WO2022200540A1 - Hetero benzyl amines and their use treating central nervous system disorders - Google Patents

Hetero benzyl amines and their use treating central nervous system disorders Download PDF

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WO2022200540A1
WO2022200540A1 PCT/EP2022/057854 EP2022057854W WO2022200540A1 WO 2022200540 A1 WO2022200540 A1 WO 2022200540A1 EP 2022057854 W EP2022057854 W EP 2022057854W WO 2022200540 A1 WO2022200540 A1 WO 2022200540A1
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alkyl
compound
independently
independently selected
halo
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PCT/EP2022/057854
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French (fr)
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WO2022200540A9 (en
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Dan Florin STOICESCU
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Floratek Pharma SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to the use of chromen-4-one derivatives and to associated salts, multi-salts, solvates, prodrugs thereof.
  • the present invention relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially those related to neurotrophic factors pathways and mitochondrial activity, in particular central nervous system diseases, disorders and conditions.
  • a first aspect of the invention provides a compound of formula (1), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition: Formula (1) wherein:
  • Z is selected from: -NR n R 12 ;
  • R 1 and R 2 are selected from -OH, -O-C1-4 alkyl, -0C(0)R 3 , -OCCOINHR ⁇ , — 0C(0)N (R 13 ) 2 ;
  • 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 ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -NHR
  • a second aspect of the invention provides a compound, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, selected from Table A herein.
  • a third aspect of the invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a fourth aspect of the invention provides a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 central nervous system disease, disorder or condition.
  • a fifth aspect of the invention provides the use of a compound of the second aspect, a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition according to the third 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, salt, 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 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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.
  • 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 may be 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 1 -C 10 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 C1-C12 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, 1-butenyl, 2-butenyl, 1- pentenyl, 1-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 SND148 at a concentration of 0.5 mM increases survival of mouse primary neurons from the toxicity induced by IAA.
  • Figure 2 shows SND170 at a concentration of 10 mM increases survival of mouse primary neurons from the toxicity induced by IAA.
  • Figure 3 shows the effect of SND148 on the survival of serum deprived primary neurons.
  • Figure 4 shows the effect of SND148 on secretion of IL6 from stimulated microglia.
  • FIG. 5 shows the effect of SND148 on Ptsg2 gene expression in stimulated microglia. Gene expression data is normalised to Mi stimulated vehicle control.
  • a first aspect of the invention provides a compound of formula (1), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition:
  • Z is selected from: –NR 11 R 12 ; –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; and –N(R 10 )-(CH2)r–N(R 10 )-(CH2)r–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 , –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; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR
  • R 1 and R 2 are selected from –OH and -O-C 1-4 alkyl.
  • R 1 and R 2 are selected from –OH and -OCH3.
  • 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, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 )2; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are 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 ⁇ ; -COOH; -COOR ⁇ ; -OCOR ⁇ ; and benzyl optional
  • R 1 and R 2 are selected from –OH, and -O-C 1-4 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -NHR ⁇ ; -N(R ⁇ )2; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 1 and R 2 independently, are selected from –OH, and -O-C 1-4 alkyl.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -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 -OCH3.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -NH 2 ; -NHR ⁇ ; -N(R ⁇ ) 2 ; -CHO; -COR ⁇ ; -COOH; -COOR ⁇ ; and -OCOR ⁇ .
  • R 1 and R 2 independently, are selected from –OH, and -OCH3.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -CN; -NO 2 ; and -NH 2 .
  • R 1 and R 2 independently, are selected from –OH, and -OCH3.
  • 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, -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; -CN; -NO2; -R ⁇ ; -OH, -OR ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -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 ⁇ ; -
  • 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; -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 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; -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; -NO 2 ; -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; -CN; -NO 2 ; -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 –OCH 3 ; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 , independently, are selected from H; halo; -CN; -NO 2 ; -SH; -SO2H; and -NH2.
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are H.
  • R 1 is -O-C 1-4 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; -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 5 , R 6 , R 7 , R 8 , and R 9 are selected from H; halo; -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 5 , R 6 , R 7 , 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 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; -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 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are 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 ⁇ ; -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 11 and R 12 are independently selected from H, C 1-2 alkyl, and benzyl substituted with –O(C1-2 alkyl).
  • -NR 11 R 12 may be –NH2, -N(- CH3)(adamantly) or -N(C1-2 alkyl)(benzyl substituted with –OCH3).
  • the 5- or 6-membered heterocycle may be morpholine, piperidine, piperazine, or pyrrolidine optionally substituted with 1 or 2 C1-4 alkyl.
  • the 5- or 6-membered heterocycle may be morpholine, 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 -CH3.
  • n is an integer from 1 to 4.
  • n may be 1.
  • n may be 3 or 4.
  • n is 0.
  • Z is –NR 11 R 12 .
  • Z is –NR 11 R 12 ;
  • R 11 and R 12 are independently selected from H, C1-6 alkyl, and benzyl substituted with –O(C1-4 alkyl); or
  • Z is –NR 11 R 12 and n is 3 or 4.
  • Z is –NR 11 R 12 and n is 1.
  • Z is –NR 11 R 12 and n is 0. In one embodiment, Z is –N(R 10 )-(CH2)p–NR 11 R 12 .
  • p may be selected from 2, 3 or 4.
  • R 10 may be H, –CH 3 or –CH 2 CH 3 .
  • Z is –N(R 10 )-(CH2)p–NR 11 R 12 ;
  • R 10 is H or C1-6 alkyl; and
  • R 11 and R 12 are independently selected from H; C1-6 alkyl and benzyl substituted with –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 –N(R 10 )-(CH 2 ) p –NR 11 R 12 ; p is 1-4; and n is 1-6.
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 .
  • each q is independently selected from 2, 3 or 4.
  • R 10 may be H, –CH 3 or –CH 2 CH 3 .
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 ; and q is independently selected from 1-4.
  • 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 C 1-6 alkyl; and R 11 and R 12 are independently selected from H, C 1-6 alkyl, and benzyl substituted with –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 C 1-4 alkyl.
  • Z is –N(R 10 )-(CH2)q–N(R 10 )-(CH2)q–NR 11 R 12 and n is 0.
  • Z is –N(R 10 )-(CH 2 ) r –N(R 10 )-(CH 2 ) r –N(R 10 )–(CH 2 ) r –NR 11 R 12 .
  • each r is selected from 3 or 4.
  • R 10 may be selected from H or – CH3.
  • Z is –N(R 10 )-(CH 2 ) r –N(R 10 )-(CH 2 ) r –N(R 10 )–(CH 2 ) r –NR 11 R 12 , and n is 0.
  • each r is selected from 3 or 4.
  • R 10 may be selected from H or –CH3.
  • 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, C 1-3 alkyl, and C 2 -C 4 alkenyl.
  • each R 10 may independently be selected from H, –CH 3 , and –CH 2 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; -C1-4 alkyl; - OH; -O-C1-4 alkyl; halo; -CN; -NO2; and –COOH.
  • the compounds have a formula (2), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof: wherein R 1 and R 2 , n and Z are as defined herein.
  • R 1 and R 2 are independently selected from –OH and -O-C1-4 alkyl, e.g. – OH and –OCH 3 .
  • the compounds have a formula (2A), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof: wherein R 1 and R 2 , n and Z are as defined herein; and R x is 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 substituted with 1-3 -R ⁇ .
  • R x is selected from H; halo; -CN; -NO2; -R ⁇ ; -SH; -SR ⁇ ; -SOR ⁇ ; -SO2H; -SO2R ⁇ ; -SO2NH2; -SO2NHR ⁇ ; -SO2N(R ⁇ )2; -NH2; -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 ⁇ ; -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; -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; -NO 2 ; -CH 3 ; and -NH 2 .
  • R x is H.
  • R 1 and R 2 are independently selected from –OH and -O-C 1-4 alkyl, e.g. – OH and –OCH 3 .
  • the compounds have a formula (3), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
  • R 1 , R 2 , and Z are as defined herein.
  • R 1 and R 2 are independently selected from -OH and -O-C 1-4 alkyl, e.g. - OH and -OCH 3 .
  • the compounds have a formula (4), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof: wherein R 1 , R 2 , and Z are as defined herein.
  • R 1 and R 2 are independently selected from -OH and -O-C 1-4 alkyl, e.g. - OH and -OCH 3 .
  • the compounds have a formula (5), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
  • R 1 , R 2 , and Z are as defined herein.
  • R 1 and R 2 are independently selected from -OH and -O-C 1-4 alkyl, e.g. - OH and -OCH 3 .
  • the compounds have a formula (6), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof: wherein R 1 , R 2 , and Z are as defined herein.
  • R 1 and R 2 are independently selected from -OH and -O-C 1-4 alkyl, e.g. - OH and -OCH 3 .
  • 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 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, 2-hydroxyethanesulfonic, benzenesulfonic, toluene-p-
  • 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.
  • 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.
  • the prodrugs are pharmacologically inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect.
  • 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, ⁇ , 2 H (D), 14 N, «N, l6 0, 13 0, l8 0, ⁇ F and 12 ?I, and any radioisotope including, but not limited to U C, 14 C, 3 H (T), 13 N, «0, l8 F, 123 1, 124 1, 125 1 and 13 T.
  • the compounds, multi-salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the second aspect of the invention, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, 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 fourth aspect of the invention provides a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 fifth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition according to the third 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 sixth 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 thereof, or a pharmaceutical composition of the third 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.
  • a seventh aspect of the invention provides a method of treatment or prevention of a central nervous system disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined in the first aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, to thereby treat or prevent the disease, disorder or condition.
  • the administration is to a subject in need thereof.
  • 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. 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.
  • the disease, disorder or condition may be a disease, disorder or condition associated with neurotrophic factors pathways. For example, the disease, disorder or condition maybe 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;
  • 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;
  • neurological disorders neuropsychiatric disorders, and metabolic disorders. Examples of neurological and neuropsychiatric disorders include depression, anxiety, Alzheimer's, CNS injuries, and the like.
  • 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; (v) cyclothymic disorders with compounds disclosed herein;
  • amyotrophic lateral sclerosis 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);
  • 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;
  • 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 maybe used for treating or preventing rare CNS disorders.
  • the compounds may be used to treat or prevent Rett Syndrome, or KBG Syndrome.
  • the compounds may be 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 thereof, or a pharmaceutical composition of the third 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 nonhuman animal subject, the method comprising the steps of administering the compound, multi-salt, solvate, prodrug or pharmaceutical composition to the nonhuman 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 nonhuman 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.
  • parental including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural
  • airway aspirin, 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, salts, multi-salts, solvates or prodrugs 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, salts, 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 o.oi to 500 mg per kilogram body weight of the recipient per day.
  • the desired dose may be 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.
  • Scheme l represents the chemical synthesis of amines toa-j.
  • Flavones loa-j were prepared following the synthesis route depicted in Scheme 1.
  • the flavone scaffold was synthesized by Claisen-Schmidt condensation between substituted acetophenone 3.3 and benzaldehyde derivative 5.6, followed by cyclization with iodine to give 8.1.
  • Alcohol 8.1 was brominated with SOBr 2 /DMF/benzotriazole mixture to give 8.2 in 55-70% yield. Benzotriazole was added to the reaction mixture to avoid bromination of additional positions.
  • Flavones 11a-f were prepared by alkylation of the corresponding secondary amine (Scheme 2), using the same method as for flavones 10a-j. It is generally known how to prepare the starting bromide compound. Since the solubilities of the 11 series compounds were considerably lower than in the case of 10a-f amines, quite pure products could already be obtained by simple filtration of the reaction mixture, once the reaction was complete. Scheme 2.
  • the dark reaction mixture was diluted with 50 mL of water, cooled to 0 °C and neutralized with approximately 55 g of citric acid until pH was neutral.
  • the orange mixture was further diluted with 200 mL of water and extracted with 3 x 100 mL of DCM.
  • the last fraction had already very little UV-activity.
  • the organic layers were combined and washed with 200 mL of brine, which in turn was extracted with 2 x 50 mL of DCM.
  • Organic fractions were combined, dried with sodium sulfate, filtered through paper filter and evaporated to dryness.
  • reaction mixture was basified with 150 mL of sat. NaHCO 3 and the aqueous layer was extracted with 8 ⁇ 100 mL of DCM. The organic layers were combined and washed with 300 mL of brine. The brine layer was in turn extracted with 2 ⁇ 50 mL of DCM. The organic fractions were combined and dried with Na2SO4, filtered and evaporated to dryness.
  • Method I Reaction mixture was quenched with saturated solution of NaHCO3. Organic layer was separated and water layer was washed with ethyl acetate. Combined organic layer was dried with anhydrous Na 2 SO 4 and concentrated in vacuo. Crude product was purified using column chromatography with silica gel and a gradient of 3.5N ammonia in methanol with DCM as eluent. 2-(4-(((3-((4-aminobutyl)amino)propyl)amino)methyl)phenyl)-7-hydroxy- 8-methoxy-4H-chromen-4-one trihydrochloride (18).
  • Synthesis of SND170 & SND171 The following scheme was employed to synthesise SND170.
  • Compound 12B is SND170, i.e. where R and R’ together with the N atom form 4-methyl piperazine.
  • the following scheme was employed to synthesise SND171.
  • Compound 12E is SND171, i.e. where R is methyl, and R’ –CH 2 CH 2 -piperidine.
  • reaction mixture was diluted with 500 ml of DCM, washed with 2 x 125 ml of 10% citric acid and 200 ml of brine. Organic layer was then dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane as the eluent system.1-(2-Hydroxy-3,4- bis(methoxymethoxy)phenyl)ethan-1-one (12.617 g, 49 mmol, 84%, 99% Purity) was obtained as a pale yellow oil.
  • reaction mixture was slowly allowed to warm to room temperature and it was stirred at room temperature for 16 h, before it was cooled with an ice-bath and quenched with 20 mL of sat. NaHCO 3 .
  • the resultant suspension was extracted with 8 x 25 mL of DCM. Organic layers were combined and washed with 75 mL of brine, which in turn was extracted with 3 x 75 mL of DCM.
  • N,N- dimethylformamide (0.9 g, 0.9 mL, 3 Eq, 0.01 mol) was then added under nitrogen flow, followed by sulfurous dibromide (1.2 g, 0.45 mL, 1.3 Eq, 5.8 mmol). After a few minutes, the cooling bath was removed and the orange solution was stirred at 20 °C. Reaction was followed by LC-MS. After 105 min, the reaction mixture was cooled with ice-bath and 50 ml of sat. NaHCO3 was added. The mixture was then extracted with 3 ⁇ 100 ml of DCM, until last fraction had very little UV-activity.
  • CMF-HBSS Calcium and Magnesium free Hanks Balanced Salt Solution
  • the cortex was isolated, chopped with a sterile razor blade in Chop solution (Hibernate-E without Calcium containing 2% B-27) and digested in 2 mg/ml papain (Worthington) dissolved in Hibernate-E without Calcium for 30 minutes ( ⁇ 5 min) at 30°C. Cortices were triturated for 10-15 times with a fire-polished silanized Pasteur pipette in Hibernate-E without Calcium containing 2% B-27, 0.01% DNasel, 1 mg/ml BSA, and 1 mg/ml Ovomucoid Inhibitor.
  • Rat neonate brains (P0-P2) were dissected and cerebellum and meninges removed. The brains were then dissociated via an enzyme digestion for up to 1 hour after which digestion was stopped by adding culture medium (Dulbecco’s modified eagle medium (DMEM), 10 % Foetal Bovine serum (FBS), 1 % Penicillin - Streptomycin). Cells were then centrifuged at 300 x g for 5 minutes; supernatant was removed, and the cells were homogenized by trituration with 18- and 23-gauge needles. Cell suspension was then added to individual T75 flasks at approximately 1.5 - 2 cortices per flask.
  • Cells were incubated for 10 days at 37°C, 7.5 % CO2 with media changes occurring every 2 - 3 days.
  • loosely adherent microglia were isolated by shaking the flasks at 250 RPM for 1 hour at 37°C.
  • Cells were collected and seeded in a 96-well flat bottom tissue culture plate at a density of 25,000 cells/well in 200 pL DMEM media supplemented with 10 % FBS, 1 % Pen/Strep and 12.5 mM HEPES.
  • Microglia were then incubated in a humidified environment for 24 hours at 37°C, 7.5 % C0 2 prior to any further treatment or experimentation.
  • Viability of cultures was determined by the MTT assay using a plate-reader (570 nm) or by CellTiter-Glo® 2.0 (Promega) using a luminescence plate reader (EnVision).
  • the MTT assay allows the measurement of the mitochondrial dehydrogenase activity, which reduces yellow MTT to dark blue formazan crystals. Since this reaction was catalyzed in living cells this assay was used for the determination of cell viability.
  • MTT solution was added to each well in a final concentration of 0.5 mg/ml. After 2 h the MTT containing medium was aspirated. Cells were lysed in 3% SDS and the formazan crystals were dissolved in isopropanol/HCl.
  • Optical density was measured with a plate-reader at wavelength 570 nm.
  • Cell survival rate was expressed as optical density (OD). Values were calculated as percent of control values (vehicle control, lesion control or maximal effect of the positive control).
  • 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. Luminescence 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.
  • cDNA was synthesised by reverse transcription using the iScript Advanced cDNA Synthesis kit (Bio-Rad, #1706691, Lot: 64355629) and the VeritiTM 96-Well Fast Thermal Cycler (Applied Biosystems, #4375305).
  • Components of qPCR master mix were mixed on ice and samples run on the QuantStudio 5 Real-Time PCR system (Thermo) with the standard thermal cycling mode consisting of a 50°C step for 2 minutes followed by an initial heat activation step of 95°C for 10 minutes, followed by 50 cycles of 95°C for 15 seconds (denaturation) and 6o°C for 60 seconds (annealing and extension).
  • Quantification of DNA was based on increased fluorescence in each reaction, expressed in terms of threshold cycle (C T ) values generated by the thermal cycler during the annealing and extension step. Each gene was run in triplicate for each sample where possible.
  • C T threshold cycle
  • the aim of this study was to test the neuroprotective effects of SND derivatives in an in vitro ischemia model. Ischemia was induced in mouse primary cortical neurons using a brief treatment with iodoacetic acid (IAA). Cell death was monitored using the MTT assay.
  • IAA iodoacetic acid
  • DIVi cortical neurons were seeded on poly-D-lysine pre- coated 96-well plates at a density of 3*io L 4 cells per well. Cells were cultured at 37°C; 95% humidity and 5% C0 2 until DIV9 with a half medium exchange on DIV4-6.
  • Figure 2 shows SND170 at a concentration of 10 mM increases survival of mouse primary neurons from the toxicity induced by IAA. Data are shown as % of vehicle control (VC) and displayed as bar graph with mean+SD and individual data points as dots. One-way ANOVA followed by Dunnett’s multiple comparison test.
  • SND170 presented protective effects both during the lesion and in the reperfusion phase.
  • Table 1 - 2 Neuroprotective activity of various SND derivatives against an in vitro model of ischemia induced by IAA.
  • the numbers represent mean % viability versus cells treated only with vehicle control (no IAA).
  • the lesion control is depicted as o mM and the numbers represent the mean % viability of IAA treated cells vs 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 a mouse hippocampal cell line.
  • PD Parkinson Disease
  • MPP + i-methyl-4-phenylpyridinium
  • 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 or vehicle control were added. Following 30 min incubation, Glutamate (Glu) 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).
  • DIV1 cortical neurons were seeded on poly-D-lysine pre- coated 96-well plates at a density of 3*10 ⁇ 4 cells per well in complete medium (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% Penicillin-Streptomycin). Cells were cultured at 37°C; 95% humidity and 5% CO 2 until DIV9 with a half medium exchange on DIV4-6. On DIV8, a full medium change was carried out and B-27 free medium was added. Thereafter cells were treated with test compounds in comparison with BDNF at 100 ng/ml. After 26 h cells were subject to MTT assay.
  • Microglia are resident macrophage-like cells in the brain and have been suggested to play a major role in host defense and tissue repair in the central nervous system (CNS). Under pathological conditions, activated microglia release pro-inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen species (ROS) and pro-inflammatory cytokines [Loane DJ and Byrnes KR: Role of microglia in neurotrauma. Neurotherapeutics.7:366–377.2010].
  • NO nitric oxide
  • PGE2 prostaglandin E2
  • ROS reactive oxygen species
  • ELISA plates were immediately read at 450 nm using an Infinite F50 (Tecan) absorbance reader and MagellanTM reader control and data analysis software.
  • Infinite F50 Tecan
  • MagellanTM reader control and data analysis software For ELISA data analysis, the four-parameter logistic regression model was used to fit standard curves (R squared value was > 0.991 for all standards) and interpolate cytokine concentrations (pg/mL). Interpolations were performed using GraphPad Prism (v8.4.2), concentrations were corrected for the sample dilution factor. Treated groups were compared against the pooled and averaged vehicle control.
  • Microglia pre-treated with SND148(C) exhibited reduced IL-6 secretion, reaching approximately 1.8-fold decrease at the highest concentrations compared to vehicle control (Figure 4).
  • Reduced relative expression of Ptgs2 was observed across multiple tested concentrations (Figure 5).
  • Figure 4 shows the effect of SND148 on secretion of IL6 from stimulated microglia.
  • Figure 5 shows the effect of SND148 on Ptsg2 gene expression in stimulated microglia.
  • Gene expression data is normalised to M1 stimulated vehicle control. Example 6.
  • Metal chelating properties of SND derivatives 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, Florêncio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res.2002 Nov;36(11):1199-208] Experimental 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 ⁇ M and added to 50 ⁇ M compound or blank wells; wavelength between 200 – 600 nm was recorded. Morin was used as a positive control. Results
  • 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;
  • OxiSelectTM 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.
  • 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. 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.
  • 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 , R 4 , and R 5 independently, are selected from –OH, -O-C1-4 alkyl, - OC(O)R13, -OC(O)NHR 13 , –OC(O)N(R 13 )2; or 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 ⁇ )
  • 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 -OCH3, or from H; halo; -CN; -NO2; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -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 -OCH 3 . 4.
  • R 1 , R 2 , R 4 , and R 5 independently, are selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; and -NH2; wherein at least two of R 1 , R 2 , R 4 , and R 5 are independently selected from –OH, and -OCH3. 5.
  • R 3 , R 6 , R 7 , R 8 , and R 9 are independently selected from H; halo; -CN; -NO 2 ; -R ⁇ ; -OH; -OR ⁇ ; -NH2; -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.
  • 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 ⁇ ; 2 -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 1 , R 2 and R 5 independently, 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; -CN; -NO2; -SH; -SO2H; and -NH2.
  • 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.
  • a pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, 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 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, or a pharmaceutical composition as defined in clause 23, to thereby treat or prevent the disease, disorder or condition.

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Abstract

The present invention relates to the use of chromen-4-one derivatives, and associated salts, multi-salts, solvates, prodrugs thereof, for 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 in the treatment and prevention of central nervous system diseases/disorders.

Description

Hetero Benzyl Amines And Their Use Treating Central Nervous System Disorders
FIELD OF THE INVENTION The present invention relates to the use of chromen-4-one derivatives and to associated salts, multi-salts, solvates, prodrugs thereof. The present invention relates to the use of such compounds in the treatment and prevention of medical disorders and diseases, most especially those related to neurotrophic factors pathways and mitochondrial activity, in particular central nervous system diseases, disorders and conditions.
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), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition:
Figure imgf000002_0001
Formula (1) wherein:
Z is selected from: -NRnR12;
-N(R10)-(CH2)P-NRUR12; -N(R10)-(CH2)q-N(R10)-(CH2)q-NR11R12; and
-N (R10)-(CH2)r-N (R10)-(CH2)r-N (R10)-(CH2)r-NRuR12; R1 and R2 , independently, are selected from -OH, -O-C1-4 alkyl, -0C(0)R 3, -OCCOINHR^, — 0C(0)N (R13)2; 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; 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 = 0-6; each p is independently an integer selected from 1 to 4; each q is independently an integer selected from 1 to 4; and each r is independently an integer selected from 1 to 4; wherein, when n=0 and Z is –NR11R12; 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. A second aspect of the invention provides a compound, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, selected from Table A herein. A third aspect of the invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient. A fourth aspect of the invention provides a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 central nervous system disease, disorder or condition. A fifth aspect of the invention provides the use of a compound of the second aspect, a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition according to the third 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, salt, 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 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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. 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 may be 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 C1-C10 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, 1-butenyl, 2-butenyl, 1- pentenyl, 1-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:
Figure imgf000009_0001
–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’, 4th edition, T.W. Greene and P.G.M Wuts, Wiley-Interscience. DESCRIPTION OF FIGURES
Figure l shows SND148 at a concentration of 0.5 mM increases survival of mouse primary neurons from the toxicity induced by IAA. Figure 2 shows SND170 at a concentration of 10 mM increases survival of mouse primary neurons from the toxicity induced by IAA.
Figure 3 shows the effect of SND148 on the survival of serum deprived primary neurons.
Figure 4 shows the effect of SND148 on secretion of IL6 from stimulated microglia.
Figure 5 shows the effect of SND148 on Ptsg2 gene expression in stimulated microglia. Gene expression data is normalised to Mi stimulated vehicle control.
PET ATT /ED DESCRIPTION OF THE INVENTION
Figure imgf000010_0001
A first aspect of the invention provides a compound of formula (1), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition:
Figure imgf000011_0001
Formula (1) wherein: Z is selected from: –NR11R12; –N(R10)-(CH2)p–NR11R12; –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12; and –N(R10)-(CH2)r–N(R10)-(CH2)r–N(R10)–(CH2)r–NR11R12; R1 and R2 , independently, are 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; -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 = 0-6; each p is independently an integer selected from 1 to 4; each q is independently an integer selected from 1 to 4; and each r is independently an integer selected from 1 to 4; wherein, when n=0 and Z is –NR11R12; 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. 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, R3, R4, R5, 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, –OC(O)N(R13)2; and 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; -OCORβ; and benzyl optionally substituted with 1-3 -Rβ. In one embodiment, R1 and R2, independently, are selected from –OH, and -O-C1-4 alkyl. For example, R3, R4, R5, 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. In one embodiment, R1 and R2, independently, are selected from –OH, and -O-C1-4 alkyl. For example, R3, R4, R5, R6, R7, R8, and R9, are independently selected from H; halo; -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. For example, R3, R4, R5, R6, R7, R8, and R9, are independently selected from H; halo; -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. For example, R3, R4, R5, 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. For example, R3, R4, R5, 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; -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; -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; and 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, 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. 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; -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 OH; 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. 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, 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; wherein when n=0 and Z is –NR11R12; R11 and R12 are independently selected from H, C1- 6 alkyl, C3-10 cycloalkyl, 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, -N(- CH3)(adamantly) or -N(C1-2 alkyl)(benzyl substituted with –OCH3). When R11 and R12 together form a 5- or 6-membered heterocycle as described above, it may be 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, 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 an integer from 1 to 4. For example, n may be 1. For example, n may be 3 or 4. In one embodiment, n is 0. 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; wherein when n = 0, R11 and R12 are independently selected from H, C1-6 alkyl, and benzyl substituted with –O(C1-4 alkyl). In one embodiment, Z is –NR11R12 and n is 3 or 4. In one embodiment, Z is –NR11R12 and n is 1. In one embodiment, Z is –NR11R12 and n is 0. In one embodiment, Z is –N(R10)-(CH2)p–NR11R12. For example, p may be selected from 2, 3 or 4. For example, R10 may be H, –CH3 or –CH2CH3. In one embodiment, Z is –N(R10)-(CH2)p–NR11R12; R10 is H or C1-6 alkyl; and 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; p is 1-4; and n is 1-6. For example, p is 2-4, for example 2 or 3; and n is 2-5, for example 3 or 4. In one embodiment, Z is –N(R10)-(CH2)q–N(R10)-(CH2)q–NR11R12. For example, each q is independently selected from 2, 3 or 4. For example, R10 may be H, –CH3 or –CH2CH3. 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 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)q–N(R10)-(CH2)q–NR11R12 and n is 0. In one embodiment, Z is –N(R10)-(CH2)r–N(R10)-(CH2)r–N(R10)–(CH2)r–NR11R12. For example, each r is selected from 3 or 4. For example, R10 may be selected from H or – CH3. In one embodiment, Z is –N(R10)-(CH2)r–N(R10)-(CH2)r–N(R10)–(CH2)r–NR11R12, and n is 0. For example, each r is selected from 3 or 4. For example, R10 may be selected from H or –CH3. 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, –CH3, and –CH2CH3. 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, the compounds have a formula (2), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000017_0001
wherein R1 and R2, 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. In one embodiment, the compounds have a formula (2A), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000018_0001
wherein R1 and R2, 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. In one embodiment, the compounds have a formula (3), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000019_0001
wherein R1, R2, 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.
In one embodiment, the compounds have a formula (4), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000019_0002
wherein R1, R2, 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.
In one embodiment, the compounds have a formula (5), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000020_0001
wherein R1, R2, 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.
In one embodiment, the compounds have a formula (6), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:
Figure imgf000020_0002
wherein R1, R2, 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.
A second aspect of the invention provides a compound selected from Table A, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof.
Table A
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
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, Ή, 2H (D), 14N, «N, l60, 130, l80, ^F and 12?I, and any radioisotope including, but not limited to UC, 14C, 3H (T), 13N, «0, l8F, 1231, 1241, 1251 and 13T.
The compounds, multi-salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form.
A third aspect of the invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, 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 maybe 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 fourth aspect of the invention provides a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 fifth aspect of the invention provides the use of a compound of the first or second aspect, a pharmaceutically effective salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition according to the third 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 sixth 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 thereof, or a pharmaceutical composition of the third 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.
A seventh aspect of the invention provides a method of treatment or prevention of a central nervous system disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined in the first aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, to thereby treat or prevent the disease, disorder or condition. Typically the administration is to a subject in need thereof.
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. The disease, disorder or condition may be a disease, disorder or condition associated with neurotrophic factors pathways. For example, the disease, disorder or condition maybe associated with BDNF pathways
In one embodiment, 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, the disease, disorder or condition is related to oxidative stress and/ or mitochondrial DNA mutation.
In one embodiment, 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 maybe 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 may be 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third 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 salt, multi-salt, solvate or prodrug thereof, or a pharmaceutical composition of the third aspect of the invention, to modulate mitochondrial function.
In one embodiment of the ninth aspect, modulating mitochondrial function includes: modulating Ca influx, energy supply, control of apoptosis and/or ROS production. In one embodiment of the ninth aspect , 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 thereof, or a pharmaceutical composition of the third 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 nonhuman animal subject, the method comprising the steps of administering the compound, multi-salt, solvate, prodrug or pharmaceutical composition to the nonhuman 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 nonhuman 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, salts, multi-salts, solvates or prodrugs 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, salts, 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 o.oi to 500 mg per kilogram body weight of the recipient per day. The desired dose may be 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
General Synthesis of Compounds
Structure of the SND derivatives and the codes used in the chemical synthesis
Figure imgf000035_0001
Scheme l represents the chemical synthesis of amines toa-j. Scheme 1.
Figure imgf000035_0002
Flavones loa-j were prepared following the synthesis route depicted in Scheme 1. The flavone scaffold was synthesized by Claisen-Schmidt condensation between substituted acetophenone 3.3 and benzaldehyde derivative 5.6, followed by cyclization with iodine to give 8.1. Alcohol 8.1 was brominated with SOBr2/DMF/benzotriazole mixture to give 8.2 in 55-70% yield. Benzotriazole was added to the reaction mixture to avoid bromination of additional positions.
A robust method using Hiinig's base and acetonitrile was chosen for the synthesis of tertiary amines from corresponding secondary amines and alkyl halides [ Arkivoc , 2005, 6, 287-292].
This method has previously proven to yield pure product in good to excellent yields. Originally this method used 1.1 eq of alkyl halide, but since the bromide 8.2 was the limiting substrate, considerably more equivalents of the secondary amines were used. At least 5 eq of the secondary amine was used, and in the case of diethylamine in total 30 eq was used and even that was not enough to drive the reaction to completion. At first, the reaction mixture was too dilute, prolonging the reaction time to more than 24 h. In order to minimize chances of quarternalization of the amine, the halide 8.2 was added to the solution of DiPEA and the corresponding secondary amine, in that case there was always an excess of amine relative to the halide. Since the starting material was not soluble in acetonitrile, a slurry of 8.2 was added to the amines, which quickly dissolved in the mixture of amines and in some cases the product started to precipitate out.
Figure imgf000036_0001
Flavones 11a-f were prepared by alkylation of the corresponding secondary amine (Scheme 2), using the same method as for flavones 10a-j. It is generally known how to prepare the starting bromide compound. Since the solubilities of the 11 series compounds were considerably lower than in the case of 10a-f amines, quite pure products could already be obtained by simple filtration of the reaction mixture, once the reaction was complete. Scheme 2.
Figure imgf000036_0002
(E)-1-(2-Hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)-3-(4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)prop-2-en-1-one (7.4). Sodium hydroxide (35 g, 55 Eq, 0.88 mol) in water (35 mL) was added at room temperature to a solution of 1-(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)ethan-1-one (3.616 g, 1 Eq, 15.98 mmol) and 4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butyl)benzaldehyde (5.048 g, 1.204 Eq, 19.24 mmol) in 1,4-dioxane (75 mL) was added. The reaction mixture was stirred vigorously for 22 hours at room temperature. The dark reaction mixture was diluted with 50 mL of water, cooled to 0 °C and neutralized with approximately 55 g of citric acid until pH was neutral. The orange mixture was further diluted with 200 mL of water and extracted with 3 x 100 mL of DCM. The last fraction had already very little UV-activity. The organic layers were combined and washed with 200 mL of brine, which in turn was extracted with 2 x 50 mL of DCM. Organic fractions were combined, dried with sodium sulfate, filtered through paper filter and evaporated to dryness. Resultant 8.952 g of orange oil was purified by normal phase flash-chromatography using ethyl acetate/heptane as eluent.6.489 g of (E)-1-(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)-3-(4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butyl)phenyl)prop-2-en-1-one (6.489 g, 13 mmol, 82% yield, 95% purity) as an orange oil was obtained. 7-Hydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4-one (8.1). A stirred solution of (E)-1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)- 3-(4-(4-((tetrahydro-2H-pyran-2-yl)oxy)butyl)phenyl)prop-2-en-1-one (5.6 g, 1 Eq, 12 mmol) and iodine (0.439 g, 0.15 Eq, 1.73 mmol) in DMSO (100 mL) was heated to 120 °C for 17 hours. The dark mixture was allowed to cool to room temperature and poured into 700 mL of water. The resultant beige suspension was extracted with 6 × 200 mL of EtOAc. The combined organic fractions were washed with 400 mL of 10% Na2S2O3, which in turn was extracted with 50 mL of EtOAc. Organic layers were combined and washed with 400 mL of water, the aqueous layer was further extracted with 50 mL of EtOAc. The combined organic fractions were washed with 400 mL of brine, dried with Na2SO4, filtered through paper filter and evaporated to dryness until the crude product solidified.7-Hydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4-one (4.1481 g, 9.7 mmol, 82% yield, 80% purity) was obtained as a brown solid and used in the next step without further purification. 2-(4-(4-Bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (8.2).7-Hydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4-one (4.148 g, 1.0 Eq, 12.19 mmol) and DCM (150 mL) were transferred to a dried 250 mL three-neck round-bottom flask under nitrogen flow. The resultant suspension was cooled to 0 °C, before 1H-benzo[d][1,2,3]triazole (1.894 g, 1.305 Eq, 15.90 mmol) and N,N-dimethylformamide (0.20 g, 0.21 mL, 0.22 Eq, 2.7 mmol) was added under nitrogen flow. After that, sulfurous dibromide (2.9 g, 1.1 mL, 1.2 Eq, 14 mmol) was added drop-wise in 2 min to the cooled suspension. The mixture was stirred for another 3 min at 0 °C before allowing it to warm to room temperature. The mixture was stirred at 20 °C for 16 hours, before a sample from the reaction mixture was treated with EtOAc and sat. NaHCO3 and analyzed by LC-MS. If very little or no starting material could be seen, the reaction mixture was basified with 150 mL of sat. NaHCO3 and the aqueous layer was extracted with 8 × 100 mL of DCM. The organic layers were combined and washed with 300 mL of brine. The brine layer was in turn extracted with 2 × 50 mL of DCM. The organic fractions were combined and dried with Na2SO4, filtered and evaporated to dryness. The resultant 6.725 g of crude material was purified by normal phase flash-chromatography using DCM:MeOH eluent system to give 2-(4- (4-bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (2.891 g, 6.7 mmol, 55% yield, 93% purity) as a grey-brown powder. General procedure for alkylation of secondary amines. A slurry of 2-(4-(4-bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (8.2) (1 Eq) in MeCN was added under nitrogen flow to a stirring solution of DiPEA (1.5 Eq) and secondary amine (5-10 Eq) in MeCN in a dried round-bottom flask. The mixture was allowed to stir at room temperature for 16 h or more until no starting material was left, based on TLC or LC-MS. The mixture was then evaporated to dryness, dissolved in DCM and washed with brine:water 1:1 mixture. The aqueous layer was extracted with DCM until no UV-activity could be seen on a TLC plate. The organic layers were combined, dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash-chromatography and dried in vacuum. Alternatively, for the less soluble series 11 compounds, filtration of the reaction mixture was used instead of an aqueous work-up and this gave mostly pure products. 7-Hydroxy-8-methoxy-2-(4-(4-(piperidin-1-yl)butyl)phenyl)-4H-chromen- 4-one (10e/ SND148). 2-(4-(4-Bromobutyl)phenyl)-7-hydroxy-8-methoxy-4H-chromen-4-one (489.4 mg, 1 Eq, 1.214 mmol) was reacted with piperidine (517 mg, 600 µL, 5.01 Eq, 6.07 mmol) according to the general procedure. Purification by normal phase flash- chromatography, using DCM:NH3 in MeOH eluent system, yielding after removal of traces of water azeotropically by toluene and drying in vacuum 7-hydroxy-8-methoxy- 2-(4-(4-(piperidin-1-yl)butyl)phenyl)-4H-chromen-4-one (0.378 g, 0.90 mmol, 74% yield, 97% purity) as a yellow solid. Synthesis of SND402
Figure imgf000039_0001
To a solution of Core H (300 mg, 551.13 umol, 1.00 eq), Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq), RuPhos (51.44 mg, 110.23 umol, 0.20 eq), Pd2(dba)3 (100.94 mg, 110.23 umol, 0.20 eq) in DMF (3 mL) was added Compound 2 (109.28 mg, 661.36 umol, 1.20 eq) and the mixture was degassed and purged with N2 for 3 times and stirred at 100 °C for 16 h under N2. LCMS (EW30065-169-P1A) showed Core H was consumed and desired mass peak was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. It was without purification. Compound 3 (320 mg, crude) was obtained as a yellow oil. LCMS: MS (ESI) Retention time: 1.213 min, (M+1) + = 582.4, EW30065-169-P1A.
Figure imgf000039_0002
A solution of Compound 3 (360 mg, 618.92 umol, 1.00 eq) in AcOH (3 mL) and HCl (0.3 mL) was stirred at 80 °C for 1 hr. LCMS (EW30065-172-P1A1) showed Compound 3 was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 × 25 mm × 5 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 42%-78%, 9 min). SND402 (60 mg, 143.73 umol, 23.22% yield, 100% purity) was obtained as a yellow solid, which was confirmed by LCMS (EW30065 -172-P1X) , HNMR ( EW30065-172-P1C). LCMS: MS (ESI) Retention time: 0.942 min, (M+1) + =418.1, EW30065-172-P1A1. LCMS: MS (ESI) Retention time: 2.133 min, (M+1) + =418.1, EW30065-172-P1X. 1H NMR (400 MHz, DMSO-d6) δ = 7.91-7.89 (d, J = 8.8 Hz, 2H), 7.34-7.32 (d, J = 8.4 Hz, 1H), 7.28-7.21 (m, 1H), 7.06-7.00 (d, J = 8.4 Hz, 1H), 6.97-6.90 (m, 1H), 6.90-6.81 (m, 2H), 6.73-6.70 ( d, J = 8.4 Hz, 2H), 6.58 (s, 1H), 4.55 (s, 2H), 3.86 (s, 3H), 3.58- 3.52 (m, 2H), 1.20-1.15 (t, J = 6.8 Hz, 3H). The HCl salt of SND402 absorbs moisture easily and turns to oil at room temperature, so we could not test the melting point. TLC (SiO2, DCM/MeOH=10/1, Rf=0.7) Synthesis of SND405
Figure imgf000040_0001
To a solution of Core H (300.00 mg, 551.13 μmol, 1.00 eq), RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (3.00 mL), then added Compound 7l (86.12 mg, 551.13 μmol, 1.00 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr. LCMS (EW30189- 170-P1A) showed Core H consumed. Several new peaks were shown on LCMS and 39.952% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (300 mg, 462.40 μmol, 83.90% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.924min (M+H)+ = 573.4, 5-95AB_R_220&254.lcm
Figure imgf000040_0002
To a solution of Compound 2 (300 mg, 523.84 μmol, 1。00 eq) in AcOH (3 mL) and HCl (0.30 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189- 177-P1A) showed Compound 2 was consumed completely and 37.914% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18; 75 × 30 mm × 3 um; mobile phase: [water (HCl) -ACN]; B%: 14%-34%, 6 min). SND405 (90 mg, 202.27 μmol, 38.61% yield, 100% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-177-P1A) and LCMS (EW30189-177-P1L). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.1) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.748min (M+H)+ = 409.3, EW30189-177-P1A LCMS: MS (ESI) Retention time: 1.414min (M+H)+ = 409.2, EW30189-177-P1L 1H NMR (400 MHz, DMSO-d6) δ = 10.53 (br s, 1H), 7.97-7.95 (d, J = 8.8 Hz, 2H), 7.36-7.34 (d, J = 8.8 Hz, 1H), 6.96-6.94 (d, J = 8.4 Hz, 1H), 6.89-6.87 (d, J = 8.8 Hz, 2H), 6.66 (s, 1H), 3.52-3.48 (t, J = 6.8 Hz, 2H), 3.39-3.36 (d, J = 11.2 Hz, 2H), 3.01 (m, 5H), 2.85-2.78 (m, 2H), 2.04-2.00 (m, 2H), 1.81-1.66 (m, 5H), 1.43-1.29 (m, 1H). Synthesis of SND406
Figure imgf000041_0001
To a solution of Core H (300 mg, 551.13 μmol, 1.00 eq), RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (3.00 mL), then added Compound 7o (125.32 mg, 551.13 μmol, 1 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr under N2. LCMS (EW30189-179-P1A) showed Core H was consumed. Several new peaks were shown on LCMS and 46.993% of desired compound was detected. Without work-up. Without purification. It was a text reaction, it was discarded. Compound 2 (300 mg, 465.97 μmol, 84.55% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.870min (M+H)+ = 644.5, 5-95AB_R_220&254.lcm
Figure imgf000042_0001
To a solution of Compound 2 (300 mg, 465.97 μmol, 1.00 eq) in AcOH (3.00 mL) and HCl (0.30 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189- 181-P1A) showed Compound 2 was consumed completely and 45.172% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18; 75 × 30 mm × 3 um; mobile phase: [water (HCl) -ACN]; B%: 1%-30%, 6 min). SND406 (195 mg, 376.34 μmol, 80.76% yield, 99.6% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-181-P1A) and LCMS (EW30189-181-P1R). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.1) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.641min (M+H)+ = 480.3 EW30189-181-P1A LCMS: MS (ESI) Retention time: 1.298min (M+H)+ = 480.3, EW30189-181-P1R 1H NMR (400 MHz, DMSO-d6) δ = 11.07-10.76 (m, 2H), 7.98-7.96 (d, J = 8.4 Hz, 2H), 7.36-7.34 (m, 1H), 6.96-6.89 (m, 3H), 6.66 (s, 1H), 3.65 (s, 2H), 3.52-3.46 (m, 6H), 3.27-3.18 (m, 1H), 3.10 (m, 1H), 3.03 (s, 3H), 2.92 (m, 2H), 2.80 (d, J = 2.8 Hz, 3H), 1.80-1.72 (m, 7H), 1.59-1.58 (m, 2H), 1.37 (m, 1H). Synthesis of SND411
Figure imgf000042_0002
To a solution of Compound 7g (93.85 mg, 551.13 μmol, 1.00 eq) and Core H (300 mg, 551.13 μmol, 1.00 eq) in DMF (3 mL) was added RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) and Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 12 hr under N2. LCMS (EW30189-236-P1A) showed Core H was consumed completely and 56.665% of desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (300 mg, 511.32 μmol, 92.78% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.855min (M+H)+ = 587.4, 5-95AB_R_220&254.lcm
Figure imgf000043_0001
To a solution of Compound 2 (300 mg, 511.32 μmol, 1 eq) in AcOH (3 mL) and HCl (0.3 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189-240- P1B) showed Compound 2 was consumed completely and 54.135% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition). SND411 (160 mg, 345.46 μmol, 67.56% yield, 99.1% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-240-P1A) and LCMS (EW30189-240-P1L). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.4) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.752min (M+H)+ = 423.3, EW30189-240-P1B LCMS: MS (ESI) Retention time: 1.472min (M+H)+ = 423.2, EW30189-240-P1L 1H NMR (400 MHz, DMSO-d6) δ = 10.14 (br s, 1H), 7.98-7.96 (d, J = 8.8 Hz, 2H), 7.37-7.35 (d, J = 8.8 Hz, 1H), 6.95-6.93 (d, J = 8.4 Hz, 1H), 6.88-6.85 (d, J = 8.8 Hz, 2H), 6.61 (s, 1H), 3.49-3.46 (t, J = 6.8 Hz, 2H), 3.40-3.37 (d, J = 11.6 Hz, 2H), 3.03- 3.00 (m, 5H), 2.82-2.79 (m, 2H), 1.77-1.68 (m, 7H), 1.59-1.55 (m, 2H), 1.43-1.33 (m, 1H). Synthesis of SND412
Figure imgf000044_0001
To a solution of Core H (300.00 mg, 551.13 μmol, 1.00 eq), RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (3 mL), then added Compound 7n (133.05 mg, 551.13 μmol, 1.00 eq) at 25 °C, The mixture was stirred at 100 °C for 12 hr under N2. LCMS (EW30189-232-P1A) showed Core H was consumed completely and 36.767% of desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (300 mg, 456.04 μmol, 82.75% yield) was obtained as a red oil LCMS: MS (ESI) Retention time: 0.849min (M+H)+ = 658.2, 5-
Figure imgf000044_0002
To a solution of Compound 2 (300 mg, 456.04 μmol, 1 eq) in AcOH (3 mL) and HCl (0.3 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189-233- P1A) showed Compound 2 was consumed completely and 34% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18; 75 × 30 mm × 3 um; mobile phase: [water (HCl) -ACN]; B%: 10%-30%, 6 min). SND412 (40 mg, 75.70 μmol, 16.60% yield, 93.42% purity) was obtained as a yellow oil. Which was determined by HNMR (EW30189-233-P1A) and LCMS (EW30189-233- P1L). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.2) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.728min (M+H)+ = 494.4, EW30189-233-P1A LCMS: MS (ESI) Retention time: 1.341min (M+H)+ = 494.4, EW30189-233-P1L 1H NMR (400 MHz, DMSO-d6) δ = 10.83-10.56 (m, 2H), 7.97-7.95 (d, J = 8.8 Hz, 2H), 7.36-7.34 (d, J = 8.8 Hz, 1H), 6.95-6.93 (d, J = 8.4 Hz, 1H), 6.88-6.86 (d, J = 8.4 Hz, 2H), 6.65 (s, 1H), 3.47-3.46 (m, 2H), 3.42-3.39 (m, 2H), 3.10-3.06 (m, 6H), 3.03 (s, 3H), 2.88-2.78 (m, 2H), 2.73-2.70 (d, J = 4.4 Hz, 3H), 2.18-2.16 (m, 2H), 1.81-1.73 (m, 7H), 1.59 (m, 2H), 1.39 (m, 1H).
Figure imgf000045_0001
To a solution of Core H (300 mg, 551.13 μmol, 1.00 eq), RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (3.00 mL), then added Compound 7p (136.90 mg, 551.13 μmol, 1.00 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr under N2. LCMS (EW30189-221-P1B) showed Core H consumed. Several new peaks were shown on LCMS and 83.928% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (300 mg, 449.91 μmol, 81.63% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.878min (M+H)+ = 667.4, 5-95AB_R_220&254.lcm
Figure imgf000045_0002
To a solution of Compound 2 (300 mg, 449.91 μmol, 1.00 eq) in AcOH (4 mL) and HCl (0.4 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189 - 227-P1B) showed Compound 2 was consumed completely and 51.59% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18; 75 × 30 mm × 3 um; mobile phase: [water (HCl) -ACN]; B%: 24%-44%, 6 min). SND413 (100 mg, 175.67 μmol, 39.05% yield, 94.697% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-227-P1C) and LCMS (EW30189-227-P1H). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.2) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.692 min (M+H)+ =503.2 EW30189-227-P1B LCMS: MS (ESI) Retention time: 1.663min (M+H)+ = 503.2, EW30189-227-P1H 1H NMR (400 MHz, DMSO-d6) δ = 9.84 (br s, 1H), 7.98-7.96 (d, J = 8.8 Hz, 2H), 7.62 (m, 1H), 7.57 (m, 1H), 7.36-7.34 (d, J = 8.8 Hz, 1H), 7.11-7.09 (d, J = 8.4 Hz, 1H), 7.01- 6.87 (m, 4H), 6.67 (s, 1H), 4.23 (m, 2H), 3.82 (s, 3H), 3.47-3.44 (m, 2H), 3.01 (s, 7H), 1.78-1.74 (m, 2H), 1.54 (m, 2H), 1.28-1.25 (t, J = 7.2 Hz, 3H).
Figure imgf000046_0001
To a solution of Core H (300 mg, 551.13 μmol, 1.00 eq), RuPhos (51.44 mg, 110.23 μmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.20 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (5 mL), then added Compound 7s (292.51 mg, 551.13 μmol, 1.00 eq) at 25 °C, the mixture was strried at 100 °C for 16 hr. LCMS (EW30189- 211-P1A) showed Core H was consumed. Several new peaks were shown on LCMS and 47.670% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (500 mg, 527.89 μmol, 95.78% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 1.269min (M+H)+ = 947.8, 5-95AB_R_220&254.lcm
Figure imgf000047_0001
To a solution of Compound 2 (500 mg, 527.89 μmol, 1.00 eq) in AcOH (5 mL) and HCl (0.50 mL) at 25 °C. The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189 - 217-P1A1) showed Compound 2 was consumed completely and 49.604% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18; 75 × 30 mm × 3 um; mobile phase: [water (HCl)-ACN]; B%: 16%-36%, 6 min). SND415 (170 mg, 327.51 μmol, 62.04% yield, 100% purity, HCl) was obtained as a yellow oil. Which was confirmed by HNMR (EW30189-217-P1A) and LCMS (EW30189-217-P1P). TLC (SiO2, DCM: MeOH = 10/1, Rf = 0.05) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.704 min (M+H)+ =483.3 EW30189-217-P1A1 LCMS: MS (ESI) Retention time: 1.225min (M+H)+ = 483.3, EW30189-217-P1P 1H NMR (400 MHz, DMSO-d6) δ = 9.29 (br s, 1H), 9.18 (br s, 1H), 8.80 (br s, 3H), 8.09 (br s, 1H), 7.97-7.95 (m, 2H), 7.36-7.33 (d, J = 8.8 Hz, 1H), 6.95-6.93 (d, J = 8.8 Hz, 1H), 6.87-6.85 (d, J = 8.8 Hz, 2H), 6.64 (s, 1H), 3.48-3.45 (m, 2H), 3.02 (s, 3H), 2.99 (m, 2H), 2.89 (s, 6H), 2.880-2.77 (m, 2H), 2.73 (s, 2H), 2.09-2.06 (m, 2H), 1.71- 1.64 (m, 8H). Synthesis of SND418
Figure imgf000048_0001
To a solution of Core H (300 mg, 551.13 pmol, 1.00 eq), RuPhos (51.44 mg, 110.23 pmol, 0.20 eq), Pd2 (dba)3 (100.94 mg, 110.23 pmol, 0.20 eq) and Cs2C03 (538.71 mg, 1.65 mmol, 3.00 eq) in DMF (5 mL), then added Compound 7U (138.02 mg, 551.13 pmol, 80.83 pL, 1.00 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr. LCMS (EW30189 - 319-PiAi) showed Core H consumed. Several new peaks were shown on LCMS and 49.109 % of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Without purification. It was put in the next reaction. Compound 2 (600 mg, 853.11 pmol, 92.88% yield, HC1) was obtained as a red oil.
LCMS: MS (ESI) Retention time: 0.875mm (M+H)+ = 667.4, 5-95AB_R_220&254.1cm
Figure imgf000048_0002
To a solution of Compound 2 (300 mg, 449.88 mihoΐ, l.oo eg) in AcOH (3 mL) and HC1 (0.30 mL). The mixture was stirred at 80 °C for 1 hr. LCMS (EW30189 - 323-P1A) showed Compound 2 was consumed completely and 32.214% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% HC1 lcondition). SND418 (440 mg, 816.17 pmol, 95.67% yield, 100% purity, HC1) was obtained as a yellow oil. Which was confirmed by HNMR (EW30189-323-P1A) and LCMS (EW30189-323-P1P)·
TLC (Si02, DCM: MeOH = 10/1, Rf = 0.2) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point. LCMS: MS (ESI) Retention time: 0.730 min (M+H)+ =503.3 EW30189-323-P1A LCMS: MS (ESI) Retention time: 1.680min (M+H)+ =503.3, EW30189-323-P1P 1H NMR (400 MHz, DMSO-d6) δ = 9.70 (br s, 1H), 7.98-7.96 (d, J = 8.8 Hz, 2H), 7.37- 7.35 (d, J = 8.8 Hz, 1H), 6.95-6.93 (d, J = 8.8 Hz, 1H), 6.91-6.84 (m, 2H), 6.66 (s, 1H), 3.50-3.47 (t, J = 7.2 Hz, 2H), 3.36 (m, 1H), 3.03 (s, 3H), 2.72-2.67 (m, 1H), 2.63-2.62 (d, J = 5.2 Hz, 3H), 2.15 (m, 3H), 1.99-1.96 (m, 3H), 1.91-1.88 (m, 3H), 1.82 (m, 3H), 1.66-1.59 (m, 7H). Synthesis of SND419
Figure imgf000049_0001
To a solution of Core H (300 mg, 551.13 μmol, 1 eq), RuPhos (51.44 mg, 110.23 μmol, 0.2 eq), Pd2 (dba)3 (100.94 mg, 110.23 μmol, 0.2 eq) and Cs2CO3 (538.71 mg, 1.65 mmol, 3 eq) in DMF (4 mL), then added Compound 7h (94.94 mg, 551.13 μmol, 80.83 μL, 1 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr under N2. LCMS (EW30189-281-P1A) showed Core H consumed. Several new peaks were shown on LCMS and 35.63% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. Without purification. It was put in the next reaction. Compound 2 (300 mg, 509.61 μmol, 92.47% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.916min (M+H)+ = 589.5, 5-95AB_R_220&254.lcm
Figure imgf000050_0001
To a solution of Compound 2 (300 mg, 509.61 pmol, 1 eq) in AcOH (1 mL) and HC1 (3 mL). The mixture was stirred at 25 °C for 1 hr. LCMS (EW30189-283-P1C) showed Compound 2 was consumed completely and 39.283% of desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% HC1 condition). SND419 (100 mg, 210.79 pmol, 41.36% yield, 97.163% purity, HC1) was obtained as a yellow oil. Which was determined by HNMR (EW30189-283-P1C) and LCMS (EW30189-283- PiL).
TLC (Si02, DCM: MeOH = 10/1, Rf = 0.4) and the salt absorbs moisture easily and turns to be oil at room temperature, so we could not test the melting point.
LCMS: MS (ESI) Retention time: 0.724mm (M+H)+ = 425.3, EW30189-283-P1C LCMS: MS (ESI) Retention time: 1.369mm (M+H)+ = 425.3, EW30189-283-P1L Ή NMR (400 MHz, DMSO+D2O) d = 7.91-7.89 (d, J = 8.8 Hz, 2H), 7.41-7.39 (d, J = 8.8 Hz, lH), 6.96-6.94 (d, J = 8.8 Hz, lH), 6.86-6.84 (d, J = 9-2 Hz, 2H), 6.62 (s, lH), 3-96-3-93 (m, 2H), 3.64 (t, J = 11.6 Hz, 2H), 3-42 (t, J = 7-2 Hz, 2H), 3-37-3-34 (d, J = 12.4 Hz, 2H), 3.08-2.99 (m, 4H), 2.97 (s, 3H), 1.70-1.62 (m, 2H), 1.57-1.52 (m, 2H). Synthesis of SND16.2
The following procedure was employed to prepare SND163. “Compound 9g” is SND163, i.e. where R and R’ together with the nitrogen atom form a pyrrolidine ring
Figure imgf000051_0001
The synthesis involved condensation of 3.3 and 9.1 to form 9.8, followed by cyclization/deprotection toward the precursor aldehyde 9.9, and reductive amination as a last step. This approach proved to be successful, as condensation proceeded to form 9.8 in high crude yields (>90%), and upon cyclization with I2 in DMSO at 120°C, protecting groups were cleaved simultaneously, leading directly to precursor 9.9, which could be easily separated in pure form by collecting the precipitate formed during quenching of the reaction mixture with saturated aqueous sodium thiosulfate. The isolated yields of 9.9 were good (78-90%).
CE)-3-(4-(diethoxymethyl)phenyl)-i-(2-hydroxy-3-methoxy-4- (methoxymethoxy)phenyl)prop-2-en-i-one (9.8).
To a 0.1M solution of acetophenone 3.3 (3.00 g, 1.00 Eq, 13.3 mmol) and aldehyde 9.1 (2.90 g, 2.77 mL, 1.05 Eq, 13.9 mmol) in dioxane a methanolic solution of sodium methoxide (85.9 mL, 5.4 molar, 35 Eq, 464 mmol) was added at o °C. The resulting mixture was allowed to warm up to room temperature and stirred for 15 hours or until full conversion was observed by LCMS. The reaction mixture was poured into ice-cold brine, neutralized with citric acid and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. The obtained crude product 9.8 (yellow oil, 5.27 g, 12.7 mmol, 95% yield) contained desired chalcone along with flavanone (~23%), and was used without further purification in the next step. 4-(7-hydroxy-8-methoxy-4-oxo-4ff-chromen-2-yl)benzaldehyde (9.9). A stirred 0.1M solution of chalcone 9.8 (2.2511 g, 1.0 Eq, 5.4052 mmol) and iodine (0.1 Eq) in DMSO was heated to 120 °C for 18 hours (or until full conversion was observed by LCMS). The mixture was cooled and poured into ice-cold water, followed by addition of aqueous sodium thiosulfate. The precipitate formed upon quenching the reaction mixture, was filtered and dried in vacuo, yielding pure product 9.9 (1.26 g, 4.257 mmol, 79 %) as a pale brown solid.
7-hydroxy-8-methoxy-2-(4-(pyrrolidin-i-ylmethyl)phenyl)-4ff-chromen-4- one hydrochloride (9g/SNDi63). Utilizing 9.9 (0.400 g, 1.00 Eq, 1.35 mmol), pyrrolidine (192 mg, 222 uL, 2.00 Eq, 2.70 mmol) and sodium triacetoxyhydroborate (629 mg, 2.20 Eq, 2.97 mmol) resulted in product 9g (0.448 g, 1.1 mmol, 85 %), obtained as a yellow solid.
A general procedure for reductive amination was followed: To a solution of aldehyde (1.00 Eq) in DCM (Note: average reaction molarity is 0.25M and in case of poor solubility of aldehydes, THF was added until the mixture became homogeneous) an appropriate amine was added (2.00 Eq). The resulting mixture was stirred at room temperature for 30 min - 1 hour to make sure imine has formed. Then the mixture was cooled down to o°C , followed by portion-wise addition of sodium triacetoxyborohydride (2.20 Eq). The resulting mixture was allowed to warm up to room temperature and was stirred for 18 hours. Upon reaction completion (controlled by LCMS), the reaction mixture was worked up as follows:
Method: The reaction mixture was quenched with methanol, concentrated in vacuo (to remove amine if possible), re-dissolved in methanol and excess of 4N HC1 in dioxane was added upon stirring (until the pH remained constantly acidic). The resulting solution was concentrated, yielding a solid residue of inorganic salts and hydrochloride of the desired product. Crude material was purified using reversed phase column chromatography (using a gradient of 0.1% HC1 in water and methanol), yielding desired product as a hydrochloride.
Having the precursor 9.9 in hand, the reductive amination step proceeded without any difficulties, leading to SND163. No side products indicating interference with different reaction centers were observed, thus aldehyde was selectively engaged in the reductive amination in presence of a cyclic enone. Finally, the desired flavone SND163 was obtained by treating the reaction mixture (upon quenching with methanol) with excess of HC1, thus forming hydrochloride, which was purified using reversed phase chromatography (using a gradient of 0.1% HCl in water/MeOH mixture) without any complications. Synthesis of SND165 The following procedure was employed to prepare SND165. “Compound 18” is SND163.
Figure imgf000053_0001
Precursor 9.9 was prepared as described above. Tert-butyl (4-((tert-butoxycarbonyl)amino)butyl) (3-((4-(7-hydroxy-8- methoxy-4-oxo-4H-chromen-2-yl)benzyl)amino)propyl)carbamate (18.1). Utilizing 9.9 (89.3 mg, 1.0 Eq, 302 µmol), tert-butyl (3-aminopropyl)(4-((tert- butoxycarbonyl)amino)butyl)carbamate (0.125 g, 1.2 Eq, 362 µmol) and sodium triacetoxyhydroborate (95.9 mg, 1.5 Eq, 452 µmol) resulted in product 18.1a (0.105 g, 168 µmol, 55.7 %), obtained as a yellow oil. A general procedure for reductive amination was followed: To a solution of aldehyde (1.00 Eq) in DCM (Note: average reaction molarity is 0.25M and in case of poor solubility of aldehydes, THF was added until the mixture became homogeneous) an appropriate amine was added (1.20 Eq). The resulting mixture was stirred at room temperature for 30 min – 1 hour to make sure imine has formed. Then the mixture was cooled down to 0℃ , followed by portion-wise addition of sodium triacetoxyborohydride (1.50 Eq). The resulting mixture was allowed to warm up to room temperature and was stirred for 18 hours. Upon reaction completion (controlled by LCMS), the reaction mixture was worked up as follows. Method I: Reaction mixture was quenched with saturated solution of NaHCO3. Organic layer was separated and water layer was washed with ethyl acetate. Combined organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. Crude product was purified using column chromatography with silica gel and a gradient of 3.5N ammonia in methanol with DCM as eluent. 2-(4-(((3-((4-aminobutyl)amino)propyl)amino)methyl)phenyl)-7-hydroxy- 8-methoxy-4H-chromen-4-one trihydrochloride (18). Treatment of 18.1a (0.400 g, 1.00 Eq, 1.35 mmol) with hydrochloric acid (612 mg, 4.19 mL, 4 molar, 100.00 Eq, 16.8 mmol) resulted in product 18 (0.070 g, 0.13 mmol, 78 %), obtained as a yellow solid. A general procedure for deprotection was followed: To a 1M solution of protected material (1.00 Eq) in methanol an excess of 4N HCl in dioxane was added (2-100 Eq), and the resulting mixture was left stirring until complete conversion was observed by LCMS. The reaction mixture was concentrated in vacuo. Purity of the crude products was very high, so no additional purification was needed. Synthesis of SND170 & SND171 The following scheme was employed to synthesise SND170. “Compound 12B” is SND170, i.e. where R and R’ together with the N atom form 4-methyl piperazine.
Figure imgf000054_0001
The following scheme was employed to synthesise SND171. “Compound 12E” is SND171, i.e. where R is methyl, and R’ –CH2CH2-piperidine.
Figure imgf000055_0001
1-(2-Hydroxy-3,4-bis(methoxymethoxy)phenyl)ethan-1-one (1.2). Chloromethyl methyl ether (10.29 g, 9.708 mL, 2.2 Eq, 127.8 mmol) was added drop- wise within 5 min to a solution of 1-(2,3,4-trihydroxyphenyl)ethan-1-one (9.769 g, 1 Eq, 58.10 mmol), DIPEA (30.04 g, 40.5 mL, 4 Eq, 232.4 mmol) in DCM (225 mL) at 0 °C. The reaction mixture was stirred for 2 h at 0 °C before it was allowed to warm to room temperature. The reaction mixture was diluted with 500 ml of DCM, washed with 2 x 125 ml of 10% citric acid and 200 ml of brine. Organic layer was then dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane as the eluent system.1-(2-Hydroxy-3,4- bis(methoxymethoxy)phenyl)ethan-1-one (12.617 g, 49 mmol, 84%, 99% Purity) was obtained as a pale yellow oil. (E)-1-(2-Hydroxy-3,4-bis(methoxymethoxy)phenyl)-3-(4-(3-((tetrahydro- 2H-pyran-2-yl)oxy)propyl)phenyl)prop-2-en-1-one (12.4). Sodium methoxide (4.1 g, 14 mL, 5.4 molar, 36 Eq, 76 mmol) in MeOH was added portion-wise under nitrogen flow to an ice/water cooled (0 °C) solution of 1-(2-hydroxy-3,4- bis(methoxymethoxy)phenyl)ethan-1-one (1.2, 0.544 g, 1 Eq, 2.124 mmol) and 4-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)benzaldehyde (12.3, 0.554 g, 1.05 Eq, 2.23 mmol) in 1,4-dioxane (8 mL). The mixture was allowed slowly to warm to room temperature and it was stirred for 15 h under nitrogen atmosphere. The reaction mixture was concentrated, until most of MeOH was evaporated, and poured to 75 ml of ice-cold brine. The aqueous layer diluted with 15 ml of water and extracted with 3 x 75 ml of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered through paper filter and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptane as the eluent system. (E)-1-(2-Hydroxy- 3,4-bis(methoxymethoxy)phenyl)-3-(4-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)phenyl-)prop-2-en-1-one (0.8957 g, 1.6 mmol, 77%, 89% Purity) was obtained as an orange oil. 7,8-Dihydroxy-2-(4-(3-hydroxypropyl)phenyl)-4H-chromen-4-one (12.5). Solution of (E)-1-(2-hydroxy-3,4-bis(methoxymethoxy)phenyl)-3-(4-(3-((tetrahydro- 2H-pyran-2-yl)oxy)propyl)phenyl)prop-2-en-1-one (12.4) (1.996 g, 1 Eq, 4.102 mmol) and iodine (114 mg, 0.109 Eq, 449 µmol) in DMSO (30 mL) was heated in nitrogen atmosphere at 120 °C for 17 h. Reaction mixture was allowed to cool to room temperature before it was poured to 300 mL of 5% of Na2SO3 and the mixture was acidified with c. HCl until pH = 2-3, filtered and washed with water. The resultant filter cake was dissolved in MeOH and dried. 7,8-Dihydroxy-2-(4-(3- hydroxypropyl)phenyl)-4H-chromen-4-one (1.22 g, 2.9 mmol, 71%, 75% purity) was obtained as a dark brown solid. 2-(4-(3-Bromopropyl)phenyl)-7,8-dihydroxy-4H-chromen-4-one (12.6).1H- Benzo[d][1,2,3]triazole (254 mg, 1.3 Eq, 2.14 mmol) and N,N-dimethylformamide (26.4 mg, 27.9 µL, 0.22 Eq, 361 µmol) were added to a suspension of 7,8-dihydroxy-2-(4-(3- hydroxypropyl)phenyl)-4H-chromen-4-one (12.5, 0.513 g, 1.0 Eq, 1.64 mmol) in dry DCM (18 mL) under nitrogen flow at 0 °C. The reaction mixture was slowly allowed to warm to room temperature and it was stirred at room temperature for 16 h, before it was cooled with an ice-bath and quenched with 20 mL of sat. NaHCO3. The resultant suspension was extracted with 8 x 25 mL of DCM. Organic layers were combined and washed with 75 mL of brine, which in turn was extracted with 3 x 75 mL of DCM. Organic layers were combined, evaporated to dryness and purified by normal phase flash-chromatography using DCM:MeOH as the eluent system.2-(4-(3- Bromopropyl)phenyl)-7,8-dihydroxy-4H-chromen-4-one (0.233 g, 0.56 mmol, 34%, 90% purity) was obtained as a brown powder. 7,8-Dihydroxy-2-(4-(3-(4-methylpiperazin-1-yl)propyl)phenyl)-4H- chromen-4-one dihydrochloride (12B/SND170). A slurry of 2-(4-(3- bromopropyl)phenyl)-7,8-dihydroxy-4H-chromen-4-one (12.6) (0.201 g, 1 Eq, 536 µmol) in MeCN (6 mL) was added to a mixture of DIPEA (0.11 g, 0.15 mL, 1.6 Eq, 0.86 mmol), 1-methylpiperazine (0.3 g, 0.3 mL, 5 Eq, 3 mmol) and MeCN (0.5 mL). Mixture was stirred at room temperature for 70 h, before it was evaporated to dryness and dissolved in 20 mL of DCM. The resultant suspension was washed with 50 mL of brine:water 1:1 mixture. Aqueous layer was extracted with 6 x 50 mL of DCM and 7 x 50 mL of DCM:MeOH 9:1 mixture. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by reversed- phase chromatography to yield 7,8-dihydroxy-2-(4-(3-(4-methylpiperazin-1- yl)propyl)phenyl)-4H-chromen-4-one dihydrochloride (65 mg, 0.13 mmol, 25%, 95% purity) as an orange powder. 2-(3-(4-Bromophenyl)propoxy)tetrahydro-2H-pyran (12.2). A solution of 3- (4-bromophenyl)propan-1-ol (12.1) (24.97 g, 1 Eq, 116.1 mmol) in dichloromethane (250 mL) was cooled under gentle nitrogen flow to 0 °C in a 500 ml round-bottom flask. p-Toluenesulfonic acid monohydrate (2.21 g, 0.111 Eq, 12.8 mmol) was then added portion-wise.3,4-Dihydro-2H-pyran (19.35 g, 1.981 Eq, 230.0 mmol) was added drop-wise from a dropping funnel within 30 min before the mixture was allowed to warm to room-temperature. The solution turned eventually to black. The reaction mixture was stirred at room temperature for 16 hours before it was concentrated. The resultant black oil was purified by flash-chromatography using ethyl acetate/heptanes to yield 2-(3-(4-bromophenyl)propoxy)tetrahydro-2H-pyran (12.2) (28.8 g, 96.3 mmol, 83%, 100% purity) as a transparent oil. 4-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propyl)benzaldehyde (12.3).2-(3-(4- Bromophenyl)propoxy)tetrahydro-2H-pyran (12.2, 27.67 g, 1 Eq, 92.48 mmol) and THF (310 mL) were transferred under nitrogen flow to a flame-dried 500 ml three-neck round-bottom flask. The solution was cooled under gentle nitrogen flow to -75 °C, before n-butyllithium (6.49 g, 40.5 mL, 2.5 molar, 1.09 Eq, 101 mmol) in hexanes was added portion-wise within 20 min. After 30 min of stirring, dry DMF was added portion-wise within 25 min and the reaction mixture was stirred for another 5 min before the cooling bath was removed. The reaction mixture was then stirred at 20 °C for 2 hour, before the reaction mixture was quenched with 100 ml of water and diluted with 900 ml of water. Resulting suspension was extracted with 3 × 750 ml of EtOAc. The organic fractions were combined, dried with sodium sulfate, filtered and concentrated to give the crude product as a yellow oil. The crude product was purified by flash-chromatography using ethyl acetate/heptanes to yield 4-(3-((tetrahydro-2H- pyran-2-yl)oxy)propyl)benzaldehyde (12.3) (18.7 g, 75 mmol, 81%, 99% purity) as a colorless oil. 1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)ethan-1-one (12.7).1- (2,3,4-Trihydroxyphenyl)ethan-1-one (10.86 g, 1 Eq, 64.59 mmol), dichlorodiphenylmethane (15.29 g, 12.38 mL, 1.00 Eq, 64.48 mmol) and diphenyl ether (85 mL) were transferred under nitrogen flow to a 250 ml three-neck flask. The reaction mixture was heated at 175 °C for 30 min. The reaction mixture was allowed to cool to room temperature before it was poured to 900 ml of heptane. After a couple of minutes, precipitate started to form. This was filtered and washed with heptane. The dark precipitate on the filter was dissolved in DCM, 25 mL of EtOAc and 25 mL of heptane was added. This mixture was then concentrated until extensive precipitate formed. This was filtered, washed with 4 x 25 mL of EtOAc:heptane 1:1 mixture and purified by normal phase flash-chromatography using EtOAc:heptane as the eluent. The filtrate of the first filtration was concentrated, cooled to 4 °C for 20 h, filtered and washed with heptane This was combined with the material recovered from flash- chromatography to yield 1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)ethan-1- one (12.7) (15.62 g, 47.0 mmol, 73%, 100% purity) as a white solid. (E)-1-(4-Hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)prop-2-en-1-one (12.8a) and 2,2-diphenyl-8-(4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)- 7,8-dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.8b). Sodium methoxide (37.9 g, 130 mL, 5.4 molar, 35.7 Eq, 702 mmol) in MeOH was added portion-wise under nitrogen flow to an ice/NaCl cooled suspension of 1-(4-hydroxy- 2,2-diphenylbenzo[d][1,3]dioxol-5-yl)ethan-1-one (6.5287 g, 1 Eq, 19.643 mmol) and 4- (3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)benzaldehyde (5.037 g, 1.033 Eq, 20.28 mmol) in 1,4-dioxane (70 mL) at 0 °C. The mixture was allowed slowly to warm to room temperature and it was stirred for 15 h under nitrogen atmosphere. The reaction mixture was then poured to 500 ml of ice-cold brine. The resultant suspension was extracted with 3 x 100 ml of EtOAc. Organic fractions were combined, dried with sodium sulfate, filtered and evaporated to dryness, yielding 14.27 g of dark orange oil. The crude product was suspended in DCM and purified twice by normal phase flash- chromatography using DCM:MeOH as the eluent, to yield (E)-1-(4-hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)-3-(4-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)phenyl)prop-2-en-1-one (12.8a) (5.16 g, 9.17 mmol, 46.7%, 100% purity) as an orange foam and 2,2-diphenyl-8-(4-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)phenyl)-7,8-dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.8b) (4.825 g, 7.7 mmol, 39%, 90% purity) a yellow foam. 2,2-Diphenyl-8-(4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)-7,8- dihydro-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.9). A solution of 2,2- diphenyl-8-(4-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)-7,8-dihydro-6H- [1,3]dioxolo[4,5-h]chromen-6-one (12.8b) (4.825 g, 1 Eq, 8.575 mmol) and diiodine (223 mg, 0.102 Eq, 879 µmol) in DMSO (60 mL) was heated at 120 °C for 17 h. Reaction mixture was then allowed to cool to room temperature before it was poured to 600 ml of 1% sodium sulfite solution. Brown precipitate formed. The organic layer was extracted with 3 x 250 ml of EtOAc. Brine was added to speed up the separation of layers. Organic layers were combined and washed with 200 ml of brine, which in turn was extracted with 100 ml of EtOAc. Organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness to yield 3.93 g of dark oil. Crude product was suspended in DCM and purified by normal phase flash-chromatography.8-(4-(3- Hydroxypropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.9) (2.151 g, 4.51 mmol, 52.6%, 100% purity) was obtained as a pale yellow solid. 8-(4-(3-Bromopropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (12.10).8-(4-(3-Hydroxypropyl)phenyl)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (12.9, 2.15 g, 1 Eq, 4.51 mmol) was dissolved in dry DCM (36 mL) and was cooled to 0 °C under nitrogen atmosphere. N,N- dimethylformamide (0.9 g, 0.9 mL, 3 Eq, 0.01 mol) was then added under nitrogen flow, followed by sulfurous dibromide (1.2 g, 0.45 mL, 1.3 Eq, 5.8 mmol). After a few minutes, the cooling bath was removed and the orange solution was stirred at 20 °C. Reaction was followed by LC-MS. After 105 min, the reaction mixture was cooled with ice-bath and 50 ml of sat. NaHCO3 was added. The mixture was then extracted with 3 × 100 ml of DCM, until last fraction had very little UV-activity. Organic layers were combined, washed with 150 ml of brine, which in turn was extracted with 2 × 50 ml of DCM and dried with sodium sulfate. The solution was filtered, evaporated to dryness and purified by normal phase flash-chromatography, using EtOAc:heptane as the eluent.8-(4-(3-Bromopropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6- one (2.014 g, 3.73 mmol, 82.8%, 100% purity) was obtained as a white solid. General method for alkylation of secondary amines with 8-(4-(3- bromopropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.10).1-5 eq. of the secondary amine with 1.5 eq. of DiPEA in MeCN was added to a suspension of 8-(4-(3-bromopropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (12.10) in MeCN. 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. 8-(4-(3-(Methyl(2-(piperidin-1-yl)ethyl)amino)propyl)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.11E). Suspension of 8-(4- (3-bromopropyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.10) (0.549 g, 1 Eq, 1.02 mmol) in MeCN (4 mL) was treated with N-methyl-2-(piperidin-1- yl)ethan-1-amine (306 mg, 2.11 Eq, 2.15 mmol) and DIPEA (197 mg, 266 µL, 1.50 Eq, 1.53 mmol) in MeCN (1 mL) at room temperature for 17 h and at 50 °C for 22 h. After work-up and purification, 8-(4-(3-(methyl(2-(piperidin-1- yl)ethyl)amino)propyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (0.584 g, 0.94 mmol, 93%, 97% purity) was obtained as an orange oil. 7,8-Dihydroxy-2-(4-(3-(methyl(2-(piperidin-1- yl)ethyl)amino)propyl)phenyl)-4H-chromen-4-one dihydrochloride (12E/SND171). 8-(4-(3-(Methyl(2-(piperidin-1-yl)ethyl)amino)propyl)phenyl)-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (12.11E) (0.555 g, 1.00 Eq, 924 µmol) was dissolved in MeOH (5 mL), 23 mL of 4 M HCl in 1,4-dioxane (3.37 g, 100 Eq, 92.4 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated, diluted with 50 mL of Et2O and filtered. The solid on the filter was then purified by reversed-phase chromatography to yield 7,8- dihydroxy-2-(4-(3-(methyl(2-(piperidin-1-yl)ethyl)amino)propyl)phenyl)-4H- chromen-4-one dihydrochloride (0.356 g, 699 mihoΐ, 75.6 %, 97% purity) an orange solid.
Compounds The following compounds were synthesised using the general process as described above.
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
EXAMPLES - BIOLOGICAL STUDIES
Experimental methodology Primary cortical neurons preparation
Primary cortical neurons were prepared from timed pregnant wild-type C57BL/6JRccHsd mice at E18. Animals were sacrificed and embryos were dissected in Calcium and Magnesium free Hanks Balanced Salt Solution (CMF-HBSS) containing 15 mM HEPES and 10 mM NaHC03, pH 7.2. Embryos were decapitated, skin and skull gently removed and cortical hemispheres were separated. After removing meninges and brain stem, the cortex was isolated, chopped with a sterile razor blade in Chop solution (Hibernate-E without Calcium containing 2% B-27) and digested in 2 mg/ml papain (Worthington) dissolved in Hibernate-E without Calcium for 30 minutes (± 5 min) at 30°C. Cortices were triturated for 10-15 times with a fire-polished silanized Pasteur pipette in Hibernate-E without Calcium containing 2% B-27, 0.01% DNasel, 1 mg/ml BSA, and 1 mg/ml Ovomucoid Inhibitor. Undispersed pieces were allowed to settle by gravity for 1 min and the supernatant was centrifuged for 3 min at 228 g. The pellet was resuspended in Hibernate-E containing 2% B-27, 0.01% DNasel, 1 mg/ml BSA, 1 mg/ ml Ovomucoid Inhibitor and diluted with Hibernate-E containing 2% B-27. After the second centrifugation step (3 min at 228 g), the pellet was resuspended in nutrition medium without glutamate (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% Penicillin- Streptomycin). Cells were counted in a hemacytometer and seeded in nutrition medium on poly-D-lysine pre-coated plates. Cells were cultured at 37°C; 95% humidity and 5% C02.
Primary rat microglia culture
Rat neonate brains (P0-P2) were dissected and cerebellum and meninges removed. The brains were then dissociated via an enzyme digestion for up to 1 hour after which digestion was stopped by adding culture medium (Dulbecco’s modified eagle medium (DMEM), 10 % Foetal Bovine serum (FBS), 1 % Penicillin - Streptomycin). Cells were then centrifuged at 300 x g for 5 minutes; supernatant was removed, and the cells were homogenized by trituration with 18- and 23-gauge needles. Cell suspension was then added to individual T75 flasks at approximately 1.5 - 2 cortices per flask. Cells were incubated for 10 days at 37°C, 7.5 % CO2 with media changes occurring every 2 - 3 days. At Day 10, loosely adherent microglia were isolated by shaking the flasks at 250 RPM for 1 hour at 37°C. Cells were collected and seeded in a 96-well flat bottom tissue culture plate at a density of 25,000 cells/well in 200 pL DMEM media supplemented with 10 % FBS, 1 % Pen/Strep and 12.5 mM HEPES. Microglia were then incubated in a humidified environment for 24 hours at 37°C, 7.5 % C02 prior to any further treatment or experimentation.
Viability assays
Viability of cultures was determined by the MTT assay using a plate-reader (570 nm) or by CellTiter-Glo® 2.0 (Promega) using a luminescence plate reader (EnVision). The MTT assay allows the measurement of the mitochondrial dehydrogenase activity, which reduces yellow MTT to dark blue formazan crystals. Since this reaction was catalyzed in living cells this assay was used for the determination of cell viability. MTT solution was added to each well in a final concentration of 0.5 mg/ml. After 2 h the MTT containing medium was aspirated. Cells were lysed in 3% SDS and the formazan crystals were dissolved in isopropanol/HCl. Optical density was measured with a plate-reader at wavelength 570 nm. Cell survival rate was expressed as optical density (OD). Values were calculated as percent of control values (vehicle control, lesion control or maximal effect of the positive control). 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. Luminescence 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.
RNA Isolation, reverse transcription and qPCR
Cells were lysed using Buffer RLT (QIAGEN) supplemented with b-mercaptoethanol (b-ME, Sigma,) at RT and stored at -8o°C until use. Lysates for each treatment group were pooled for RNA isolation to ensure sufficient RNA recovery for downstream analysis. RNA was isolated using standard RNA isolation kit (RNeasy Mini kit, QIAGEN,), treated with DNase (Qiagen,) and eluted into 50 mΐ ddH20 (Qiagen, #1018017, Lot: 163041698). RNA concentration was then quantified using the Nanodrop (Thermo) according to the manufacturer’s instructions. Then cDNA was synthesised by reverse transcription using the iScript Advanced cDNA Synthesis kit (Bio-Rad, #1706691, Lot: 64355629) and the Veriti™ 96-Well Fast Thermal Cycler (Applied Biosystems, #4375305). Components of qPCR master mix were mixed on ice and samples run on the QuantStudio 5 Real-Time PCR system (Thermo) with the standard thermal cycling mode consisting of a 50°C step for 2 minutes followed by an initial heat activation step of 95°C for 10 minutes, followed by 50 cycles of 95°C for 15 seconds (denaturation) and 6o°C for 60 seconds (annealing and extension). Quantification of DNA was based on increased fluorescence in each reaction, expressed in terms of threshold cycle (CT) values generated by the thermal cycler during the annealing and extension step. Each gene was run in triplicate for each sample where possible.
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 l. 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 mouse primary cortical neurons using a brief treatment with iodoacetic acid (IAA). Cell death was monitored using the MTT assay.
Experimental method: IAA toxicity
On the day of preparation (DIVi), cortical neurons were seeded on poly-D-lysine pre- coated 96-well plates at a density of 3*ioL4 cells per well. Cells were cultured at 37°C; 95% humidity and 5% C02 until DIV9 with a half medium exchange on DIV4-6.
On DIV9, cells were treated with test compounds and controls: negative control vehicle only (DMSO 0.1 %), positive control Trolox at 10 uM. After 10 min pre-incubation, 50 mM IAA (Sigma Aldrich;) was added as lesion agent and exactly after 110 min cells were subject to MTT assay. The experiment was carried out with n=6 technical replicates per condition.
Results:
The presence of 0.5 mM SND148 (Figure 1) and 10 mM SNDiyo (Figure 2) during the incubation of the neurons with iodoacetic acid led to statistical significant protection from cell death. Both compounds exhibited approximately 63% of the effect induced by the positive control Trolox.
Figure 1 shows SND148 at a concentration of 0.5 mM increases survival of mouse primary neurons from the toxicity induced by IAA. Data are shown as % of vehicle control (VC) and displayed as bar graph with mean+SD and individual data points as dots. One-way ANOVA followed by Dunnett’s multiple comparison test. *p<0.05; **p<o.oi; ***p<o.ooi. VC = vehicle control; LC = lesion control. Figure 2 shows SND170 at a concentration of 10 mM increases survival of mouse primary neurons from the toxicity induced by IAA. Data are shown as % of vehicle control (VC) and displayed as bar graph with mean+SD and individual data points as dots. One-way ANOVA followed by Dunnett’s multiple comparison test. *p<0.05; **p<o.oi; ***p<o.ooi. VC = vehicle control; LC = lesion control. To test if the SND derivatives protect cells from the toxicity induced by IAA when added after the cells were lesioned, mimicking the reperfusion phase in ischemia, a mouse hippocampal cell line, 3000 HT-22 cells were plated in a 96-well plate overnight and then treated with 10 mM IAA for 2 hours. The medium was aspirated and replaced with fresh medium with vehicle (DMSO at a final concentration of 0.5%) or the test compounds for 24 h, followed by viability measurement using CellTiter-Glo. The experiment was conducted in triplicate.
As shown in Table 1 -2 multiple SND derivatives have shown a concentration dependent neuroprotective activity against in vitro ischemia model. 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 1)
Interestingly, SND170 presented protective effects both during the lesion and in the reperfusion phase.
Table 1 - 2. Neuroprotective activity of various SND derivatives against an in vitro model of ischemia induced by IAA. The numbers represent mean % viability versus cells treated only with vehicle control (no IAA). The lesion control is depicted as o mM and the numbers represent the mean % viability of IAA treated cells vs the vehicle control from the same 96 well plate as the tested compounds.
Figure imgf000068_0001
Table 2
Figure imgf000068_0002
Figure imgf000069_0001
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 a mouse hippocampal cell line.
Experimental methods
Cells (3000 cells/well) were seeded in a 96-well plate and grown overnight, then test compounds at various concentrations and 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
SND derivatives were effective in protecting the cells from MPP+ injury in a concentration dependent manner as shown in Table 3. 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 10 mM - i mM).
Table 3. Neuroprotective activity of various SND derivatives against an in vitro model of PD induced by MPP+. The numbers represent mean % viability versus cells treated only with vehicle control (no MPP+). The lesion control is depicted as o mM and the numbers represent the mean % viability of MPP+ treated cells vs the vehicle control from the same 96 well plate as the tested compounds.
Figure imgf000069_0002
Example ¾. 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 or vehicle control were added. Following 30 min incubation, Glutamate (Glu) 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 compounds were effective at reducing the toxic effects of Glutamate when tested at a concentration that was not in itself toxic for the cells. 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 4. Neuroprotective activity of various SND derivatives against oxidative stress induced by Glutamate (Glu). Numbers represent fold increase in viability over cells treated with the lesion
Figure imgf000070_0001
Figure imgf000071_0001
Example 4. Neuron rescue from serum starvation Trophic deprivation-mediated neuronal death is important during development, after acute brain or nerve trauma, and in neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro. In agreement with the hypothesis that SND derivatives present neurotrophic activity similar with Brain-derived neurotrophic factor (BDNF), they could rescue primary neurons from cell death induced SD. Experimental method On the day of preparation (DIV1), cortical neurons were seeded on poly-D-lysine pre- coated 96-well plates at a density of 3*10^4 cells per well in complete medium (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% Penicillin-Streptomycin). Cells were cultured at 37°C; 95% humidity and 5% CO2 until DIV9 with a half medium exchange on DIV4-6. On DIV8, a full medium change was carried out and B-27 free medium was added. Thereafter cells were treated with test compounds in comparison with BDNF at 100 ng/ml. After 26 h cells were subject to MTT assay. The experiment was carried out with n=6 technical replicates per condition, vehicle treated cells served as control on each plate. Results SND148 increases viability of neurons with statistical significance at a concentration of 5 µM as shown in Figure 3. Figure 3 shows the effect of SND148 on the survival of serum deprived primary neurons. BDNF - Brain-derived neurotrophic factor. Data are shown as % of vehicle control (VC) and displayed as bar graph with mean+SD and individual data points as dots. One-way ANOVA followed by Dunnett’s multiple comparison test. *p<0.05; **p<0.01; ***p<0.001. Example 5. Attenuating the anti-inflammatory effects of stimulated primary microglia. Microglia are resident macrophage-like cells in the brain and have been suggested to play a major role in host defense and tissue repair in the central nervous system (CNS). Under pathological conditions, activated microglia release pro-inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen species (ROS) and pro-inflammatory cytokines [Loane DJ and Byrnes KR: Role of microglia in neurotrauma. Neurotherapeutics.7:366–377.2010]. The overproduction of these inflammatory mediators and cytokines causes severe forms of various neurodegenerative diseases, such as Alzheimer’s disease (AD), cerebral ischemia, multiple sclerosis and trauma [Liu B and Hong JS: Role of microglia in inflammation- mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther.304:1–7.2003.] Experimental method Primary microglia cells were prepared as described. Once microglial culture had settled for 24 hours, half the well volume (100 μL) was aspirated and replaced with fresh medium containing test compound or vehicle (0.1 % DMSO). Cultures were then incubated in the presence of treatment for 2 hours at 37°C, 7.5 % CO2. Following this 2- hour pre-treatment with test compound, cells were activated with the addition of LPS (100 ng/mL) and murine IFN-γ (20 ng/mL) and cultured for further 16 hours at approximately 37°C, 7.5% CO2 in the presence of test substance and vehicle control. At the end of the culture period, supernatants were removed and stored frozen (-20°C) prior to assessment of IL-6 by ELISA using a DueSet kit from R&D Systems. ELISAs for the cytokine of interest were performed on three technical replicates for each test group. Control group readings from two plates were pooled and averaged for data analysis. Cytokine standards were performed in duplicate on the same plates using a 7- point standard curve. ELISA plates were immediately read at 450 nm using an Infinite F50 (Tecan) absorbance reader and Magellan™ reader control and data analysis software. For ELISA data analysis, the four-parameter logistic regression model was used to fit standard curves (R squared value was > 0.991 for all standards) and interpolate cytokine concentrations (pg/mL). Interpolations were performed using GraphPad Prism (v8.4.2), concentrations were corrected for the sample dilution factor. Treated groups were compared against the pooled and averaged vehicle control. The expression of two house-keeping genes (ACTB and Ywhab) and M1 responsive gene Ptgs2 (Prostaglandin-Endoperoxide Synthase 2, Cox-2) were evaluated in triplicate via qPCR in all treatment groups with the Taqman Gene expression primers (Thermo Fisher Scientific). Results Stimulation of microglia with LPS/IFN-γ resulted in an increased secretion of pro- inflammatory cytokines and expression of M1-responsive genes, which was successfully suppressed by 0.1 µg/mL dexamethasone used as a positive control (pooled and averaged control data included in each plot for reference). Microglia pre-treated with SND148(C) exhibited reduced IL-6 secretion, reaching approximately 1.8-fold decrease at the highest concentrations compared to vehicle control (Figure 4). Reduced relative expression of Ptgs2 was observed across multiple tested concentrations (Figure 5). Figure 4 shows the effect of SND148 on secretion of IL6 from stimulated microglia. Figure 5 shows the effect of SND148 on Ptsg2 gene expression in stimulated microglia. Gene expression data is normalised to M1 stimulated vehicle control. Example 6. 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, Florêncio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res.2002 Nov;36(11):1199-208] Experimental 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 µM and added to 50 µM 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 SND165, SND170 and SND171 showed a certain degree of selectively in ion chelating potential. 7,8 DHF was used as a comparator in this experiment.
Table 4. 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 imgf000074_0001
Example 7. In vitro anti-oxidant properties
An accumulating amount of data proves the pivotal role of free radicals in various (patho)physiological processes, like ageing, cancer 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 5.
Table 5. Antioxidant activity of SND derivatives expressed as TEAC values (pM Trolox equivalents).
Figure imgf000075_0001
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. The invention is further described in the following clauses:
1. A compound of formula (I):
Figure imgf000076_0001
Formula (I) 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 = 0-6; 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 claimed in any preceding claim, 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; 2 -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 compound as defined in clause 1, wherein the compound is selected from the following:
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
22. A pharmaceutically acceptable salt, multi-salt, solvate or prodrug of a compound as defined in any one of clauses l to 21. 23. A pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, and a pharmaceutically acceptable excipient.
24. A compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, or a pharmaceutical composition as defined in clause 23, for use in medicine.
25. A compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, or a pharmaceutical composition as defined in clause 23, for use treating or preventing a disease, disorder or condition associated with neurotrophic pathways function or is a mitochondrial disease.
26. A compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, or a pharmaceutical composition as defined in clause 23, for use treating or preventing a central nervous system disease, disorder or condition.
27. 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 21, or a pharmaceutically acceptable multi-salt, solvate or prodrug as defined in clause 22, or a pharmaceutical composition as defined in clause 23, to thereby treat or prevent the disease, disorder or condition. A method of treatment as claimed 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.

Claims

CLAIMS 1. A compound of formula (1), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition:
Figure imgf000087_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, –OC(O)N(R13)2; 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; 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 = 0-6; each p is independently an integer selected from 1 to 4; and each q is independently an integer selected from 1 to 4; wherein, when n=0 and Z is –NR11R12; 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.
2. A compound for use as claimed in claim 1, wherein R1 and R2, independently, are selected from –OH and -O-C1-4 alkyl.
3. A compound for use as claimed in claim 2, wherein R1 and R2, independently, are selected from –OH and -OCH3
4. A compound for use as claimed in any preceding claim, wherein R3, R4, R5, 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.
5. A compound for use as claimed in claim 4, wherein R3, R4, R5, R6, R7, R8, and R9,are independently selected from H; halo; -CN; -NO2; and -NH2.
6. A compound for use as claimed in claim 5, wherein R3, R4, R5, R6, R7, R8, and R9 are H.
7. A compound for use as claimed in any preceding claim, wherein n = 0, and R11 and R12 are independently selected from H, C1-6 alkyl, and benzyl substituted with – O(C1-4 alkyl).
8. A compound for use as claimed in any of claims 1 to 6, wherein n = 1-6, and 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.
9. A compound for use as claimed in any preceding claim, wherein n is an integer from 1 to 4.
10. A compound for use as claimed in any of claims 1 to 8, wherein n is 0.
11. A compound for use as claimed in any of the preceding claims, wherein Z is – NR11R12.
12. A compound for use as claimed in any of claims 1 to 10, wherein Z is –N(R10)- (CH2)p–NR11R12.
13. A compound for use as claimed in claim 12, wherein p is selected from 2, 3 or 4.
14. A compound for use as claimed in any of claims 1 to 10, wherein Z is –N(R10)- (CH2)q–N(R10)-(CH2)q–NR11R12.
15. A compound for use as claimed in claim 14, wherein each q is independently selected from 2, 3 or 4.
16. A compound for use as claimed in any of claims 1 to 10, wherein Z is –N(R10)- (CH2)r–N(R10)-(CH2)r–N(R10)–(CH2)r–NR11R12.
17. A compound for use as claimed in claim 16, wherein each r is independently 3 or 4.
18. A compound for use as claimed in any preceding claim, wherein each R10 is independently selected from H and –CH3.
19. A method of treatment or prevention of a central nervous system disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined in any of the preceding claims, or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, to thereby treat or prevent the disease, disorder or condition.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064673A1 (en) * 2000-02-29 2001-09-07 Aventis Pharma S.A. Flavone derivatives, preparation method and use as medicines
WO2010011836A2 (en) * 2008-07-25 2010-01-28 Emory University Treating various disorders with 7,8-dihydroxyflavone and derivatives thereof
WO2011156479A2 (en) * 2010-06-09 2011-12-15 Emory University Trkb agonists and methods of use
WO2014018741A1 (en) * 2012-07-27 2014-01-30 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
WO2014100433A1 (en) * 2012-12-19 2014-06-26 Brown University Methods for treatment of microcephaly associated autism disorders
WO2020154434A1 (en) * 2019-01-24 2020-07-30 Pharmatrophix, Inc. Compositions and methods for treating and preventing cognitive dysfunction
WO2020228513A1 (en) * 2019-05-13 2020-11-19 中国药科大学 Novel cdk9 inhibitor based on benzopyran structure, preparation method therefor and use thereof
US20200390755A1 (en) * 2018-08-01 2020-12-17 Shaanxi Micot Technology Co., Ltd. Compound for treating nervous system diseases and use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8138165B2 (en) * 2002-10-22 2012-03-20 Jenken Biosciences, Inc. Chromones and chromone derivatives and uses thereof
CN102558164B (en) * 2010-12-31 2016-06-15 北京盛诺基医药科技有限公司 Benzofurantone estrogenic agents

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064673A1 (en) * 2000-02-29 2001-09-07 Aventis Pharma S.A. Flavone derivatives, preparation method and use as medicines
WO2010011836A2 (en) * 2008-07-25 2010-01-28 Emory University Treating various disorders with 7,8-dihydroxyflavone and derivatives thereof
WO2011156479A2 (en) * 2010-06-09 2011-12-15 Emory University Trkb agonists and methods of use
WO2014018741A1 (en) * 2012-07-27 2014-01-30 Emory University Heterocyclic flavone derivatives, compositions, and methods related thereto
WO2014100433A1 (en) * 2012-12-19 2014-06-26 Brown University Methods for treatment of microcephaly associated autism disorders
US20200390755A1 (en) * 2018-08-01 2020-12-17 Shaanxi Micot Technology Co., Ltd. Compound for treating nervous system diseases and use thereof
WO2020154434A1 (en) * 2019-01-24 2020-07-30 Pharmatrophix, Inc. Compositions and methods for treating and preventing cognitive dysfunction
WO2020228513A1 (en) * 2019-05-13 2020-11-19 中国药科大学 Novel cdk9 inhibitor based on benzopyran structure, preparation method therefor and use thereof

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ARKIVOC, vol. 6, 2005, pages 287 - 292
DE MATOS ANA M. ET AL: "Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and A[beta]1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells", PHARMACEUTICALS, vol. 12, no. 2, 21 June 2019 (2019-06-21), pages 98, XP055934846, DOI: 10.3390/ph12020098 *
FREE RADIC RES, vol. 36, no. 11, November 2002 (2002-11-01), pages 1199 - 208
LIU XIA ET AL: "Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 19, 3 October 2012 (2012-10-03), US, pages 8524 - 8537, XP055896585, ISSN: 0022-2623, DOI: 10.1021/jm301099x *
M. E. AULTONK. M. G. TAYLOR: "Aulton's Pharmaceutics - The Design and Manufacture of Medicines", 2013, CHURCHILL LIVINGSTONE ELSEVIER
M. JIANG ET AL: "Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease", HUMAN MOLECULAR GENETICS, vol. 22, no. 12, 27 February 2013 (2013-02-27), GB, pages 2462 - 2470, XP055340409, ISSN: 0964-6906, DOI: 10.1093/hmg/ddt098 *
SHENG R ET AL: "Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors", BIOORGANIC, ELSEVIER, AMSTERDAM, NL, vol. 17, no. 18, 15 September 2009 (2009-09-15), pages 6692 - 6698, XP026545208, ISSN: 0968-0896, [retrieved on 20090803], DOI: 10.1016/J.BMC.2009.07.072 *
XIA LIU ET AL: "A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 23, 9 December 2010 (2010-12-09), pages 8274 - 8286, XP055084240, ISSN: 0022-2623, DOI: 10.1021/jm101206p *

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