WO2022200541A1 - Heterocyclic substituted polyamine compounds having neuroprotective activity - Google Patents

Heterocyclic substituted polyamine compounds having neuroprotective activity Download PDF

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Publication number
WO2022200541A1
WO2022200541A1 PCT/EP2022/057855 EP2022057855W WO2022200541A1 WO 2022200541 A1 WO2022200541 A1 WO 2022200541A1 EP 2022057855 W EP2022057855 W EP 2022057855W WO 2022200541 A1 WO2022200541 A1 WO 2022200541A1
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Prior art keywords
alkyl
independently
compound
independently selected
optionally substituted
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PCT/EP2022/057855
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French (fr)
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Dan Florin STOICESCU
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Floratek Pharma SA
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Publication of WO2022200541A1 publication Critical patent/WO2022200541A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4

Definitions

  • the present invention relates to chromen-4-one derivatives and to associated multi- salts, solvates, prodrugs and pharmaceutical compositions.
  • the present invention also relates to the use of such compounds and compositions in the treatment and prevention of medical disorders and diseases, most especially those related to neurotrophic factors pathways and mitochondrial activity.
  • BACKGROUND There is a need to provide compounds with improved pharmacological and/or physiological and/or physiochemical properties and/or those that provide a useful alternative to known compounds.
  • a first aspect of the invention provides a compound of formula (1): wherein: Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH2)p–NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; R 1 , and R 2 , independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , and –OC(O)N(R 13 ) 2 ; R 5 is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , and – OC(O)N(R 13 )2; or from H; halo; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇
  • a second aspect of the invention provides a compound selected from Table A herein.
  • a third aspect of the invention provides pharmaceutically acceptable salt, multi-salt, solvate or prodrug of the compound of the first or second aspect of the invention.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.
  • a fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition.
  • the disease, disorder or condition is a central nervous system disease, disorder or condition.
  • a sixth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
  • the treatment or prevention comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject.
  • the disease, disorder or condition is a disease, disorder or condition of the central nervous system.
  • a seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • the disease, disorder or condition is a disease, disorder or condition of the central nervous system.
  • hydrocarbyl substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • a hydrocarbyl group/moiety maybe saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton.
  • hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties.
  • a hydrocarbyl group is a C 1 -C 12 hydrocarbyl group. More typically a hydrocarbyl group is a C -C 0 hydrocarbyl group.
  • a “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group.
  • An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear or branched.
  • alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties.
  • alkyl does not include “cycloalkyl”.
  • an alkyl group is a C 1 -C 12 alkyl group. More typically an alkyl group is a C 1 -C 6 alkyl group.
  • An “alkylene” group is similarly defined as a divalent alkyl group.
  • alkenyl substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds.
  • alkenyl groups/moieties include ethenyl, propenyl, l-butenyl, 2-butenyl, l- pentenyl, l-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/moieties. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”.
  • an alkenyl group is a C 2 -C 12 alkenyl group. More typically an alkenyl group is a C 2 -C 6 alkenyl group.
  • An “alkenylene” group is similarly defined as a divalent alkenyl group.
  • An “alkynyl” substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl.
  • an alkynyl group is a C 2 -C 12 alkynyl group.
  • an alkynyl group is a C 2 -C 6 alkynyl group.
  • An “alkynylene” group is similarly defined as a divalent alkynyl group.
  • a “haloalkyl” substituent group or haloalkyl group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more halo atoms, e.g. Cl, Br, I, or F. Each halo atom replaces a hydrogen of the alkyl, alkenyl, or alkynyl substituent group or moiety.
  • alkoxy substituent group or alkoxy group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more oxygen atoms. Each oxygen atom replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety.
  • alkylthio substituent group or alkylthio group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more sulphur atoms. Each sulphur atom replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety.
  • alkylsulfonyl substituent group or alkylsulfonyl group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more sulfonyl groups (-SO 2 -). Each sulfonyl group replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety.
  • arylsulfonyl substituent group or arylsulfonyl group in a substituent group refers to an aryl substituent group or moiety including one or more carbon atoms and one or more sulfonyl groups (-SO2-). Each sulfonyl group replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety.
  • a “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton.
  • Examples of cyclic groups include aliphatic cyclic, cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups as discussed below.
  • a cyclic group may be monocyclic, bicyclic (e.g.
  • a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms.
  • a “heterocyclic” substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more heteroatoms, e.g. N, O or S, in the ring structure.
  • heterocyclic groups include heteroaryl groups as discussed below and non-aromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
  • An “aliphatic cyclic” substituent group or aliphatic cyclic moiety in a substituent group refers to a hydrocarbyl cyclic group or moiety that is not aromatic.
  • the aliphatic cyclic group may be saturated or unsaturated and may include one or more heteroatoms, e.g.
  • Examples include cyclopropyl, cyclohexyl and morpholinyl.
  • an aliphatic cyclic substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • a “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • a “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-i-en-i-yl, cyclohex-i-en-i-yl and cyclohex-i,3-dien-i-yl.
  • a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
  • aryl substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring.
  • aryl includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”.
  • heteroaryl substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety.
  • heteroaryl includes monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic.
  • arylalkyl arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl
  • the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
  • An example of an arylalkyl group is benzyl.
  • a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and even more typically 1 substituent.
  • any divalent bridging substituent e.g.
  • halo includes fluoro, chloro, bromo and iodo.
  • a C x -C y group is defined as a group containing from x to y carbon atoms.
  • a C 1 -C 4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms.
  • Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and/or containing the optional moieties.
  • replacement heteroatoms e.g. N, O or S
  • a morpholinyl group is to be considered a C6 heterocyclic group, not a C 4 heterocyclic group.
  • Figure l shows SND224 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner.
  • Figure 2 shows SND221 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner.
  • Figure 3 shows SND226 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner.
  • Figure 4 shows SND224 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner.
  • Figure 5 shows SND222 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner.
  • FIG. 6 shows SND221 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner.
  • a first aspect of the invention provides a compound of formula (1):
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ;
  • R 1 , and R 2 independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , and –OC(O)N(R 13 )2;
  • R 5 is selected from –OH, -O-C 1-4 alkyl, -OC(O)R 13 , -OC(O)NHR 13 , and – OC(O)N(R 13 )2; or from H; halo; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -
  • R 1 and R 2 are selected from –OH and -O-C1-4 alkyl.
  • R 1 and R 2 are selected from –OH and -OCH3.
  • R 5 is selected from –OH and -O-C 1-4 alkyl; or H.
  • R 5 is selected from –OH and -OCH3; or H.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 and R 2 are selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR 13 , and –OC(O)N(R 13 )2;
  • R 5 is selected from –OH, -O-C1-4 alkyl, - OC(O)R 13 , -OC(O)NHR 13 , and –OC(O)N(R 13 ) 2 , or from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -
  • R 1 and R 2 are selected from –OH, -O-C 1-4 alkyl, - OC(O)R 13 , -OC(O)NHR 13 , and –OC(O)N(R 13 ) 2 ;
  • R 5 is selected from –OH, -O-C 1-4 alkyl, - OC(O)R13, -OC(O)NHR 13 , and –OC(O)N(R 13 )2, or from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇
  • R 1 and R 2 are selected from –OH, and -O-C1-4 alkyl;
  • R 5 is selected from –OH, and -O-C1-4 alkyl; or from H; halo; -C1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -OH; -OR ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 1 and R 2 are selected from –OH, and -OCH 3 ;
  • R 5 is selected from –OH and -OCH3, or from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ ,.
  • R 1 and R 2 are selected from –OH, and -O-C 1-4 alkyl;
  • R 5 is selected from–OH, and -O-C1-4 alkyl, or from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 1 and R 2 are selected from –OH, and -OCH3;
  • R 5 is selected from –OH, and -OCH 3 , or from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 1 and R 2 independently, are selected from –OH, and -OCH 3 ;
  • R 5 is selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; and -NH2.
  • R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are independently selected from H; halo; -CN; -NO2; and -NH2.
  • R 1 and R 2 independently, are selected from –OH, and -OCH 3 ;
  • R 5 is selected from–OH, and -OCH3, or from H.
  • R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are H.
  • R 1 and R 2 are independently selected from –OH, -O-C 1-4 alkyl, - OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 )2;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 and R 2 are independently selected from –OH and -O-C 1-4 alkyl, e.g.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 - R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 and R 2 are independently selected from –OH and -O-C 1-4 alkyl; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , and R 2 are selected from –OH and –OCH3; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; and -NH 2 .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 is -O-C1-4 alkyl, e.g.
  • R 2 is OH; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 and R 2 are OH; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 - R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , R 2 and R 5 are selected from –OH, -O-C 1-4 alkyl, -OC(O)R 13 , -OC(O)NHR 13 , and –OC(O)N(R 13 ) 2 ; and R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , R 2 and R 5 are independently selected from –OH and -O-C 1-4 alkyl, e.g.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 - R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; - C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , R 2 and R 5 are selected from –OH and –O-C 1-4 alkyl; and R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C 1-4 alkyl; -CN; -NO2; -SH; -SO2H; and -NH2.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , R 2 and R 5 are selected from –OH and –OCH 3 ; and R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C 1-4 alkyl; -CN; -NO2; -SH; -SO2H; and -NH2.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 is -O-C 1-4 alkyl, e.g.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 is -O-C 1-4 alkyl, e.g. –O-Me
  • R 2 is -OH
  • R 5 is -O-C 1-4 alkyl, e.g.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 , R 2 , and R 5 are -OH ; and R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 - R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; - C 1-4 alkyl; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 11 and R 12 are independently selected from H, C1-6 alkyl, and benzyl substituted with –O(C 1-4 alkyl).
  • R 11 and R 12 are independently selected from H, C1-2 alkyl, and benzyl substituted with –O(C1-2 alkyl).
  • -NR 11 R 12 may be –NH2 or -N(C1-2 alkyl)(benzyl substituted with –OCH 3 ).
  • R 11 is selected from H and C1-4 alkyl; and R12 is benzyl substituted with –O(C1-4 alkyl).
  • R12 is benzyl substituted with–O(C1-2 alkyl).
  • R 12 is benzyl substituted with –O(CH 3 ).
  • R 12 is benzyl substituted with –O(C1-2 alkyl) at the ortho position.
  • R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 may together form a 5- or 6-membered heterocycle optionally having one additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • the 5- or 6-membered heterocycle may be morpholine, piperidine, piperazine, or pyrrolidine optionally substituted with 1 or 2 C 1-4 alkyl.
  • the 5- or 6- membered heterocycle may be morpholine, piperidine, piperazine, 4-methyl piperazine, or pyrrolidine.
  • each R 10 is independently selected from H and C 1-2 alkyl.
  • each R 10 is independently selected from H and -CH 3 .
  • n is 3.
  • n is 4.
  • Z is –NR 11 R 12 .
  • Z is –NR 11 R 12 ;
  • R 11 and R 12 are independently selected from H, C 1-6 alkyl, and benzyl substituted with –O(C 1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –N(R 10 )-(CH 2 ) p –NR 11 R 12 .
  • Z is –N(R 10 )-(CH 2 ) p – NR 11 R 12 ;
  • R 10 is H or C1-6 alkyl; and
  • R 11 and R 12 are independently selected from H and C1-6 alkyl; or
  • R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • p is selected from 2 or 3.
  • Z is –N(R 10 )-(CH 2 ) p –NR 11 R 12 .
  • Z is –N(R 10 )-(CH 2 ) p – NR 11 R 12 ; p is 2 or 3; R 10 is H or C1-2 alkyl; and R 11 and R 12 are independently selected from H, and C1-2 alkyl; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C 1-2 alkyl.
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; and q is independently selected from 1-4. For example, q may be 2, 3 or 4.
  • Z is – N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; each R 10 is independently selected from H and C1-6 alkyl; and and R 11 and R 12 are independently selected from H; C1-6 alkyl; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • q is independently selected from 3 or 4.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; q is independently selected from 3 and 4.
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; each R 10 is independently selected from H and C1-2 alkyl; and R 11 and R 12 are independently selected from H and C 1-2 alkyl; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ .
  • each R 10 may independently be selected from H, C1-3 alkyl, and C2-C4 alkenyl.
  • each R 10 may independently be selected from H and –CH 3 .
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g.
  • R 3 is H; and R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; -C 1-4 alkyl; -OH; -O-C 1-4 alkyl; halo; -CN; -NO 2 ; -COOH; and -COOR ⁇ .
  • R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently, are selected from H; -C 1-4 alkyl; - OH; -O-C1-4 alkyl; halo; -CN; -NO2; and –COOH.
  • R 1 , R 2 , and R 5 are independently selected from –OH and -O-C 1-4 alkyl, e.g. –OH and –OCH3; R 3 is H; and R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; -C1-4 alkyl; -OH; -O-C1-4 alkyl; halo; -CN; -NO2; -COOH; and -COOR ⁇ .
  • R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; -C 1-4 alkyl; - OH; -O-C 1-4 alkyl; halo; -CN; -NO 2 ; and –COOH.
  • R 1 , R 2 , R 5 , n and Z are as defined herein, and R x is selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R x is selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R x is selected from H; halo; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R x is selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R x is selected from H; halo; -CN; -NO2; -R ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; and -COOR ⁇ .
  • R x is selected from H; halo; -CN; -NO2; -CH3; and -NH2.
  • R x is H.
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R 5 is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H.
  • R 1 and R 2 are independently selected from –OH and -O-C 1-4 alkyl, e.g. – OH and –OCH3; and R 5 is H.
  • R 1 , R 2 , and R 5 are independently selected from –OH and -O-C 1-4 alkyl, e.g. –OH and –OCH 3 .
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R 5 is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H.
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R 5 is H.
  • R 1 , R 2 , and R 5 are independently selected from –OH and -O-C 1-4 alkyl, e.g. –OH and –OCH3.
  • a compound of formula (2) is provided:
  • R1-R8, and Z are as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH2)p–NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ;
  • R 1 and R 2 are independently selected from –OH, -O-C 1-4 alkyl, -OC(O)R 13 , -OC(O)NHR 13 , –OC(O)N(R 13 ) 2 ;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl.
  • R 1 and R 2 are independently selected from –OH and -O-CH 3 .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benz
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -C 1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • -R ⁇ is independently selected from a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 14 cyclic group.
  • -R ⁇ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl.
  • R 11 and R 12 are independently selected from H, C 1-6 -alkyl, benzyl, and benzyl substituted with –O(C 1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C 1-3 -alkyl, benzyl and benzyl substituted with –O(CH3); optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3- alkyl, benzyl and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with – CH 3 , or -OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is C 1-3 alkyl and R 12 is benzyl substituted by –OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is ethyl and R 12 is benzyl ortho-substituted by –OCH3.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH2)p–NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle
  • Z is --N(R 10 )-(CH 2 ) 3 –NR 11 R 12 ; wherein R 10 is –H or –C 1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is -NH-(CH 2 ) 3 –NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is —NH-(CH 2 ) 3 -NH-(CH 2 ) 3 -NH 2 .
  • a compound of formula (2A) wherein R 1 , R 2 , and Z are as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH2)p–NR 11 R 12 ; and –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ;
  • R 1 and R 2 are independently selected from –OH, -O-C 1-4 alkyl, -OC(O)R 13 , -OC(O)NHR 13 , –OC(O)N(R 13 )2; each -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C 3 -C 14 cyclic group, and wherein any -
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl.
  • R 1 and R 2 are independently selected from –OH and -O-CH 3 .
  • -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group.
  • -R ⁇ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl.
  • R 11 and R 12 are independently selected from H, C 1-6 -alkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3- alkyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is C 1-3 alkyl and R 12 is benzyl substituted by –OCH3.
  • Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH3.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH 2 ) p –NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C 1-6 -alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, benzyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a
  • Z is --N(R 10 )-(CH 2 ) 3 –NR 11 R 12 ; wherein R 10 is –H or –C1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is -NH-(CH 2 ) 3 –NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is —NH-(CH2)3-NH-(CH2)3-NH2.
  • a compound of formula (2B) wherein Z is as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; each -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -R ⁇ may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, -O(C 1 -C 4 alkyl), -O(C 1 -C 4
  • -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group.
  • -R ⁇ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl.
  • R 11 and R 12 are independently selected from H, C 1-6 -alkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3- alkyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is C 1-3 alkyl and R 12 is benzyl substituted by –OCH3.
  • Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH3.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH 2 ) p –NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C 1-6 -alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, benzyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a
  • Z is --N(R 10 )-(CH 2 ) 3 –NR 11 R 12 ; wherein R 10 is –H or –C1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is -NH-(CH 2 ) 3 –NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is —NH-(CH2)3-NH-(CH2)3-NH2.
  • a compound of formula (2C) wherein Z is as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; each -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C 3 -C 14 cyclic group, and wherein any -R ⁇ may optionally be substituted with one or more C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 7 cycloalkyl, -O(C 1 -C 4 alkyl), -O(C 1 -C 4 haloalkyl),
  • -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group.
  • -R ⁇ is independently selected from a C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
  • R 11 and R 12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or – O(C 1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 are independently selected from C 1-3 - alkyl, and benzyl substituted with –C 1-4 alkyl or –O(C 1-4 alkyl); or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH3.
  • Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3.
  • Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH 2 ) p –NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C 1-6 -alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membere
  • Z is --N(R 10 )-(CH2)3–NR 11 R 12 ; wherein R 10 is –H or –C1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is -NH-(CH2)3–NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 .
  • Z is –N(R 10 )- (CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH 3 ; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NH-(CH2)3-NH-(CH2)3-NH2.
  • R 1 -R 8 , and Z are as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ;
  • R 1 , R 2 , and R 5 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 ) 2 ;
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 independently, are selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H;
  • R 1 , R 2 , and R 7 are independently selected from –OH and -O-C 1-4 alkyl.
  • R 1 , R 2 , and R 7 are independently selected from –OH and -O-CH3.
  • R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are selected from H; halo; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally
  • R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are selected from H; halo; -CN; -NO 2 ; -SH; -SO 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 5 , R 6 , R 8 , and R 9 are H.
  • -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group.
  • -R ⁇ is independently selected from a C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
  • R 11 and R 12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3- alkyl, and benzyl optionally substituted with 1 or 2 -R ⁇ , or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is C 1-3 alkyl and R 12 is benzyl substituted by –OCH 3 .
  • Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by – OCH3.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH 2 ) p –NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C 1-6 -alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-
  • Z is --N(R 10 )- (CH 2 ) 3 –NR 11 R 12 ; wherein R 10 is –H or –C 1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is -NH-(CH 2 ) 3 –NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NH-(CH 2 ) 3 -NH-(CH 2 ) 3 -NH 2 .
  • R 1 , R 2 , R 7 , and Z are as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ;
  • R 1 , R 2 , and R 7 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 ) 2 ; each -R ⁇ is independently selected from a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C3-C14 cyclic group, and wherein any -R ⁇ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3
  • R 1 , R 2 , and R 7 are independently selected from –OH and -O-C 1-4 alkyl.
  • R 1 , R 2 , and R 7 are independently selected from –OH and -O-CH 3 .
  • -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group.
  • -R ⁇ is independently selected from a C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
  • R 11 and R 12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 are independently selected from C 1-3 - alkyl, and benzyl optionally substituted with 1 or 2 -R ⁇ , or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 are independently selected from C 1-3 -alkyl, and benzyl optionally substituted with –CH 3 , or -OCH 3 .
  • Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3.
  • Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by – OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH 2 ) p –NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C 1-6 -alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered
  • Z is --N(R 10 )- (CH2)3–NR 11 R 12 ; wherein R 10 is –H or –C1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is -NH-(CH 2 ) 3 –NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NH-(CH2)3-NH-(CH2)3-NH2.
  • a compound of formula (3B) wherein is as defined above.
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; and –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ;
  • R 1 , R 2 , and R 5 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 )2;
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 independently, are selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO
  • R 1 , R 2 , and R 5 are independently selected from -OH and -O-C 1-4 alkyl.
  • R 1 , R 2 , and R 5 are independently selected from -OH and -0-CH 3 .
  • R 3 , R 4 , R 6 , R 3 , R 8 , and R 9 are selected from H; halo; -CN; -N0 2 ; -RP; -OH, -ORP; -SH; -SRP; -SORP; -S0 2 H; -S0 2 RP; -S0 2 NH 2 ; -S0 2 NHRP; -S0 2 N(RP) 2 ; -NH 2 ; -NHRP; -N(RP) 2 ; -CHO; -CORP; -COOH; -COORP; -OCORP; and benzyl optionally substituted with 1-3 -RP.
  • R 3 , R 4 , R 6 , R 7, R 8 , and R 9 are selected from H; halo; -CN; -N0 2 ; -RP; -SH; -SRP; -SORP; -S0 2 H; -S0 2 RP; -S0 2 NH 2 ; -S0 2 NHRP; -S0 2 N(RP) 2 ; -NH 2 ; -NHRP; -N(RP) 2 ; -CHO; -CORP; -COOH; -COORP; and benzyl optionally substituted with 1-3 -RP.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -N0 2 ; -SH; -S0 2 H; -NH 2 ; -CHO; -COOH.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are H.
  • -RP is independently selected from a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 3 -C 14 cyclic group.
  • -RP is independently selected from a C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
  • R 11 and R 12 are independently selected from H, Ci- 6 -alkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -RP; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • R 11 and R 12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3- alkyl, and benzyl optionally substituted with 1 or 2 -R ⁇ , or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is –NR11R12, wherein R 11 and R 12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3.
  • Z is –NR 11 R 12 , wherein R 11 is C 1-3 alkyl and R 12 is benzyl substituted by –OCH 3 .
  • Z is –NR 11 R 12 , wherein R 11 is ethyl and R 12 is benzyl ortho-substituted by – OCH3.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NR 11 R 12 , wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O.
  • Z is –NR11R12, wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O.
  • Z may be morpholine or piperidine.
  • Z is -N(R 10 )-(CH2)p–NR 11 R 12 ; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R 10 is independently selected from H, C 1-6 alkyl, C 2 -C 6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, and benzyl, wherein each R 10 , when not H, is independently optionally substituted with 1 or 2 -R ⁇ ; R 11 and R 12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R 11 and R 12 , when is not H, are independently optionally substituted with 1 or 2 -R ⁇ ; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally
  • Z is --N(R 10 )- (CH 2 ) 3 –NR 11 R 12 ; wherein R 10 is –H or –C 1-3 alkyl, and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl.
  • Z is -NH-(CH2)3–NR 11 R 12 ; wherein R 11 and R 12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R 11 and R 12 together form a piperidine ring.
  • Z is –N(R 10 )-(CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 .
  • Z is –N(R 10 )- (CH 2 ) q –N(R 10 )-(CH 2 ) q –NR 11 R 12 ; wherein each R 10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C 1-4 alkyl.
  • Z is –NH-(CH 2 ) 3 -NH-(CH 2 ) 3 -NH 2 .
  • a second aspect of the invention provides a compound selected from Table A, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof.
  • a third aspect of the invention provides pharmaceutically acceptable multi-salt, solvate or prodrug of the compound of the first or second aspect of the invention.
  • a pharmaceutically acceptable salt for example, can be formed between an anion and a positively charged group (e.g., amino).
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
  • the compounds of the present invention can be used both in their quaternary salt form (as a single salt). Additionally, the compounds of the present invention may contain one or more (e.g. one or two) acid addition or alkali addition salts to form a multi-salt.
  • a multi-salt includes a quaternary salt group as well as a salt of a different group of the compound of the invention.
  • a “multi-salt” of a compound of the present invention includes an acid addition salt.
  • Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic
  • a “multi-salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium.
  • the salt may be a mono-, di-, tri- or multi-salt.
  • the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono- or di-sodium salt or a mono- or di- potassium salt.
  • any multi-salt is a pharmaceutically acceptable non-toxic salt.
  • other salts are included in the present invention, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of the free acid or base.
  • the compounds and/or multi-salts of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate.
  • solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention.
  • the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound.
  • the present invention also encompasses multi-salts and solvates of such prodrugs as described above.
  • the compounds, multi-salts, solvates and prodrugs of the present invention may contain at least one chiral centre.
  • the compounds, multi-salts, solvates and prodrugs may therefore exist in at least two isomeric forms.
  • the present invention encompasses racemic mixtures of the compounds, multi-salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers.
  • a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight.
  • the compounds, multi-salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to 12 C, 13 C, 1 H, 2 H (D), 14 N, 15 N, 16 O, 17 O, 18 O, 19 F and 127 I, and any radioisotope including, but not limited to 11 C, 14 C, 3 H (T), 13 N, 15 O, 18 F, 123 I, 124 I, 125 I and 131 I.
  • the compounds, multi-salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4 th Ed., 2013.
  • compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • a fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition.
  • the use comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject.
  • the disease, disorder or condition is a central nervous system disease, disorder or condition.
  • a sixth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition.
  • the treatment or prevention comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject.
  • the disease, disorder or condition is a central nervous system disease, disorder or condition.
  • a seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • the disease, disorder or condition is a central nervous system disease, disorder or condition.
  • treatment refers equally to curative therapy, and ameliorating or palliative therapy.
  • the term includes obtaining beneficial or desired physiological results, which may or may not be established clinically.
  • beneficial or desired clinical results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptoms, the amelioration or palliation of the condition/symptoms, and remission (whether partial or total), whether detectable or undetectable.
  • prevention means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering a compound, multi-salt, solvate, prodrug or pharmaceutical composition of the present invention.
  • prevention as used herein in relation to a disease, disorder or condition, relates to prophylactic or preventative therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition.
  • prevention includes both the avoidance of occurrence of the disease, disorder or condition, and the delay in onset of the disease, disorder or condition.
  • Any statistically significant avoidance of occurrence, delay in onset or reduction in risk as measured by a controlled clinical trial maybe deemed a prevention of the disease, disorder or condition.
  • Subjects amenable to prevention include those at heightened risk of a disease, disorder or condition as identified by genetic or biochemical markers.
  • the genetic or biochemical markers are appropriate to the disease, disorder or condition under consideration and may include for example, beta-amyloid 42, tau and phosphor-tau.
  • the disease, disorder or condition is a disease, disorder or condition associated with neurotrophic factors pathways.
  • the disease, disorder or condition may be associated with BDNF pathways
  • the disease, disorder or condition is a mitochondrial disease, disorder or condition.
  • mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria.
  • Dysfunctional mitochondria may exhibit one of the following: impaired Ca influx, energy supply, and/or control of apoptosis.
  • Dysfunctional mitochondria may also or alternatively exhibit increased ROS production.
  • the disease, disorder or condition is related to oxidative stress and/ or mitochondrial DNA mutation.
  • the disease, disorder or condition is selected from but not limited to:
  • central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, and brain injury from pneumococcal meningitis;
  • neurological disorders neuropsychiatric disorders, and metabolic disorders.
  • neurological and neuropsychiatric disorders include depression, anxiety,
  • metabolic disorders include obesity and hyperphagia;
  • mental disorders and conditions include, but are not limited to, acute stress disorder, adjustment disorder, adolescent antisocial behaviour, adult antisocial behaviour, age-related cognitive decline, agoraphobia, alcohol-related disorder, Alzheimer's, amnestic disorder, anorexia nervosa, anxiety, attention deficit disorder, attention deficit hyperactivity disorder, autophagia, bereavement, Bibliomania, binge eating disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, circadian rhythm sleep disorder, cocaine-addition, dysthymia, exhibitionism, gender identity disorder, Huntington's disease, hypochondria, multiple personality disorder, obsessive- compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), posttraumatic stress disorder (PTSD), Rett syndrome, sadomasochism, and stuttering;
  • OCD obsessive- compulsive disorder
  • OCPD obsessive-compulsive personality disorder
  • a central nervous system injury includes, for example, a brain injury, a spinal cord injury, or a cerebrovascular event (e.g., a stroke);
  • cardiovascular diseases such as coronary artery disease, heart attack, abnormal heart rhythms or arrhythmias, pericardial disease, heart failure, heart valve disease, congenital heart disease, heart muscle disease (cardiomyopathy), aorta disease and vascular disease;
  • ageing related diseases and/or ageing per se and
  • the subject in need thereof can be a patient diagnosed as suffering from being overweight or obese.
  • Anxiety can be a symptom of an underlying health issue such as chronic obstructive pulmonary disease (COPD), heart failure, or heart arrhythmia.
  • COPD chronic obstructive pulmonary disease
  • the disease, disorder or condition is a central nervous system disease.
  • the compounds maybe used for treating or preventing a neurodegenerative disorder.
  • the compounds maybe used for treating or preventing Alzheimer’s Disease, Parkinson’s Disease, or ischemia.
  • the compounds may be used for treating or preventing rare CNS disorders.
  • the compounds may be used to treat or prevent Rett Syndrome, or KBG Syndrome.
  • the compounds maybe used for treating or preventing anti-aging or mitochondria linked disorders.
  • the disease, disorder or condition is selected from but not limited to Parkinson’s disease, Alzheimer’s disease, and depression.
  • the disease, disorder or condition is Alzheimer’s disease.
  • An eighth aspect of the invention provides a method of modulating neurotrophic factors pathways (such as BDNF pathways), the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to modulate neurotrophic factors pathways (such as BDNF pathways).
  • neurotrophic factors pathways such as BDNF pathways
  • a ninth aspect of the invention provides a method of modulating mitochondrial function, the method comprising the use of compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to modulate mitochondrial function.
  • modulating mitochondrial function includes: modulating Ca influx, energy supply, control of apoptosis and/or ROS production.
  • the method comprises delivering a compound of the first or second aspect of the invention to the mitochondria of a cell.
  • the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of neurotrophic factors pathways modulation or mitochondrial function modulation.
  • the method is performed in vivo.
  • the method may comprise the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby modulate neurotrophic factors pathways or modulate mitochondrial function.
  • the administration is to a subject in need thereof.
  • the method of the eighth or ninth aspect of the invention may be a method of modulating factors pathways or modulating mitochondrial function in a non human animal subject, the method comprising the steps of administering the compound, multi-salt, solvate, prodrug or pharmaceutical composition to the non human animal subject and optionally subsequently mutilating or sacrificing the non human animal subject.
  • a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non human animal subject.
  • the subject maybe any human or other animal.
  • the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, goat, horse, cat, dog, etc. Most typically, the subject is a human.
  • any of the medicaments employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration.
  • the mode of administration selected is that most appropriate to the disorder or disease to be treated or prevented.
  • the compounds, multi-salts, solvates or prodrugs of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.
  • Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose.
  • Corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatine.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/ or dissolving tablets.
  • Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Powders or granules for oral use maybe provided in sachets or tubs.
  • Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.
  • Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.
  • Formulations for rectal administration maybe presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration maybe presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds, multi-salts, solvates or prodrugs of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer’s solution and isotonic sodium chloride or glucose.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • the compounds, multi-salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
  • the dose of the compounds, multi-salts, solvates or prodrugs of the present invention will, of course, vary with the disorder or disease to be treated or prevented.
  • a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day.
  • the desired dose maybe presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day.
  • the desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.
  • any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention.
  • any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.
  • Benzaldehyde 1.4 was prepared by coupling 4-hydroxybenzaldehyde (1.2) with 2-(4- chloro-butoxy)tetrahydro-2H-pyran in the presence of Cs2CO3. Claisen–Schmidt condensation between acetophenone 12.7 and benzaldehyde 1.4 afforded a mixture of the chalcone 1.5a and the flavanone 1.5b, which both gave cyclized and deprotected alcohol 1.6 when treated with iodine at 120 °C in DMSO. Bromination of alcohol 1.6 with SOBr2/DMF allowed to isolate bromide 1.7.
  • Target 1 was prepared by a coupling reaction between PPh 3 and bromide 1.7 in the presence of KI, and by deprotection with c. HBr in MeCN.
  • the target compounds were synthesized from the bromide 1.7 by coupling it with the corresponding amines in the presence of either DIPEA or K2CO3/KI. Protecting groups were then cleaved by c. HCl in MeCN at RT. 4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzaldehyde (1.4).
  • the reaction mixture was diluted with 500 mL of 10% Na2CO3 and the aqueous layer was extracted with 3 x 250 mL of EtOAc. Organic layers were combined and washed with 250 mL of brine, which in turn was extracted with 50 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane.4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzaldehyde (1.4) (19.45 g, 68.1 mmol, 87.7%, 97.5% purity) was obtained as a transparent liquid.
  • the mixture was allowed slowly to warm to room temperature and it was stirred at that temperature for 15 h.
  • the reaction mixture was then poured to 50 mL of ice-cold brine.
  • the aqueous mixture was then extracted with 3 x 50 mL of EtOAc. Organic fractions were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • Reaction mixture was then allowed to cool to room temperature and poured to 120 mL of 1% sodium sulfite solution.
  • the resultant suspension was extracted with 3 x 50 mL of EtOAc. Organic layers were combined and washed with 100 mL of brine, which in turn was extracted with 25 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • reaction mixture was then heated under nitrogen at 70 °C for 12 h before it was allowed to cool to room temperature.
  • the reaction mixture was diluted with 25 mL of 10 of Na 2 CO 3 and extracted with 3 x 15 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • Crude product was purified by normal phase flash- chromatography using EtOAc:heptanes to yield 3-methoxy-4-(4-((tetrahydro-2H- pyran-2-yl)oxy)butoxy)benzaldehyde (5.4) (1.471, 4.8 mmol, 73%) as a transparent oil.
  • reaction mixture was then allowed to slowly warm to room temperature and stirred under nitrogen for 18 h.
  • the reaction mixture was poured to 80 mL of ice-cold brine.
  • the resultant orange suspension was extracted with 4 x 80 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • reaction mixture was allowed to cool to room temperature, before it was poured to 500 mL of 10% of Na 2 S 2 O 3 solution.
  • the aqueous solution was extracted with 3 x 200 mL of EtOAc. Organic layers were combined and washed with 200 mL of brine, which in turn was extracted with 50 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • the mixture was then stirred at room temperature for 1 h, before it was cooled with an ice-bath and quenched with 50 mL of saturated NaHCO 3 .
  • the mixture was then extracted with 2 x 100 mL of DCM. Organic layers were combined, washed with 100 mL of brine, which in turn was extracted with 50 mL of DCM. Organic layers were dried with sodium sulfate, filtered and evaporated to dryness.
  • reaction mixture was then evaporated to dryness, dissolved in 50 mL of DCM and washed with 25 mL of brine:water 1:1 mixture. The aqueous layer was extracted with 2 x 25 mL of DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • the mixture was stirred at 0 °C for 15 min before it was stirred at room temperature for 20 h.
  • the aqueous solution was then extracted with 3 x 100 mL of EtOAc. Organic fractions were combined and washed with 100 mL of brine, which in turn was extracted with 25 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness.
  • reaction mixture was stirred at room temperature for 1.5 h before it was cooled with an ice-bath and quenched with 55 mL of sat. NaHCO3. The mixture was then extracted with 2 x 75 mL of DCM. Organic layers were combined, washed with 50 mL of brine, dried with sodium sulfate, filtered and evaporated to dryness.
  • the CellTiter-Glo® 2.0 Assay determines the number of viable cells in culture by quantifying ATP, which indicates the presence of metabolically active cells. It is a single reagent added directly to the cells in 96 well plates. Luminesence readout is directly proportional to the number of viable cells in culture.
  • Toxicity of compounds alone was tested prior to the initiation of the assays and concentrations well below the toxicity threshold were used for evaluation.
  • Mitochondria function The Agilent Seahorse XF Cell Mito Stress Test (#103015-100) and Seahorse XFe96 FluxPak mini (#102601-100) were used to measure key parameters of mitochondrial function by directly assessing the oxygen consumption rate (OCR) of cells, according to the manufacturer’s instruction.
  • OCR oxygen consumption rate
  • HT-22 mouse hippocampal cell line (Millipore) were plated in the Seahorse XF Cell Culture Microplate at a density of 4800 cells/well in the Seahorse 96 well plates and grown for i6-24h before the initiation of the assay.
  • Example 1 Neuron protection in an in vitro model of ischemia
  • the aim of this study was to test the neuroprotective effects of SND derivatives in an in vitro ischemia model. Ischemia was induced in a mouse hippocampal cell line, HT-22 (Millipore) using a brief treatment with iodoacetic acid (IAA). Compounds were added after the removal of the lesion, mimicking the reperfusion phase. Cell death was monitored using the CellTiter-Glo® assay.
  • IAA iodoacetic acid
  • SND derivatives SND221, SND224 and SND226 have shown a concentration dependent neuroprotective activity against in vitro ischemia model, when added in the reperfusion phase. All compounds significantly increased cell survival in the mM range.
  • the known flavonoid 7,8 DHF which has been previously shown to possess broad neuroprotective activity increased cell survival only at the highest concentration of 30 mM (Table lB)
  • Table lA and lB depict the neuroprotective activity of SND222, SND223, SND242 and comparator 7,8 DHF.
  • Table lA and lB Neuroprotective activity of SND222, SND223 and SND242 derivatives and control 7,8 DHF against an in vitro model of ischemia induced by IAA.
  • the numbers represent mean % viability vs cells treated only with vehicle control (no IAA).
  • the lesion control is depicted as o mM and the numbers represent the mean % of sample versus the vehicle control from the same 96 well plate as the tested compounds.
  • SND derivatives were evaluated in a widely used cellular Parkinson Disease (PD) model in which neurotoxicity was induced by i-methyl-4-phenylpyridinium (MPP + ) in cultured hippocampal cells.
  • PD Parkinson Disease
  • MPP + i-methyl-4-phenylpyridinium
  • mice hippocampal HT-22 cells (3000 cells/well) were seeded in a 96-well plate and grown overnight, then test compounds at various concentrations or vehicle control (DMSO at a final concentration of 0.5%) were added. Following 30 min incubation, MPP + was added to a final concentration of 200 mM and the cells were further incubated for 24h. The plates were equilibrated at RT for 10 min, 50 m ⁇ of CellTiter Glo reagent was added and cells were further kept at RT for 30 min in the dark. Luminescence was read using an EnVision instrument and data was analyzed using prism software (Supplier: GraphPad Software, Inc., Software version: 5.00) Results
  • SND221, SND222 and SND224 derivatives were effective in protecting the cells from MPP + injury in a concentration dependent manner as shown in Figures 4, 5 and 6.
  • 78 DHF derivative, used as a comparator in the study did not rescue the cells from MMP + toxicity at any concentration tested (between 30 mM - l mM).
  • Example A Neuroprotective effects against an in vitro model of neuronal oxidative stress (oxytosis)
  • ROS reactive oxygen species
  • HT-22 cells (3000 cells/well) were seeded in a 96-well plate and grown overnight, then test compounds at various concentrations and vehicle control were added. Following 30 min incubation, Glutamate was added to a final concentration of 5 mM and the cells were further incubated for 24h. The plates were equilibrated at RT for 10 min, 50 m ⁇ of CellTiter Glo reagent was added and cells were further kept at RT for 30 min in the dark. Luminescence was read using an EnVision instrument and data was analyzed using prism software (Supplier: GraphPad Software, Inc., Software version: 5.00).
  • test compounds were evaluated in the hippocampal cell line using the Agilent Seahorse XF Cell Mito Stress Test.
  • OCR is a direct measurement of mitochondrial respiration rate.
  • Metal chelating properties of SND derivatives The metal chelating properties of molecules with polyphenolic structures suggest they may play a role in metal-overload diseases and in all oxidative stress conditions involving a transition metal ion [Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002 Nov;36(n):ii99-2o8]
  • test compounds were evaluated for the ability to form complexes with Al, Fe, Cu and Zu ions by using a spectrophotometric method.
  • Different salts of these metals were dissolved in MeOH to concentrations of 50 and 200 mM and added to 50 mM compound or blank wells; wavelength between 200 - 600 nm was recorded. Morin was used as a positive control.
  • SND221, SND223, SND224 and SND226 selectively chelated the Al ion.
  • SND222 formed complexes with Fe, Cu and Zn ions as presented in Table 5.
  • TEAC Trolox Equivalent Antioxidant Capacity
  • ABTS Cell biolabs #XAN5040
  • HAT hydrogen atom transfer
  • SET single electron transfer
  • the TEAC Assay is based on the conversion of oxidized probe ABTS * + radical to ABTS via SET or HAT antioxidant mechanisms.
  • Antioxidants neutralize the radical ion in a concentration dependent manner, which correlates with a proportional decrease in colour intensity.
  • Antioxidant activity is compared to the water soluble vitamin E analog Trolox.
  • the assay has been optimized for 384 well plates.
  • the compounds were dispensed at multiple concentrations and the vehicle DMSO 2% was used as a negative control.
  • SND derivatives showed increased antioxidant potential as shown in Table 6. Table 6. Antioxidant activity of SND derivatives expressed as TEAC values (pM Trolox equivalents).
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH2)p–NR 11 R 12 ; and –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ;
  • R 1 , R 2 , R 4 , and R 5 independently, are selected from –OH, -O-C 1-4 alkyl, - OC(O)R 13 , -OC(O)NHR 13 , –OC(O)N(R 13 ) 2 ; or from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ;
  • R 1 , R 2 , R 4 , and R 5 independently, are selected from –OH, and -O-C1-4 alkyl, or from H; halo; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ , wherein at least two of R 1 , R 2 , R 4 , and R 5 are independently selected from –OH, and -O-C 1-4 alkyl 3.
  • R 1 , R 2 , R 4 , and R 5 are independently selected from -OH and -OCH 3 , or from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH; -OR ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ ; wherein at least two of R 1 , R 2 , R 4 , and R 5 are independently selected from –OH, and -OCH3. 4.
  • R 1 , R 2 , R 4 , and R 5 independently, are selected from –OH, and -OCH 3 , or from H; halo; -CN; -NO 2 ; and -NH 2 ; wherein at least two of R 1 , R 2 , R 4 , and R 5 are independently selected from –OH, and -OCH 3 . 5.
  • R 3 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ . 6.
  • R 3 , R 6 , R 7 , R 8 , and R 9 are H. 7.
  • a compound as defined in any preceding clause, wherein -R ⁇ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -R ⁇ may optionally be substituted with one or more halo, -OH, -NH 2 , -CN, -NO2, -C ⁇ CH, -CHO, -CON(CH3)2 or oxo ( O) groups.
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1- 3 -R ⁇ .
  • R 1 , and R 2 are selected from –OH and –OCH3; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2.
  • R 2 , and R 4 are independently selected from –OH and -O-C1-4 alkyl, e.g.
  • R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO 2 H; -SO 2 R ⁇ ; -SO 2 NH 2 ; -SO 2 NHR ⁇ ; -SO 2 N(R ⁇ ) 2 ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1- 3 -R ⁇ .
  • R 2 , and R 4 independently, are selected from –OH and –OCH3; and R 1 , R 3 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -CN; -NO 2 ; -SH; -SO 2 H; and -NH 2 .
  • R 1 , R 2 and R 5 are independently selected from –OH and -O-C 1-4 alkyl, e.g.
  • R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optionally substituted with 1-3 -R ⁇ .
  • R 1 , R 2 and R 5 independently, are selected from –OH and –O-C 1-4 alkyl; and R 3 , R 4 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -CN; -NO 2 ; -SH; -SO 2 H; and -NH 2 . 14.
  • R 11 and R 12 are independently selected from H and C1-6 alkyl; or R 11 and R 12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. 16.
  • a pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 21, and a pharmaceutically acceptable excipient.
  • a method of treatment or prevention of a disease, disorder or condition comprising the step of administering an effective amount of a compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clauses 21, or a pharmaceutical composition as defined in clause 22, to thereby treat or prevent the disease, disorder or condition.

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Abstract

The present invention relates to chromen-4-one derivatives, and to associated salts, multi-salts, solvates, prodrugs and pharmaceutical compositions. The present invention also relates to the use of such compounds and compositions in the treatment and prevention of a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease. In particular, the present invention relates to the use of such compounds and compositions in the treatment and prevention of central nervous system diseases/disorders.

Description

Heterocyclic Substituted Polyamine Compounds Having Neuroprotective Activity FIELD OF THE INVENTION The present invention relates to chromen-4-one derivatives and to associated multi- salts, solvates, prodrugs and pharmaceutical compositions. The present invention also relates to the use of such compounds and compositions in the treatment and prevention of medical disorders and diseases, most especially those related to neurotrophic factors pathways and mitochondrial activity. BACKGROUND There is a need to provide compounds with improved pharmacological and/or physiological and/or physiochemical properties and/or those that provide a useful alternative to known compounds. SUMMARY OF THE INVENTION A first aspect of the invention provides a compound of formula (1):
Figure imgf000002_0001
wherein: Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 , and R2, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; R5 is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and – OC(O)N(R13)2; or from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –O(C1-4 alkyl), wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 - Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N -dimethylsulfamoyl N,N -diethylsulfamoyl, N-methyl-N -ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; n = 3 or 4; each p is independently an integer selected from l to 4; and each q is independently an integer selected from 1 to 4.
A second aspect of the invention provides a compound selected from Table A herein. A third aspect of the invention provides pharmaceutically acceptable salt, multi-salt, solvate or prodrug of the compound of the first or second aspect of the invention.
A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.
A fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition. A sixth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition. Typically the treatment or prevention comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the disease, disorder or condition is a disease, disorder or condition of the central nervous system.
A seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition. Typically the administration is to a subject in need thereof. In one embodiment, the disease, disorder or condition is a disease, disorder or condition of the central nervous system.
Definitions
In the context of the present specification, a “hydrocarbyl” substituent group or a hydrocarbyl moiety in a substituent group only includes carbon and hydrogen atoms but, unless stated otherwise, does not include any heteroatoms, such as N, O or S, in its carbon skeleton. A hydrocarbyl group/moiety maybe saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties. Typically a hydrocarbyl group is a C1-C12 hydrocarbyl group. More typically a hydrocarbyl group is a C -C 0 hydrocarbyl group. A “hydrocarbylene” group is similarly defined as a divalent hydrocarbyl group. An “alkyl” substituent group or an alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl and n-pentyl groups/moieties. Unless stated otherwise, the term “alkyl” does not include “cycloalkyl”. Typically an alkyl group is a C1-C12 alkyl group. More typically an alkyl group is a C1-C6 alkyl group. An “alkylene” group is similarly defined as a divalent alkyl group.
An “alkenyl” substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups/moieties include ethenyl, propenyl, l-butenyl, 2-butenyl, l- pentenyl, l-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/moieties. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C2-C12 alkenyl group. More typically an alkenyl group is a C2-C6 alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group. An “alkynyl” substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-1-ynyl and but-2- ynyl. Typically an alkynyl group is a C2-C12 alkynyl group. More typically an alkynyl group is a C2-C6 alkynyl group. An “alkynylene” group is similarly defined as a divalent alkynyl group. A “haloalkyl” substituent group or haloalkyl group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more halo atoms, e.g. Cl, Br, I, or F. Each halo atom replaces a hydrogen of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include -CH2F -CHF2, -CHI2, -CHBr2,-CHCl2,-CF3, -CH2CF3 and CF2CH3. An “alkoxy” substituent group or alkoxy group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more oxygen atoms. Each oxygen atom replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)(CH3). An “alkylthio” substituent group or alkylthio group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more sulphur atoms. Each sulphur atom replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include -SCH3, -SCH2CH3, -SCH2CH2CH3, and - SCH(CH3)(CH3). An “alkylsulfinyl” substituent group or alkylsulfinyl group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more sulfinyl groups (-S(=O)-). Each sulfinyl group replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include - S(=O)CH3, - S(=O)CH2CH3, - S(=O)CH2CH2CH3, and - S(=O)CH(CH3)(CH3). An “alkylsulfonyl” substituent group or alkylsulfonyl group in a substituent group refers to an alkyl, alkenyl, or alkynyl substituent group or moiety including one or more carbon atoms and one or more sulfonyl groups (-SO2-). Each sulfonyl group replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include – SO2(CH3), - SO2(CH2CH3), - SO2(CH2CH2CH3), and - SO2(CH(CH3)(CH3)). An “arylsulfonyl” substituent group or arylsulfonyl group in a substituent group refers to an aryl substituent group or moiety including one or more carbon atoms and one or more sulfonyl groups (-SO2-). Each sulfonyl group replaces a carbon atom (for example the terminal or bonding carbon) of the alkyl, alkenyl, or alkynyl substituent group or moiety. Examples include – SO2(CH3), - SO2(CH2CH3), - SO2(CH2CH2CH3), and - SO2(CH(CH3)(CH3)). A “cyclic” substituent group or a cyclic moiety in a substituent group refers to any hydrocarbyl ring, wherein the hydrocarbyl ring may be saturated or unsaturated and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton. Examples of cyclic groups include aliphatic cyclic, cycloalkyl, cycloalkenyl, heterocyclic, aryl and heteroaryl groups as discussed below. A cyclic group may be monocyclic, bicyclic (e.g. bridged, fused or spiro), or polycyclic. Typically, a cyclic group is a 3- to 12-membered cyclic group, which means it contains from 3 to 12 ring atoms. More typically, a cyclic group is a 3- to 7-membered monocyclic group, which means it contains from 3 to 7 ring atoms. A “heterocyclic” substituent group or a heterocyclic moiety in a substituent group refers to a cyclic group or moiety including one or more carbon atoms and one or more heteroatoms, e.g. N, O or S, in the ring structure. Examples of heterocyclic groups include heteroaryl groups as discussed below and non-aromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups. An “aliphatic cyclic” substituent group or aliphatic cyclic moiety in a substituent group refers to a hydrocarbyl cyclic group or moiety that is not aromatic. The aliphatic cyclic group may be saturated or unsaturated and may include one or more heteroatoms, e.g. N, O or S, in its carbon skeleton. Examples include cyclopropyl, cyclohexyl and morpholinyl. Unless stated otherwise, an aliphatic cyclic substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings. A “cycloalkyl” substituent group or a cycloalkyl moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, a cycloalkyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
A “cycloalkenyl” substituent group or a cycloalkenyl moiety in a substituent group refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon- carbon double bonds and containing, for example, from 3 to 7 carbon atoms, examples of which include cyclopent-i-en-i-yl, cyclohex-i-en-i-yl and cyclohex-i,3-dien-i-yl. Unless stated otherwise, a cycloalkenyl substituent group or moiety may include monocyclic, bicyclic or polycyclic hydrocarbyl rings.
An “aryl” substituent group or an aryl moiety in a substituent group refers to an aromatic hydrocarbyl ring. The term “aryl” includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless stated otherwise, the term “aryl” does not include “heteroaryl”.
A “heteroaryl” substituent group or a heteroaryl moiety in a substituent group refers to an aromatic heterocyclic group or moiety. The term “heteroaryl” includes monocyclic aromatic heterocycles and polycyclic fused ring aromatic heterocycles wherein all of the fused ring systems (excluding any ring systems which are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups/moieties include the following:
Figure imgf000008_0001
wherein G = O, S or NH. For the purposes of the present specification, where a combination of moieties is referred to as one group, for example, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl. Typically a substituted group comprises 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, and even more typically 1 substituent. Unless stated otherwise, any divalent bridging substituent (e.g. -O-, -S-, -NH-, -N(Rβ)- or -Rα-) of an optionally substituted group or moiety must only be attached to the specified group or moiety and may not be attached to a second group or moiety, even if the second group or moiety can itself be optionally substituted. The term “halo” includes fluoro, chloro, bromo and iodo. Where reference is made to a carbon atom of a group being replaced by an N, O or S atom, what is intended is that: CH . N . . . is replaced by ; –CH2– is replaced by –NH–, –O– or –S–; –CH3 is replaced by –NH2, –OH, or –SH; –CH= is replaced by –N=; CH2= is replaced by NH=, O= or S=; or CH≡ is replaced by N≡. In the context of the present specification, unless otherwise stated, a Cx-Cy group is defined as a group containing from x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing from 1 to 4 carbon atoms. Optional substituents and moieties are not taken into account when calculating the total number of carbon atoms in the parent group substituted with the optional substituents and/or containing the optional moieties. For the avoidance of doubt, replacement heteroatoms, e.g. N, O or S, are counted as carbon atoms when calculating the number of carbon atoms in a Cx-Cy group. For example, a morpholinyl group is to be considered a C6 heterocyclic group, not a C4 heterocyclic group. A "protecting group" refers to a grouping of atoms that when attached to a reactive functional group (e.g. OH) in a compound masks, reduces or prevents reactivity of the functional group. In the context of the present specification, = is a double bond; º is a triple bond.
The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Synthesis’, 2nd edition, T.W. Greene and P.G.M Wuts, Wiley-Interscience. DESCRIPTION OF FIGURES
Figure l shows SND224 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner. Figure 2 shows SND221 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner.
Figure 3 shows SND226 increases survival of hippocampal cells from the toxicity induced by IAA in a concentration dependent manner.
Figure 4 shows SND224 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner.
Figure 5 shows SND222 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner.
Figure 6 shows SND221 increases survival of hippocampal cells from the toxicity induced by MPP+ in a concentration dependent manner. PET ATT /ED DESCRIPTION OF THE INVENTION
Figure imgf000010_0001
A first aspect of the invention provides a compound of formula (1):
Figure imgf000011_0001
wherein: Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 , and R2, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; R5 is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and – OC(O)N(R13)2; or from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –O(C1-4 alkyl), wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 - Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; n = 3 or 4; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. In one embodiment, R1 and R2, independently, are selected from –OH and -O-C1-4 alkyl. For example, R1 and R2, independently, are selected from –OH and -OCH3. In one embodiment, R5 is selected from –OH and -O-C1-4 alkyl; or H. For example, R5 is selected from –OH and -OCH3; or H. In one embodiment, R3, R4, R6, R7, R8, and R9, are H. In one embodiment, R1 and R2, independently, are selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; R5 is selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2, or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. In one embodiment, R1 and R2, independently, are selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; R5 is selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2, or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 - Rβ; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. In one embodiment, R1 and R2, independently, are selected from –OH, and -O-C1-4 alkyl; R5 is selected from –OH, and -O-C1-4 alkyl; or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. For example, R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. In one embodiment, R1 and R2, independently, are selected from –OH, and -OCH3; R5 is selected from –OH and -OCH3, or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ,. In one embodiment, R1 and R2, independently, are selected from –OH, and -O-C1-4 alkyl; R5 is selected from–OH, and -O-C1-4 alkyl, or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. For example, R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. In one embodiment, R1 and R2, independently, are selected from –OH, and -OCH3; R5 is selected from –OH, and -OCH3, or from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. For example, R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. In one embodiment, R1 and R2, independently, are selected from –OH, and -OCH3; R5 is selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; and -NH2. For example, R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -CN; -NO2; and -NH2. In one embodiment, R1 and R2, independently, are selected from –OH, and -OCH3; R5 is selected from–OH, and -OCH3, or from H. For example, R3, R4, R6, R7, R8 and R9 are H. In one embodiment, R1 and R2 are independently selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 - Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1, and R2, independently, are selected from –OH and –OCH3; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1 is -O-C1-4 alkyl, e.g. –O-Me; R2 is OH; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1 and R2 are OH; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 - Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. In one embodiment, R1, R2 and R5, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 - Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R1, R2 and R5 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 - Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R1, R2 and R5, independently, are selected from –OH and –O-C1-4 alkyl; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R1, R2 and R5, independently, are selected from –OH and –OCH3; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R3, R4, R6, R7, R8, and R9are H. In one embodiment, R1 is -O-C1-4 alkyl, e.g. –O-Me; R2 is -OH; R5 is -OH ; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R1 is -O-C1-4 alkyl, e.g. –O-Me; R2 is -OH; R5 is -O-C1-4 alkyl, e.g. – O-Me; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R1, R2, and R5 are -OH ; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 - Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H. In one embodiment, R11 and R12 are independently selected from H, C1-6 alkyl, and benzyl substituted with –O(C1-4 alkyl). In one embodiment, R11 and R12 are independently selected from H, C1-2 alkyl, and benzyl substituted with –O(C1-2 alkyl). For example, -NR11R12 may be –NH2 or -N(C1-2 alkyl)(benzyl substituted with –OCH3). In one embodiment, R11 is selected from H and C1-4 alkyl; and R12 is benzyl substituted with –O(C1-4 alkyl). For example, R12 is benzyl substituted with–O(C1-2 alkyl). For example, R12 is benzyl substituted with –O(CH3). For example, R12 is benzyl substituted with –O(C1-2 alkyl) at the ortho position. In one embodiment, R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 may together form a 5- or 6-membered heterocycle optionally having one additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. In this respect, the 5- or 6-membered heterocycle may be morpholine, piperidine, piperazine, or pyrrolidine optionally substituted with 1 or 2 C1-4 alkyl. For example, the 5- or 6- membered heterocycle may be morpholine, piperidine, piperazine, 4-methyl piperazine, or pyrrolidine. In one embodiment, each R10 is independently selected from H and C1-2 alkyl. For example, each R10 is independently selected from H and -CH3. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, Z is –NR11R12. For example, Z is –NR11R12; R11 and R12 are independently selected from H, C1-6 alkyl, and benzyl substituted with –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. In one embodiment, Z is –N(R10)-(CH2)p–NR11R12. For example, Z is –N(R10)-(CH2)p– NR11R12; R10 is H or C1-6 alkyl; and R11 and R12 are independently selected from H and C1-6 alkyl; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. In one embodiment, p is selected from 2 or 3. In one embodiment, Z is –N(R10)-(CH2)p–NR11R12. For example, Z is –N(R10)-(CH2)p– NR11R12; p is 2 or 3; R10 is H or C1-2 alkyl; and R11 and R12 are independently selected from H, and C1-2 alkyl; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-2 alkyl. In one embodiment, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; and q is independently selected from 1-4. For example, q may be 2, 3 or 4. For example, Z is – N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; each R10 is independently selected from H and C1-6 alkyl; and and R11 and R12 are independently selected from H; C1-6 alkyl; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. In one embodiment, q is independently selected from 3 or 4. In one embodiment, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; q is independently selected from 3 and 4. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; each R10 is independently selected from H and C1-2 alkyl; and R11 and R12 are independently selected from H and C1-2 alkyl; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. Each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ. For example, each R10 may independently be selected from H, C1-3 alkyl, and C2-C4 alkenyl. For example, each R10 may independently be selected from H and –CH3. In one embodiment, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; R3 is H; and R4, R5, R6, R7, R8, and R9, independently, are selected from H; -C1-4 alkyl; -OH; -O-C1-4 alkyl; halo; -CN; -NO2; -COOH; and -COORβ. For example, R4, R5, R6, R7, R8, and R9, independently, are selected from H; -C1-4 alkyl; - OH; -O-C1-4 alkyl; halo; -CN; -NO2; and –COOH. In one embodiment, R1, R2, and R5 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; R3 is H; and R4, R6, R7, R8, and R9, independently, are selected from H; -C1-4 alkyl; -OH; -O-C1-4 alkyl; halo; -CN; -NO2; -COOH; and -COORβ. For example, R4, R6, R7, R8, and R9, independently, are selected from H; -C1-4 alkyl; - OH; -O-C1-4 alkyl; halo; -CN; -NO2; and –COOH. In one embodiment is provided a compound of formula (1A):
Figure imgf000020_0001
wherein R1, R2, R5, n and Z are as defined herein, and Rx is selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. In one embodiment, Rx is selected from H; halo; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. In one embodiment, Rx is selected from H; halo; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. In one embodiment, Rx is selected from H; halo; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. In one embodiment, Rx is selected from H; halo; -CN; -NO2; -Rβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; and -COORβ. In one embodiment, Rx is selected from H; halo; -CN; -NO2; -CH3; and -NH2. In one embodiment, Rx is H. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R5 is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R5 is H. For example, R1, R2, and R5 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3. In one embodiment is provided a compound of formula (1B):
Figure imgf000021_0001
wherein R1, R2, R5, n and Z are as defined herein. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R5 is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH3; and R5 is H. For example, R1, R2, and R5 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3. In one embodiment is provided a compound of formula (2):
Figure imgf000022_0001
wherein R1-R8, and Z are as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 and R2 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl. For example, R1 and R2 are independently selected from –OH and -O-CH3. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; - C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R7, R8, and R9 are H. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, benzyl, and benzyl substituted with –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, benzyl and benzyl substituted with –O(CH3); optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, benzyl and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with – CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by –OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)-(CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (2A):
Figure imgf000025_0001
wherein R1, R2, and Z are as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 and R2 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, R1 and R2 are independently selected from –OH and -O-C1-4 alkyl. For example, R1 and R2 are independently selected from –OH and -O-CH3. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)-(CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (2B):
Figure imgf000029_0001
wherein Z is as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)-(CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (2C):
Figure imgf000032_0001
wherein Z is as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl substituted with –C1-4 alkyl or – O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho- substituted by –OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6- membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)-(CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (3):
Figure imgf000035_0001
wherein R1-R8, and Z are as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1, R2, and R5 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, R1, R2, and R7 are independently selected from –OH and -O-C1-4 alkyl. For example, R1, R2, and R7 are independently selected from –OH and -O-CH3. For example, R3, R4, R5, R6, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and benzyl optionally substituted with 1-3 -Rβ. For example, R3, R4, R5, R6, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R3, R4, R5, R6, R8, and R9 are H. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl optionally substituted with 1 or 2 -Rβ, or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by – OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)- (CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (3A):
Figure imgf000039_0001
wherein R1, R2, R7, and Z are as defined above. For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1, R2, and R7 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. For example, R1, R2, and R7 are independently selected from –OH and -O-C1-4 alkyl. For example, R1, R2, and R7 are independently selected from –OH and -O-CH3. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, or oxo (=O) groups. For example, -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -Rβ is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl. For example, R11 and R12 are independently selected from H, C1-6-alkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl optionally substituted with 1 or 2 -Rβ, or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by – OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)- (CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (3B):
Figure imgf000042_0001
wherein is as defined above. In one embodiment is provided a compound of formula (4):
Figure imgf000042_0002
wherein R1-R8, and Z are as defined above. 41 For example, Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1, R2, and R5 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with –C1-4 alkyl or –O(C1-4 alkyl); wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6- membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each -R13 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methyl carbamoyl N-ethyl carbamoyl N,N-dimethyl carbamoyl, N,N-diethyl carbamoyl,
N-methyl-N-ethyl carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N -dimethylsulfamoyl N,N -diethylsulfamoyl, N-methyl-N -ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; each p is independently an integer selected from l to 4; and each q is independently an integer selected from 1 to 4.
For example, R1, R2, and R5 are independently selected from -OH and -O-C1-4 alkyl. For example, R1, R2, and R5 are independently selected from -OH and -0-CH3.
For example, R3, R4, R6, R3, R8, and R9, independently, are selected from H; halo; -CN; -N02; -RP; -OH, -ORP; -SH; -SRP; -SORP; -S02H; -S02RP; -S02NH2; -S02NHRP; -S02N(RP)2; -NH2; -NHRP; -N(RP)2; -CHO; -CORP; -COOH; -COORP; -OCORP; and benzyl optionally substituted with 1-3 -RP. For example, R3, R4, R6, R 7, R8, and R9, independently, are selected from H; halo; -CN; -N02; -RP; -SH; -SRP; -SORP; -S02H; -S02RP; -S02NH2; -S02NHRP; -S02N(RP)2; -NH2; -NHRP; -N(RP)2; -CHO; -CORP; -COOH; -COORP; and benzyl optionally substituted with 1-3 -RP. For example, R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -N02; -SH; -S02H; -NH2; -CHO; -COOH. For example, R3, R4, R6, R7, R8, and R9 are H.
For example, -RP is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group, and wherein any -RP may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -0(Ci-C4 alkyl), -0(Ci-C4 haloalkyl), -0(C3-C7 cycloalkyl), halo, or oxo (=0) groups. For example, -RP is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, or C3-C14 cyclic group. For example, -RP is independently selected from a C1-C4 alkyl, or C2-C4 alkenyl.
For example, R11 and R12 are independently selected from H, Ci-6-alkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -RP; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, R11 and R12 are independently selected from H, C1-3-alkyl, and benzyl optionally substituted with 1 or 2 - Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3- alkyl, and benzyl optionally substituted with 1 or 2 -Rβ, or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 are independently selected from C1-3-alkyl, and benzyl optionally substituted with –CH3, or -OCH3. For example, Z is –NR11R12, wherein R11 is C1-3 alkyl and R12 is benzyl substituted by –OCH3. For example, Z is –NR11R12, wherein R11 is ethyl and R12 is benzyl ortho-substituted by – OCH3. For example, Z is –NR11R12, wherein R11 and R12 together form a 5- or 6- membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from N and O. For example, Z is –NR11R12, wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O. For example, Z may be morpholine or piperidine. For example, Z is -N(R10)-(CH2)p–NR11R12; each p is independently an integer selected from 1 to 4, e.g.2 or 3; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is --N(R10)- (CH2)3–NR11R12; wherein R10 is –H or –C1-3 alkyl, and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is -NH-(CH2)3–NR11R12; wherein R11 and R12 together form a 6-membered heterocycle optionally having an additional heteroatom selected from O; e.g. R11 and R12 together form a piperidine ring. For example, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; wherein each R10 is independently selected from –H and –CH3; p is 2 or 3; q is 2 or 3; and R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. For example, Z is –NH-(CH2)3-NH-(CH2)3-NH2. In one embodiment is provided a compound of formula (4A):
Figure imgf000046_0001
wherein R1 and Z are as defined above. A second aspect of the invention provides a compound selected from Table A, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof.
Figure imgf000046_0002
Figure imgf000047_0001
Figure imgf000048_0001
A third aspect of the invention provides pharmaceutically acceptable multi-salt, solvate or prodrug of the compound of the first or second aspect of the invention. A pharmaceutically acceptable salt, for example, can be formed between an anion and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).
The compounds of the present invention can be used both in their quaternary salt form (as a single salt). Additionally, the compounds of the present invention may contain one or more (e.g. one or two) acid addition or alkali addition salts to form a multi-salt. A multi-salt includes a quaternary salt group as well as a salt of a different group of the compound of the invention.
For the purposes of this invention, a “multi-salt” of a compound of the present invention includes an acid addition salt. Acid addition salts are preferably pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic or hydroiodic acid) or other inorganic acids (for example, nitric, perchloric, sulfuric or phosphoric acid); or organic acids such as organic carboxylic acids (for example, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, salicylic, succinic, malic or hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, mucic or galactaric, gluconic, pantothenic or pamoic acid), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulfonic or camphorsulfonic acid) or amino acids (for example, ornithinic, glutamic or aspartic acid). The acid addition salt may be a mono-, di-, tri- or multi-acid addition salt. A preferred salt is a hydrohalogenic, sulfuric, phosphoric or organic acid addition salt. A preferred salt is a hydrochloric acid addition salt.
The compounds of the present invention can be used both, in quaternary salt form and their multi-salt form. For the purposes of this invention, a “multi-salt” of a compound of the present invention includes one formed between a protic acid functionality (such as a carboxylic acid group) of a compound of the present invention and a suitable cation. Suitable cations include, but are not limited to lithium, sodium, potassium, magnesium, calcium and ammonium. The salt may be a mono-, di-, tri- or multi-salt. Preferably the salt is a mono- or di-lithium, sodium, potassium, magnesium, calcium or ammonium salt. More preferably the salt is a mono- or di-sodium salt or a mono- or di- potassium salt.
Preferably any multi-salt is a pharmaceutically acceptable non-toxic salt. However, in addition to pharmaceutically acceptable multi-salts, other salts are included in the present invention, since they have potential to serve as intermediates in the purification or preparation of other, for example, pharmaceutically acceptable salts, or are useful for identification, characterisation or purification of the free acid or base.
The compounds and/or multi-salts of the present invention may be anhydrous or in the form of a hydrate (e.g. a hemihydrate, monohydrate, dihydrate or trihydrate) or other solvate. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
In some embodiments of the present invention, therapeutically inactive prodrugs are provided. Prodrugs are compounds which, when administered to a subject such as a human, are converted in whole or in part to a compound of the invention. In most embodiments, the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include, but are not limited to, compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound. The present invention also encompasses multi-salts and solvates of such prodrugs as described above. The compounds, multi-salts, solvates and prodrugs of the present invention may contain at least one chiral centre. The compounds, multi-salts, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, multi-salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight. The compounds, multi-salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to 12C, 13C, 1H, 2H (D), 14N, 15N, 16O, 17O, 18O, 19F and 127I, and any radioisotope including, but not limited to 11C, 14C, 3H (T), 13N, 15O, 18F, 123I, 124I, 125I and 131I. The compounds, multi-salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form. A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, “Aulton’s Pharmaceutics - The Design and Manufacture of Medicines”, M. E. Aulton and K. M. G. Taylor, Churchill Livingstone Elsevier, 4th Ed., 2013.
Pharmaceutically acceptable excipients including adjuvants, diluents or carriers that may be used in the pharmaceutical compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
A fifth aspect of the invention provides a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition. Typically the use comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject.
In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition.
A sixth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition. Typically the treatment or prevention comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition. A seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition. Typically the administration is to a subject in need thereof. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition.
The term “treatment” as used herein refers equally to curative therapy, and ameliorating or palliative therapy. The term includes obtaining beneficial or desired physiological results, which may or may not be established clinically. Beneficial or desired clinical results include, but are not limited to, the alleviation of symptoms, the prevention of symptoms, the diminishment of extent of disease, the stabilisation (i.e., not worsening) of a condition, the delay or slowing of progression/worsening of a condition/symptoms, the amelioration or palliation of the condition/symptoms, and remission (whether partial or total), whether detectable or undetectable. The term “palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering a compound, multi-salt, solvate, prodrug or pharmaceutical composition of the present invention. The term “prevention” as used herein in relation to a disease, disorder or condition, relates to prophylactic or preventative therapy, as well as therapy to reduce the risk of developing the disease, disorder or condition. The term “prevention” includes both the avoidance of occurrence of the disease, disorder or condition, and the delay in onset of the disease, disorder or condition. Any statistically significant avoidance of occurrence, delay in onset or reduction in risk as measured by a controlled clinical trial maybe deemed a prevention of the disease, disorder or condition. Subjects amenable to prevention include those at heightened risk of a disease, disorder or condition as identified by genetic or biochemical markers.
Typically, the genetic or biochemical markers are appropriate to the disease, disorder or condition under consideration and may include for example, beta-amyloid 42, tau and phosphor-tau.
In one embodiment of the fifth, sixth, or seventh aspect of the present invention, the disease, disorder or condition is a disease, disorder or condition associated with neurotrophic factors pathways. For example, the disease, disorder or condition may be associated with BDNF pathways In one embodiment of the fifth, sixth, or seventh aspect of the present invention, the disease, disorder or condition is a mitochondrial disease, disorder or condition. For example, mitochondrial diseases are a group of disorders caused by dysfunctional mitochondria. Dysfunctional mitochondria may exhibit one of the following: impaired Ca influx, energy supply, and/or control of apoptosis. Dysfunctional mitochondria may also or alternatively exhibit increased ROS production.
In one embodiment of the fifth, sixth, or seventh aspect of the present invention, the disease, disorder or condition is related to oxidative stress and/ or mitochondrial DNA mutation.
In one embodiment of the fifth, sixth, or seventh aspect of the present invention, the disease, disorder or condition is selected from but not limited to:
(i) central nervous system diseases such as Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, and brain injury from pneumococcal meningitis; (ii) depression, anxiety, amytrophic later sclerosis, Autism spectrum disorders, Rett syndrome, epilepsy, Parkinson's disease, post-traumatic stress disorder, diabetic neuropathy, peripheral neuropathy, obesity, or stroke;
(iii) neurological disorders, neuropsychiatric disorders, and metabolic disorders. Examples of neurological and neuropsychiatric disorders include depression, anxiety,
Alzheimer's, CNS injuries, and the like. Examples of metabolic disorders include obesity and hyperphagia;
(iv) mental disorders and conditions include, but are not limited to, acute stress disorder, adjustment disorder, adolescent antisocial behaviour, adult antisocial behaviour, age-related cognitive decline, agoraphobia, alcohol-related disorder, Alzheimer's, amnestic disorder, anorexia nervosa, anxiety, attention deficit disorder, attention deficit hyperactivity disorder, autophagia, bereavement, bibliomania, binge eating disorder, bipolar disorder, body dysmorphic disorder, bulimia nervosa, circadian rhythm sleep disorder, cocaine-addition, dysthymia, exhibitionism, gender identity disorder, Huntington's disease, hypochondria, multiple personality disorder, obsessive- compulsive disorder (OCD), obsessive-compulsive personality disorder (OCPD), posttraumatic stress disorder (PTSD), Rett syndrome, sadomasochism, and stuttering;
(v) cyclothymic disorders with compounds disclosed herein;
(vi) amyotrophic lateral sclerosis (ALS) or a central nervous system injury. A central nervous system injury includes, for example, a brain injury, a spinal cord injury, or a cerebrovascular event (e.g., a stroke); (vii) cardiovascular diseases, such as coronary artery disease, heart attack, abnormal heart rhythms or arrhythmias, pericardial disease, heart failure, heart valve disease, congenital heart disease, heart muscle disease (cardiomyopathy), aorta disease and vascular disease; (viii) ageing related diseases and/or ageing per se; and
(ix) the subject in need thereof can be a patient diagnosed as suffering from being overweight or obese. Anxiety can be a symptom of an underlying health issue such as chronic obstructive pulmonary disease (COPD), heart failure, or heart arrhythmia.
In one embodiment, the disease, disorder or condition is a central nervous system disease.
In one embodiment, the compounds maybe used for treating or preventing a neurodegenerative disorder. For example, the compounds maybe used for treating or preventing Alzheimer’s Disease, Parkinson’s Disease, or ischemia. In one embodiment, the compounds may be used for treating or preventing rare CNS disorders. For example, the compounds may be used to treat or prevent Rett Syndrome, or KBG Syndrome.
In one embodiment, the compounds maybe used for treating or preventing anti-aging or mitochondria linked disorders. In one embodiment, the disease, disorder or condition is selected from but not limited to Parkinson’s disease, Alzheimer’s disease, and depression.
In one embodiment, the disease, disorder or condition is Alzheimer’s disease.
An eighth aspect of the invention provides a method of modulating neurotrophic factors pathways (such as BDNF pathways), the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to modulate neurotrophic factors pathways (such as BDNF pathways).
A ninth aspect of the invention provides a method of modulating mitochondrial function, the method comprising the use of compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, to modulate mitochondrial function.
In one embodiment of the ninth aspect of the present invention, modulating mitochondrial function includes: modulating Ca influx, energy supply, control of apoptosis and/or ROS production.
In one embodiment of the ninth aspect of the present invention, the method comprises delivering a compound of the first or second aspect of the invention to the mitochondria of a cell.
In one embodiment of the eighth or ninth aspect of the present invention, the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of neurotrophic factors pathways modulation or mitochondrial function modulation.
In another embodiment of the eighth or ninth aspect of the present invention, the method is performed in vivo. For example, the method may comprise the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby modulate neurotrophic factors pathways or modulate mitochondrial function. Typically the administration is to a subject in need thereof.
Alternately, the method of the eighth or ninth aspect of the invention may be a method of modulating factors pathways or modulating mitochondrial function in a non human animal subject, the method comprising the steps of administering the compound, multi-salt, solvate, prodrug or pharmaceutical composition to the non human animal subject and optionally subsequently mutilating or sacrificing the non human animal subject. Typically such a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non human animal subject.
Unless stated otherwise, in any aspect of the invention, the subject maybe any human or other animal. Typically, the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, goat, horse, cat, dog, etc. Most typically, the subject is a human.
Any of the medicaments employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration.
Typically, the mode of administration selected is that most appropriate to the disorder or disease to be treated or prevented.
For oral administration, the compounds, multi-salts, solvates or prodrugs of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.
Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/ or dissolving tablets.
Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Powders or granules for oral use maybe provided in sachets or tubs. Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets. Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.
Formulations for rectal administration maybe presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Formulations suitable for vaginal administration maybe presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For parenteral use, the compounds, multi-salts, solvates or prodrugs of the present invention will generally be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity. Suitable aqueous vehicles include Ringer’s solution and isotonic sodium chloride or glucose. Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate. The compounds of the invention may also be presented as liposome formulations. For transdermal and other topical administration, the compounds, multi-salts, solvates or prodrugs of the invention will generally be provided in the form of ointments, cataplasms (poultices), pastes, powders, dressings, creams, plasters or patches. Suitable suspensions and solutions can be used in inhalers for airway (aerosol) administration.
The dose of the compounds, multi-salts, solvates or prodrugs of the present invention will, of course, vary with the disorder or disease to be treated or prevented. In general, a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day. The desired dose maybe presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.
For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.
EXAMPLES - COMPOUND SYNTHESIS The compounds disclosed herein can be synthesised using the following general formula. The compounds were synthesised according to the following scheme:
Figure imgf000059_0001
Benzaldehyde 1.4 was prepared by coupling 4-hydroxybenzaldehyde (1.2) with 2-(4- chloro-butoxy)tetrahydro-2H-pyran in the presence of Cs2CO3. Claisen–Schmidt condensation between acetophenone 12.7 and benzaldehyde 1.4 afforded a mixture of the chalcone 1.5a and the flavanone 1.5b, which both gave cyclized and deprotected alcohol 1.6 when treated with iodine at 120 °C in DMSO. Bromination of alcohol 1.6 with SOBr2/DMF allowed to isolate bromide 1.7. Target 1 was prepared by a coupling reaction between PPh3 and bromide 1.7 in the presence of KI, and by deprotection with c. HBr in MeCN. The target compounds were synthesized from the bromide 1.7 by coupling it with the corresponding amines in the presence of either DIPEA or K2CO3/KI. Protecting groups were then cleaved by c. HCl in MeCN at RT. 4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzaldehyde (1.4). Cs2CO3 (28.0 g, 1.11 Eq, 85.9 mmol) was added to a solution of 4-hydroxybenzaldehyde (1.2) (10.00 g, 1.055 Eq, 81.89 mmol) in dry DMF (50 mL). The mixture was stirred at room temperature for 30 min before 2-(4-chlorobutoxy)tetrahydro-2H-pyran (14.96 g, 14.0 mL, 1 Eq, 77.64 mmol) in dry DMF (10 mL) was added under nitrogen flow. The reaction mixture was heated at 70 °C for 12 h, before it was allowed to cool to room temperature. The reaction mixture was diluted with 500 mL of 10% Na2CO3 and the aqueous layer was extracted with 3 x 250 mL of EtOAc. Organic layers were combined and washed with 250 mL of brine, which in turn was extracted with 50 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane.4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzaldehyde (1.4) (19.45 g, 68.1 mmol, 87.7%, 97.5% purity) was obtained as a transparent liquid. (E)-1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)prop-2-en-1-one (1.5a) and 2,2-diphenyl-8-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)-7,8- dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.5b). Sodium methoxide (5.689 g, 19.50 mL, 5.4 molar, 35.0 Eq, 105.3 mmol) in MeOH was added portion-wise under nitrogen flow to a suspension of 1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol- 5-yl)ethan-1-one (12.7) (1.000 g, 1.0 Eq, 3.009 mmol) and 4-(4-((tetrahydro-2H- pyran-2-yl)oxy)butoxy)benzaldehyde (1.4) (0.859 g, 1.03 Eq, 3.09 mmol) in 1,4- dioxane (10 mL) at 0 °C. The mixture was allowed slowly to warm to room temperature and it was stirred at that temperature for 15 h. The reaction mixture was then poured to 50 mL of ice-cold brine. The aqueous mixture was then extracted with 3 x 50 mL of EtOAc. Organic fractions were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using DCM:MeOH to afford the product as a mixture of (E)-1-(4- Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)phenyl)prop-2-en-1-one (1.5a) and 2,2-diphenyl-8-(4-(4-((tetra-hydro- 2H-pyran-2-yl)oxy)butoxy)phenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.5b) (1.632 g, 2.7 mmol, 90% yield, 98% purity) as an orange powder. 8-(4-(4-Hydroxybutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (1.6). A solution of ((E)-1-(4-hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)phenyl)prop-2-en-1-one (1.5a) and 2,2-diphenyl-8-(4-(4-((tetrahydro- 2H-pyran-2-yl)oxy)butoxy)phenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.5b) (0.506 g, 1 Eq, 854 µmol) and in DMSO (12 mL) was heated with iodine (42 mg, 0.19 Eq, 0.17 mmol) at 120 °C for 18 h. Reaction mixture was then allowed to cool to room temperature and poured to 120 mL of 1% sodium sulfite solution. The resultant suspension was extracted with 3 x 50 mL of EtOAc. Organic layers were combined and washed with 100 mL of brine, which in turn was extracted with 25 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane.8-(4-(4-Hydroxybutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo-[4,5- h]chromen-6-one (1.6) (268 mg, 515 µmol, 60% yield, 97.4% purity) was obtained as a yellow solid. 8-(4-(4-Bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (1.7). A suspension of 8-(4-(4-hydroxybutoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.6) (2.266 g, 1 Eq, 4.473 mmol) in dry DCM (38 mL) and dry DMF (1.65 g, 1.75 mL, 5.05 Eq, 22.6 mmol) was treated with thionyl bromide (1.2 g, 0.45 mL, 1.3 Eq, 5.8 mmol) at 0 °C under nitrogen atmosphere. After 45 min, the reaction mixture was cooled to with an ice-bath and quenched with 50 mL of sat. NaHCO3 and stirred for 15 min before it was extracted with 3 x 100 mL of DCM. Organic layers were combined and washed with 100 mL of brine, which in turn was extracted with 2 x 50 mL of DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:MeOH.8-(4-(4- Bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) (1.98 g, 4.47 mmol, 75%, 96% purity) was obtained as a beige powder. General methods for alkylation of amines: Method 1. Compounds 1.9A, 1.9C, 1.9E and 1K were prepared by treatment of 8-(4- (4-bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) suspension in MeCN with 1-6 eq. of the secondary amine and 1.5 Eq. of DIPEA. Reaction mixture was stirred at room temperature or at 50 °C under nitrogen atmosphere until full conversion was achieved by TLC or LC-MS. Reaction mixture was then concentrated, dissolved in DCM and washed with brine:water 1:1 mixture. The aqueous layer was extracted twice with DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:NH3 in MeOH as the eluent. Method 2. Compound 1.9L was prepared by treatment of 8-(4-(4- bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) with either 1.75 Eq of N1,N4-Bis-Boc-spermidine or with 2.08 Eq of N-(2- methoxybenzyl)ethanamine hydrochloride in the presence of 2 Eq of K2CO3 and 0.2 Eq of KI in dry DMF. The reaction mixture was stirred at room temperature or at 60 °C until no starting material was left, before it was evaporated to dryness. The residue was then dissolved in DCM, washed with brine:water 1:1 mixture. The aqueous layer was extracted once more with DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:NH3 in MeOH as the eluent. 8-(4-(4-Morpholinobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (1.9A). Suspension of 8-(4-(4-bromobutoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) (230 mg, 1 Eq, 404 µmol) in MeCN (1 mL) was treated with a solution of morpholine (216 mg, 214 µL, 6.14 Eq, 2.48 mmol) and DIPEA (80.1 mg, 108 µL, 1.54 Eq, 620 µmol) in MeCN (4 mL). After 16 h stirring at 50 °C, the reaction mixture was worked-up and purified by normal phase flash-chromatography.8-(4-(4-Morpholinobutoxy)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (1.9A) (226 mg, 0.38 mmol, 94%, 97% purity) was obtained as an off-white foam. 2,2-Diphenyl-8-(4-(4-(piperidin-1-yl)butoxy)phenyl)-6H-[1,3]dioxolo[4,5- h]chromen-6-one (1.9C). Suspension of 8-(4-(4-bromobutoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) (252 mg, 1 Eq, 443 µmol) in MeCN (1 mL) was treated with a solution of piperidine (188 mg, 214 µL, 5 Eq, 2.21 mmol) and DIPEA (86.1 mg, 116 µL, 1.50 Eq, 666 µmol) in MeCN (2.5 mL). After 20 h stirring at 50 °C, the reaction mixture was worked-up and purified by normal phase flash-chromatography.2,2-Diphenyl-8-(4-(4-(piperidin-1-yl)butoxy)phenyl)-6H- [1,3]dioxolo[4,5-h]chromen-6-one (1.9C) (217 mg, 365 µmol, 82.4%, 96.4% purity) was obtained as a beige powder. 8-(4-(4-(Methyl(2-(piperidin-1-yl)ethyl)amino)butoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9E). Suspension of 8-(4-(4- bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) (260 mg, 1 Eq, 457 µmol) in MeCN (1 mL) was treated with a solution of N-methyl-2- (piperidin-1-yl)ethan-1-amine (96 mg, 1.5 Eq, 0.67 mmol) and DIPEA (85.3 mg, 115 µL, 1.45 Eq, 660 µmol) in MeCN (2 mL). After 10 h at 50 °C and 15 h at 60 °C, the reaction mixture was worked-up and purified by normal phase flash-chromatography.8-(4-(4- (methyl(2-(piperidin-1-yl)ethyl)amino)butoxy)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (194 mg, 0.30 mmol, 65%, 97% purity) was obtained as a brown oil. 8-(4-(4-(Methyl(3-(piperidin-1-yl)propyl)amino)butoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9K). Suspension of 8-(4-(4- bromobutoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.7) (280 mg, 1 Eq, 492 µmol) in MeCN (1 mL) was treated with a solution of N-methyl-3- (piperidin-1-yl)propan-1-amine (134 mg, 1.75 Eq, 860 µmol) and DIPEA (95.3 mg, 128 µL, 1.5 Eq, 738 µmol) in MeCN (2 mL). After 18 h at 60 °C, the reaction mixture was worked-up and purified by normal phase flash-chromatography.8-(4-(4-(Methyl(3- (piperidin-1-yl)propyl)amino)butoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (1.9K) (267 mg, 408 µmol, 82.9%, 98.5% purity) was obtained as an orange oil. 8-(4-(4-(Ethyl(2-methoxybenzyl)amino)butoxy)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (1.9L). N-(2-Methoxybenzyl)ethanamine hydrochloride (149 mg, 2.08 Eq, 739 µmol) was suspended in DMF (1 mL) and K2CO3 (194 mg, 3.96 Eq, 1.40 mmol) was added to convert it to the free base. After 5 min, KI (12 mg, 0.20 Eq, 72 µmol) and 8-(4-(4-bromobutoxy)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (1.7) (202 mg, 1 Eq, 355 µmol) were added as a suspension in DMF (1 mL). After 18 h at 60 °C, the reaction mixture was worked-up and purified by normal phase flash-chromatography.8-(4-(4-(Ethyl(2- methoxybenzyl)amino)butoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (1.9L) (156 mg, 0.21 mmol, 61%, 90% purity) was obtained as a transparent oil. General method for diphenylmethylene ketal, Boc and MOM protecting group cleavage and formation of HCl salt. Protected substrate was either dissolved or suspended in MeCN and 20-25 eq. of aqueous c. HCl or HBr was added under nitrogen flow. The mixture was stirred at room temperature for 2 h, the reaction mixture was then concentrated and traces of water were azeotropically removed with 2 x 5 mL of toluene. The residue was then suspended in 1-2 mL of abs. EtOH, 5 mL of Et2O was added, the suspension was briefly sonicated, filtered and washed with 4 x 5 mL of Et2O. The solid was then rapidly transferred to a vial and dried. 7,8-Dihydroxy-2-(4-(4-morpholinobutoxy)phenyl)-4H-chromen-4-one hydrochloride (1A – SND221).8-(4-(4-Morpholinobutoxy)phenyl)-2,2-diphenyl- 6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9A) (224 mg, 1 Eq, 389 µmol) in MeCN (1 mL) was deprotected with c. HCl (0.73 g, 0.65 mL, 12 molar, 20 Eq, 7.8 mmol) by using the general method for deprotection.7,8-Dihydroxy-2-(4-(4- morpholinobutoxy)phenyl)-4H-chromen-4-one hydrochloride (1A) (174 mg, 374 µmol, 96.0%, 96.2% purity) was obtained as a yellow powder. 7,8-Dihydroxy-2-(4-(4-(piperidin-1-yl)butoxy)phenyl)-4H-chromen-4-one hydrochloride (1C – SND222).2,2-Diphenyl-8-(4-(4-(piperidin-1- yl)butoxy)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9C) (213 mg, 1 Eq, 371 µmol) in MeCN (1 mL) was deprotected with c. HCl (0.71 g, 0.63 mL, 12 molar, 20 Eq, 7.6 mmol) by using the general method for deprotection.7,8-Dihydroxy-2-(4-(4- (piperidin-1-yl)butoxy)phenyl)-4H-chromen-4-one hydrochloride (1C) (140 mg, 313 µmol, 84.3%, 99.7% purity) was obtained as a yellow powder. 7,8-Dihydroxy-2-(4-(4-(methyl(2-(piperidin-1- yl)ethyl)amino)butoxy)phenyl)-4H-chromen-4-one dihydrochloride (1E - SND223).8-(4-(4-(Methyl(2-(piperidin-1-yl)ethyl)amino)butoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9E) (194 mg, 1 Eq, 308 µmol) in MeCN (1 mL) was deprotected with c. HCl (0.58 g, 0.52 mL, 12 molar, 20 Eq, 6.2 mmol) by using the general method for deprotection.7,8-Dihydroxy-2-(4-(4-(methyl(2- (piperidin-1-yl)ethyl)amino)butoxy)phenyl)-4H-chromen-4-one dihydrochloride (1E) (115 mg, 208 µmol, 67.6%, 97.5% purity) was obtained as a yellow powder. 7,8-Dihydroxy-2-(4-(4-(methyl(3-(piperidin-1- yl)propyl)amino)butoxy)phenyl)-4H-chromen-4-one dihydrochloride (1K – SND224).8-(4-(4-(Methyl(3-(piperidin-1-yl)propyl)amino)butoxy)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (1.9K) (257 mg, 1 Eq, 399 µmol) in MeCN (1.5 mL) was deprotected with c. HCl (0.78 g, 0.70 mL, 12 molar, 21 Eq, 8.4 mmol) by using the general method for deprotection.7,8-Dihydroxy-2-(4-(4-(methyl(3- (piperidin-1-yl)propyl)amino)butoxy)phenyl)-4H-chromen-4-one dihydrochloride (1K) (97 mg, 0.17 mmol, 44%, 99.2% purity) was obtained as an orange powder. 2-(4-(4-(Ethyl(2-methoxybenzyl)amino)butoxy)phenyl)-7,8-dihydroxy-4H- chromen-4-one hydrochloride (1L – SND226).8-(4-(4-(Ethyl(2- methoxybenzyl)amino)butoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (269 mg, 1 Eq, 411 µmol) (1.9L) in MeCN (1.5 mL) was deprotected with c. HCl (0.78 g, 0.70 mL, 12 molar, 20 Eq, 8.4 mmol) by using the general method for deprotection. The resultant solid was then purified by preparative LC to yield 2-(4-(4- (ethyl(2-methoxybenzyl)amino)butoxy)phenyl)-7,8-dihydroxy-4H-chromen-4-one hydrochloride (1L) (189 mg, 0.35 mmol, 85%, 97% purity) as an orange powder. Synthesis of SND242 3-Methoxy-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)benzaldehyde (5.4).4-Hydroxy-3-methoxybenzaldehyde (1.000 g, 1 Eq, 6.57 mmol) in dry DMF (4 mL) was treated with Cs2CO3 (2.677 g, 1.25 Eq, 8.216 mmol) under nitrogen atmosphere before 2-(4-chlorobutoxy)tetrahydro-2H-pyran (1.279 g, 1.20 mL, 1.01 Eq, 6.638 mmol) in DMF (2 mL) was added. The reaction mixture was then heated under nitrogen at 70 °C for 12 h before it was allowed to cool to room temperature. The reaction mixture was diluted with 25 mL of 10 of Na2CO3 and extracted with 3 x 15 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using EtOAc:heptanes to yield 3-methoxy-4-(4-((tetrahydro-2H- pyran-2-yl)oxy)butoxy)benzaldehyde (5.4) (1.471, 4.8 mmol, 73%) as a transparent oil. (E)-1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-4- (4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)prop-2-en-1-one (5.5a) and 8-(3-methoxy-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)- 2,2-diphenyl-7,8-dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (5.5b). Sodium methoxide (9.017 g, 30.91 mL, 5.4 molar, 35 Eq, 166.9 mmol) in MeOH was added portion-wise under nitrogen flow to an ice/water cooled (10 °C) suspension of 1- (4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)ethan-1-one (12.7) (1.585 g, 1 Eq, 4.769 mmol) and 3-methoxy-4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)benzaldehyde (5.4) (1.471 g, 1 Eq, 4.769 mmol) in 1,4-dioxane (18 mL). The reaction mixture was then allowed to slowly warm to room temperature and stirred under nitrogen for 18 h. The reaction mixture was poured to 80 mL of ice-cold brine. The resultant orange suspension was extracted with 4 x 80 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptanes to yield (E)-1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)prop-2-en-1-one (5.5a) and 8-(3- methoxy-4-(4-((tetrahydro-2H-pyran-2-yl)oxy)-butoxy)phenyl)-2,2-diphenyl-7,8- dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (5.5b) (1.9 g, 3.1 mmol, 64%) as an orange oil that solidified upon standing. 8-(4-(4-Hydroxybutoxy)-3-methoxyphenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (5.6). A solution of (E)-1-(4-Hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)-3-(3-methoxy-4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)-phenyl)prop-2-en-1-one (5.5a) and 8-(3-methoxy-4-(4-((tetrahydro- 2H-pyran-2-yl)oxy)butoxy)-phenyl)-2,2-diphenyl-7,8-dihydro-6H-[1,3]dioxolo[4,5- h]chromen-6-one (5.5b) (2.125 g, 1 Eq, 3.413 mmol) and diiodine (173.2 mg, 0.2 Eq, 682.5 µmol) in DMSO (51 mL) was stirred at 120 °C for 17 h. The reaction mixture was allowed to cool to room temperature, before it was poured to 500 mL of 10% of Na2S2O3 solution. The aqueous solution was extracted with 3 x 200 mL of EtOAc. Organic layers were combined and washed with 200 mL of brine, which in turn was extracted with 50 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using DCM:MeOH to yield 8-(4-(4-hydroxybutoxy)-3- methoxyphenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (5.6) (1.700 g, 2.3 mmol, 68%, 73% purity) as a yellow solid. 8-(4-(4-Bromobutoxy)-3-methoxyphenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (5.7). A suspension of 8-(4-(4- hydroxybutoxy)-3-methoxyphenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6- one (5.6) (1.7 g, 1 Eq, 3.2 mmol) in dry DCM (20 mL) and dry DMF (4.7 g, 5.0 mL, 20 Eq, 65 mmol) was cooled to 0 °C before thionyl bromide (724 mg, 0.270 mL, 1.1 Eq, 3.48 mmol) was added under nitrogen flow. The mixture was then stirred at room temperature for 1 h, before it was cooled with an ice-bath and quenched with 50 mL of saturated NaHCO3. The mixture was then extracted with 2 x 100 mL of DCM. Organic layers were combined, washed with 100 mL of brine, which in turn was extracted with 50 mL of DCM. Organic layers were dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:EtOAc to yield 8-(4-(4-bromobutoxy)-3-methoxyphenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (5.7) (802 mg, 1.3 mmol, 42%, 99% purity) as an off-white solid. 8-(3-Methoxy-4-(4-(piperidin-1-yl)butoxy)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (5.9C – SND242). A solution of piperidine (143 mg, 214 µL, 5 Eq, 1.68 mmol) and DIPEA (65.0 mg, 87.6 µL, 1.5 Eq, 503 µmol) in MeCN (1.5 mL) was added to a suspension of 8-(4-(4-bromobutoxy)-3- methoxyphenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (5.7) (201 mg, 1 Eq, 335 µmol) in MeCN (1 mL) under nitrogen flow. Reaction mixture was then stirred at 50 °C for 18 h before it was allowed to cool to room temperature. The reaction mixture was then evaporated to dryness, dissolved in 50 mL of DCM and washed with 25 mL of brine:water 1:1 mixture. The aqueous layer was extracted with 2 x 25 mL of DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using DCM:NH3 in MeOH to yield 8-(3-methoxy-4-(4-(piperidin-1- yl)butoxy)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (5.9C) (185 mg, 0.31 mmol, 91%, 100% purity) as a beige foam. Synthesis of SND272 7-Hydroxy-2,2-diphenyl-8-(4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (33.1). Hydrogen peroxide (806 µL, 35% Wt, 2.2 Eq, 9.413 mmol) was added to a solution of sodium hydroxide (864 µL, 30% Wt, 2 Eq, 8.56 mmol), (E)-1-(4-hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)phenyl)prop-2-en-1-one (1.5a) and 2,2-diphenyl-8-(4-(4-((tetrahydro- 2H-pyran-2-yl)oxy)-butoxy)phenyl)-7,8-dihydro-6H-[1,3]dioxolo-[4,5-h]chromen-6- one (1.5b) (2.536 g, 1 Eq, 4.279 mmol) in MeOH (26 mL) at 0 °C. The mixture was stirred at 0 °C for 15 min before it was stirred at room temperature for 20 h. The reaction mixture was cooled with an ice-bath, diluted with 50 mL of water and neutralized to pH = 7 with 10% of citric acid. The aqueous solution was then extracted with 3 x 100 mL of EtOAc. Organic fractions were combined and washed with 100 mL of brine, which in turn was extracted with 25 mL of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:EtOAc as the eluent to yield 7-hydroxy-2,2-diphenyl-8-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)- 6H-[1,3]dioxolo[4,5-h]chromen-6-one (33.1) (1.327 g, 2.1 mmol, 49%, 95% purity) as a beige solid. 8-(4-(4-Bromobutoxy)phenyl)-7-hydroxy-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (33.2). Thionyl bromide (1.13 g, 423 µL, 2.50 Eq, 5.45 mmol) was added to a solution of 7-hydroxy-2,2-diphenyl-8-(4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butoxy)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (33.1) (1.325 g, 1 Eq, 2.184 mmol) and dry DMF (1.9 g, 2.0 mL, 12 Eq, 26 mmol) in dry DCM (18 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h before it was cooled with an ice-bath and quenched with 55 mL of sat. NaHCO3. The mixture was then extracted with 2 x 75 mL of DCM. Organic layers were combined, washed with 50 mL of brine, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using DCM:EtOAc as the eluent to yield 8-(4-(4-bromobutoxy)phenyl)-7-hydroxy-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (33.2) (1.058 g, 1.81 mmol, 83%, 100% purity) as a beige solid. 7-Hydroxy-2,2-diphenyl-8-(4-(4-(piperidin-1-yl)butoxy)phenyl)-6H- [1,3]dioxolo[4,5-h]chromen-6-one (33.3C – SND272). A solution of piperidine (217 mg, 252 µL, 6 Eq, 2.55 mmol) and DIPEA (82.5 mg, 111 µL, 1.5 Eq, 638 µmol) in MeCN (2 mL) was added to a suspension of 8-(4-(4-bromobutoxy)phenyl)-7-hydroxy- 2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (33.2) (249 mg, 1 Eq, 425 µmol) in MeCN (2 mL) at room temperature under nitrogen flow. The reaction mixture was then heated at 50 °C for 18 h before it was allowed to cool to room temperature and evaporated to dryness. The residue was then dissolved in 50 mL of DCM and washed with 30 mL of brine:water 1:1 mixture. The aqueous layer was extracted with 2 x 25 mL of DCM. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using DCM:NH3 in MeOH as the eluent to yield 7-hydroxy-2,2- diphenyl-8-(4-(4-(piperidin-1-yl)butoxy)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6- one (33.3C) (180 mg, 0.31 mmol, 72%, 100% purity) as a yellow solid. COMPOUNDS The following compounds were synthesised using the general processes described above.
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
EXAMPLES - BIOLOGICAL STUDIES
Experimental methodology Viability assays
The CellTiter-Glo® 2.0 Assay (Promega # G7572) determines the number of viable cells in culture by quantifying ATP, which indicates the presence of metabolically active cells. It is a single reagent added directly to the cells in 96 well plates. Luminesence readout is directly proportional to the number of viable cells in culture.
Toxicity of compounds alone was tested prior to the initiation of the assays and concentrations well below the toxicity threshold were used for evaluation.
Mitochondria function The Agilent Seahorse XF Cell Mito Stress Test (#103015-100) and Seahorse XFe96 FluxPak mini (#102601-100) were used to measure key parameters of mitochondrial function by directly assessing the oxygen consumption rate (OCR) of cells, according to the manufacturer’s instruction. HT-22 mouse hippocampal cell line (Millipore) were plated in the Seahorse XF Cell Culture Microplate at a density of 4800 cells/well in the Seahorse 96 well plates and grown for i6-24h before the initiation of the assay. Test compounds at various concentrations and vehicle, DMSO at a final concentration of 0.5%, were added to the 96 well plates and incubated at 37°C overnight. Before the determination of the various mitochondrial functions, the cells were washed twice with fresh medium and incubated in to mΐ/well DMEM at 37°C in a C02-free incubator for l h. Cellular bioenergetics was determined using the extracellular flux analyzer (Seahorse Bioscience). Sequential injection of mitochondrial inhibitors oligomycin (2 mM), FCCP (2 mM), and antimycin A/ rotenone (Mix, 0.5 mM) were used to evaluate basal respiratory capacity, maximal respiration in the presence of FCCP, oligomycin- sensitive O2 consumption coupled to ATP synthesis, proton leak, spare respiratory capacity and non-mitochondrial respiration. The Seahorse XF Mito Stress Test Report Generator automatically calculates the Seahorse XF Cell Mito Stress Test parameters from the instrument readings.
Statistics
Basic statistical analysis was performed. If appropriate, data were presented as mean ± standard error of mean (SEM) and group differences were evaluated by e.g. one or two- way ANOVA or T-test.
Example 1. Neuron protection in an in vitro model of ischemia
The aim of this study was to test the neuroprotective effects of SND derivatives in an in vitro ischemia model. Ischemia was induced in a mouse hippocampal cell line, HT-22 (Millipore) using a brief treatment with iodoacetic acid (IAA). Compounds were added after the removal of the lesion, mimicking the reperfusion phase. Cell death was monitored using the CellTiter-Glo® assay.
Experimental method: IAA toxicity
Cells were plated in 96-well plates at a density of 3000 cells per well. Cells were cultured at 37°C; 95% humidity and 5% C02 for 24 h then IAA was added to a final concentration of 10 mM. Following a 2h incubation, medium was replaced with fresh medium containing the test compounds or vehicle control (DMSO at a final concentration of 0.5%) and incubated for an additional 24h. Viability was measured using CellTiter-Glo® as per manufacturer’s instructions and luminescence was read using an EnVision instrument. The experiment was carried out with n=3 technical replicates per condition. Data was analyzed using prism software (Supplier: GraphPad Software, Inc., Software version: 5.00) Results:
As shown in Figure l, Figure 2 and Figure 3 SND derivatives SND221, SND224 and SND226 have shown a concentration dependent neuroprotective activity against in vitro ischemia model, when added in the reperfusion phase. All compounds significantly increased cell survival in the mM range. In the same experiment the known flavonoid 7,8 DHF (Tocris) which has been previously shown to possess broad neuroprotective activity increased cell survival only at the highest concentration of 30 mM (Table lB) Table lA and lB depict the neuroprotective activity of SND222, SND223, SND242 and comparator 7,8 DHF.
Table lA and lB. Neuroprotective activity of SND222, SND223 and SND242 derivatives and control 7,8 DHF against an in vitro model of ischemia induced by IAA. The numbers represent mean % viability vs cells treated only with vehicle control (no IAA). The lesion control is depicted as o mM and the numbers represent the mean % of sample versus the vehicle control from the same 96 well plate as the tested compounds.
Table lA
Figure imgf000072_0001
Table lB
Figure imgf000072_0002
Example 2. Neuroprotective effects against an in vitro model of Parkinson.
SND derivatives were evaluated in a widely used cellular Parkinson Disease (PD) model in which neurotoxicity was induced by i-methyl-4-phenylpyridinium (MPP+) in cultured hippocampal cells.
Experimental methods The mouse hippocampal HT-22 cells (3000 cells/well) were seeded in a 96-well plate and grown overnight, then test compounds at various concentrations or vehicle control (DMSO at a final concentration of 0.5%) were added. Following 30 min incubation, MPP+ was added to a final concentration of 200 mM and the cells were further incubated for 24h. The plates were equilibrated at RT for 10 min, 50 mΐ of CellTiter Glo reagent was added and cells were further kept at RT for 30 min in the dark. Luminescence was read using an EnVision instrument and data was analyzed using prism software (Supplier: GraphPad Software, Inc., Software version: 5.00) Results
SND221, SND222 and SND224 derivatives were effective in protecting the cells from MPP+ injury in a concentration dependent manner as shown in Figures 4, 5 and 6. In the same experiment 7,8 DHF derivative, used as a comparator in the study did not rescue the cells from MMP+ toxicity at any concentration tested (between 30 mM - l mM).
Example A ‘ . Neuroprotective effects against an in vitro model of neuronal oxidative stress (oxytosis)
Excessive glutamate stimulation on neuronal cells leads to accumulation of reactive oxygen species (ROS) which ultimately contribute to cell death in stroke, trauma and other neurodegenerative disorders. In this study, hippocampal cells were used to determine the effect of SND derivatives on glutamate neurotoxicity.
Experimental method HT-22 cells (3000 cells/well) were seeded in a 96-well plate and grown overnight, then test compounds at various concentrations and vehicle control were added. Following 30 min incubation, Glutamate was added to a final concentration of 5 mM and the cells were further incubated for 24h. The plates were equilibrated at RT for 10 min, 50 mΐ of CellTiter Glo reagent was added and cells were further kept at RT for 30 min in the dark. Luminescence was read using an EnVision instrument and data was analyzed using prism software (Supplier: GraphPad Software, Inc., Software version: 5.00).
Results
SND derivatives were effective at reducing the toxic effects of Glutamate when tested at a concentration that was not in itself toxic to the cells (Table 2). In the same experiment 7,8 DHF derivative, used as a comparator in the study did not rescue the cells from Glutamate toxicity at any concentration tested (between 30 mM - i mM).
Table 2. Neuroprotective activity of various SND derivatives against oxidative stress induced by Glutamate
Figure imgf000074_0001
Example 4. Effect of SND derivatives on the mitochondria function
Given the neuroprotective effects exhibited by the SND novel compounds and the hypothesis they exert their activity by protecting against mitochondrial dysfunction, the test compounds were evaluated in the hippocampal cell line using the Agilent Seahorse XF Cell Mito Stress Test. OCR is a direct measurement of mitochondrial respiration rate. Experimental method
4800 HT-22 cells/well were grown overnight and then treated for 24h with vehicle, DMSO at a final concentration of 0.5% or test compounds at non-toxic concentrations. The bioenergetic profiles were generated to ensure the derivatives do not inhibit the mitochondria function.
When the compounds were assessed for their potential to protect the mitochondria from the toxic effect of i-methyl-4-phenylpyridinium (MPP+), the cells were grown overnight as above, vehicle or compounds were added for 30 min, followed by the addition of too mM MPP+ for a duration of 24h. Bioenergetic profiles demonstrated that the ATP production, measured following oligomycin injection and the maximal respiration (FCCP-induced OCR) of MPP+ treated cells was significantly suppressed. Results
Bioenergetic profiles generated following the treatment of the cells with the compounds alone were unchanged or slightly increased compared with the vehicle control, demonstrating that the novel derivatives do not have a toxic effect, as shown in Table 3. Table 3. Mitochondrial respiration parameters upon treatment with the SND derivatives
Figure imgf000075_0001
The decreased maximal respiration rate due to the MPP+ treatment could be partially restored by SND242 as shown in Table 4. Interestingly, a higher concentration of SND242 showed a lesser effect, even if this concentration was not in itself toxic to the mitochondria (Table 3).
Table 4. Effect of SND derivatives on mitochondria respiration treated with MPP+. The values represent mean % of the sample versus controls (cells treated only with the lesion)
Figure imgf000075_0002
Figure imgf000076_0002
Example . Metal chelating properties of SND derivatives The metal chelating properties of molecules with polyphenolic structures suggest they may play a role in metal-overload diseases and in all oxidative stress conditions involving a transition metal ion [Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002 Nov;36(n):ii99-2o8]
Exp erimental Method
The test compounds were evaluated for the ability to form complexes with Al, Fe, Cu and Zu ions by using a spectrophotometric method. Different salts of these metals were dissolved in MeOH to concentrations of 50 and 200 mM and added to 50 mM compound or blank wells; wavelength between 200 - 600 nm was recorded. Morin was used as a positive control.
Results
As expected, morin was able to form a complex with all four ions, whereas SND221, SND223, SND224 and SND226 selectively chelated the Al ion. In contrast, SND222 formed complexes with Fe, Cu and Zn ions as presented in Table 5.
Table 5. Metal chelating properties of SND derivatives - represents no chelation detected
+ signifies a slight red shift: absorbance increased less than 0.5 compared with the compound signal, or wavelength of feature peak shift less 30nm;
++ represents a significant red shift: mean absorbance increased over 0.5 compared with compound signal, or wavelength of feature peak shift over 30nm;
Figure imgf000076_0001
Figure imgf000077_0001
Example 6. In vitro anti-oxidant properties
An accumulating amount of data proves the pivotal role of free radicals in various (patho)physiological processes, like ageing and the toxicity of numerous compounds. Various in vitro tests to evaluate the efficacy of the antioxidants have been reported. A comparison of these studies indicated that the improved TEAC method can be used to screen structurally related compounds to predict their antioxidant capacity.
Experimental Method OxiSelect™ Trolox Equivalent Antioxidant Capacity (TEAC) Assay Kit (ABTS; Cell biolabs #XAN5040) was used to assess the TEAC of a selection of the novel compound library. Antioxidants commonly neutralize radicals via a hydrogen atom transfer (HAT) or single electron transfer (SET) mechanism. The TEAC Assay is based on the conversion of oxidized probe ABTS*+ radical to ABTS via SET or HAT antioxidant mechanisms. Antioxidants neutralize the radical ion in a concentration dependent manner, which correlates with a proportional decrease in colour intensity. Antioxidant activity is compared to the water soluble vitamin E analog Trolox.
The assay has been optimized for 384 well plates. The compounds were dispensed at multiple concentrations and the vehicle DMSO 2% was used as a negative control.
Following the addition of the reagents according to the kit instructions the plates were incubated for 5 min (total TEAC determination) under orbital mixing and the absorbance was then read in kinetic mode at 405-415 nm. The antioxidant concentration, as mM Trolox equivalents (TEAC value) was determined in the samples using the equation obtained from the linear regression analysis of the standard curve.
Results
SND derivatives showed increased antioxidant potential as shown in Table 6. Table 6. Antioxidant activity of SND derivatives expressed as TEAC values (pM Trolox equivalents).
Figure imgf000078_0002
The subject-matter of the current disclosure is further defined in the following clauses:
Figure imgf000078_0001
wherein: Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 , R2, R4, and R5, independently, are selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; or from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; wherein at least two of R1 , R2, R4, and R5 are independently selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, –OC(O)N(R13)2; R3, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; n = 1-6; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4. 2. A compound as defined in clause 1, wherein R1 , R2, R4, and R5, independently, are selected from –OH, and -O-C1-4 alkyl, or from H; halo; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ, wherein at least two of R1 , R2, R4, and R5 are independently selected from –OH, and -O-C1-4 alkyl 3. A compound as defined in clause 2, wherein R1, R2, R4, and R5 are independently selected from -OH and -OCH3, or from H; halo; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ; wherein at least two of R1 , R2, R4, and R5 are independently selected from –OH, and -OCH3. 4. A compound as defined in clause 2; wherein R1, R2, R4, and R5, independently, are selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; and -NH2; wherein at least two of R1 , R2, R4, and R5 are independently selected from –OH, and -OCH3. 5. A compound as defined in any one or more of the preceding clauses, wherein R3, R6, R7, R8, and R9, are independently selected from H; halo; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ. 6. A compound as defined in any preceding clause, wherein R3, R6, R7, R8, and R9 are H. 7. A compound as defined in any preceding clause, wherein -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, -CON(CH3)2 or oxo (=O) groups. 8. A compound as defined in clause 1; wherein R1 and R2 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1- 3 -Rβ. 9. A compound as defined in clause 8; wherein R1, and R2, independently, are selected from –OH and –OCH3; and R3, R4, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. 10. A compound as defined in clause 1; wherein R2, and R4 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R1, R3, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1- 3 -Rβ. 11. A compound as defined in clause 10; wherein R2, and R4, independently, are selected from –OH and –OCH3; and R1, R3, R5, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. 12. A compound as defined in clause 1; wherein R1, R2 and R5 are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. 13. A compound as defined in clause 1 wherein R1, R2 and R5, independently, are selected from –OH and –O-C1-4 alkyl; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. 14. A compound as defined in clause 13; wherein R1, R2 and R5, independently, are selected from –OH and –OCH3; and R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. 15. A compound as defined in any one or more of the preceding clauses; wherein R11 and R12 are independently selected from H and C1-6 alkyl; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl. 16. A compound as defined in clause 15; wherein R11 and R12 together form a 5- or 6- membered heterocycle optionally substituted with 1 or 2 C1-4 alkyl. 17. A compound as defined in clause 16; wherein the 5- or 6-membered heterocycle is morpholine, piperidine, piperazine, or pyrrolidine optionally substituted with 1 or 2 C1-4 alkyl. 18. A compound as defined in any one or more of the preceding clauses; wherein Z is – NR11R12 and n is 3 or 4. 19. A compound as defined in any one or more of clauses 1 to 17; wherein Z is –N(R10)- (CH2)p–NR11R12; p is 1-4; and n is 1-6. 20. A compound as defined in any one or more of clauses 1 to 17; wherein Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12; and q is independently selected from 1-4. 21. A pharmaceutically acceptable multi-salt, solvate or prodrug of a compound as defined in any one of clauses 1 to 20. 22. A pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 21, and a pharmaceutically acceptable excipient. 23. A compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 21, or a pharmaceutical composition as defined in clause 22, for use in medicine. 24. A compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 21, or a pharmaceutical composition as defined in clause 22, for use treating or preventing a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease.
25. A compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 21, or a pharmaceutical composition as defined in clause 22, for use treating or preventing a central nervous system disease, disorder or condition.
26. A method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined in any one of clauses 1 to 20, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clauses 21, or a pharmaceutical composition as defined in clause 22, to thereby treat or prevent the disease, disorder or condition.
27. A method of treatment as defined in clause 26, wherein the disease, disorder or condition is (i) a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease and/or (ii) a central nervous system disease, disorder or condition.
It will be understood that the present invention has been described above by way of example only. The examples are not intended to limit the scope of the invention.
Various modifications and embodiments can be made without departing from the scope and spirit of the invention, which is defined by the following claims only.

Claims

CLAIMS 1. A compound of formula (1):
Figure imgf000084_0001
Formula (1) wherein: Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; and –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; R1 and R2, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and –OC(O)N(R13)2; R5 is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR13, and – OC(O)N(R13)2; or from H; halo; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; R3, R4, R6, R7, R8, and R9, independently, are selected from H; halo; -C1-4 alkyl; -CN; -NO2; -Rβ; -OH, -ORβ; -SH; -SRβ; -SORβ; -SO2H; -SO2Rβ; -SO2NH2; -SO2NHRβ; -SO2N(Rβ)2; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ; each -Rβ is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -Rβ may optionally be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, C3-C7 cycloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), -O(C3-C7 cycloalkyl), halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, - CON(CH3)2 or oxo (=O) groups; each R10 is independently selected from H, C1-6 alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R10, when not H, is independently optionally substituted with 1 or 2 -Rβ; R11 and R12 are independently selected from H, C1-6-alkyl, C2-C6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, benzyl, and benzyl substituted with C1-4 alkyl or –O(C1-4 alkyl), wherein each R11 and R12, when is not H, are independently optionally substituted with 1 or 2 -Rβ; or R11 and R12 together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl; each -R13 is independently selected from a H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any -R13 may optionally be substituted with one or more –R14; each R14 is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-14 cyclic group, halo, -NO2, -CN, -OH, -NH2, mercapto, formyl, carboxy, carbamoyl, C1-6 alkoxy, C1-6 alkylthio, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, or arylsulfonyl, wherein any –R14 may optionally be substituted with one or more –R15; each –R15 is independently selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N- methylcarbamoyl N-ethylcarbamoyl N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; n = 3 or 4; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4.
2. A compound as claimed in claim 1, wherein R1 and R2, independently, are selected from –OH, and -O-C1-4 alkyl.
3. A compound as claimed in claim 1 or claim 2, wherein R1 and R2, independently, are selected from –OH, and -O-CH3.
4. A compound as claimed in any preceding claim, wherein R5 is selected from – OH and -O-C1-4 alkyl.
5. A compound as claimed in claim 4, wherein R5 is selected from –OH and - OCH3.
6. A compound as claimed in any of claims 1 to 3, wherein R5 is H.
7. A compound as claimed in any preceding claim, wherein R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -CN; -NO2; -Rβ; -OH; -ORβ; -NH2; -NHRβ; -N(Rβ)2; -CHO; -CORβ; -COOH; -COORβ; and -OCORβ.
8. A compound as claimed in claim 7, wherein R3, R4, R6, R7, R8 and R9 are independently selected from H; halo; -CN; -NO2; and -NH2.
9. A compound as claimed in any preceding claim, wherein R3, R4, R6, R7, R8 and R9 are H.
10. A compound for use as claimed in any preceding claim, wherein R11 and R12 are independently selected from H, C1-2 alkyl, and benzyl substituted with –O(C1-4 alkyl).
11. A compound for use as claimed in any of claims 1 to 9, wherein R11 and R12 together form a 5- or 6-membered heterocycle optionally having one additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with a C1-2 alkyl.
12. A compound as claimed in any preceding claim, wherein Z is –NR11R12.
13. A compound as claimed in any of claims 1 to 11, wherein Z is –N(R10)-(CH2)p– NR11R12.
14. A compound as claimed in claim 13, wherein p is 2, 3, or 4.
15. A compound for use as claimed in any of claims 1 to 11, wherein Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12.
16. A compound for use as claimed in claim 15, wherein each q is independently 3 or 4.
17. A compound as claimed in claim 1, wherein the compound is selected from the following:
Figure imgf000087_0001
Figure imgf000088_0001
18. A pharmaceutically acceptable salt, multi-salt, solvate or prodrug of a 5 compound as defined in any one of claims l to 17.
19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug as defined in claim 18, and a pharmaceutically acceptable excipient.
20. A compound as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug as defined in claim 18, or a pharmaceutical composition as defined in claim 19, for use in medicine.
21. A compound as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug as defined in claim 18, or a pharmaceutical composition as defined in claim 19, for use treating or preventing a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease.
22. A compound as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug as defined in claim 18, or a pharmaceutical composition as defined in claim 19, for use treating or preventing a central nervous system disease, disorder or condition.
23. A method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined in any one of claims 1 to 17, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug as defined in claim 18, or a pharmaceutical composition as defined in claim 19, to thereby treat or prevent the disease, disorder or condition.
24. A method of treatment as claimed in claim 23, wherein the disease, disorder or condition is (i) a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease and/or (ii) a central nervous system disease, disorder or condition.
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Citations (1)

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