodiment, at least one of A1 Rio, Rn1 Rn and Ri3 comprises an alkenyl moiety. In another embodiment, when any one or more of A, Rio, and Rn is alkenyl, the alkene portion branches off the direct chain connecting the nitrogen atoms; that is, no more than one sp2-hybridized carbon occurs in the carbon nodes along the shortest path from one nitrogen flanking A, Rio, and/or Rn to the other flanking nitrogen. For example, when A is ethene, the segment containing A is of the form -CH2C(=CH2)-CH2- and the three nodes in the shortest carbon path between the nitrogens containing the A moiety has only one sp2-hybridized carbon. When A is propene, the segment containing A can be of the form -CH2C(=CHCH3)-CH2- or - CH2C(-CH=CH2)-CH2-.
[0053] In one embodiment, A is (CH2)n and n is 1. In one embodiment, A is ethene- 1 ,1 -diyl. In one embodiment, A is (CH2)n and one or both of R]2 and Ri3 comprises an alkenyl moiety, such as propen-2-yl.
[0054] In one embodiment at least one or both of Rio and Rn is ethene-1, 1 -diyl. In one embodiment, both Rio and Rn are (CH2)n such as CH2 (where n = 1). [0055] In one embodiment, at least one of R]2 and Ri3 is hydrogen. In one embodiment, at least one Of Ri2 and R)3 is a C2-C8 substituted or unsubstituted alkenyl, such as propen-2-yl. In one embodiment, at least one of Ri2 and R)3 is a Ci-C8 substituted or unsubstituted alkyl, such as methyl or ethyl or any Ci-C8 substituted or unsubstituted alkyl mentioned above in reference to any one of formulae (I), (II) or (III). [0056] In another embodiment, at least one of Ri2 and Ri3 is Ci-C8 alkyl-CH=C=CH2. In one embodiment, the at least one of Ri2 and Rn that is C)-C8 alkyl-CH=C=CH2 is CrC8 n-alkyl-CH=C=CH2. In another embodiment, the at least one Of Ri2 and R,3 that is C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0057] In another embodiment, at least one of Ri2 and Rn is Ci-C8 alkyl-C≡CH.
In one embodiment, the at least one of R]2 and Rj3 that is Ci-C8 alkyl-C≡CH is Q-C8 n- alkyl-C≡CH In another embodiment, the at least one of R]2 and R]3 that is Ci-C8 alkyl- C≡CH is propargyl (CH2-C≡CH).
[0058] In another embodiment, at least one of Ri2 and Ri3 is Ci-C8 alkyl- cyclopropane. In one embodiment, the at least one of Ri2 and R]3 that is Ci-C8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one Of R)2
and Rn that is Ci-C8 alkyl-cyclopropane is cyclopropylmethyl (
Figure imgf000017_0001
).
[0059] In another embodiment, at least one of R]2 and R)3 is CC=O)C1 -Qalkyl substituted with at least one halo group. In one embodiment, the at least one Of Ri2 and Rn that is C(=O)CrC8alkyl substituted with at least one halo group is C(=O)CrC8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of Ri2 and R]3 that is C(=O)C]-C8alkyl substituted with at least one halo group is
Figure imgf000017_0002
n-alkyl substituted with at least one chloro group. In another embodiment, the at least one OfRi2 and Ri3 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of Ri2 and Rn that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1).
[0060] In another embodiment, at least one of Ri2 and R]3 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of Ri2 and R)3 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a Ci-C8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl, which may be a C]-C8 n-alkyl. In another embodiment, the at least one of Ri2 and Ri3 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is 1-N-
methylaminecycloprop-2-yl ( N(CH3)R where R is c,-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R)2 and Ri3 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
[0061] It is understood and clearly conveyed by this disclosure that each A, n, Rio,
Rn1 Ri2 and R)3 disclosed in reference to formula (IV) intends and includes all combinations thereof the same as if each and every combination of A, n, Ri0 Rn R!2 and
RB were specifically and individually listed.
[0062] In one embodiment, the polyamine is of the formula (V):
Figure imgf000018_0001
(V) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 8; m is an integer from 1 to 8; Ri5 and Ri4 are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted n-alkyl or (C3-C8) branched alkyl, C6-C20 substituted or unsubstituted aryl or heteroaryl, C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl, C-C8 alkyl-CH=C=CH2, C1-C8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)C)-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of R15 and RH is Ci-C8 alkyl-CH=C=CH2 or CrC8 alkyl-C≡CH or CrC8 alkyl-cyclopropane or C(O)C-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; Rj6 and Ri7 are independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; and wherein the compound contains no more than three secondary amino groups except when R)7 is a Ci-C8 substituted or unsubstituted alkyl and wherein the compound is free from a methylphosphonate or hydroxy moiety. [0063] In one embodiment, at least one of Ri5 and Ri4 is hydrogen. In one embodiment, at least one of R15 and R]4 is a Ci-C8 substituted or unsubstituted n-alkyl or (C3-C8) branched alkyl, such as methyl, ethyl, 3-methyl-butyl, 2-ethyl-butyl, 5-NH2-pent- 1 -yl, prop-l-yl-methyl(phenyl)phosphinate and the like or any Q-C8 substituted or unsubstituted n-alkyl or (C3-C8) branched alkyl listed above in reference to formulae (I)- (IV). In one embodiment, at least one of R15 and Rj4 is a Ci-C8 substituted or unsubstituted n-alkyl, such as an n-alkyl substituted with a methyl(phenyl)phosphinate moiety or a NH2-substitued n-alkyl. In one embodiment, one of R15 and Ri4 is Ci-C8 substituted or unsubstituted n-alkyl or (C3-C8) branched alkyl moieties, such as when one of Ri5 and R]4 is 3-methyl-butyl or when one of R15 and R)4 is 2-ethyl-butyl. [0064] In one embodiment, at least one of Ris and Ri4 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl. In one embodiment, at least one of Ri 5 and R14 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl having two rings, such as 2- phenylbenzyl, 4-phenylbenzyl, 2-benzylbenzyl, 3-benzylbenzyl, 3,3,-diphenylpropryl, 3- (benzoimidazolyl)-propyl and the like. In one embodiment, at least one of Ri5 and R)4 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl having one ring, such as 4- isopropylbenzyl, 4-fluorobenzyl, 4-rer/-butylbenzyl, 3-imidazolyl-propyl, 2-phenylethyl and the like. In one embodiment, one of R15 and R)4 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl, such as any of the specific substituted or unsubstituted aralkyl or heteroaralkyl moieties listed for any other formula. [0065] In another embodiment, at least one of R15 and R]4 is Ci-C8 alkyl-CH=C=CH2. In one embodiment, the at least one of R15 and Ri4 that is Ci-C8 alkyl-CH=C=CH2 is Ci-C8 n-alkyl-CH=C=CH2. In another embodiment, the at least one Of R15 and R,4 that is Ci-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0066] In another embodiment, at least one of R15 and R14 is Ci-C8 alkyl-C≡CH.
In one embodiment, the at least one of R]5 and Ri4 that is Ci-C8 alkyl-C≡CH is Ci-C8 n- alkyl-C≡CH In another embodiment, the at least one of Ri5 and Ri4 that is Cj-C8 alkyl- C≡CH is propargyl (CH2-C=CH).
[0067] In another embodiment, at least one of Ri5 and Ri4 is Ci-C8 alkyl- cyclopropane. In one embodiment, the at least one of Rj5 and Ri4 that is Ci-C8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one of Ri5
and R)4 that is Ci-C8 alkyl-cyclopropane is cyclopropylmethyl
Figure imgf000019_0001
).
[0068] In another embodiment, at least one of Ri5 and Ri4 is C(=O)C]-C8alkyl substituted with at least one halo group. In one embodiment, the at least one Of R]5 and Ri4 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)Ci-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of R)5 and R14 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)Ci-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of R] 5 and Rj4 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of Ri5 and R)4 that is C(=O)C|-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1). [0069] In another embodiment, at least one of Ri 5 and R]4 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of Ri5 and R|4 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a Ci-C8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC8 alkyl, which may be a Ci-C8 n-alkyl. In another embodiment, the at least one Ri that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
( N(CH3)R wnere R is c,-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R15 and R)4 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is
Figure imgf000020_0001
dimethylaminocycloprop-2-yl.
[0070] For any compound of formula (V), m and n may be the same or different.
In one embodiment, m does not equal n, such as when m is 1 and n is 2. For instance, in one embodiment, m is 1 , and n is 2. However, it is understood that all possible combinations of m, n, R15 and Ri4 are intended.
[0071] In one embodiment, at least one or both of R|6 and Ri7 is hydrogen. In one embodiment, at least one or both of R16 and Ri 7 is a Ci-C8 substituted or unsubstituted alkyl, such as a methyl, ethyl and a Ci-C8 alkyl substituted with e.g., an -NH-Cj-C8 alkyl such as when at least one or both of R)6 and Rn is -(CH2)SNHCH2CH3.
[0072] It is understood and clearly conveyed by this disclosure that each R]4, Ri 5,
R16, Ri7, m, and n disclosed in reference to formula (V) intends and includes all combinations thereof the same as if each and every combination Of Ri4, R15, Ri6, Rn, m, and n were specifically and individually listed.
[0073] In one embodiment, the polyamine is of the formula (VI):
Figure imgf000020_0002
(VI) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R]8 and R19 are independently selected from the group consisting of hydrogen, C]-C8 unsubstituted alkyl (e.g., methyl, ethyl, /er/-butyl, isopropyl, pentyl, cyclobutyl), C)-C8 n-alkyl substituted with a cycloalkyl group comprising at least two rings, C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings, C1-C8 alkyl-CH=C=CH2, CrC8 alkyl-C≡CH, C1-C8 alkyl- cyclopropane, CC=O)C1 -C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of R18 and R19 is C1-C8 alkyl-CH=C=CH2 or C1-C8 alkyl-C≡CH or Q-C8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl. In one variation, n is 1 when R18 and Ri9 are identical.
[0074] In one embodiment, at least one of R18 and R19 is a C1-C8 n-alkyl substituted with a cycloalkyl group comprising at least two rings. The cycloalkyl group comprising at least two rings may be a spiro, fused or bridged cycloalkyl group. Representative examples of a C1-C8 n-alkyl substituted with a cycloalkyl group comprising two rings include moieties such as 2-(6,6-dimethylbicyclo[3.1.1]heptyl)ethyl and 2-(decahydronaphthyl)ethyl. In one embodiment, at least one Of R18 and Ri9 is 2-(6,6- dimethylbicyclo[3.1.1]heptyl)ethyl. In one embodiment, at least one of R18 and Ri9 are 2- (decahydronaphthyl)ethyl.
[0075] In one embodiment, at least one of R18 and R19 is a C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings, which rings may be but are not required to be fused. A substituted aralkyl or heteroaralkyl with reference to formula (VI) intends and includes alkanoyl moieties substituted with an aryl or heteroaryl group, i.e., -C(=O)-aryl, -C(=O)-aralkyl, -C(=O)-heteroaryl, and -C(=O)-heteroaralkyl. In one embodiment, the alkyl portion of the aralkyl or heteroaralkyl moiety is connected to the molecule via its alkyl moiety. For instance at least one of R18 and R19 may be an aralkyl moiety such as 2-phenylbenzyl, 4-phenylbenzyl, 3,3,-diphenylpropyl, 2-(2- phenylethyl)benzyl, 2-methyl-3-phenylbenzyl, 2-napthylethyl, 4-(pyrenyl)butyl, 2-(3- methylnapthyl)ethyl, 2-(l ,2-dihydroacenaphth-4-yl)ethyl and the like. In another embodiment, at least one of R18 and R]9 may be a heteroaralkyl moiety such as 3- (benzoimidazolyl)propanoyl, l-(benzoimidazolyl)methanoyl, 2- (benzoimidazolyl)ethanoyl, 2-(benzoimidazolyl)ethyl and the like. [0076] In another embodiment, at least one of R]8 and R19 is C1-C8 alkyl-CH=C=CH2. In one embodiment, the at least one of R18 and R19 that is C1-C8 alkyl-CH=C=CH2 is Ci-C8 n-alkyl-CH=C=CH2. In another embodiment, the at least one R1 that is C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0077] In another embodiment, at least one Of Ri8 and Ri9 is Q-C8 alkyl-C≡CH.
In one embodiment, the at least one of R) 8 and Ri 9 that is Ci-C8 alkyl-C≡CH is C)-C8 n- alkyl-C≡CH In another embodiment, the at least one of R)8 and R19 that is Ci-C8 alkyl- C≡CH is propargyl (CH2-C≡CH).
[0078] In another embodiment, at least one of R) 8 and R19 is CpC8 alkyl- cyclopropane. In one embodiment, the at least one of R)8 and R19 that is C)-C8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one of Ri8
and Ri9 that is Ci-C8 alkyl-cyclopropane is cyclopropylmethyl
Figure imgf000022_0001
).
[0079] In another embodiment, at least one of of Ri8 and R19 is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of Ri8 and Ri9 that is C(O)C i-C8alkyl substituted with at least one halo group is C(=O)CrC8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one OfRi8 and R19 that is C(O)Ci -Qalkyl substituted with at least one halo group is C(O)C 1-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of Ri8 and R19 that is C(O)C i-Cgalkyl substituted with at least one halo group is C(O)(CH2)nCH2Cl where n is 1 -7. In another embodiment, the at least one Of Ri8 and R19 that is C(O)C i-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(O)CH2Cl).
[0080] In another embodiment, at least one of Ri8 and R19 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of Ri8 and R]9 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, CrC8 alkyl, which may be a CpC8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a C]-C8 alkyl, which may be a CpC8 n-alkyl. In another embodiment, the at least one of Ri8 and R19 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is 1 -N-
methylaminecycloprop-2-yl ( N(CH3)R wnere R JS crC8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R) 8 and R19 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l -N,N-dimethylaminocycloprop-2-yl.
[0081] In one embodiment, each of m, n and p is the same, such as when m, n and p are each 1. [0082] It is understood and clearly conveyed by this disclosure that each Ri 8, R|9, m, n and p disclosed in reference to formula (VI) intends and includes all combinations thereof the same as if each and every combination of Ri8, R19, m, n and p were specifically and individually listed. [0083] In one embodiment, the polyamine is of the formula (VII):
Figure imgf000023_0001
(VIl) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1 ; R20 and R2) are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted alkyl, -C(=O)-Ci-C8 substituted or unsubstituted alkyl, -C(=O)-Ci-C8 substituted or unsubstituted alkenyl, -C(=O)-C)-C8 substituted or unsubstituted alkynyl, C7-C24 substituted or unsubstituted aralkyl, Ci-C8 alkyl-CH=C=CH2, C]-C8 alky 1-C≡CH, CpC8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of R20 and R2, is Q-C8 alkyl-CH=C=CH2 or Ci-C8 alkyl-C≡CH or CrC8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl. In one embodiment, the compound also comprises at least one moiety selected from the group consisting of /-butyl, isopropyl, 2-ethylbutyl, 1 -methylpropyl, 1-methylbutyl, 3-butenyl, isopent-2-enyl, 2-methylpropan- 3-olyl, ethylthiyl, phenylthiyl, propynoyl, 1 -methyl- lH-pyrrole-2-yl, trifluoromethyl, cyclopropanecarbaldehyde, halo-substituted phenyl, nitro-substituted phenyl, alkyl- substituted phenyl, 2,4,6-trimethylbenzyl, halo-S- substituted phenyl (such as para-(F3S)- phenyl, azido and 2-methylbutyl.
[0084] In one embodiment, q is 1. In one embodiment, q is 1 and n is 1.
[0085] In one embodiment one Of R20 and R2i is hydrogen. In one embodiment one Of R20 and R2] is Ci-C8 substituted or unsubstituted alkyl, such as any of the substituted or unsubstituted alkyl moieties mentioned above for formulas (I)-(VI). In one embodiment one of R20 and R2) is a C7-C24 substituted or unsubstituted aralkyl, such as any of the C7-C24 substituted or unsubstituted aralkyl mentioned above for formulas (I)-
(VI).
[0086] In another embodiment, at least one of R20 and R2| is CpC8 alkyl-CH=C=CH2. In one embodiment, the at least one of R20 and R21 that is C)-C8 alkyl-CH=C=CH2 is CpC8 n-alkyl-CH=C=CH2. In another embodiment, the at least one Of R20 and R2, that is C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0087] In another embodiment, at least one of R20 and R2) is Ci-C8 alkyl-C≡CH.
In one embodiment, the at least one of R20 and R2] that is Ci-C8 alkyl-C≡CH is Ci-C8 n- alkyl-C≡CH In another embodiment, the at least one of R20 and R2i that is Ci-C8 alkyl- C≡CH is propargyl (CH2-C=CH).
[0088] In another embodiment, at least one of R20 and R2) is CpC8 alkyl- cyclopropane. In one embodiment, the at least one of R20 and R2) that is CpC8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one of R20
and R2i that is Q-C8 alkyl-cyclopropane is cyclopropylmethyl (
Figure imgf000024_0001
).
[0089] In another embodiment, at least one of R20 and R2] is C(=O)C]-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of R20 and R2I that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)Ci-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of R20 and R2i that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)C]-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of R20 and R2) that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1-7. In another embodiment, the at least one of R20 and R2) that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1).
[0090] In another embodiment, at least one Of R20 and R2] is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of R20 and R2] that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, CpC8 alkyl, which may be a CpC8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC8 alkyl, which may be a CpC8 n-alkyl. In another embodiment, the at least one of R20 and R2) that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is 1-N-
Figure imgf000025_0001
where R is Ci-Cgalkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R20 and R2i that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N,N-dimethylaminocycloprop-2-yl.
[0091] It is understood and clearly conveyed by this disclosure that each R20, R2i, m, n, q and p disclosed in reference to formula (VII) intends and includes all combinations thereof the same as if each and every combination of R20, R2i, m, n, q and p were specifically and individually listed.
[0092] In one embodiment, the polyamine is of the formula (VIII):
Figure imgf000025_0002
(VIII) or a salt, solvate, or hydrate thereof, wherein m and p are independently an integer from 1 to 5; X is-(CH2)n- or cyclohex-l,3-diyl; n is an integer from 1 to 5; R22 and R23 are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexyleth-2-yl, benzyl, C1-C8 alkyl-CH=C=CH2, C1-C8 alkyl-C≡CH, C1-C8 alkyl- cyclopropane, C^O)C1 -C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of R22 and R23 is C1-C8 alkyl-CH=C=CH2 or CrC8 alkyl-C≡CH or CrC8 alkyl- cyclopropane or C(=O)Ci-C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a C1-C8 substituted or unsubstituted alkyl. In one embodiment, n is 5, and at least one Of R22 and R23 is hydrogen. In another embodiment, when X is cyclohex-1,3- diyl, R22 and R23 are not both benzyl or cyclopropylmethyl. [0093] In one embodiment, X is-(CH2)n (e.g., CH2 where n is 1 ). In one embodiment, X is CH2 and m and p are both 1. In one embodiment, X is cyclohex-1 ,3- diyl. In one embodiment, X is cyclohex-l,3-diyl and m and p are both 1. In other embodiments, m and p are not the same, e.g., when m is 3 and p is 4. [0094] In another embodiment, at least one of R22 and R23 is C1-C8 alky 1-CH=C=CH2. In one embodiment, the at least one of R22 and R23 that is Ci-C8 aIkyl-CH=C=CH2 is Ci -C8 n-alkyl-CH=C=CH2. In another embodiment, the at least one Of R22 and R23 that is C1-C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2. [0095] In another embodiment, at least one of R22 and R23 is CpC8 alkyl-C≡CH.
In one embodiment, the at least one of R22 and R23 that is Ci-C8 alkyl-C≡CH is CpC8 n- alkyl-C≡CH In another embodiment, the at least one Of R22 and R23 that is Ci-C8 alkyl- C≡CH is propargyl (CH2-C≡CH).
[0096] In another embodiment, at least one Of R22 and R23 is Ci-C8 alkyl- cyclopropane. In one embodiment, the at least one of R22 and R23 that is CpC8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one Of R22
and R23 that is CpC8 alkyl-cyclopropane is cyclopropylmethyl
Figure imgf000026_0001
).
[0097] In another embodiment, at least one of R22 and R23 is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of R22 and R23 that is C(=O)CrC8alkyl substituted with at least one halo group is C(=O)Ci-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of R22 and R23 that is C(=O)Ci-C8alkyl substituted with at least one halo group is
Figure imgf000026_0002
n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of R22 and R23 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1 -7. In another embodiment, the at least one Of R22 and R23 that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1).
[0098] In another embodiment, at least one of R22 and R23 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of R22 and R23 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, Ci-C8 alkyl, which may be a Ci-C8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a CpC8 alkyl, which may be a Ci-C8 n-alkyl. In another embodiment, the at least one of R22 and R23 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is 1-N-
methylaminecycloprop-2-yl ( N(CH3)R whepe R js c,-C8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one Of R22 and R23 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l -N,N-dimethylaminocycloprop-2-yl. [0099] It is understood and clearly conveyed by this disclosure that each R22, R23, m, n and p disclosed in reference to formula (VIII) intends and includes all combinations thereof the same as if each and every combination Of R22, R23, m, n and p were specifically and individually listed. [00100] In one embodiment, the polyamine is of the formula (IX):
\ 24 -
* M -^ V / ^"
^25
H (IX) or a salt, solvate, or hydrate thereof, wherein p is an integer from 1 to 5; R24 is an amino- substituted cycloalkyl (e.g., a cycloalkyl group substituted with a primary, secondary, tertiary or quaternary amine), a C2-C8 substituted or unsubstituted alkanoyl (which substituted alkanoyl may be substituted with one or more substituents such as those listed for "Substituted alkyl" including without limitation an alkanoyl substituted with a methyl and an alkylazide group), Ci-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, d-Cg alkyl- cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and R25 is a Ci-C8 substituted or unsubstituted alkyl, a C7-C24 substituted or unsubstituted aralkyl, such as those listed above for any of formulae (I)-(VIII), C-C8 alkyl-CH=C=CH2, C,-C8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl with the proviso that at least one of R24 and R25 is Ci-C8 alkyl-CH=C=CH2 or C-C8 alky 1-C≡CH or CpC8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Cj-C8 substituted or unsubstituted alkyl.
[00101] In one embodiment, R24 is an amino-substituted C3-C24 cycloalkyl, such as
5-NH2-cycloheptyl, 3-NH2-cyclopentyl and the like. In one embodiment, R25 is a Ci-C8 substituted or unsubstituted alkyl, which includes an n-alkyl group substituted with a cycloalkyl, such as in cyclopropylmethyl. In one embodiment, R25 is cyclopropylmethyl or ethyl. In one embodiment, R24 is 5-NH2-cycloheptyl or 3-NH2-cyclopentyl. In one embodiment, R24 is a C2-C8 substituted or unsubstituted alkanoyl or R24 is a C7-C24 substituted or unsubstituted aralkyl, such as 4-phenylbenzyl. [00102] In another embodiment, at least one of R24 and R25 is Ci-C8 alkyl-CH=C=CH2. In one embodiment, the at least one Of R24 and R25 that is Ci-C8 alkyl-CH=C=CH2 is CrC8 n-alkyl-CH=C=CH2. In another embodiment, the at least one
Of R24 and R25 that is C, -C8 alkyl-CH=C=CH2 is -CH2-CH=C=CH2.
[00103] In another embodiment, at least one Of R24 and R25 is Ci-C8 alkyl-C≡CH. In one embodiment, the at least one of R24 and R25 that is Ci-C8 alkyl-C≡CH is Ci-C8 n-alkyl-
C≡CH In another embodiment, the at least one of R24 and R25 that is Ci-C8 alkyl-C≡CH is propargyl (CH2-C≡CH).
[00104] In another embodiment, at least one Of R24 and R25 is Ci -C8 alkyl- cyclopropane. In one embodiment, the at least one of R24 and R25 that is Ci-C8 alkyl- cyclopropane is Ci-C8 n-alkyl-cyclopropane. In another variation, the at least one of R24
and R25 that is CpC8 alkyl-cyclopropane is cyclopropylmethyl
Figure imgf000028_0001
).
[00105] In another embodiment, at least one of R24 and R25 is C(=O)Ci-C8alkyl substituted with at least one halo group. In one embodiment, the at least one of R24 and R25 that is C(O)C i-C8alkyl substituted with at least one halo group is C(=O)Ci-C8 n-alkyl substituted with at least one halo group selected from chloro or fluoro. In one embodiment, the at least one of R24 and R25 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(K))Ci-C4 n-alkyl substituted with at least one chloro group. In another embodiment, the at least one of R24 and R25 that is C(=O)Ci-C8alkyl substituted with at least one halo group is C(=O)(CH2)nCH2Cl where n is 1 -7. In another embodiment, the at least one of R24 and R25 that is C(=O)Ci-C8alkyl substituted with at least one halo group is chloromethylcarbonyl (C(=O)CH2C1).
[00106] In another embodiment, at least one of R24 and R25 is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl. In one embodiment, the at least one of R24 and R25 that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is cyclopropyl-NR2 where each R is independently H, CpC8 alkyl, which may be a Ci-C8 n- alkyl, or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl, which may be a CpC8 n-alkyl. In another embodiment, the at least one Ri that is cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl is l-N-methylaminecycloprop-2-yl
( N(CH3)R where R is crc8alkyl or aralkyl where the alkyl moiety of the aralkyl group is a Ci-C8 alkyl). In another embodiment, the at least one of R24 and R25 that is cyclopropyl-N^ where each R is independently H, alkyl, or aralkyl is 1 -N5N- dimethylaminocycloprop-2-yl.
[00107] It is understood and clearly conveyed by this disclosure that each R24, R25 and p disclosed in reference to formula (IX) intends and includes all combinations thereof the same as if each and every combination Of R24, R25 and p were specifically and individually listed.
[00108] In one embodiment, the compound is of the formula (X):
Figure imgf000029_0001
(X) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, C|-C8alkyl or aralkyl where
NH
-N^N- the alkyl moiety of the aryl group is a Ci-C8alkyl, W is -NH-, guanidino ( H H ) or
biguanido (
Figure imgf000029_0002
p and n are independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; X is -O-Ci-C8alkyl, OH or NHR28, where R28 is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl; R27 is is hydrogen, CrC8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl. In one embodiment, X is -OCH3. In one embodiment, q is 3. In one embodiment, q is 4. In one embodiment, q is 5. [00109] In one embodiment, the compound is of the formula (XI):
Figure imgf000029_0003
(XI) or a salt, solvate, or hydrate thereof, wherein R26, W, p, n, t, s, q and R27 are as defined for
compound (X) and W2 is -NH-, guanidino
Figure imgf000029_0004
).
[00110] In one embodiment, the compound is of the formula (XII):
Figure imgf000030_0001
(XII) or a salt, solvate, or hydrate thereof, wherein R26, W, p, n, t, s, X, q and R27 are as defined for formula (X) and R29 is Ci-C8 alkyl-C≡CH, d-C8cyclopropane or C(O)Ci -C8alkyl substituted with at least one halo group. In one embodiment, R29 is propargyl, cyclopropylmethyl or chloromethylcarbonyl.
[00111] In one embodiment, the compound is of the formula (XIII):
Figure imgf000030_0002
(XIII) or a salt, solvate, or hydrate thereof, wherein R26, W, W2, p, n, t, s, q, R27 and R29 are as defined above. [00112] In one embodiment, the compound is of the formula (XIV):
Figure imgf000030_0003
(XlV) or a salt, solvate, or hydrate thereof, wherein R26, W, p, n, t, s, q, R27 and R29 are as defined above.
[00113] In one embodiment, the compound is of the formula (XV):
Figure imgf000030_0004
(XV) or a salt, solvate, or hydrate thereof, wherein R26, W, W2, p, n, t, s, q, R27 and R29 are as defined above.
29 [00114] In one embodiment, the compound is of the formula (XVI):
Figure imgf000031_0001
(XVI) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, CrC8alkyl or aralkyl where
the alkyl moiety of the aryl group is a Ci-C8alkyl, W is -NH-, guanidino
Figure imgf000031_0002
Figure imgf000031_0003
biguanido ( H H H ); p and n are independently an integer from 1 to 5; integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; X is -O-Ci-C8alkyl, OH or NHR28, where R28 is hydrogen, C|-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl; and R29 is Ci-C8 alkyl-C≡CH, Ci-C8cyclopropane or C(=O)C|-C8alkyl substituted with at least one halo group. In one embodiment, R29 is propargyl, cyclopropylmethyl or chloromethylcarbonyl. In one embodiment, X is -OCH3. In one embodiment, q is 3. In one embodiment, q is 4. In one embodiment, q is 5. [00115] For all formulae listed herein, such as formulae (I)-(XVI), even if not explicitly stated, any substituent mentioned in one formula is intended to describe the same substituent in any other formula to the extent that the description conforms to the structural characterization of the formula described. For example, Ri in formula I is intended to describe any other Ri found in any other formula to the extent that the description conforms to the structural characterization of the formula described. Similarly, any description of, e.g., C)-C8 substituted or unsubstituted alkyl is intended to describe any other Ci-C8 substituted or unsubstituted alkyl found in any other formula to the extent that the description conforms to the structural characterization of the formula described. [00116] It is also recognized that any compounds listed as a particular salt thereof is not intended to limit the compound to such salt or form thereof. Similarly, where compounds are listed as a salt, the structure may or may not explicitly indicate positive or negative charges or the location thereof, and all possibilities thereof are intended. For instance, a compound listed as a 4HBr salt does not limit the compound to only the HBr salt and the compound may or may not show the + or - charges of the HBr salt, but rather all possibilities are intended.
[00117] Any of the polyamine compounds, such as compounds of the formula (I)-
(IX) may be in a protected form, such as when any one or more amine (e.g., -NH-) is protected by a protecting group (Pg), such as in (-NPg-). Pg may be any protecting group, such as mesityl (e.g., NMes), Boc (e.g., -NBoc) or any other protecting group such as those described in, e.g. T. W. Green, P. G. M. Wuts, Protective Groups in Organic
Synthesis, Wiley-Interscience, New York, 1999, which is incorporated herein by reference in its entirety.
[00118] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (M).
[00119] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (I).
[00120] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (II).
[00121] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (III).
[00122] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (IV).
[00123] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (V).
[00124] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VI).
[00125] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VII). [00126] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (VIII).
[00127] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (IX).
[00128] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (X).
[00129] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XI).
[00130] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XII).
[00131] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XIII).
[00132] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XIV).
[00133] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XV).
[00134] In another embodiment, the invention embraces a method of treating cancer, by administering a therapeutically effective amount of one or more of the compounds of formula (XVI).
[00135] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more compounds, where the compound has an allene, propargyl, alkynyl, cyclopropyl, choromethyl ketone, and also at least one guanidine moiety or at least one biguanide moiety, in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. [00136] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (M) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00137] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (I) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00138] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (II) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00139] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (III) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00140] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (IV) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00141] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (V) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00142] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VI) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00143] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VII) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00144] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (VIII) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00145] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (IX) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00146] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (X) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00147] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XI) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00148] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XII) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
[00149] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XIII) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. [00150] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XIV) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. [00151] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XV) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%. [00152] In another embodiment, the invention embraces a method of inhibiting a histone demethylase enzyme, such as LSDl, by contacting the enzyme with an amount of one or more of the compounds of formula (XVI) in an amount sufficient to inhibit the enzyme. The enzyme can be inhibited by at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99%.
DETAILED DESCRIPTION OF THE INVENTION
[00153] The disclosure includes all salts of the compounds described herein. The invention also includes all non-salt compounds of any salt of a compound named herein, as well as other salts of any salt of a compound named herein. In one embodiment, the salts of the compounds comprise pharmaceutically acceptable salts. Pharmaceutically acceptable salts are those salts which retain the biological activity of the free compounds and which can be administered as drugs or pharmaceuticals to humans and/or animals. The desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared. The desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base. Examples of inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared. [00154] The disclosure includes all solvates of the compounds described herein, such as hydrates (in any ratios, e.g. monohydrates, dihydrates, hemihydrates, sesquihydrates), methanolates, ethanolates, etc.
[00155] Any compound described herein may occur in a combined salt and solvate form, for example the hyclate (monohydrochloride hemiethanolate hemihydrate) form. [00156] The disclosure includes all stereoisomers of the compounds described herein, including diastereomers and enantiomers in optically pure or substantially optically pure form, as well as mixtures of stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers of the compound depicted. For cyclopropyl groups, the structures are intended to embrace all stereoisomers of both cis- and trans-substituted cyclopropyl groups.
[00157] The disclosure includes all crystal and non-crystalline forms of the compounds described herein, including all polymorphs, polycrystalline, and amorphous forms and any mixtures thereof.
[00158] The term "alkyl" refers to saturated aliphatic and alicyclic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. "Straight-chain alkyl" or "linear alkyl" groups refers to alkyl groups that are neither cyclic nor branched, commonly designated as "n-alkyl" groups. Ci-C8 n-alkyl consists of the following groups: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2-, and -CH2CH2CH2CH2CH2CH2CH2CH2-. Other examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec- butyl, t-butyl, pentyl, n-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Cycloalkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple bridged or fused rings, including, but not limited to, groups such as adamantyl or norbornyl groups. Cycloalkyl groups can also contain alkyl groups in addition to the cyclic portion, e.g., 2,6,6-trimethylbicyclo[3.1.1]heptane, 2-methyldecalin (2- methyldecahydronaphthalene), cyclopropylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.
[00159] "Substituted alkyl" refers to alkyl groups substituted with one or more substituents including, but not limited to, groups such as halogen (including fluoro, chloro, bromo, and/or iodo-substituted alkyl such as a monohaloalkyl, dihaloalkyl, trihaloalkyl or multihaloalkyl, including a perhalooalkyl, for example, perfluoroalkyl, percholoralkyl, trifluoromethyl or pentachloroethyl), alkoxy, acyloxy, amino (including NH2, NHalkyl and N(alkyl)2), hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, acyl, acylamino, amidino, alkyl amidino, thioamidino, aminoacyl, aryl, substituted aryl, aryloxy, azido, thioalkyl, -OS(O)2-alkyl, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of substituted alkyl groups include, but are not limited to, CF3, CF2CF3, and other perfluoro and perhalo groups; -CH2-OH; -CH2CH2CH(NH2)CH3, etc. Alkyl groups can be substituted with other alkyl groups, e.g., C3-C24 cycloalkyl groups.
[00160] The term "alkenyl" refers to unsaturated aliphatic and alicyclic groups including straight-chain (linear), branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, which contain at least one double bond (-C=C-). Examples of alkenyl groups include, but are not limited to, -CH2-CH=CH-CH3; and -CH2-CH2-cyclohexenyl, where the ethyl group can be attached to the cyclohexenyl moiety at any available carbon valence. The term "alkynyl" refers to unsaturated aliphatic and alicyclic groups including straight-chain (linear), branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms, which contain at least one triple bond (-C≡C-). "Hydrocarbon chain" or "hydrocarbyl" refers to any combination of straight-chain, branched-chain, or cyclic alkyl, alkenyl, or alkynyl groups, and any combination thereof. "Substituted alkenyl," "substituted alkynyl," and "substituted hydrocarbon chain" or "substituted hydrocarbyl" refer to the respective group substituted with one or more substituents, including, but not limited to, groups such as halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl," or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. [00161] "Aryl" or "Ar" refers to an aromatic carbocyclic group having a single ring
(including, but not limited to, groups such as phenyl), two or more rings connected to each other (including, but not limited to, groups such as biphenyl and p-diphenylbenzene) or two or more condensed rings (including, but not limited to, groups such as naphthyl, anthryl, or pyrenyl), and includes both unsubstituted and substituted aryl groups. Aryls, unless otherwise specified, contain from 6 to 20 carbon atoms in the ring portion. A preferred range for aryls contains 6 to 12 carbon atoms in the ring portion. "Substituted aryls" refers to aryls substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl," or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. "Aralkyl" designates an alkyl-substituted aryl group, where any aryl can be attached to the alkyl; the alkyl portion can comprise one, two, or three straight chains of 1 to 6 carbon atoms each or one, two, or three branched chains of 3 to 6 carbon atoms each or any combination thereof. Aralkyl groups can consist of two aryl groups connected by an alkyl group, such as diphenylmethane or 2-methyl-l-(phenethyl)benzene. When an aralkyl group is indicated as a substituent, the aralkyl group can be connected to the remainder of the molecule at any available valence on either its alkyl moiety or aryl moiety; e.g., the tolyl aralkyl group can be connected to the remainder of the molecule by replacing any of the five hydrogens on the aromatic ring moiety with the remainder of the molecule, or by replacing one of the alpha-hydrogens on the methyl moiety with the remainder of the molecule. Preferably, the aralkyl group is connected to the remainder of the molecule via the alkyl moiety. [00162] A preferred aryl group is phenyl, which can be substituted or unsubstituted.
Substituents for substituted phenyl groups include lower alkyl (-C1-C4 alkyl), or a halogen (chlorine ( Cl), bromine ( Br), iodine ( 1), or fluorine ( F); hydroxy (-OH), or lower alkoxy (-C1-C4 alkoxy), such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i- propoxy), and butoxy (either n-butoxy, i-butoxy, sec-butoxy, or tert-butoxy); a preferred alkoxy substituent is methoxy. Substituted phenyl groups preferably have one or two substituents; more preferably, one substituent. For aralkyl groups, a preferred group for the aryl portion is phenyl, which can be unsubstituted or substituted as described immediately above.
[00163] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to alkyl, alkenyl, and alkynyl groups, respectively, that contain the number of carbon atoms specified (or if no number is specified, having up to 12 carbon atoms) which contain one or more heteroatoms as part of the main, branched, or cyclic chains in the group. Heteroatoms include, but are not limited to, N, S, O, and P; N and O are preferred. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule at any valence where a hydrogen can be removed, for example, at a heteroatom or at a carbon atom (if a valence is available at such an atom by removing a hydrogen). Examples of heteroalkyl groups include, but are not limited to, groups such as -O-CH3, -CH2-O-CH3, -CH2-CH2-O-CH3, -S-CH2-CH2-CH3, -CH2-CH(CH3)-S-CH3, -CH2-CH2-NH-CH2-CH2-, l-ethyl-6-propylpiperidino, and morpholino. Examples of heteroalkenyl groups include, but are not limited to, groups such as -CH=CH-NH-CH(CH3)-CH2-. "Heteroaryl" or "HetAr" refers to an aromatic carbocyclic group having a single ring (including, but not limited to, examples such as pyridyl, imidazolyl, thiophene, or furyl) or two or more condensed rings (including, but not limited to, examples such as indolizinyl, indole, benzimidazole, benzotriazole, or benzothienyl) and having at least one hetero atom, including, but not limited to, heteroatoms such as N, O, P, or S, within the ring. Unless otherwise specified, heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups have between one and five heteroatoms and between one and twelve carbon atoms. "Substituted heteroalkyl," "substituted heteroalkenyl," "substituted heteroalkynyl," and "substituted heteroaryl" groups refer to heteroalkyl, heteroalkenyl, heteroalkynyl, and heteroaryl groups substituted with one or more substituents, including, but not limited to, groups such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted benzyl, substituted or unsubstituted hydrocarbon chains, halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or any group listed above for "Substituted alkyl," or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group. Examples of such substituted heteroalkyl groups include, but are not limited to, piperazine, substituted at a nitrogen or carbon by a phenyl or benzyl group, and attached to the remainder of the molecule by any available valence on a carbon or nitrogen, -NH-SO2-phenyl, -NH-(C=O)O-alkyl, -NH-(C=O)O-alkyl-aryl, and -NH-(C=O)-alkyl. If chemically possible, the heteroatom(s) and/or the carbon atoms of the group can be substituted. A "heteroaralkyl" group is a heteroaryl group substituted with at least one alkyl group. The heteroatom(s) can also be in oxidized form, if chemically possible.
[00164] The term "alkoxy" as used herein refers to an alkyl, alkenyl, alkynyl, or hydrocarbon chain linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. Examples of alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, propyloxy (propoxy) (either n-propoxy or i-propoxy), and butoxy (either n-butoxy, i-butoxy, sec- butoxy, or tert-butoxy).
[00165] The terms "halo" and "halogen" as used herein refer to the Group Vila elements (Group 17 elements in the 2005 IUPAC Periodic Table, IUPAC Nomenclature of Inorganic Chemistry) and include Cl, Br, F and I substituents.
[00166] "Protecting group" refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1999) Protective Groups in Organic Synthesis, (Wiley-Interscience., New York). Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t-butyloxycarbonyl (Boc), t- butyldimethylsilyl (TBS or TBDMS), 9-fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6- nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5 bromo 7-nitroindolinyl, and the like. Hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether), NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4 nitrophenethyloxymethyloxycarbonyl). Synthetic methods — synthesis of alkylpolyamines
[00167] Several synthetic methods are available for synthesis of polyamine analog compounds, including both symmetrically-substituted and asymmetrically-substituted polyamine analogs. Some of these methods are described in the following publications: Saab et al., J. Med. Chem. 36:2998 (1993); Bellevue et al., Bioorg. Med. Chem. Lett. 6:2765 (1996); Sirisoma et al., Tetrahedron Lett. 39: 1489 (1998); Zou et al., Bioorg. Med. Chem. Lett. 1 1 : 1613 (2001), and Casero et al., J. Med. Chem. 44: 1 (2001).
Scheme 1. "Mest" indicates mesitylene sulfonyl (2,4,6-trimethylbenzene-l-sulfonyl) moiety.
Figure imgf000042_0001
[00168] Scheme 1 illustrates a useful pathway to various polyamine analogs. The tetramesitylated intermediate 8 can be readily alkylated at both terminal nitrogens, since the hydrogens on these nitrogens are rendered acidic by the adjacent mesityl protecting group. Alkylation in the presence of 1.2 to 1.4 equivalents of alkyl halide or tosylate affords primarily the monosubstituted product 9, and disubstituted materials and unreacted starting material can then be separated and recycled (Bellevue et al., Bioorg. Med. Chem. Lett. 6:2765 (1996); Zou et al., Bioorg. Med. Chem. Lett. 1 1 : 1613 (2001)). The resulting monoalkylated derivative 9 can then be deprotected (30% HBr in AcOH), or realkylated with a different alkyl halide to provide the asymmetrically substituted intermediate 11. Deprotection of 11 then provides the desired asymmetrically substituted alkylpolyamine. Treatment of 8 with 2.2 equivalents of alkyl halide in the presence of NaH and DMF affords the bis-substituted intermediate 10, which upon deprotection yields the corresponding symmetrically substituted alkylpolyamine. Thus three distinct alkylpolyamines can be readily synthesized from a single intermediate, and the central carbon chain can be made in any desired length (n = 0 - 8). Synthesis of the intermediate 8 is readily accomplished in large quantities using previously reported synthetic strategies (Bellevue et al., Bioorg. Med. Chem. Lett. 6:2765 (1996); Zou et al., Bioorg. Med. Chem. Lett. 1 1 : 1613 (2001)). A similar strategy can be used to access spermidine-like analogs of the form:
Figure imgf000043_0001
[00169] Other methods can be used for synthesis of the requisite polyamine backbone structures, which involve carbon nitrogen bond formation and selective nitrogen protection; some of these procedures are shown in Scheme 2. Scheme 2
Method A
Figure imgf000043_0002
R = protected alkylamino chain
R2 = allylic alkyl group B 27Hπ,6
Z = nitrogen protecting group
Method B
NaCNBH
H2N' VN'
H ^N^^H ^N' ~N' H H H
12 15 16
Method C
Figure imgf000043_0003
[00170] Aminopropyl (or other aminoalkyl) moieties can be added to selectively protected primary amines such as 12 by standard peptide coupling techniques (Method A, Woster et al., J. Med. Chem. 32: 1300 (1989)). Thus treatment of 12 with the protected beta-aminopropionate 13 (DCC, HoBt, N-methylmorpholine) affords the corresponding amide 14, which is then reduced in the presence of diborane (Woster et al., 1989) to afford the desired secondary amine 16. Compound 16 may be synthesized directly by reductive amination (Method B), in which the appropriate aldehyde 15 is added to 12 in the presence of sodium cyanoborohydride. Alkyl substituents that contain an allylic acetate functionality can also be appended to 12 using a palladium catalyzed coupling reaction that proceeds with retention of configuration (Method C, Sirisoma et al., Tetrahedron Lett. 39: 1489 (1998)). This method can also be used to introduce phthalimide or benzylamine to an allylic acetate site as a synthetic equivalent for nitrogen. These nitrogens can then be deprotected and functionalized.
Synthetic methods — synthesis of polyaminoguanidines Scheme 3
Figure imgf000044_0001
General structure 3
[00171] Synthesis of polyaminoguanidines can be carried out as outlined in Scheme
3. The requisite amine 19 (produced when necessary from the corresponding alkyl or aralkylcyanide) is reacted with cyanogen bromide (Goldin et al., U.S. Patent No. 6,288,123 (2001)) to afford the corresponding aminocyanogen 20. When the desired amine is not commercially available, it can be prepared from the appropriate cyano compound by catalytic reduction (Bellevue et al., 1996, Zou et al., 2001). Intermediate 21 (Bellevue et al., 1996; Zou et al., 2001) is then coupled to 20 (chlorobenzene, reflux), followed by deprotection (30% Hbr in AcOH) to produce alkylpolyaminoguanidines of general structure 3. Using these methods, substituted polyaminoguanidine analogs (e.g., R = H, methyl, ethyl, cyclopropylmethylene, cycloheptylmethylene, phenyl, benzyl) can be synthesized. An analogous route (not shown) utilizing the N-Boc protection group was also employed.
Synthetic methods — synthesis of polyaminobiguanides
[00172] The synthesis of polyaminobiguanides is described in Bi et al., Bioorg.
Med. Chem. Lett. 16:3229 (2006), and is also outlined in Scheme 4.
Scheme 4
Figure imgf000045_0001
General structure 4
[00173] A similar strategy is employed for the synthesis of alkylpolyaminobiguanides of general structure 4, as outlined in Scheme 4. Amines 23 (produced when necessary from the corresponding alkyl or aralkylcyanide) are converted to the corresponding cyanoguanidines 24 (NaN(CN)2, BuOH/H20) (Gerhard, R.; Heinz, B.; Herbert, F. J. Praktische Chem. (Leipzig), 1964, 26, 414-418), which were combined with 21 as previously described to afford the mesityl protected target molecules. Deprotection as described above then provided the substituted biguanides 4. An analogous route (not shown) utilizing the N-Boc protection group was also employed, as above.
Synthetic methods — solid phase synthesis
Scheme 4 or
Figure imgf000045_0002
[00174] Solid phase synthetic techniques can be used for the rapid and efficient synthesis of both alkylpolyamines and their alpha-methyl homologs, as shown in Scheme 4 above. Compound 22 can be produced using a commercially available trityl chloride resin, as described in Wang et al. , J. Am. Chem. Soc, 95(4): 1328 (1973), where the attached amine is primary or secondary prior to attachment, an alpha-methyl is present or absent, and the X group is either a protected amine or a synthetic equivalent such as an azide or a phthalamide. This intermediate is then deprotected or converted to the corresponding primary amine 23. Three strategies can be used for chain elongation: 1. reductive amination with aldehydes 24 in the presence of sodium cyanoborohydride to produce 25; 2. addition of an appropriate carboxylate 26 under peptide coupling conditions (Woster et al., J. Med. Chem. 32: 1300 (1989)), followed by diborane reduction of the resulting amide, yielding 27; 3. direct alkylation with a protected halide (Woster et al., J. Med. Chem. 32: 1300 (1989)) such as 28, to afford intermediates 29. Repetition of these steps then allows the synthesis of a variety of alkylpolyamines and alpha-methyl- alkylpolyamines with substituents as desired.
Synthesis of Compounds of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), and Formula (XVI)
[00175] Synthesis of the compounds of formula (X) and formula (XI) can proceed via use of lysine-mimic synthons such as 107, 112 and 116 (Schemes 1-3). The synthesis of compound 107 is outlined in Scheme 1, starting from the α-N-Boc-lysine methyl ester 105 (R = Ci-C8 alkyl, e.g., CH3). The starting material 105 is conveniently prepared from α-N-Boc-lysine methyl ester (with an unprotected primary ε-amino group), commercially available from Bachem AG Biosciences. The ε-amino group can be alkylated, e.g., with a Ci-C8 alkyl group or Ci-C8 alkyl-Cβ-Cio aryl group, using an alkyl chloride, aralkyl chloride or other alkyl or aralkyl derivative reactive towards the amino group. Should an ester other than the methyl ester be desired, transesterification can be readily performed to replace the -OMe group with the desired ester, e.g., -O-Ci-C8 alkyl. Alternatively, the ester can be easily converted to the -COOH group, which in turn can be reacted with an amine to form an amide group. Scheme 1
e,
Figure imgf000047_0001
[00176] Compound 105 is reacted with propargyl bromide (NaH, DMF) ( Bellevue,
F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993)) to afford the alkylated amino acid 106. The acetylene moiety is then converted to the corresponding 2,3-butadiene moiety by treating it with cupric bromide and formaldehyde in the presence of diisopropylamine (Bey, P. et al., J. Med. Chem., 28: 1-2 (1985)) to afford the desired synthon 107 (R = CH3). Cleavage of the methyl ester (LiOH) (Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996), Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993), Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005)) produces the corresponding carboxylate substrate (as shown in 108) for coupling to an appropriate free amine (using DCC, HOBT) (Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996), Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993), Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005)), while removal of the N-Boc protecting group (with trifluoroacetic acid) (as shown in 108) affords a free amine useful for peptide coupling or reductive amination reactions (see, e.g., Casero, Jr. R.A. et al., J. Med. Chem, 44: 1 -26 (2001), Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996), Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993), and Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005)). A similar strategy, as outlined in Scheme 2, can be used to convert l -N-(methyl)-5-N-(tertbutyloxycarbonyl)- 1 ,5-diaminopentane 109 (R = CH3) to the corresponding synthon 112 (R = CH3). Treatment of 109 with propargyl bromide as described above results in intermediate 110, and subsequent conversion of the propargyl acetylene to the corresponding allene (Bey, P. et al., J. Med. Chem., 28:1-2 (1985)) then affords 111. (It should be noted that, when the propargyl group is desired instead of the allene group, this step can be omitted to obtain the propargyl-containing synthon). Removal of the N-Boc protecting group (e.g., with trifluoroacetic acid) then affords the desired free amine 112, which is also useful for peptide coupling or reductive amination reactions as indicated above. Finally, the O- methoxymethyl protected version of l-hydroxy-5-[N-(methyl)]aminopentane 113 (Scheme 3) can be converted to the N-propargyl derivative 114, and then to the 2,3-butadienyl derivative 115, as described above (Bey, P. et al., J. Med. Chem., 28: 1-2 (1985)), followed by acid deprotection of the alcohol and conversion of the corresponding hydroxyl group to a mesylate (Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993)) to afford 116. Compound 116 can then be appended to a variety of aldehydes, amines, guanidines and guanides by nucleophilic substitution (see Casero, Jr. R.A. et al., J. Med. Chem, 44: 1-26 (2001), Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996), Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993), and Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005)).
Scheme 2
Figure imgf000048_0001
CuBr, formaldehyde, diisopropylamine
Figure imgf000048_0002
112 111
Scheme 3
Figure imgf000049_0001
z = methoxymethyl (MOM) CuBr, formaldehyde, diisopropylamine
Figure imgf000049_0002
[00177] The elaboration of synthons 107, 112 and 116 to provide compounds of formula (X) and formula (XI) is outlined in Scheme 4, Scheme 5, and Scheme 6. Removal of the N-Boc protecting group in synthon 107 (Scheme 4) affords the free amine 119, which is then appended to a protected polyaminocarboxylate of general structure 120, (Casero, Jr. R.A. et al., J. Med. Chem, 44: 1-26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem. Lett., 16:3229-3232 (2006)) as previously described (using DCC, HOBT, DMF; see Bellevue, Saab, and Varghese references immediately preceding) to afford 121a. The ester functionality of 121a is hydrolyzed (LiOH) (see Bellevue, Saab, and Varghese references) to produce carboxylate 121b, and this intermediate is in turn converted to substituted amide 121c (using DCC, HOBT, DMF; see Bellevue, Saab, and Varghese references). The mesitylenesulfonyl protecting groups in compounds 121a-c are then removed (Yajima, H. et al., Chem. Pharm. Bull., 26:3752-3757 (1978); Roemmele, R.C., Rappoport, H., J. Org. Chem., 53:2367-2371 (1988)) to afford potential LSDl inhibitors of formula (X) (X = OCH3, OH or NH-R3, W2 = NH).
Scheme 4
Figure imgf000050_0001
Scheme 5
Figure imgf000050_0002
[00178] Molecules of formula (XI) can be synthesized using the route shown in
Scheme 5. Synthon 112 is coupled to polyaminocarboxylate of general structure 120 (Casero, Jr. R.A. et al., J. Med. Chem, 44: 1-26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem. Lett., 16:3229-3232 (2006)) as described above to yield intermediate 122. Removal of the mesityl protecting group (Yajima, H. et al., Chem. Pharm. Bull., 26:3752- 3757 (1978); Roemmele, R.C., Rappoport, H., J. Org. Chem., 53:2367-2371 (1988)) then affords target molecules of formula (XI). [00179] Synthetic routes to other compounds of formula (XI) are shown in Scheme
6 and Scheme 7. As shown in Scheme 6, intermediate 112 is reacted with aldehydes of general structure 123 (previously described in Casero, Jr. R. A. et al., J. Med. Chem, 44: 1- 26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem. Lett., 16:3229-3232 (2006)) using standard reductive amination conditions, followed by deprotection (30% HBr in AcOH) (Yajima, H. et al., Chem. Pharm. Bull., 26:3752-3757 (1978); Roemmele, R.C., Rappoport, H., J. Org. Chem., 53:2367-2371 (1988)) to afford compounds of formula (Xl). Alternatively, synthon 116 is reacted with amines, guanidines or biguanides of general structure 124, and subsequent deprotection (30% HBr in AcOH) then affords compounds of formula (XI).
Scheme 6
H9N N I ^^
R
112
EtOH
Figure imgf000051_0001
Figure imgf000051_0002
R = H, alkyl, aralkyl
R2 = H, alkyl, aralkyl
Y = null p = 1 -5; m = 1-5; n = 1-5
W = NH, guanidino, guanido
W2 = NH Scheme 7
ne
Figure imgf000052_0001
R = H, alkyl, aralkyl
R2 = H, alkyl, aralkyl
Y = null p = 1-5; m = 1 -5; n = 1 -5
W = NH, guanidino, guanido
W2 = NH, guanidino, guanido
[00180] Compounds of Formula (XII) and Formula (XIII) can be synthesized using routes similar to those shown in Schemes 1-7. Intermediate 105 (Scheme 8) is alkylated (Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993)) followed by ester hydrolysis and removal of the N-Boc group as described above to afford synthon 129. Compound 129 is then appended to a suitable polyamine precursor (Casero, Jr. R.A. et al., J. Med. Chem, 44:1-26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem. Lett., 16:3229-3232 (2006)) and elaborated as described above to yield target compounds of Formula (XII). [00181] The chloromethyl ketone compounds of formula (XVI) are synthesized by substituting intermediate 130 for 129, as indicated in Scheme 8, followed by elaboration as described. Chloromethyl ketone derivatives act as irreversible, active site-directed inhibitors of proteases and other enzymes, and would also be expected to inactivate LSDl . Intermediates of general structure 130 are commercially available or readily synthesized (Shaw, E.; Glover, G., Arch. Bioch. Bioph., 139:298-305 (1970); Biaas, A. et al., J. Med. Chem., 49: 1744-1753 (2006)), and can be coupled to the appropriate polyamine precursor via peptide coupling, as described above and previously reported (Biaas, A. et al., J. Med. Chem., 49: 1744-1753 (2006)). Scheme 8
Figure imgf000053_0001
Formula (XII)
Figure imgf000053_0002
R, R4 = alkyl, H
Figure imgf000053_0003
Formula (XVI)
[00182] Two synthetic pathways are utilized to produce target compounds of
Formula (XIII), as shown in Scheme 9. Intermediate 109 is alkylated (Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993)) using a variety of electrophilic or latent electrophilic alkyl halides (e.g. propargyl, cyclopropylmethyl, 1-difluoroethyl, etc.), followed by removal of the N-Boc group as described above to afford synthon 132. Compound 132 is then appended to a suitable polyamine precursor (Casero, Jr. R.A. et al., J. Med. Chem, 44:1-26 (2001); Bellevue, F.H. et al., Bioorg. Med. Chem. Lett., 6:2765-2770 (1996); Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993); Varghese, S. et al., J. Med. Chem., 48:6350-6365 (2005); Bi, X. et al., Bioorg. Med. Chem. Lett., 16:3229-3232 (2006)) and elaborated as described above to yield target compounds of formula (XlII). Alternatively, synthon 113 (Scheme 9) is alkylated (Saab, ibid.) followed by acid deprotection of the alcohol and conversion of the corresponding hydroxyl group to mesylate to afford 133. Compound 133 is then appended to a suitable polyamine precursor (Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.) and elaborated as described above to yield target compounds of formula (XIII).
Scheme 9
1 . R3-X, NaH, DMF
H2N
Ek)C-HN' NH
2. TFAA I
132 R
109
Figure imgf000055_0001
Formula (XII)
R = H, alkyl, aralkyl
R2 = H, alkyl, aralkyl
R3 = propargyl, cyclopropy Im ethyl, chloromethylcarbonyl Y = O or null p = 1-5; m = 1-5; n = 1-5 y
W = NH, guanidino, guanido ^\ W2 = NH, guanidino, guanido
Figure imgf000055_0002
z = methoxymethyl (MOM)
[00183] Formula (XIV) and formula (XV) contain a cyclopropylamine moiety. The synthesis of these analogues proceeds via the production of substituted cyclopropanes 120, 122 and 124, which are accessed from terminal olefins 134, 136 and 138, respectively by cyclopropanation/amination (Raju, B. et al., Bioorg. Med. Chem. Lett., 14:3103-3107 (2004)), followed by alkylation (Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.) of the resulting terminal amine as described above. The synthesis leading to compounds of Formula (XIV) is shown in Scheme 10. The commercially available olefin 134 undergoes cyclopropanation using the method of Borne et al. (N2CHCO2C2Hs followed by ethyl chloroformate and sodium azide) (Raju, B. et al., Bioorg. Med. Chem. Lett., 14:3103-3107 (2004)), after which alkyl substituents are added to the nitrogen using reductive amination and then nucleophilic substitution, as previously described to afford 135 (Casero et al.; Bellevue et al.; Saab et al.; Varghese et al. Bi et al., ibid.). Synthon 135 is then elaborated as described above to yield compounds of Formula (XIV).
Scheme 10
Figure imgf000056_0001
Formula (XIV)
R = H, alkyl, aralkyl
R2 = H, alkyl, aralkyl
R3 = H, alkyl, aralkyl
R4 = propargyl, cyclopropylmethyl, chlorom ethylcarbonyl X = OCH31 OH Or NH-R3 Y = O or null p = 1 -5; m = 1-5; n = 1-5 W = amino, guanidino, guanido
[00184] A similar approach can be used to produce compounds of formula (XV), as shown in Scheme 1 1. The commercially available olefin 136 is converted to the corresponding cyclopropylamine as described above, followed by sequential addition of the N-alkyl groups by reductive amination and nucleophilic substitution (see above). Removal of the N-Boc protecting group then affords 137, which is elaborated as described to afford compounds of formula (XV). Olefin 138 is likewise converted to the cyclopropylamine derivative and bis-alkylated, after which acid-catalyzed removal of the MOM protecting group (indicated by Z in Scheme 1 1 and other schemes) and subsequent mesylation (Saab, N.H. et al., J. Med. Chem., 36:2998-3004 (1993)) yields the desired synthon 139. Elaboration as described above then affords compounds of formula (XV). Scheme 11
1 . N2CHCO2C2H5
Bo C-HN Boc-HN N
2. ethyl chloroformate,
NaN3 R
136 137
3. R-CHO1 NaCNBH3
4. R3-X /
5. TFAA
/
Figure imgf000057_0001
Formula (XV)
R = H, alkyl, aralkyl
R2 = H, alkyl, aralkyl
R3 = propargyl, cyclopropylmethyl, chloromethylcarbonyl Y = O or null
P = 1-5; m = 1 -5; n = 1 -5 \
W = NH, guanidino, guanido ^ W2 = NH, guanidino, guanido
\
Figure imgf000057_0002
3. R-CHO, NaCNBH3
4. R3-X
5. H+
6. mesyl chloride, pyridine
Biological applications — lysine-specific demethylase- 1 (LSDl) inhibitors [00185] Histories are proteins found in eukaryotic cells which act as support scaffolds for DNA (sometimes compared to a protein spool supporting the DNA thread). Histones, together with other proteins and DNA, form the chromatin of the cell nucleus. Because of their close association with DNA, histones play a role in gene regulation. The tails of histone proteins are a frequent site for covalent modifications which affect gene expression.
[00186] The enzyme lysine-specific demethylase- 1 (LSDl ; also known as lysine- specific histone demethylase, BHCl 10 and KIAA0601) is an enzyme that affects the covalent modification of histone tails, by demethylating lysine 4 of the histone H3. Shi et al. (Cell, 1 19:941 (2004)) showed that RNAi inhibition of LSDl led to an increase in H3 lysine 4 methylation, followed by de-repression of the target genes. Thus LSDl apparently represses transcription by demethylating histone H3. Conversely, inhibition of LSDl allows transcription by preventing demethylation.
[00187] Because of the observed homology between the active site of LSDl and monoamine oxidase (MAO), Lee et al. (Chemistry & Biology 13:563 (2006)) tested various MAO inhibitors for their ability to inhibit LSDl. They identified tranylcypromine ((lR,2S)-2-phenylcyclopropan-l-amine) as an inhibitor with an IC50 less than 2 micromolar. Treating Pl 9 embryonal carcinoma cells with tranylcypromine led to transcriptional de-repression of the Egrl and Oct4 genes.
[00188] International Patent Application No. WO 2006/071608 is directed to a method for monitoring eukaryotic histone demethylase activity, methods for up-regulating and down-regulating methylated histone-activated genes, and a method for treating or preventing a disease (e.g., a hyperproliferative disease such as cancer) by modulating the level of protein or the activity of a histone demethylase. In view of the importance of gene regulation, and the ability to affect gene regulation by inhibiting or modulating LSDl, inhibitors of the enzyme may have significant therapeutic potential; Bi, X. et al., Bioorg. Med. Chem. Lett. 16:3229-3232 (2006) and International Patent Application No. WO 2007/021839 describes certain compounds useful as inhibitors of LSDl . [00189] Lysine-specific demethylase- 1 -inhibiting compounds of the current inventions can inhibit LSDl by at least about 25%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; by at least about 50%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 75%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 90%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; at least about 95%, at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less; or at least about 99% at a concentration of the compound of about 10 micromolar or less, about 1 micromolar or less, about 100 nanomolar or less, about 10 nanomolar or less, or about 1 nanomolar or less.
Biological applications — treatment of cancer
[00190] "Treating" or "to treat" a disease using the methods of the invention is defined as administering one or more polyamines or polyamine analogs, with or without additional therapeutic agents, in order to palliate, ameliorate, stabilize, reverse, slow, delay, prevent, reduce, or eliminate either the disease or the symptoms of the disease, or to retard or stop the progression of the disease or of symptoms of the disease. "Therapeutic use" of the polyamines and polyamine analogs is defined as using one or more polyamines or polyamine analogs to treat a disease (including to prevent a disease), as defined above. A "therapeutically effective amount" is an amount sufficient to treat (including to prevent) a disease, as defined above. Prevention or suppression can be partial or total. [00191] The compounds disclosed herein have anticancer activity, which has been demonstrated in a variety of human tumor cell types representing the major forms of lung, breast, prostate, and colon cancers. Thus the compounds disclosed herein can be used to treat cancer, including lung cancer (including, but not limited to, small cell lung cancer or SCLC, non-small cell lung cancer or NSCLC, alveolar epithelial cell cancer, bronchial epithelial cell cancer, and squamous cell carcinoma), breast cancer, prostate cancer, and colon cancer, or to prevent cancer, including prevention of lung cancer (including, but not limited to, small cell lung cancer or SCLC, non-small cell lung cancer or NSCLC, alveolar epithelial cell cancer, bronchial epithelial cell cancer, and squamous cell carcinoma), breast cancer, prostate cancer, and colon cancer.
EXAMPLES Example 1
Testing of compounds for inhibition of LSDl
[00192] Compounds of the invention are tested for inhibitory activity against lysine- specific demethylase-1 as outlined in Bi, X. et al., Bioorg. Med. Chem. Lett. 16:3229-3232 (2006) (see also Supplementary Data).
Example 2
In vitro testing of compounds against cancer cell lines
[00193] MTS dose response experiments in H 157, H82, A549, and/or Beas2B cells cells following a 96hr exposure with compounds of the invention are performed. MTS is a standard colorimetric assay used for measuring metabolic activity in cells. MTS experiments are performed by CellTiter 96® AQueUos One Solution Cell Proliferation Assay from Promega Corporation. Cells are seeded at 3000 cells/well on a 96 well tissue culture plate containing lOOul of medium/well and are allowed to attach overnight. The medium is aspirated and replaced with l OOul of fresh medium containing the appropriate concentration of the compound being tested; the cells are then incubated for 96 hrs at 37°C and 5% CO2. Compounds are tested at concentrations ranging from 0.1 micromolar to 50 micromolar. Wells not containing the test compound are used as a control. Following treatment, 20ul of MTS reagent is added to each well and incubated at 37°C for 1.5 hrs. The absorbance of each well is then measured at 490 nm and used to determine the metabolic activity of the cells in the presence of the test compound, relative to the control. IC50 values for the test compounds are extracted based on the results. [00194] MTT dose response experiments in 235, MCF7, 435, and 1OA cells following exposure to compounds of the invention are performed. MTT is a standard colorimetric assay used for measuring metabolic activity in cells. About 200 ul of media not containing cells are added to column A of a 96 well plate and used as a blank. About 200 ul of media containing cells are added to the remaining wells and incubated overnight. The remaining wells contain about 4000-5000 MCF7 cells/well, 3000 231 cells/wells, 12,000 468 cells/well, or 9000 MCF 1OA cells/ well. Following incubation, the media in the wells is aspirated and replaced with 200 ul of fresh media in columns A and B of the 96 well plate. Column B is used as a control. Next 200ul of fresh media containing the compound being tested is added to the remaining wells and incubated for 96 hrs. Compounds are routinely tested at concentrations ranging from 0.1 micromolar to 50 micromolar. Following incubation for 96 hrs, the media in each well is aspirated and replaced with 100 ul of 5mg/ml MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) solution in Serum-Free media and incubated for 4 hours. Following incubation with MTT solution, the MTT solution is removed from the wells and replaced with 200 ul of a 1 : 1 EtOH + DMSO solution and incubated for 20 minutes. Following incubation with the EtOH + DMSO solution the plates are read at 540 nm and are used to determine the metabolic activity of the cells in the presence of the test compound, relative to the control. IC50 values for the test compounds are extracted based on the results.
[00195] SSAT (spermidine/spermine-N'-acetyltransferase) activity experiments in
Hl 57, H82, and A549 cells following exposure to compounds of the invention are performed. A detailed protocol for determining SSAT activity is described in Casero et al., Cancer Research, 49:3829 (1989). Briefly, the SSAT activity is measured by harvesting the treated cells at the exposure time. The cells are then lysed and treated with spermidine, and l-[14C]acetyl coenzyme A for 5 minutes. Enzyme activity is measured in term of picomoles of [14C]acetylspermidine formed per mg of cell protein per min (pmol/mgP/min).
[00196] Experiments to measure putrescine, spermidine, and spermine polyamine levels in H 157 and H82 cells following exposure to compounds of the invention are performed. Polyamine levels are determined using the precolumn dansylation labeling, reverse-phase high-pressure liquid chromatography method as described by Kabra et al., J. Chromotography, 380: 19 (1986).
[00197] SMO (Spermine Oxidase) activity in Hl 57 cells following exposure to compounds of the invention is performed. A detailed protocol for measuring SMO activity is described in Wang et al., Cancer Research, 61 :5370 (2001). [00198] ODC (Ornithine decarboxylase) activity experiments in Hl 57 following exposure to compounds of the invention are performed. A detailed protocol for measuring ODC activity is described in Pegg et al., Methods Enzymology, 94: 158 (1983). [00199] Treatment induced cell cycle measurements in Hl 57 cells are performed.
Following exposure of the cells to a compound of interest, at a concentration of 1 OuM, for 24hrs, the cells are harvested, prepared and transferred to a FACS for cell cycle analysis. (See Carlisle et al., Clinical Cancer Research 8:2684 (2002) and references therein.) [00200] The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
[00201] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

What is claimed is:
1. A compound of the following formula (I):
Figure imgf000062_0001
or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1, each Ri is independently selected from the group consisting of Ci-C8 substituted or unsubstituted alkyl, C4-C]5 substituted or unsubstituted cycloalkyl, C3-C15 substituted or unsubstituted branched alkyl, C6-C20 substituted or unsubstituted aryl, C6-C20 substituted or unsubstituted heteroaryl, C7-C24 substituted or unsubstituted aralkyl, C7-C24 substituted or unsubstituted heteroaralkyl or Ci-C8 alkyl-CH=C=CH2 or CrC8 alkyl-C≡CH or Ci-C8 alkyl-cyclopropane or C(O)Ci- C8alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Ri is Ci-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, C-C8 alkyl-cyclopropane, or C(=O)C,-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently selected from hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
2. A compound of the following formula (II):
Figure imgf000062_0002
(H) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12, m and p are independently an integer from 1 to 5, q is 0 or 1, each Ri is independently selected from the group consisting Of CpC8 substituted or unsubstituted alkyl, C6-C2O substituted or unsubstituted aryl, C6-C20 substituted or unsubstituted heteroaryl, C7-C24 substituted or unsubstituted aralkyl, C7-C24 substituted or unsubstituted heteroaralkyl,
Ci-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, C,-C8 alkyl-cyclopropane, C(=O)C,-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Ri is
Ci-C8 alkyl-CH=C=CH2 or C-C8 alkyl-C≡CH or C-C8 alkyl-cyclopropane or C(=O)CrC8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
3. A compound of the following formula (III):
Figure imgf000063_0001
(111) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; R3 and R4 are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted alkyl, C6-C20 substituted or unsubstituted aryl, C7-C24 substituted or unsubstituted aralkyl, Ci-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of R3 and R4 is Ci-C8 alkyl-CH=C=CH2 or C1-C8 alkyl- C≡CH or Ci-C8 alkyl-cyclopropane or C(=O)Ci-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; Rs1 R9, R6, R7 and R8 are independently selected from the group consisting of hydrogen and Ci-C8 substituted or unsubstituted alkyl; and wherein either m and p are not the same integer or at least one of R5, R9, R6, R7 and R8 is a Ci-C8 substituted or unsubstituted alkyl.
4. A compound of the following formula (IV):
Figure imgf000064_0001
(IV) or a salt, solvate, or hydrate thereof, wherein A, Ri0 and Rn are independently (CH2),, or ethene-l, l-diyl; n is an integer from 1 to 5; Ri2 and Rn are independently selected from the group consisting of hydrogen, C2-C8 substituted or unsubstituted alkenyl, Ci-C8 substituted or unsubstituted alkyl, C1-C8 alkyl-CH=C=CH2, CrC8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of Ri2 and Ri3 is CrC8 alkyl-CH=C=CH2 or C,-C8 alkyl-C≡CH or CrC8 alkyl- cyclopropane or C(=O)Ci-C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a CpC8 substituted or unsubstituted alkyl.
5. A compound of the following formula (V):
Figure imgf000064_0002
(V) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 8; m is an integer from 1 to 8; Ri5 and RH are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted n-alkyl or (C3-C8) branched alkyl, C6-C2O substituted or unsubstituted aryl or heteroaryl, C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl, C-C8 alkyl-CH=C=CH2, Ci-C8 alkyl-C≡CH, C-C8 alkyl-cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of Ri 5 and R)4 is Ci-C8 alkyl-CH=C=CH2 or C-C8 alkyl-C≡CH or C-C8 alkyl-cyclopropane or C(O)C-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; R]6 and R)7 are independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl; and wherein the compound contains no more than three secondary amino groups except when R)7 is a Ci-C8 substituted or unsubstituted alkyl and wherein the compound is free from a methylphosphonate or hydroxy moiety.
6. A compound of the following formula (VI):
Figure imgf000065_0001
(VI) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; Ri8 and R19 are independently selected from the group consisting of hydrogen, Ci-C8 unsubstituted alkyl (e.g., methyl, ethyl, ter/-butyl, isopropyl, pentyl, cyclobutyl), Ci-C8 n-alkyl substituted with a cycloalkyl group comprising at least two rings, C7-C24 substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings, Ci-C8 alkyl-CH=C=CH2, Ci-C8 alky 1-C≡CH, Ci-C8 alkyl- cyclopropane, C(=O)Ci-C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one of Ri8 and R,9 is C-C8 alkyl-CH=C=CH2 or C-C8 alky 1-C≡CH or Ci-C8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
7. A compound of the following formula (VII):
Figure imgf000065_0002
(VII) or a salt, solvate, or hydrate thereof, wherein n is an integer from 1 to 12; m and p are independently an integer from 1 to 5; q is 0 or 1 ; R20 and R2) are independently selected from the group consisting of hydrogen, Ci-C8 substituted or unsubstituted alkyl, -C(=O)-Ci-C8 substituted or unsubstituted alkyl, -C(=O)-Ci-C8 substituted or unsubstituted alkenyl, -C(=O)-C)-C8 substituted or unsubstituted alkynyl, C7-C24 substituted or unsubstituted aralkyl, CrC8 alkyl-CH=C=CH2, C1-C8 alkyl-C≡CH, Ci-C8 alkyl-cyclopropane, C(=O)Ci-Cgalkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of R20 and R2] is C1-C8 alkyl-CH=C=CH2 or C-C8 alky 1-C≡CH or Ci-C8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
8. A compound of the following formula (VIII):
Figure imgf000066_0001
(VIII) or a salt, solvate, or hydrate thereof, wherein m and p are independently an integer from 1 to 5; X is-(CH2)n- or cyclohex-l ,3-diyl; n is an integer from 1 to 5; R22 and R23 are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexyleth-2-yl, benzyl, Ci-C8 alkyl-CH=C=CH2, CrC8 alkyl-C≡CH, C1-C8 alkyl- cyclopropane, C(=O)C)-C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl, with the proviso that at least one Of R22 and R23 is Ci-C8 alkyl-CH=C=CH2 or Ci-C8 alkyl-C≡CH or CrC8 alkyl- cyclopropane or C(=O)Ci -C8 alkyl substituted with at least one halo group or cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
9. A compound of the following formula (IX):
R
/T T^
"R 25
H (IX) or a salt, solvate, or hydrate thereof, wherein p is an integer from 1 to 5; R24 is an amino- substituted cycloalkyl (e.g., a cycloalkyl group substituted with a primary, secondary, tertiary or quaternary amine), a C2-C8 substituted or unsubstituted alkanoyl (which substituted alkanoyl may be substituted with one or more substituents such as those listed for "Substituted alkyl" including without limitation an alkanoyl substituted with a methyl and an alkylazide group), C1-C8 alkyl-CH=C=CH2, C1-C8 alkyl-C≡CH, C1-C8 alkyl- cyclopropane, Q=O)C1 -C8alkyl substituted with at least one halo group and cyclopropyl- NR2 where each R is independently H, alkyl, or aralkyl; and R25 is a Ci-C8 substituted or unsubstituted alkyl, a C7-C24 substituted or unsubstituted aralky (I)-(VIII), C1-C8 alkyl-CH=C=CH2, C1-C8 alky 1-C≡CH, C1-C8 alkyl-cyclopropane, C(=O)C,-C8alkyl substituted with at least one halo group and cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl with the proviso that at least one Of R24 and R25 is C1-C8 alkyl-CH=C=CH2 or C1-C8 alkyl-C≡CH or C1-C8 alkyl-cyclopropane or Q=O)C1-C8 alkyl substituted with at least one halo group or cyclopropyl-NR2 where each R is independently H, alkyl, or aralkyl; and each R2 is independently hydrogen or a Ci-C8 substituted or unsubstituted alkyl.
10. A compound of the following formula (X):
Figure imgf000067_0001
(X) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, Ci-C8alkyl or aralkyl where
NH
-N^N- the alkyl moiety of the aryl group is a Ci-C8alkyl, W is -NH-, guanidino ( H H ) or
Figure imgf000067_0002
integer from 1 to 6; q is an integer from 1 to 10; s is O or 1 ; X is -O-CrQalkyl, OH or NHR28, where R28 is hydrogen, C)-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a d-C8alkyl; R27 is is hydrogen, Cj-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl.
1 1. A compound of the following formula (XI):
Figure imgf000068_0001
(XI) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, Ci-C8alkyl or aralkyl where
the alkyl moiety of the aryl group is a Ci-C8alkyl, W is -NH-, guanidino
Figure imgf000068_0002
or
biguanido
Figure imgf000068_0003
p and n are independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl; and W2 is -NH-,
Figure imgf000068_0004
12. A compound of the following formula (XII):
Figure imgf000068_0005
(XII) or a salt, solvate, or hydrate thereof,
wherein R26 is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the
aryl group is a Ci-C8alkyl; W is -NH-,
Figure imgf000068_0006
or biguanido
Figure imgf000068_0007
( H H H ); p and n are independently an integer from 1 to 5; t is an integer to 6; q is an integer from 1 to 10; s is 0 or 1 ; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl; and R29 is Ci-C8 alkyl-C≡CH, Q- Qcyclopropane or C(=O)C|-Cgalkyl substituted with at least one halo group.
13. A compound of the following formula (XIII):
Figure imgf000069_0001
(XIIl) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, Ct-Cgalkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl;
NH NH NH
— N N— — N N N—
W is -NH-, guanidino ( M H ) or biguanido ( H H H ); p and n are independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl; and R29 is CrC8 alkyl-C≡CH, Ci-C8cyclopropane or C(=O)Cr
NH
-N^-N- C8alkyl substituted with at least one halo group; and W2 is -NH-, guanidino ( H H )
Figure imgf000069_0002
14. A compound of the following formula (XIV):
Figure imgf000069_0003
(XIV) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl;
Figure imgf000070_0001
independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; R27 is is hydrogen, CrC8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl; and R29 is C|-C8 alkyl-C≡CH, Ci-C8cyclopropane or C(=O)Ci- C8alkyl substituted with at least one halo group.
15. A compound of the following formula (XV):
Figure imgf000070_0002
(XV) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Ci-C8alkyl;
Figure imgf000070_0003
independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl; and R29 is Ci-C8 alkyl-C≡CH, C)-C8cyclopropane or C(=O)Ci- C8alkyl substituted with at least one halo group.
16. A compound of the following formula (XVI):
Figure imgf000070_0004
(XVI) or a salt, solvate, or hydrate thereof, wherein R26 is hydrogen, C|-C8alkyl or aralkyl where the alkyl moiety of the aryl
group is a Ci-Cgalkyl, W is -NH-,
Figure imgf000071_0001
or biguanido
Figure imgf000071_0002
p and n are independently an integer from 1 to 5; t is an integer from 1 to 6; q is an integer from 1 to 10; s is 0 or 1 ; X is -O-Ci-C8alkyl, OH or NHR28, where R28 is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a Cr Qalkyl; R27 is is hydrogen, Ci-C8alkyl or aralkyl where the alkyl moiety of the aryl group is a C|-C8alkyl; and R29 is Ci-C8 alkyl-C≡CH, CrC8cyclopropane or C(=O)CrC8alkyl substituted with at least one halo group.
17. A pharmaceutical composition comprising a compound of any one of claims 1 through 16 and a pharmaceutically acceptable carrier.
18. A kit comprising a compound of any one of claims 1 through 16 and instructions for thereapeutic use of the compound.
19. The kit of claim 18 wherein the instructions are written insutrction for use of the compound for treatment of cancer.
20. A method of treating cancer in a subject, comprising administering to the subject a compound of any one of claims 1 through 16, or any salt, solvate, hydrate or stereoisomer thereof.
21. The method of claim 20 wherein the subject is identified as suffering from cancer and the compound is administered to the identified subject.
22. The method of claim 20 or 21 wherein the subject is a mammal.
23. The method of claim 20 or 21 wherein the subject is a human.
24. Use of compound of any one of claims 1 through 16, or any salt, solvate, hydrate or stereoisomer thereof as a medicament.
25. Use of compound of any one of claims 1 through 16, or any salt, solvate, hydrate or stereoisomer thereof for preparation of medicament for the treatment of cancer.
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EP2142287A4 (en) 2012-05-23

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