WO2022200542A1

WO2022200542A1 - Flavonoid polyamines and their use treating central nervous system disorders

Info

Publication number: WO2022200542A1
Application number: PCT/EP2022/057856
Authority: WO
Inventors: Dan Florin STOICESCU
Original assignee: Floratek Pharma SA
Priority date: 2021-03-24
Filing date: 2022-03-24
Publication date: 2022-09-29
Also published as: GB202104122D0; WO2022200540A1; WO2022200540A9

Abstract

The present invention relates to the use of chromen-4-one derivatives, and to 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

Flavonoid Polyamines 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 multi-salts, solvates, prodrugs, in the treatment and prevention of medical disorders and diseases, most especially those related to neurotrophic factors pathways and mitochondrial activity, in particular a disease, disorder or condition of the central nervous system. 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 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: –NR¹¹R¹²; –N(R¹⁰)-(CH2)p–NR¹¹R¹²; and –N(R¹⁰)-(CH₂)_q–N(R¹⁰)-(CH₂)_q–NR¹¹R¹²; –N(R¹⁰)-(CH2)r–N(R¹⁰)-(CH2)r–N(R¹⁰)–(CH2)r–NR¹¹R¹² R¹ , R², and R⁵, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, –OC(O)N(R¹³)2; R⁴ is selected from –OH, -O-C_1-4 alkyl, -OC(O)R₁₃, -OC(O)NHR¹³, – OC(O)N(R¹³)2, or from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; each -R^β is independently selected from a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C3-C14 cyclic group, and wherein any -R^β 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, C_1-6 alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R¹⁰, when not H, is independently optionally substituted with 1 or 2 -R^β; R¹¹ and R¹² are independently selected from H, C_1-6-alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, benzyl, and benzyl substituted with –O(C_1-4 alkyl); wherein each R¹¹ and R¹², when is not H, are independently optionally substituted with 1 or 2 - R^β; 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 C_1-4 alkyl or with benzyl; 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, C_1-6 alkoxy, C_1-6 alkylthio, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, C_1-6 alkylsulfinyl, C_1-6 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, C_3-14 cyclic group, halo, -NO₂, -CN, -OH, -NH₂, mercapto, formyl, carboxy, carbamoyl, C_1-6 alkoxy, C_1-6 alkylthio, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, C_1-6 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- methyl carbamoyl N-ethyl carbamoyl N,N-dimethyl carbamoyl, N,N-diethyl carbamoyl, N-methyl-N-ethyl carbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl N-ethylsulfamoyl N,N -dimethylsulfamoyl N,N -diethylsulfamoyl, N-methyl-N -ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; n = 0-6; each p is independently an integer selected from l 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.

A second aspect of the invention provides a compound selected from Table A herein.

A third aspect of the invention provides pharmaceutically acceptable salt, multi-salt, solvate or prodrug of the compound of the first or second aspect of the invention.

A fourth aspect of the invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, and a pharmaceutically acceptable excipient.

A fifth aspect of the invention provides a compound of the second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use in medicine, and/ or for use in the treatment or prevention of a disease, disorder or condition. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition.

A sixth aspect of the invention provides the use of a compound of the second aspect, a pharmaceutically effective multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for the treatment or prevention of a disease, disorder or condition. Typically the treatment or prevention comprises the administration of the compound, multi-salt, solvate, prodrug or pharmaceutical composition to a subject. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition. A seventh aspect of the invention provides a method of treatment or prevention of a disease, disorder or condition, the method comprising the step of administering an effective amount of a compound of the second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby treat or prevent the disease, disorder or condition.

Typically the administration is to a subject in need thereof. In one embodiment, the disease, disorder or condition is a central nervous system disease, disorder or condition. An eight aspect of the invention provides a method of treatment or prevention of disease, disorder or condition, the method comprising the step of administering an effective amount of a compound as defined herein, e.g. according to the first aspect of the invention, or a pharmaceutically acceptable salt, 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. 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 maybe saturated or unsaturated (including aromatic), and may be straight-chained or branched, or be or include cyclic groups wherein, unless stated otherwise, the cyclic group does not include any heteroatoms, such as N, O or S, in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and aryl groups/moieties and combinations of all of these groups/moieties. Typically a hydrocarbyl group is a C₁-C₁₂ hydrocarbyl group. More typically a hydrocarbyl group is a 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, l-butenyl, 2-butenyl, 1- pentenyl, l-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl and 1,4- hexadienyl groups/moieties. Unless stated otherwise, the term “alkenyl” does not include “cycloalkenyl”. Typically an alkenyl group is a C₂-C₁₂ alkenyl group. More typically an alkenyl group is a C₂-C₆ alkenyl group. An “alkenylene” group is similarly defined as a divalent alkenyl group.

An “alkynyl” substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups/moieties include ethynyl, propargyl, but-i-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, -0CH₂CH₂CH₃, 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 “alkylsulfmyl” substituent group or alkylsulfmyl 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 sulfmyl groups (-S(=0)-). Each sulfmyl 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(=0)CH₃, - S(=0)CH₂CH₃, - S(=0)CH₂CH₂CH₃, and - S(=0)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 (-S0₂-). 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 - S0₂(CH₃), - S0₂(CH₂CH₃), - S0₂(CH₂CH₂CH₃), and - S0₂(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 (-S0₂-). 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 - S0₂(CH₃), - S0₂(CH₂CH₃), - S0₂(CH₂CH₂CH₃), and - S0₂(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 maybe 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-1-en-1-yl, cyclohex-1-en-1-yl and cyclohex-1,3-dien-1-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:

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(R^β)- or -R^α-) 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:

–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 C_x-C_y 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; ≡ is a triple bond. The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Synthesis’, 4^th edition, T.W. Greene and P.G.M Wuts, Wiley-Interscience. DETAILLED DESCRIPTION OF THE INVENTION A first aspect of the invention provides a compound of formula (1), or pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof, for use treating or preventing a central nervous system disease, disorder or condition:

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 , R², and R⁵, independently, are selected from –OH, -O-C_1-4 alkyl, -OC(O)R₁₃, -OC(O)NHR¹³, –OC(O)N(R¹³)2; R⁴ is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, – OC(O)N(R¹³)₂, or from H; halo; -CN; -NO₂; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; each -R^β is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C₃-C₁₄ cyclic group, and wherein any -R^β 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, C_3-10 cycloalkyl, and benzyl, wherein each R¹⁰, when not H, is independently optionally substituted with 1 or 2 -R^β; 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 - R^β; 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 or with benzyl; each -R¹³ is independently selected from a H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C_3-14 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, C_1-6 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. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH and -O-C_1-4 alkyl. For example, R¹ , R², and R⁵, independently, are selected from –OH and -OCH3. In one embodiment, R⁴ is selected from –OH and -O-C_1-4 alkyl; or H. For example, R⁴ is selected from –OH and -OCH₃; or H. In one embodiment, R³, R⁶, R⁷, R⁸, and R⁹, are H. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH, -O-C_1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, –OC(O)N(R¹³)2; R⁴ is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, –OC(O)N(R¹³)2; or from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 - R^β; and R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH, and -O-C1-4 alkyl; R⁴ is selected from –OH and -O-C_{1 4} alkyl or from H; halo; -CN; -NO₂; -R^β; -OH; -OR^β; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. For example, R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -NO2; -R^β; -OH; -OR^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH, and -OCH₃; R⁴ is selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; -R^β; -OH; -OR^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH, and -O-C_1-4 alkyl; R⁴ is selected from –OH, and -O-C1-4 alkyl, or from H; halo; -CN; -NO2; -R^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. For example, R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -NO₂; -R^β; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R¹ , R², and R⁵, independently, are selected from –OH, and -OCH3; R⁴ is selected from –OH, and -OCH₃, or from H; halo; -CN; -NO₂; -R^β; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. For example, R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -NO2; -R^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R¹, R², and R⁵, independently, are selected from –OH, and -OCH₃; R⁴ is selected from –OH, and -OCH3, or from H; halo; -CN; -NO2; and -NH2. For example, R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -NO2; and -NH₂. In one embodiment, R¹, R², and R⁵, independently, are selected from –OH, and -OCH3; R⁴ is selected from –OH, and -OCH3, or from H. For example, R³, R⁶, R⁷, R⁸ and R⁹ are H. In one embodiment, R¹, R² and R⁵, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, –OC(O)N(R¹³)2; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 - R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -R^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are H. In one embodiment, R¹, R² and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; -NH2; -CHO; -COOH. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are H. In one embodiment, R¹, R² and R⁵, independently, are selected from –OH and –O-C_1-4 alkyl; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are H. In one embodiment, R¹, R² and R⁵, independently, are selected from –OH and –OCH₃; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹are H. In one embodiment, R¹ is -O-C_1-4 alkyl, e.g. –O-Me; R² is -OH; R⁵ is -OH ; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -SH; -SO₂H; -NH₂; -CHO; -COOH. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are H. In one embodiment, R¹, R², and R⁵ are -OH ; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 - R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -SH; -SO₂H; -NH₂; -CHO; -COOH. For example, R³, R⁴, R⁶, R⁷, R⁸, and R⁹ are H. In one embodiment, R¹, R², R⁴ _, and R⁵, independently, are selected from –OH, -O-C_1-4 alkyl, -OC(O)R₁₃, -OC(O)NHR¹³, –OC(O)N(R¹³)₂; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 - R^β. For example, R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁶, R⁷, R⁸, and R⁹,independently, are selected from H; halo; -CN; -NO₂; -SH; -SO₂H; -NH₂; -CHO; -COOH. For example, R³, R⁶, R⁷, R⁸, and R⁹,are H. In one embodiment, R¹, R², R⁴ _, and R⁵, are independently selected from –OH and -O-C_1- ₄ alkyl, e.g. –OH and –OCH₃; and R³, R⁶, R⁷, R⁸, and R⁹,independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁶, R⁷, R⁸, and R⁹,independently, are selected from H; halo; -CN; -NO₂; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. For example, R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -SH; -SO₂H; -NH₂; -CHO; -COOH. For example, R³, R⁶, R⁷, R⁸, and R⁹, are H. In one embodiment, R¹, R², R⁴ _, and R⁵, independently, are selected from –OH and –O- C1-4 alkyl; and R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R³, R⁶, R⁷, R⁸, and R⁹, are H. In one embodiment, R¹, R², R⁴ _, and R⁵, independently, are selected from –OH and – OCH3; and R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -SH; -SO2H; and -NH2. For example, R³, R⁶, R⁷, R⁸, and R⁹, are H. In one embodiment, R¹¹ and R¹² are independently selected from H, C_1-6 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 C_1-4 alkyl. In one embodiment, R¹¹ and R¹² are independently selected from H, C_1-2 alkyl, and benzyl substituted with –O(C1-2 alkyl). For example, -NR¹¹R¹² may be –NH2 or -N(C1-2 alkyl)(benzyl substituted with –OCH3). 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 C_1-4 alkyl or with benzyl. 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 or with benzyl. For example, the 5- or 6-membered heterocycle may be piperidine, 4-benzyl piperidine, piperazine, 4-methyl piperazine, or pyrrolidine. In one embodiment, each R¹⁰ is independently selected from H and C1-2 alkyl. For example, each R¹⁰ is independently selected from H and -CH3. In one embodiment, n is an integer from 1 to 4. For example, n can be 1. For example, n can be 3. For example, n can be 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 or with benzyl. 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, 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 C_1-4 alkyl or with benzyl. In one embodiment, p is selected from 2, 3 or 4. In one embodiment, Z is –N(R¹⁰)-(CH2)p–NR¹¹R¹², and n = 0. For example, p may be 2, 3, or 4. 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. In one embodiment, each q is independently selected from 3 or 4. In one embodiment, Z is –N(R¹⁰)-(CH₂)_q–N(R¹⁰)-(CH₂)_q–NR¹¹R¹²; and q is independently selected from 1-4. For example, q may be 2, 3 or 4. For example, Z is – N(R¹⁰)-(CH2)q–N(R¹⁰)-(CH2)q–NR¹¹R¹²; each R¹⁰ is independently selected from H and C1-6 alkyl; and and R¹¹ and R¹² are independently selected from H; C1-6 alkyl; or R¹¹ and R¹² together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with 1 or 2 C1-4 alkyl or with benzyl. In one embodiment, Z is –N(R¹⁰)-(CH₂)_q–N(R¹⁰)-(CH₂)_q–NR¹¹R¹² and n is 0. For example, each q may be selected from 2, 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. 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 -R^β. For example, each R¹⁰ may independently be selected from H, C_1-3 alkyl, and C₂-C₄ alkenyl. For example, each R¹⁰ may independently be selected from H and –CH3. In one embodiment, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; R³ is H; and R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; -C1-4 alkyl; -OH; -O-C1-4 alkyl; halo; -CN; -NO2; -COOH; and -COOR^β. For example, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; -C_1-4 alkyl; - OH; -O-C_1-4 alkyl; halo; -CN; -NO₂; and –COOH. In one embodiment, R¹, R², R⁴ and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH₃; R³ is H; and R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; -C_1-4 alkyl; -OH; -O-C_1-4 alkyl; halo; -CN; -NO₂; -COOH; and -COOR^β. For example, 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:

wherein R¹, R², R⁴, R⁵, n and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R¹, R², R⁴, R⁵ are independently selected from –OH and -O-C_1-4 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:

wherein R¹, R², R⁴, R⁵, n and Z are as defined herein, and R^x is selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. In one embodiment, R^x is selected from H; halo; -CN; -NO2; -R^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOR^β; and benzyl optionally substituted with 1-3 -R^β. In one embodiment, R^x is selected from H; halo; -CN; -NO2; -R^β; -OH; -OR^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R^x is selected from H; halo; -CN; -NO₂; -R^β; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. In one embodiment, R^x is selected from H; halo; -CN; -NO2; -R^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; and -COOR^β. In one embodiment, R^x is selected from H; halo; -CN; -NO2; -CH3; and -NH2. In one embodiment, R^x is H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is H. For example, R¹, R², R⁴, R⁵ are independently selected from –OH and -O-C_1-4 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:

wherein R¹, R², R⁵, n and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 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:

wherein R¹, R², R⁴, R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is H. For example, R¹, R², R⁴, R⁵ 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:

wherein R¹, R², R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ 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:

wherein R¹, R², R⁴, R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is H. For example, R¹, R², R⁴, R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3. In one embodiment, the compounds have a formula (7), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:

wherein R¹, R², R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3. In one embodiment, the compounds have a formula (8), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:

wherein R¹, R², R⁴, R⁵ and Z are as defined herein. 22 For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3, or H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3; and R⁴ is H. For example, R¹, R², R⁴, R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH₃. In one embodiment, the compounds have a formula (9), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:

wherein R¹, R², R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH3. In one embodiment, the compounds have a formula (10), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:

wherein R¹, R², R⁴, R⁵ and Z are as defined herein. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH₃; and R⁴ is selected from –OH and -O-C_1-4 alkyl, e.g. –OH and –OCH₃, or H. For example, R¹, R², and R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH₃; and R⁴ is H. For example, R¹, R², R⁴, R⁵ are independently selected from –OH and -O-C1-4 alkyl, e.g. –OH and –OCH3. In one embodiment, the compounds have a formula (9), or a pharmaceutically acceptable salt, multi-salt, solvate or prodrug thereof:

wherein R¹, R², R⁵ and Z are as defined herein. 24 For example, R¹, R², and R⁵ are independently selected from –OH and -O-C_1-4 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

25

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, salts 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, salts, multi-salts, solvates and prodrugs of the present invention may contain at least one chiral centre. The compounds, multi-salts, solvates and prodrugs may therefore exist in at least two isomeric forms. The present invention encompasses racemic mixtures of the compounds, multi-salts, solvates and prodrugs of the present invention as well as enantiomerically enriched and substantially enantiomerically pure isomers. For the purposes of this invention, a “substantially enantiomerically pure” isomer of a compound comprises less than 5% of other isomers of the same compound, more typically less than 2%, and most typically less than 0.5% by weight. The compounds, multi-salts, solvates and prodrugs of the present invention may contain any stable isotope including, but not limited to ¹²C, ¹³C, ¹H, ²H (D), ¹⁴N, ¹⁵N, ¹⁶O, ¹⁷O, ¹⁸O, ¹⁹F and ¹²⁷I, and any radioisotope including, but not limited to ¹¹C, ¹⁴C, ³H (T), ¹³N, ¹⁵O, ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The compounds, multi-salts, solvates and prodrugs of the present invention may be in any polymorphic or amorphous form. A 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, 4^th 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, or a pharmaceutically effective 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.

In one embodiment, the disease, disorder or condition is a disease, disorder or condition associated with neurotrophic factors pathways. For example, the disease, disorder or condition may be associated with BDNF pathways In one embodiment, 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 may be 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 maybe used for treating or preventing anti-aging or mitochondria linked disorders. In one embodiment, the disease, disorder or condition is selected from but not limited to Parkinson’s disease, Alzheimer’s disease, and depression.

In one embodiment, the disease, disorder or condition is Alzheimer’s disease. An eighth aspect of the invention provides a method of modulating neurotrophic factors pathways (such as BDNF pathways), the method comprising the use of a compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, to modulate neurotrophic factors pathways (such as BDNF pathways).

A ninth aspect of the invention provides a method of modulating mitochondrial function, the method comprising the use of compound of the first or second aspect of the invention, or a pharmaceutically acceptable multi-salt, solvate or prodrug thereof, to modulate mitochondrial function.

In one embodiment of the ninth aspect of the present invention, modulating mitochondrial function includes: modulating Ca influx, energy supply, control of apoptosis and/or ROS production. In one embodiment of the ninth aspect of the present invention, the method comprises delivering a compound of the first or second aspect of the invention to the mitochondria of a cell. In one embodiment of the eighth or ninth aspect of the present invention, the method is performed ex vivo or in vitro, for example in order to analyse the effect on cells of neurotrophic factors pathways modulation or mitochondrial function modulation.

In another embodiment of the eighth or ninth aspect of the present invention, the method is performed in vivo. For example, the method may comprise the step of administering an effective amount of a compound of the first or second aspect, or a pharmaceutically acceptable multi-salt, solvate or prodrug of the third aspect, or a pharmaceutical composition of the fourth aspect, to thereby modulate neurotrophic factors pathways or modulate mitochondrial function. Typically the administration is to a subject in need thereof.

Alternately, the method of the eighth or ninth aspect of the invention may be a method of modulating factors pathways or modulating mitochondrial function in a non human animal subject, the method comprising the steps of administering the compound, multi-salt, solvate, prodrug or pharmaceutical composition to the non human animal subject and optionally subsequently mutilating or sacrificing the non human animal subject. Typically, such a method further comprises the step of analysing one or more tissue or fluid samples from the optionally mutilated or sacrificed non human animal subject.

Unless stated otherwise, in any aspect of the invention, the subject maybe any human or other animal. Typically, the subject is a mammal, more typically a human or a domesticated mammal such as a cow, pig, lamb, goat, horse, cat, dog, etc. Most typically, the subject is a human.

Any of the medicaments employed in the present invention can be administered by oral, parental (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intraarticular, intracranial and epidural), airway (aerosol), rectal, vaginal or topical (including transdermal, buccal, mucosal and sublingual) administration. Typically, the mode of administration selected is that most appropriate to the disorder or disease to be treated or prevented.

For oral administration, the compounds, salts, multi-salts, solvates or prodrugs of the present invention will generally be provided in the form of tablets, capsules, hard or soft gelatine capsules, caplets, troches or lozenges, as a powder or granules, or as an aqueous solution, suspension or dispersion.

Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose. Corn starch and alginic acid are suitable disintegrating agents. Binding agents may include starch and gelatine. The lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material, such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract. Tablets may also be effervescent and/ or dissolving tablets. Capsules for oral use include hard gelatine capsules in which the active ingredient is mixed with a solid diluent, and soft gelatine capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

Powders or granules for oral use maybe provided in sachets or tubs. Aqueous solutions, suspensions or dispersions may be prepared by the addition of water to powders, granules or tablets.

Any form suitable for oral administration may optionally include sweetening agents such as sugar, flavouring agents, colouring agents and/or preservatives.

Formulations for rectal administration maybe presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration maybe presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. For parenteral use, the compounds, 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 maybe presented at an appropriate interval such as once every other day, once a day, twice a day, three times a day or four times a day. The desired dose may be administered in unit dosage form, for example, containing 1 mg to 50 g of active ingredient per unit dosage form.

For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the present invention may occur in combination with any other embodiment of the same aspect of the present invention. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the present invention should also be considered as a preferred, typical or optional embodiment of any other aspect of the present invention.

EXAMPLES - SYNTHESIS OF COMPOUNDS

5,7-Dihydroxy-2-(4-(4-morpholinobutyl)phenyl)-4ff-chromen-4-one General synthesis of Compounds 15 is depicted in the Scheme 3.

Scheme 3: Synthesis of compounds 15

The synthesis of precursor 14.2 is described in Scheme 4.

Scheme 4: Synthesis of precursor 14.2

4-(4-Bromophenyl)butan-1-ol (5.9). Borane tetrahydrofuran complex solution (26.51 g, 308.5 mL, 1 molar in THF, 3.00 Eq, 308.5 mmol) was added at 0 °C to a solution of 4-(4-bromophenyl)butanoic acid (5.8) (25.00 g, 1.00 Eq, 102.8 mmol) in THF (200 mL), and the resulting mixture was left warming up to room temperature overnight. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4 and concentrated in vacuo, yielding crude 4-(4-bromophenyl)butan-1-ol (5.9) (23.4 g, 102 mmol, 99.3 %), which was used without further purification. 1H NMR (400MHz, DMSO): 2-(4-(4-Bromophenyl)butoxy)tetrahydro-2H-pyran (5.10). To a stirred solution of the 4-(4-bromophenyl)butan-1-ol (5.9) (20.00 g, 1.00 Eq, 87.29 mmol) and 3,4-dihydro-2H-pyran (22.03 g, 23.9 mL, 3.00 Eq, 261.9 mmol) in DCM (200 mL) at 0 °C was added p-toluenesulfonic acid monohydrate (332.1 mg, 0.02 Eq, 1.746 mmol). The reaction was stirred at room temperature and progress was monitored by LCMS. Upon completion, the reaction mixture was washed with a 1:1:2 mixture of saturated aqueous NaHCO3/brine/water (200 mL). The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The resulting material was purified on silica gel (0-10% EtOAc/hexane), yielding 2-(4-(4-bromophenyl)butoxy)tetrahydro-2H-pyran (5.10) (18.647 g, 59.529 mmol, 68.20 %) as a transparent colourless oil. 1H NMR (400MHz, DMSO): 4-(4-((Tetrahydro-2H-pyran-2-yl)oxy)butyl)benzaldehyde (5.6). To 2-(4-(4-bromophenyl)butoxy)tetrahydro-2H-pyran (5.10) (10.00 g, 1.00 Eq, 31.92 mmol) dissolved in dry THF (150 mL) at -78 °C was added dropwise a solution of n- butyllithium (2.250 g, 14.05 mL, 2.5 molar, 1.10 Eq, 35.12 mmol) in hexane. After stirring at -78 °C for 1 hour, dry DMF (6.534 g, 6.92 mL, 2.80 Eq, 89.39 mmol) was added dropwise at -78 °C. The reaction mixture was stirred for 1 hour at -78 °C, then allowed to warm up to room temperature and stirred for additional 2 hours before pouring into saturated aqueous solution of NH₄Cl (1 L) and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Purification with column chromatography provided 4-(4- ((tetrahydro-2H-pyran-2-yl)oxy)butyl)benzaldehyde (5.6) (7.379 g, 28.13 mmol, 88.1 %) as a transparent colourless oil. (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). To a solution of 1-(2-hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)ethan-1-one (3.3) (4.00 g, 1.00 Eq, 17.7 mmol) and 4-(4-((tetrahydro-2H-pyran-2- yl)oxy)butyl)benzaldehyde (5.6) (4.87 g, 1.05 Eq, 18.6 mmol) in dioxane (100 mL) at 0 °C, a methanolic solution of sodium methoxide (33.4 g, 115 mL, 5.4 molar, 35 Eq, 619 mmol) was added. and the mixture was allowed to warm up to room temperature and stirred for 18 hours. LCMS was used to confirm that conversion of the starting materials was complete. Then, the reaction mixture was poured into ice-cold brine and extracted EtOAc (3 × 200 mL). The combined extracts were dried over Na2SO4 and then evaporated in vacuo. Obtained crude material was purified by column chromatography, yielding (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) (7.00 g, 14.9 mmol, 84.1 %, containing ~4% of flavanone) as a yellow oil. 3,7-Dihydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4- one (14.1). An aqueous solution of hydrogen peroxide (1.36 g, 1.23 mL, 35% Wt, 2.20 Eq, 14.0 mmol) was added to an ice-cold suspension 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 (7.4) (3.00 g, 1.00 Eq, 6.38 mmol) and sodium hydroxide (1.70 g, 1.28 mL, 30% Wt, 2.00 Eq, 12.8 mmol) in methanol. Reaction was controlled by LCMS, and temperature was allowed to raise gradually. Upon full conversion was confirmed by LCMS (~18 hours), the reaction mixture was cooled in an ice bath and distilled water (2-4 mL) was added, followed by a small amount of saturated aqueous citric acid (until the aqueous layer becomes neutral or slightly acidic). The mixture was extracted with DCM and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was treated with solution of HCl (23.2 g, 159 mL, 4 molar, 100 Eq, 638 mmol) in dioxane. Upon completion, the reaction mixture was concentrated in vacuo. The residue was washed with a small amount of DCM and filtered. The resulting yellow precipitate is a pure 3,7-dihydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4-one (14.1) (1.00 g, 2.81 mmol, 44.0 %). Note: DCM filtrate has been analyzed, and it contained small amount of product. Upon re-concentrating in vacuo, pure product precipitated again, and was filtered off. The residual DCM filtrate was purified by normal phase column chromatography, but only 25 mg of product were recovered from it, so vast majority of the pure flavonol 14.1 is obtained by precipitation. 2-(4-(4-Bromobutyl)phenyl)-3,7-dihydroxy-8-methoxy-4H-chromen-4-one (14.2). A solution of 3,7-dihydroxy-2-(4-(4-hydroxybutyl)phenyl)-8-methoxy-4H-chromen-4- one (14.1) (0.988 g, 1.00 Eq, 2.77 mmol) in dry DCM (10 mL) and DMF (2.03 g, 2.15 mL, 10.00 Eq, 27.7 mmol) was cooled to 0 °C under nitrogen atmosphere. Then, thionyl bromide (749 mg, 280 µL, 1.30 Eq, 3.60 mmol) was added dropwise. After 10 minutes, the cooling bath was removed and the orange solution was stirred at room temperature. Reaction progress was controlled by LCMS. Upon completion (~4 hours), the reaction mixture was cooled with ice-bath and 50 mL of saturated NaHCO₃ were added. The mixture was then extracted with 3 × 100 mL of DCM. Organic layers were combined, washed with 150 mL of saturated aqueous LiCl (instead of brine, to bind DMF), which in turn was extracted with 2 × 50 ml of DCM and dried with sodium sulfate. The solution was filtered and concentrated, yielding crude product, which was suspended in DCM and purified by column chromatography (DCM:MeOH gradient), yielding 2-(4- (4-bromobutyl)phenyl)-3,7-dihydroxy-8-methoxy-4H-chromen-4-one (14.2) (1.12 g, 2.67 mmol, 96.4 %) as a pale yellow solid. 3,7-Dihydroxy-8-methoxy-2-(4-(4-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)butyl)phenyl)-4H-chromen-4-one trihydrochloride (15F/SND193). A mixture of N-methyl-2-(4-methylpiperazin-1-yl)ethan-1-amine (188 mg, 2.5 Eq, 1.19 mmol) and DIPEA (92.5 mg, 125 µL, 1.5 Eq, 716 µmol) in acetonitrile (3 mL) was added to a suspension of 2-(4-(4-bromobutyl)phenyl)-3,7-dihydroxy-8- methoxy-4H-chromen-4-one (14.2) (0.200 g, 1.00 Eq, 477 µmol) in acetonitrile (3 mL) under nitrogen flow. The mixture was heated to 50 °C and stirred for 20 hours. Upon completion, solvent and excess of amines were removed in vacuo. When dissolving the residue in DCM, part started precipitating, but the precipitate was too fine to be filtered. Thus, 5 mL of 4N HCl in dioxane were added, and the resulting mixture was stirred for 1 hour before being concentrated in vacuo. Resulting solid residue was highly soluble in water, so purification by reversed phase chromatography (using a gradient mixture of 0.1% HCl in water and methanol) was performed, yielding 203 mg of yellow material containing trihydrochloride of 15F. LCMS determined that the purity was not sufficient, so the material was re-purified by reversed phase chromatography. This allowed obtaining sufficiently pure (>95% by LCMS) 3,7- dihydroxy-8-methoxy-2-(4-(4-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)butyl)phenyl)-4H-chromen-4-one trihydrochloride (15F) (0.115 g, 190 µmol, 39.8 %) as a dark-green solid, which is highly soluble in water and/or methanol. General synthesis route Compounds SND180-183

General Procedure for Reductive Amination. 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 0 °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 in one of the following manners: Method I. Reaction mixture was quenched with methanol and concentrated in vacuo (to remove amine if possible). Residue was dissolved in DCM and filtered from any formed debris. Then, DCM filtrate was washed with minimum volume of 1:1 mixture of water and brine, dried over Na2SO4 and concentrated in vacuo. Crude product was purified using normal phase column chromatography (with silica gel and a gradient of 3.5N ammonia in methanol with DCM as eluent). After identifying, combining and concentrating appropriate fractions, resulting material was re-dissolved in methanol, and excess of 4N HCl was 4N HCl in dioxane was added upon stirring (until the pH remained constantly acidic). The resulting solution was concentrated, yielding desired product as a hydrochloride. Method II. The reaction mixture was quenched with methanol, concentrated in vacuo (to remove amine if possible), re-dissolved in methanol and excess of 4N HCl 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% HCl in water and methanol), yielding desired product as a hydrochloride. 4-(3,7-Dihydroxy-8-methoxy-4-oxo-4H-chromen-2-yl)benzaldehyde (16.1). An aqueous solution of hydrogen peroxide (513.3 mg, 454 µL, 35% Wt, 2.20 Eq, 5.282 mmol) was added to an ice-cold suspension of (E)-3-(4-(diethoxymethyl)phenyl)-1-(2- hydroxy-3-methoxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (9.8) (1.000 g, 1.00 Eq, 2.401 mmol) and sodium hydroxide (640.3 mg, 481 µL, 30% Wt, 2.00 Eq, 4.802 mmol) in methanol. Reaction was controlled by LCMS, and temperature was allowed to raise gradually. Upon full conversion was confirmed by LCMS (~18 hours), the reaction mixture was cooled in an ice bath and distilled water (2-4 mL) was added, followed by a small amount of saturated aqueous citric acid (until the aqueous layer becomes neutral or slightly acidic). The mixture was extracted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was treated with solution of HCl (8.755 g, 60.03 mL, 4 molar, 100.00 Eq, 240.1 mmol) in dioxane. Upon completion, the reaction mixture was concentrated in vacuo. The residue was washed with a small amount of DCM and filtered. The resulting yellow precipitate was a pure 4-(3,7-dihydroxy-8-methoxy-4-oxo-4H-chromen-2- yl)benzaldehyde (16.1) (0.406 g, 2.401 mmol, 54.1 %). Note: DCM filtrate has been analyzed, and it contained small amount of product. Upon re-concentrating in vacuo, pure product precipitated again, and was filtered off. The residual DCM filtrate did not contain any flavonol 16.1 and was discarded. Compounds 16 were prepared as hydrochlorides from aldehyde 16.1 and respective amines following the General Procedure for Reductive Amination, using work up Method I or Method II. 3,7-Dihydroxy-8-methoxy-2-(4-(morpholinomethyl)phenyl)-4H-chromen- 4-one hydrochloride (16A/SND183). Utilizing 4-(3,7-dihydroxy-8-methoxy-4- oxo-4H-chromen-2-yl)benzaldehyde (16.1) (0.376 g, 1.00 Eq, 1.20 mmol), morpholine (210 mg, 208 µL, 2.00 Eq, 2.41 mmol) and sodium triacetoxyhydroborate (561 mg, 2.20 Eq, 2.65 mmol), and following workup Method I, pure 3,7-dihydroxy-8-methoxy-2-(4- (morpholinomethyl)phenyl)-4H-chromen-4-one hydrochloride (16A) (0.056 g, 0.13 mmol, 11 %) was obtained as a beige solid, solubility of which in water and/or methanol is mediocre. 3,7-Dihydroxy-8-methoxy-2-(4-(piperidin-1-ylmethyl)phenyl)-4H- chromen-4-one hydrochloride (16C/SND180). Utilizing 4-(3,7-dihydroxy-8- methoxy-4-oxo-4H-chromen-2-yl)benzaldehyde (16.1) (0.173 g, 1.00 Eq, 554 µmol), piperidine (94.3 mg, 109 µL, 2.00 Eq, 1.11 mmol) and sodium triacetoxyhydroborate (258 mg, 2.20 Eq, 1.22 mmol), and following workup Method II, pure 3,7-dihydroxy- 8-methoxy-2-(4-(piperidin-1-ylmethyl)phenyl)-4H-chromen-4-one hydrochloride (16C) (0.061 g, 0.16 mmol, 29 %) was obtained as a dark golden solid, with mediocre solubility in water and/or methanol, but good solubility in DMSO. 3,7-Dihydroxy-8-methoxy-2-(4-((methyl(2-(piperidin-1- yl)ethyl)amino)methyl)phenyl)-4H-chromen-4-one dihydrochloride (16E/SND181). Utilizing 4-(3,7-dihydroxy-8-methoxy-4-oxo-4H-chromen-2- yl)benzaldehyde (16.1) (0.130 g, 1.00 Eq, 416 µmol), N-methyl-2-(piperidin-1-yl)ethan- 1-amine (118 mg, 2.00 Eq, 833 µmol) and sodium triacetoxyhydroborate (194 mg, 2.20 Eq, 916 µmol), and following workup Method II, pure 3,7-Dihydroxy-8-methoxy-2-(4- ((methyl(2-(piperidin-1-yl)ethyl)amino)methyl)phenyl)-4H-chromen-4-one dihydrochloride (16E) (0.144 g, 282 µmol, 67.6 %) was obtained as a yellow solid, which is highly soluble in water and/or methanol. 3,7-Dihydroxy-8-methoxy-2-(4-((methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)methyl)phenyl)-4H-chromen-4-one trihydrochloride (16F/SND182). Utilizing 4-(3,7-dihydroxy-8-methoxy-4-oxo-4H-chromen-2- yl)benzaldehyde (16.1) (0.130 g, 1.00 Eq, 416 µmol), N-methyl-2-(4-methylpiperazin-1- yl)ethan-1-amine (131 mg, 2.00 Eq, 833 µmol) and sodium triacetoxyhydroborate (194 mg, 2.20 Eq, 916 µmol), and following workup Method II, pure 3,7-dihydroxy-8- methoxy-2-(4-((methyl(2-(4-methylpiperazin-1-yl)ethyl)amino)methyl)phenyl)-4H- chromen-4-one trihydrochloride (16F) (0.147 g, 261 µmol, 62.7 %) was obtained as a pale yellow powder, which is highly soluble in water and/or methanol. 3,7-Dihydroxy-8-methoxy-2-(4-(4-(methyl(2-(piperidin-1- yl)ethyl)amino)butyl)phenyl)-4H-chromen-4-one dihydrochloride (15E/SND192). A mixture of N-methyl-2-(piperidin-1-yl)ethan-1-amine (170 mg, 2.5 Eq, 1.19 mmol) and DIPEA (92.5 mg, 125 µL, 1.5 Eq, 716 µmol) in acetonitrile (3 mL) was added to a suspension of 2-(4-(4-bromobutyl)phenyl)-3,7-dihydroxy-8-methoxy-4H- chromen-4-one (14.2) (0.200 g, 1.00 Eq, 477 µmol) in acetonitrile (3 mL) under nitrogen flow. The mixture was heated to 50 °C and stirred for 20 hours. Upon completion, solvent and excess of amines were removed in vacuo. When dissolving the residue in DCM, part started precipitating. This precipitate did not dissolve in water, DCM, acetone, methanol, but immediately dissolved in HCl. Thus, 5 mL of 4N HCl in dioxane were added, and the resulting mixture was stirred for 1 hour before being concentrated in vacuo. Resulting solid residue was highly soluble in water, so purification by reversed phase chromatography (using a gradient mixture of 0.1% HCl in water and methanol) was performed, yielding 3,7-dihydroxy-8-methoxy-2-(4-(4- (methyl(2-(piperidin-1-yl)ethyl)amino)butyl)phenyl)-4H-chromen-4-one dihydrochloride (15E) (0.170 g, 307 µmol, 64.4 %) as a yellow crystalline solid, which is highly soluble in water and/or methanol. Synthesis of SND441

Core I 3

To a solution of Compound 7g (102.53 mg, 602.09 mihoΐ, 5.72 pL, l.oo eq) and Core I (300 mg, 602.09 mihoΐ, l.oo eq) in DMF (1 mL) was added RuPhos (56.19 mg, 120.42 mihoΐ, 0.20 eq), Cs₂C0₃ (588.52 mg, 1.81 mmol, 3.00 eq) and Pd₂ (dba)₃ (110.27 mg, 120.42 mmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 12 hr. LCMS (EW30189-352-P1A) showed Core I was consumed. Several new peaks were shown on LCMS and 48.736% 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 3 (300 mg, 560.14 pmol, 93.03% yield) was obtained as a red oil.

LCMS: MS (ESI) Retention time: 0.740mm (M+H)⁺ = 541.4, 5-95AB_R_220&254.1cm

To a solution of Compound 3 (300 mg, 554.89 pmol, 1.00 eq) in EtOH (3.5 mL) and DCM (0.5 mL) was added methanesulfonic acid (639.94 mg, 6.66 mmol, 474.03 pL, 12 eq). The mixture was stirred at 60 °C for 0.5 hr. LCMS (EW30189 - 356-PiA) showed Compound 3 was consumed completely and 55.545% 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% HCl condition). SND441 (190 mg, 381.94 μmol, 68.83% yield, 98.3% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-356-P1A), LCMS (EW30189-356-P1P) and Melting Point (EW30189-356-P1A). TLC (SiO₂, DCM: MeOH = 10/1, Rf = 0.4) and Melting Point = 189.4 ^oC. LCMS: MS (ESI) Retention time: 0.689min (M+H)⁺ = 453.2, EW30189-356-P1A LCMS: MS (ESI) Retention time: 1.573min (M+H)⁺ = 453.2, EW30189-356-P1P ¹H NMR (400 MHz, DMSO-d₆) δ = 10.40 (br s, 1H), 8.11-8.09 (d, J = 9.2 Hz, 2H), 7.6- 7.64 (d, J = 8.8 Hz, 1H), 7.04-7.02 (d, J = 8.8 Hz, 3H), 3.92 (s, 3H), 3.48-3.44 (t, J = 7.2 Hz, 2H), 3.38-3.35 (d, J = 11.6 Hz, 2H), 3.03-2.99 (m, 5H), 2.80-2.78 (m, 2H), 1.76- 1.71 (m, 7H), 1.58-1.54 (m, 2H), 1.37 (m, 1H). Synthesis of SND 341

To a solution of Compound 1 (2 g, 8.62 mmol, 1.00 eq) and Compound 2 (1.30 g, 12.93 mmol, 1.43 mL, 1.50 eq) in DMF (20 mL) was added Cs2CO3 (8.43 g, 25.86 mmol, 3.00 eq), Pd2(dba)3 (1.58 g, 1.72 mmol, 0.20 eq) and RuPhos (804.49 mg, 1.72 mmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 16 hr. LCMS (EW30189-31-P1B) showed Compound 1 was consumed completely 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 C18; 150 × 50 mm × 10 um; mobile phase: [water(10mM NH4HCO3)-ACN]; B%: 44%-74%, 7 min). Compound 3 (1 g, 4.90 mmol, 56.79% yield) was obtained as a yellow oil. LCMS: MS (ESI) Retention time: 0.222 min, (M+1) + = 205.1, EW30189-31-P1B.

Pyrrolidine (1.49 g, 20.96 mmol, 1.75 mL, 10 eq) was added to a solution of Compound 3 (600 mg, 2.10 mmol, 1.00 eq), Compound 4 (428.12 mg, 2.10 mmol, 1.00 eq) in H2O (6 mL) at 25 °C, and the mixture was stirred at 50 °C for 16 hrs. LCMS (EW30065-75-P1A) showed Compound 3 was consumed and desired mass was detected. The reaction mixture was extracted with EtOAc (20 ml x 3) and H2O (10 ml x 3), the organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from H2O (10 ml) at 25 °C. Compound 5 (1 g, 2.01 mmol, 96.11% yield, 98% purity) was obtained as a brown solid, which was confirmed by LCMS (EW30065-75-P1A2), HNMR (EW30065-75-P1A).

LCMS: MS (ESI) Retention time: 0.694 min, (M+i) + =487.3, EW30065-75-P1A. LCMS: MS (ESI) Retention time: 0.785 min, (M+i) + =487.3, EW30065-75-1A2. lH NMR (400 MHz, DMSO-d6) d = 8.o8-8.o6 (d, J = 8.8 Hz, 2H), 7.11-7.09 (d, J = 8.9 Hz, 2H), 6.84 (s, lH), 5.36 (s, 2H), 5.24 (s, 2H), 3.89 (s, 3H), 3-47 (m, 6H),

3.32-3-29 (m, 4H), 2.45 (m, 4H), 2.22 (s, 3H).

To a solution of compound 5 (1 g, 2.06 mmol, 1 eq) in dioxane (5 mL) was added HCl (12M, 171.29 uL, 1 eq), and the mixture was stirred at 25 °C for 6 hr. LCMS (EW30065-79-P1A) showed compound 5 was consumed and desired mass was detected . The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from H2O (10 ml). SND341 (404.05 mg, 929.13 umol, 45.20% yield, 100% purity, HCl) was obtained as a yellow solid, which was confirmed by LCMS (EW30065-79-P1E), HNMR (EW30065-79-P1B2), Melting point (EW30065-79-P1A). LCMS: MS (ESI) Retention time: 0.751 min, (M+1) + =399.1, EW30065-79-P1A. LCMS: MS (ESI) Retention time: 1.453 min, (M+1) + =399.1, EW30065-75-P1E. 1H NMR (400 MHz, DMSO-d6) δ = 8.09 (br d, J = 8.3 Hz, 2H), 7.17 (br d, J = 7.9 Hz, 2H), 6.30 (br s, 1H), 3.81 (s, 3H), 3.58 - 3.49 (m, 4H), 3.31 (br s, 4H), 2.82 (s, 3H) Melting point : 270.3℃ TLC (SiO2, ethyl acetate, Rf = 0.2) Synthesis of SND342

Pyrrolidine (994 mg, 13.97 mmol, 1.17 mL, 10.0 eq) was added to a solution of Compound 2 (400 mg, 1.40 mmol, 1.00 eq), Compound 1 (264 mg, 1.40 mmol, 1.00 eq) in H2O (4 mL) at 25 °C, and the mixture was stirred at 50 °C for 16 hrs. LCMS (EW30065-130-P1A) showed Compound 2 was consumed and desired mass was detected. The reaction mixture was extracted with EA (20 ml x 3) and H2O (10 ml x 3), the organic phase was dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 x 40 mm x 15 um; mobile phase: [water (FA)-ACN]; B%: 50%-8o%, 10 min). Compound 3 (200 mg, 377.52 umol, 27.02% yield, 89% purity) was obtained as a yellow solid, which was confirmed by LCMS (EW30065-130--P1B).

LCMS: MS (ESI) Retention time: 0.788 min, (M+i) + = 472.2, EW30065-130- PiA. LCMS: MS (ESI) Retention time: 0.781 min, (M+i) + = 472.2, EW30065-130-P1B.

To a solution of Compound 3 (150 mg, 318.13 umol, 1.00 eq) in EtOH (1.40 mL) and DCM (0.20 mL) was added PTSA (657 mg, 3.82 mmol, 12.0 eq), and the mixture was stirred at 60°C for 3 hr. LCMS (EW30065-137-P1A) showed Compound 3 was consumed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by re-crystallization from MeOH (5ml) and H2O (15 ml) at 25 °C. SND342 (50 mg, 126.94 umol, 39.90% yield, 97.333% purity) was obtained as a yellow solid, which was confirmed by HNMR (EW30065-137-P1B), LCMS (EW30065-137-P1F). LCMS: MS (ESI) Retention time: 0.759 min, (M+1) + =384.1, EW30065-137-P1A. LCMS: MS (ESI) Retention time: 1.743 min, (M+1) + =384.1, EW30065-137-P1F 1H NMR (400 MHz, DMSO-d6) δ = 12.24-12.19 (br s, 1H), 8.10-8.08 (d, J = 8.4 Hz, 2H), 7.08-7.06 (d, J = 8.8 Hz, 2H), 6.22 (s, 1H), 3.81 (s, 3H), 1.60 (s, 9H), 1.23 (s, 1H). 1H NMR (400 MHz, DMSO-d6) δ = 12.30 - 12.16 (m, 1H), 8.10-8.08 ( d, J = 8.4 Hz, 2H), 7.08-7.06 ( d, J = 8.8 Hz, 2H), 6.22 ( s, 1H), 3.81 (s, 3H), 3.48 - 3.43 (m, 4H), 1.60 ( s, 6H) Synthesis of SND343

To a solution of Compound 1 (300 mg, 1.29 mmol, 1.00 eq) and Compound 7e (220.19 mg, 1.29 mmol, 1.28 mL, 1.00 eq) in DMF (5 mL) was added Cs2CO3 (1.26 g, 3.88 mmol, 3.00eq), Pd2 (dba)3 (236.81 mg, 258.60 μmol, 0.20 eq) and RuPhos (120.67 mg, 258.60 μmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 16 hr. LCMS (EW30189-117-P1A) showed Compound 1 was consumed completely and 27% 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: Phenomenex luna C18; 250 × 50 mm × 15 um; mobile phase: [water (FA) -ACN]; B%: 7%-37%, 10 min). Compound 2 (130 mg, 473.76 μmol, 36.64% yield) was obtained as a yellow oil. LCMS: MS (ESI) Retention time: 0.607 min (M+H)+ = 275.1, 5-95AB_R_220&254.lcm

To a solution of Compound 2 (130 mg, 473.76 μmol, 1.00 eq) and Core 2A (135.63 mg, 473.76 μmol, 1.00 eq) in H2O (2 mL), then added PYRROLIDINE (336.94 mg, 4.74 mmol, 395.47 μL, 10.0 eq) was strried at 50 °C for 16 hrs. LCMS (EW30189-123-P1A) showed Compound 2 was consumed completely and 56% 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: Phenomenex luna C18; 250 × 50 mm × 15 um; mobile phase: [water (FA) -ACN]; B%: 20%-50%, 10 min). Compound 3 (90 mg, 161.68 μmol, 34.13% yield) was obtained as a yellow oil. LCMS: MS (ESI) Retention time: 0.802min (M+H)+ = 557.2, 5-95AB_R_220&254.lcm

To a solution of Compound 3 (90 mg, 161.68 μmol, 1.00 eq) in EtOH (1.4 mL) and DCM (0.2 mL) was added PTSA (334.10 mg, 1.94 mmol, 12.0 eq). The mixture was stirred at 60°C for 3 hrs. LCMS (EW30189-131-P1A) showed Compound 3 was consumed completely and 88% 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%: 25%-45%, 7 min). Floratek-002-007 (69.57 mg, 148.48 μmol, 91.84% yield, 100% purity) was obtained as a yellow oil, which was determined by HNMR (EW30189-131-P1C) and LCMS (EW30189-131-P1S). 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: 0.819min (M+H)+ = 469.3, EW30189-131-P1A LCMS: MS (ESI) Retention time: 1.679min (M+H)+ = 469.2, EW30189-131-P1S 1H NMR (400 MHz, DMSO+D2O) δ = 8.15-8.12 (d, J = 9.2 Hz, 1H), 7.59-7.57 (d, J = 8.0 Hz, 1H), 7.23-7.22 (d, J = 7.6 Hz, 1H), 6.95-6.93 (d, J = 9.2 Hz, 1H), 6.36 (s, 1H), 3.89 (s, 3H), 3.54-3.45 (m, 4H), 3.12-3.07 (m, 5H), 2.90-3.87 (m, 2H), 1.90- 1.63 (m, 10H). Synthesis of SND421 & SND422

(E)-3-(4-(Diethoxymethyl)phenyl)-1-(4-hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)prop-2-en-1-one (36.1). To a solution of 1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5-yl)ethan-1-one (12.7) (3.255 g, 1.00 Eq, 9.794 mmol) and 4-(diethoxymethyl)benzaldehyde (9.1) (2.142 g, 2.045 mL, 1.05 Eq, 10.28 mmol) in 1,4-dioxane (100 mL) at 0 °C, a methanolic solution of sodium methoxide (18.5 g, 64 mL, 5.4 molar, 35 Eq, 343 mmol) was added. Resulting mixture was allowed to warm up to room temperature and stirred for 18 hours. Upon reaction completion was confirmed by LCMS (after 18 hours), reaction mixture was poured into ice-cold brine and extracted with EtOAc (3 × 250 mL). The combined extracts were dried over Na₂SO₄, and then evaporated in vacuo. Obtained crude sodium phenolate of (E)-3-(4- (diethoxymethyl)phenyl)-1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5- yl)prop-2-en-1-one (36.1) (5.340 g, 10.22 mmol, 100 %) as a bright-orange oil, which solidifies with friction. 4-(7-hydroxy-6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-8- yl)benzaldehyde (36.2). An aqueous solution of hydrogen peroxide (1.23 g, 1.09 mL, 35% Wt, 2.20 Eq, 12.6 mmol) was added to an ice-cold suspension of (E)-3-(4-(diethoxymethyl)phenyl)-1-(4-hydroxy-2,2- diphenylbenzo[d][1,3]dioxol-5-yl)prop-2-en-1-one (36.1) (3.00 g, 1.00 Eq, 5.74 mmol) and sodium hydroxide (1.5 g, 1.2 mL, 30% Wt, 2.00 Eq, 11.5 mmol) in methanol. Reaction was controlled by LCMS, and temperature was allowed to raise gradually. As after 18 hours conversion was incomplete, addition of hydrogen peroxide and sodium hydroxide was repeated. Upon full conversion was confirmed by LCMS (~3 days), the reaction mixture was cooled in an ice bath and distilled water (2-4 mL) was added, followed by a small amount of aqueous HCl (until the aqueous layer becomes neutral or slightly acidic). The mixture was extracted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was re- dissolved in DCM and treated with solution of HCl (3.14 g, 21.5 mL, 4 molar, 15 Eq, 86.1 mmol) in 1,4-dioxane. Upon completion, the reaction mixture was concentrated in vacuo. The residue was washed with a small amount of DCM and filtered. The resulting orange precipitate contained 4-(7-hydroxy-6-oxo-2,2- diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-8-yl)benzaldehyde (36.2) (819 mg, 1.53 mmol, 23%). 4-(3,7,8-Trihydroxy-4-oxo-4H-chromen-2-yl)benzaldehyde (36.4). An aqueous solution of hydrogen peroxide (140 mg, 124 µL, 35% Wt, 2.20 Eq, 1.44 mmol) was added to an ice-cold suspension of (E)-3-(4- (diethoxymethyl)phenyl)-1-(4-hydroxy-2,2-diphenylbenzo[d][1,3]dioxol-5- yl)prop-2-en-1-one (36.1) (341 mg, 1.00 Eq, 653 µmol) and sodium hydroxide (170 mg, 0.13 mL, 30% Wt, 2.00 Eq, 1.30 mmol) in ethanol. Reaction was controlled by LCMS, and temperature was allowed to raise gradually. After 18 hours conversion was incomplete, so same amount of reagents was added, and reaction mixture was left stirring for another 24 hours. Upon full conversion was confirmed by LCMS (~2-3 days, depending on a scale), the reaction mixture was cooled in an ice bath and distilled water (2-4 mL) was added, followed by a small amount of saturated aqueous citric acid (until the aqueous layer becomes neutral or slightly acidic). The mixture was extracted with DCM and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was re-dissolved in DCM and ethanol, and treated with a 4M solution of HCl (3.75 g, 2.51 mL, 10.00 Eq, 103 mmol) in 1,4-dioxane. Upon completion, the reaction mixture was concentrated in vacuo. The residue was washed with a small amount of DCM and filtered. The resulting red precipitate was a pure 4-(3,7,8-trihydroxy-4-oxo-4H-chromen-2-yl)benzaldehyde (36.4) (102 mg, 342 µmol, 52%). 7-Hydroxy-2,2-diphenyl-8-(4-(piperidin-1-ylmethyl)phenyl)-6H- [1,3]dioxolo[4,5-h]chromen-6-one (36.3C). Utilizing 4-(7-hydroxy-6-oxo- 2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-8-yl)benzaldehyde (36.2) (410 mg, 1.00 Eq, 887 µmol), piperidine (151 mg, 175 µL, 2 Eq, 1.77 mmol) and sodium triacetoxyborohydride (432 mg, 2.3 Eq, 2.04 mmol), and following workup Method I (up until treatment with HCl) crude 7-hydroxy-2,2-diphenyl-8-(4- (piperidin-1-ylmethyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (36.3C) (187 mg, 352 µmol, 40%) was obtained as a yellow powder. 3,7,8-Trihydroxy-2-(4-(piperidin-1-ylmethyl)phenyl)-4H-chromen-4- one hydrochloride (36C/SND422). Solution of 7-hydroxy-2,2-diphenyl-8- (4-(piperidin-1-ylmethyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (36.3C) (206 mg, 1.00 Eq, 388 µmol) in acetonitrile (2 mL) was treated with excess of 4N HCl solution in 1,4-dioxane, and following workup Method II, pure 3,7,8- trihydroxy-2-(4-(piperidin-1-ylmethyl)phenyl)-4H-chromen-4-one hydrochloride (36C) (78 mg, 0.19 mmol, 50%) was obtained as a yellow solid, which dissolves well in DMSO and methanol, but poorly in water. 3,7,8-Trihydroxy-2-(4-((methyl(3-(piperidin-1- yl)propyl)amino)methyl)phenyl)-4H-chromen-4-one dihydrochloride (36K/SND421). Utilizing 4-(3,7,8-trihydroxy-4-oxo-4H-chromen-2- yl)benzaldehyde (36.4) (102 mg, 1.00 Eq, 342 µmol), N-methyl-3-(piperidin-1- yl)propan-1-amine (107 mg, 2.00 Eq, 684 µmol) and sodium triacetoxyborohydride (159 mg, 2.20 Eq, 752 µmol), and following workup Method II, pure 3,7,8-trihydroxy-2-(4-((methyl(3-(piperidin-1- yl)propyl)amino)methyl)phenyl)-4H-chromen-4-one dihydrochloride (36K) (67 mg, 0.13 mmol, 38%) was obtained as a yellow solid, which is highly soluble in water, methanol, or DMSO. Synthesis of SND443

To a solution of Core I (300 mg, 602.09 μmol, 1.00 eq), RuPhos (56.19 mg, 120.42 μmol, 0.20 eq), Pd2 (dba)3 (110.27 mg, 120.42 μmol, 0.20 eq) and Cs2CO3 (588.52 mg, 1.81 mmol, 3.00 eq) in DMF (3 mL), then added Compound 7p (150.75 mg, 602.09 μmol, 1.00 eq) at 25 °C, the mixture was strried at 100 °C for 16 hr. LCMS (EW30189-362-P1A) showed Core I consumed. Several new peaks were shown on LCMS and 33.183% 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 3 (300 mg, 483.30 μmol, 80.27% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.776min (M+H)⁺ = 621.4, 5- 95AB_R_220&254.lcm

To a solution of Compound 3 (300 mg, 483.30 μmol, 1.00 eq) in MeOH (2.1 mL) and DCM (0.3 mL) was added methanesulfonic acid (557.38 mg, 5.80 mmol, 412.87 μL, 12 eq). The mixture was stirred at 60 °C for 0.5 hr. LCMS (EW30189 - 366-P1A) showed Compound 3 was consumed completely and 41.981% 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% HCl condition). Compound SND443 (155 mg, 258.85 μmol, 53.56% yield, 95.036% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-366-P1A) and LCMS (EW30189-366-P1J). 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: 0.830min (M+H)⁺ = 533.4, EW30189-366-P1A LCMS: MS (ESI) Retention time: 1.755min (M+H)⁺ = 533.3, EW30189-366-P1J ¹H NMR (400 MHz, DMSO-d6) δ = 9.82 (br s, 1H), 8.11-8.09 (d, J = 9.2 Hz, 2H), 7.67-7.64 (d, J = 8.8 Hz, 1H), 7.57 (m, 1H), 7.46-7.44 (m, 1H), 7.11-7.09 (d, J = 8.4 Hz, 1H), 7.04-6.99 (m, 4H), 4.24-4.22 (t, J = 4.4 Hz, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.46 (m, 2H), 3.01 (s, 7H), 1.79-1.73 (m, 2H), 1.56-1.53 (m, 2H), 1.28- 1.25 (t, J = 7.2 Hz, 3H).

To a solution of Compound 7l (94.09 mg, 602.09 μmol, 5.72 μL, 1.00 eq) and Core I (300 mg, 602.09 μmol, 1.00 eq) in DMF (3 mL) was added RuPhos (56.19 mg, 120.42 μmol, 0.20 eq), Cs2CO3 (588.52 mg, 1.81 mmol, 3.00 eq) and Pd2 (dba)₃ (110.27 mg, 120.42 μmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 12 hr under N₂. LCMS (EW30189-375-P1A) showed Core I consumed. Several new peaks were shown on LCMS and 24.518% 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 3 (300 mg, 569.67 μmol, 94.62% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.735min (M+H)⁺ = 527.4, 5- 95AB_R_220&254.lcm

To a solution of Compound 3 (300 mg, 569.67 μmol, 1.00 eq) in MeOH (2.1 mL) and DCM (0.3 mL) was added methanesulfonic acid (54.75 mg, 569.67 μmol, 40.55 μL, 1 eq). The mixture was stirred at 60 °C for 1 hr. LCMS (EW30189 - 377-P1A) showed Compound 3 was consumed completely and 24.010% 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%: 20%-40%, 6 min). SND444 (40 mg, 84.21 μmol, 14.78% yield, 100% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-377-P1A) and LCMS (EW30189-377-P1J). 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: 0.782min (M+H)⁺ = 439.2, EW30189-377-P1A LCMS: MS (ESI) Retention time: 1.189min (M+H)⁺ = 439.1, EW30189-377-P1J ¹H NMR (400 MHz, DMSO-d6) δ = 8.10-8.08 (d, J = 9.2 Hz, 2H), 7.66-7.64 (d, J = 8.8 Hz, 1H), 7.02-7.00 (m, 1H), 6.95-6.93 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H), 3.50 (m, 2H), 3.40-3.37 (m, 2H), 3.37-3.03 (m, 2H), 3.01 (s, 3H), 2.83-2.81 (m, 2H), 2.02-1.98 (m, 2H), 1.76-1.66 (m, 5), 1.37-1.34 (m, 1H).

To a solution of Compound 7s (200 mg, 401.39 μmol, 1.00 eq), RuPhos (37.46 mg, 80.28 μmol, 0.20 eq), Pd₂ (dba)₃ (73.51 mg, 80.28 μmol, 0.20 eq) and Cs2CO3 (392.35 mg, 1.20 mmol, 3.00 eq) in DMF (1 mL), then added Core I (213.04 mg, 401.39 μmol, 1.00 eq) at 25 °C, the mixture was stirred at 100 °C for 16 hr. LCMS (EW30189- 367-P1A) showed Core I was consumed. Several new peaks were shown on LCMS and 47.340% 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 3 (300 mg, 332.93 μmol, 82.94% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 1.157min (M+H)⁺ = 901.7, 5- 95AB_R_220&254.lcm

To a solution of Compound 3 (300 mg, 332.93 μmol, 1.00 eq) in MeOH (2.1 mL) and DCM (0.3 mL) was added methanesulfonic acid (383.96 mg, 4.00 mmol, 284.41 μL, 12 eq). The mixture was stirred at 60 °C for 1 hr. LCMS (EW30189 - 372-P1D) showed Compound 3 was consumed completely and 47.286% 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% HCl condition). SND445 (135 mg, 245.86 μmol, 73.85% yield, 100% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-372-P1B) and LCMS (EW30189-372-P1F). 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: 0.710min (M+H)⁺ = 513.4, EW30189-372-P1B LCMS: MS (ESI) Retention time: 0.962min (M+H)⁺ = 513.2, EW30189-372-P1F ¹H NMR (400 MHz, DMSO-d6) δ = 8.10-8.08 (d, J = 8.8 Hz, 2H), 7.66-7.64 (d, J = 8.8 Hz, 1H), 7.07-7.06 (m, 2H), 7.01-6.99 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H), 3.48-3.46 (m, 2H), 3.02 (s, 3H), 2.99-2.96 (t, J = 7.6 Hz, 4H), 2.9-2.89 (m, 4H), 2.79 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.60 (m, 8H). Synthesis of SND446

65 To a solution of Compound 7s (208.01 mg, 602.09 μmol, 1.00 eq) and Core I (300 mg, 602.09 μmol, 1.00 eq) in DMF (3 mL) was added RuPhos (56.19 mg, 120.42 μmol, 0.20 eq), Cs2CO3 (588.52 mg, 1.81 mmol, 3.00 eq) and Pd2 (dba)3 (110.27 mg, 120.42 μmol, 0.20 eq) at 25 °C. The mixture was stirred at 100 °C for 12 hr under N₂. LCMS (EW30189-369-P1A) showed Core I was consumed completely and 40.463% 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 3 (300 mg, 419.10 μmol, 69.61% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 1.056min (M+H)⁺ = 716.5, 5- 95AB_R_220&254.lcm

To a solution of Compound 3 (300 mg, 419.10 μmol, 1.00 eq) in MeOH (2.1 mL) and DCM (0.3 mL) was added methanesulfonic acid (483.33 mg, 5.03 mmol, 358.02 μL, 12 eq). The mixture was stirred at 60 °C for 1 hr. LCMS (EW30189 - 373-P1D) showed Compound 3 was consumed completely and 28.727% 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% HCl condition). Compound Floratek-006-020 (105 mg, 216.61 μmol, 51.69% yield, 95.712% purity, HCl) was obtained as a yellow solid, which was determined by HNMR (EW30189-373-P1C) and LCMS (EW30189-373-P1J). 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: 0.699min (M+H)⁺ = 428.3, EW30189-373-P1D LCMS: MS (ESI) Retention time: 1.283min (M+H)⁺ = 428.2, EW30189-373-P1J ¹H NMR (400 MHz, DMSO-d6) δ = 8.02-7.80 (d, J = 8.8 Hz, 2H), 7.67-7.65 (d, J = 8.8 Hz, 1H), 7.00-6.98 (d, J = 8.8 Hz, 1H), 6.83-6.80 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.17-3.15 (m, 2H), 2.99-2.86 (m, 6H), 1.94-1.90 (m, 2H), 1.71-1.63 (m, 4H). Synthesis of SND447

Core I 3 To a solution of Compound 7f (99.48 mg, 602.09 μmol, 5.72 μL, 1.00 eq) and Core I (300 mg, 602.09 μmol, 1。00 eq) in DMF (3 mL) was added RuPhos (56.19 mg, 120.42 μmol, 0.20 eq), Cs₂CO₃ (588.52 mg, 1.81 mmol, 3.00 eq) and Pd₂ (dba)₃ (110.27 mg, 120.42 μmol, 0.20 eq) at 25 °C. And that mixture was degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 12 hr under N2 atmosphere. LCMS (EW30189-379-P1A) showed Core I was consumed. Several new peaks were shown on LCMS and 28.925% of desired compound was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18150×50 mm× 10um;mobile phase: [water (NH4HCO3) - ACN];B%: 50%-80%, 10min). Compound 3 (100 mg, 186.71 μmol, 31.01% yield) was obtained as a red oil. LCMS: MS (ESI) Retention time: 1.003min (M+H)⁺ = 536.2, 5- 5AB_R_220&254.lcm 67

To a solution of Compound 3 (100 mg, 186.71 μmol, 1 eq) in MeOH (1.4 mL) and DCM (0.2 mL) was added methanesulfonic acid (215.33 mg, 2.24 mmol, 159.50 μL, 12 eq). The mixture was stirred at 60 °C for 1 hr. LCMS (EW30189 - 394- P1A) showed Compound 3 was consumed completely and 90.397% 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%: 51%-71%, 6 min). SND447 (90 mg, 185.97 μmol, 99.60% yield, 100% purity, HCl) was obtained as a yellow oil. Which was determined by HNMR (EW30189-394-P1A) and LCMS (EW30189-394-P1F). TLC (SiO₂, PE: EA = 0/1, Rf = 0.5) 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: 0.960min (M+H)⁺ = 448.2, EW30189-394-P1A LCMS: MS (ESI) Retention time: 1.872min (M+H)⁺ = 448.2, EW30189-394-P1F ¹H NMR (400 MHz, DMSO-d₆) δ = 8.03-8.00 (d, J = 9.2 Hz, 2H), 7.66-7.63 (d, J = 8.8 Hz, 1H), 7.25 (m, 1H), 7.05-7.03 (d, J = 8.4 Hz, 1H), 6.98-6.95 (m, 2H), 6.88-6.86 (m, 1H), 6.78-6.76 (d, J = 8.4 Hz, 2H), 4.55 (s, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 3.58-3.53 (q, J = 6.8 Hz, 2H), 1.20-1.17 (t, J = 7.2 Hz, 3H). Synthesis of SND448

To a solution of Core I (300 mg, 602.09 umol, 1.00 eq), Compound 2(85.64 mg, 602.09 umol, 1.00 eq) in DMF (3 mL) was added Cs2CO3 (588.52 mg, 1.81 mmol, 3.00 eq), RuPhos (28.10 mg, 60.21 umol, 0.10 eq), Pd₂(dba)₃ (55.13 mg, 60.21 umol, 0.10 eq), and the mixture was stirred at 100 °C for 16h under N₂. LCMS (EW30065-265-P1A) showed Core I was consumed and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. Compound 3(300 mg, crude) was obtained as a red oil. LCMS: MS (ESI) Retention time: 0.714 min, (M+1) ⁺ = 513.3, EW30065-265-P1A.

To a solution of Compound 3 (300 mg, 585.26 umol, 1.00 eq) in DCM (0.3 mL) and EtOH (2.1 mL) was added methanesulfonic acid (674.96 mg, 7.02 mmol, 499.97 uL, 12.0 eq) , and the mixture was stirred at 60 °C or 1 h. LCMS (EW30065-267-P1A) showed Compound 3 was consumed and 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% HCl condition). Compound Floratek-006-004 (180 mg, 382.69 umol, 65.39% yield, 98% purity, HCl) was obtained as a yellow solid, which was confirmed by LCMS (EW30065-267-P1F), HNMR (EW30065-267-P1A). LCMS: MS (ESI) Retention time: 0.679 min, (M+1) ⁺ =425.2, EW30065-267-P1A. LCMS: MS (ESI) Retention time: 1.127 min, (M+1) ⁺ =425.1, EW30065-267-P1F. ¹H NMR (400 MHz, DMSO-d6) δ = 11.03 ( s, 1H), 8.10-8.08 (d, J = 9.2 Hz, 2H), 7.66-7.64 (d, J = 8.8 Hz, 1H), 7.04-7.00 (t, J = 9.2 Hz, 3H), 3.92 (s, 5H), 3.49- 3.46 ( d, J = 11.2 Hz, 2H), 3.17-3.16 (d, J = 2.8 Hz, 2H), 3.02 (s, 3H), 2.95-2.88 (m, 2H), 1.85-1.69 (m, 5H), 1.38-1.35 (m, 1H). Synthesis of SND202, 203 & 206

7-Hydroxy-2,2-diphenyl-8-(4-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen-6-one (17.6). (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 (12.8) (3.527 g, 1 Eq, 6.268 mmol) was dissolved in a mixture of MeOH (37 mL) and sodium hydroxide in water (1.65 g, 1.25 mL, 30% Wt, 1.97 Eq, 12.4 mmol). The resultant red solution was stirred for 10 min at room temperature before hydrogen peroxide (1.4 g, 1.2 mL, 35% Wt, 2.2 Eq, 14 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 10 min before it was allowed to warm to room temperature and stirred at room temperature for 18 h. The reaction mixture was then cooled to 0 °C and 70 mL of water was added. The resultant yellow suspension was acidified with 10% of citric acid until pH was between 2 and 4. The aqueous layer was extracted with 2 x 200 mL of DCM, organic layers were combined and evaporated to dryness. Crude product was purified by normal phase flash- chromatography using EtOAc:heptanes. 7-Hydroxy-2,2-diphenyl-8-(4-(3- ((tetrahydro-2H-pyran-2-yl)oxy-propyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (17.6) (1.651 g, 2.863 mmol, 41%, 90% purity) was obtained as a beige powder. 8-(4-(3-Bromopropyl)phenyl)-7-hydroxy-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (17.7). Thionyl bromide (1.5 g, 0.55 mL, 2.5 Eq, 7.1 mmol) was added to a solution of 7-hydroxy-2,2-diphenyl-8-(4-(3- ((tetrahydro-2H-pyran-2-yl)oxy)propyl)phenyl)-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (17.6) (1.65 g, 1 Eq, 2.86 mmol) and dry DMF (2.2 g, 2.3 mL, 10 Eq, 30 mmol) in dry DCM (23 mL) at 0 °C. After 5 min at 0 °C, cooling bath was removed and the solution was stirred at room temperature for 1.5 h. The reaction mixture was cooled with an ice-bath before it was quenched with 70 mL of sat. aq. NaHCO3. The mixture was then extracted with 2 x 100 ml of DCM. Organic layers were combined and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptanes. 8-(4-(3- Bromopropyl)phenyl)-7-hydroxy-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (17.7) (1.398 g, 2.3 mmol, 79%, 90% purity) was obtained as a light brown solid. 8-(4-(3-Bromopropyl)phenyl)-7-(methoxymethoxy)-2,2-diphenyl-6H- [1,3]dioxolo[4,5-h]chromen-6-one (17.10). Chloromethyl methyl ether (84 mg, 79 µL, 1.2 Eq, 1.0 mmol) was added to a solution of 8-(4-(3- bromopropyl)phenyl)-7-hydroxy-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen- 6-one (17.7) (500 mg, 1 Eq, 900 µmol) and DIPEA (233 mg, 314 µL, 2.00 Eq, 1.80 mmol) in dry DCM (10 mL) at 0 °C. After 45 min stirring at 0 °C, full conversion was achieved. The mixture was allowed to warm to room temperature, before it was diluted with 40 mL of DCM and washed with 25 mL of 5% citric acid. The aqueous layer was extracted with 15 mL of DCM. Organic layers were combined and washed with 20 mL of brine, which in turn was extracted with 10 mL of DCM. Organic layers were dried with sodium sulfate, filtered and evaporated to dryness. Crude product was purified by normal phase flash-chromatography using EtOAc:heptanes as the eluent to give 8-(4-(3- Bromopropyl)phenyl)-7-(methoxymethoxy)-2,2-diphenyl-6H-[1,3]-dioxolo[4,5- h]chromen-6-one (17.10) (399 mg, 0.61 mmol, 67%, 91% purity). 7-Hydroxy-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 (17.8E). Suspension of 8-(4-(3-bromopropyl)phenyl)-7- hydroxy-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (17.7) (207 mg, 1 Eq, 373 µmol) in MeCN (1 mL) was treated with a mixture of N-methyl-2- (piperidin-1-yl)ethan-1-amine (271 mg, 5.11 Eq, 1.91 mmol) and DIPEA (72 mg, 97 µL, 1.5 Eq, 0.56 mmol) in MeCN (2 mL). After 18 h of stirring at room temperature, work-up and purification, 7-hydroxy-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 (17.8E) (194 mg, 0.30 mmol, 80%, 95% purity) was obtained as a yellow foam. 7-Hydroxy-8-(4-(3-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)propyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-6-one (17.8F). Suspension of 8-(4-(3-bromopropyl)phenyl)-7- hydroxy-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (17.7) (200 mg, 1 Eq, 360 µmol) in MeCN (1 mL) was treated with a mixture of N-methyl-2-(4- methylpiperazin-1-yl)ethan-1-amine (314 mg, 5.55 Eq, 2.00 mmol) and DIPEA (70 mg, 94 µL, 1.5 Eq, 0.54 mmol) in MeCN (2 mL). The reaction mixture was stirred at room temperature for 18 h, before it was worked-up. In order to extract the product fully from the aqueous layer, it was extracted with 50 mL of 10% of MeOH in DCM, 50 mL of 20% of i-PrOH in DCM, 50 mL of chloroform and 50 mL of 10% MeOH in chloroform in addition to extraction with DCM. After work- up and purification, 7-hydroxy-8-(4-(3-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)propyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6- one (17.8F) (172 mg, 0.26 mmol, 72%, 95% purity) was obtained as a yellow foam. tert-Butyl-(3-((tert-butoxycarbonyl)amino)propyl)(4-((3-(4-(7- (methoxymethoxy)-6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5- h]chromen-8-yl)phenyl)propyl)amino)butyl)carbamate (17.11H). tert- Butyl (4-aminobutyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (253 mg, 2.12 Eq, 732 µmol) in DMF (2 mL) was added to a mixture of tert-butyl-(4- aminobutyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate (17.10) (253 mg, 2.12 Eq, 732 µmol), potassium carbonate (100 mg, 2.1 Eq, 725 µmol) and potassium iodide (11.5 mg, 0.2 Eq, 69.1 µmol). The mixture was stirred for 56 h before it was worked-up and purified by normal phase flash-chromatography. tert-Butyl (3-((tert-butoxycarbonyl)amino)propyl)(4-((3-(4-(7- (methoxymethoxy)-6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-8- yl)phenyl)propyl)amino)butyl)carbamate (17.11H) (281 mg, 0.28 mmol, 81%, 86% purity) was obtained as an orange oil. 3,7,8-Trihydroxy-2-(4-(3-(methyl(2-(piperidin-1- yl)ethyl)amino)propyl)phenyl)-4H-chromen-4-one dihydrochloride (17E/SND202). 7-Hydroxy-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 (17.8E) (191 mg, 1 Eq, 310 µmol) was suspended in MeCN (1 mL) and deprotected with c. HCl (0.71 g, 0.60 mL, 37% Wt, 23 Eq, 7.2 mmol), by using the general method for deprotection. 3,7,8-Trihydroxy-2-(4-(3-(methyl(2- (piperidin-1-yl)ethyl)amino)propyl)phenyl)-4H-chromen-4-one dihydrochloride (17E) (159 mg, 0.29 mmol, 95%, 97% purity) was obtained as a light brown solid. 3,7,8-Trihydroxy-2-(4-(3-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)propyl)phenyl)-4H-chromen-4-one trihydrochloride (17F/SND203). 7-Hydroxy-8-(4-(3-(methyl(2-(4-methylpiperazin-1- yl)ethyl)amino)propyl)phenyl)-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-6- one (17.8F) (169 mg, 1 Eq, 268 µmol) was suspended in MeCN (1 mL) and deprotected with c. HCl (0.65 g, 0.55 mL, 37% Wt, 25 Eq, 6.6 mmol), by using the general method for deprotection. 3,7,8-Trihydroxy-2-(4-(3-(methyl(2-(4- methylpiperazin-1-yl)ethyl)amino)propyl)phenyl)-4H-chromen-4-one trihydrochloride (17F) (130 mg, 0.21 mmol, 80%, 95% purity) was obtained as a pale yellow powder. 2-(4-(3-((4-((3-Aminopropyl)amino)butyl)amino)propyl)phenyl)- 3,7,8-trihydroxy-4H-chromen-4-one trihydrochloride (17H/SND206). tert-Butyl-(3-((tert-butoxycarbonyl)amino)propyl)(4-((3-(4-(7- (methoxymethoxy)-6-oxo-2,2-diphenyl-6H-[1,3]dioxolo[4,5-h]chromen-8- yl)phenyl)propyl)amino)butyl)carbamate (17.11H) (177 mg, 1 Eq, 205 µmol) was dissolved in MeCN (0.5 mL) and deprotected with c. HCl (0.52 g, 0.35 mL, 12 molar, 21 Eq, 4.2 mmol) by using the general method for deprotection. 2-(4-(3- ((4-((3-Aminopropyl)amino)butyl)amino)propyl)phenyl)-3,7,8-trihydroxy-4H- chromen-4-one trihydrochloride (78 mg, 0.13 mmol, 65%, 96.4% purity) as a yellow powder. Compounds The following compounds were synthesised using the general process as described above.

74

EXAMPLES - BIOLOGICAL STUDIES

Experimental methodology Viability assays

Viability of cultures was determined by the by CellTiter-Glo® 2.0 (Promega # G7572) using a luminescence plate reader (EnVision). 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. 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 a mouse hippocampal cell line, HT-22 with iodoacetic acid (IAA) and test compounds were added in the reperfusion state.

Cell death was monitored 24h later using the CellTiter-Glo® 2.0 .

Experimental method: IAA toxicity

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, the mouse hippocampal cell line HT-22 was treated with 10 mM IAA for 2 hours in a 96-well plate. 3000 cells wells were plated in each well and grown overnight at 37°C in the presence of 5% CO2, followed by the addition of the lesion, IAA. After 2h, 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 Table 1 - 3 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 at the highest concentration of 30 mM (Table 1)

Table 1 - 3. 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 viability is depicted as o mM and the numbers represent the mean % of the sample vs the vehicle control from the same 96 well plate as the tested compounds.

Table 2

Table 3

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, HT-22. 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 showed a degree of protection from MPP⁺ injury at the higher concentrations as shown in Table 4 - 5. 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).

Tables 4-5. Neuroprotective activity of various SND derivatives against an in vitro model of PD by MPP+. The numbers represent mean % viability versus cells treated only with vehicle control (no MPP+). The lesion control viability is depicted as o mM and the numbers represent the mean % of the sample vs the vehicle control from the same 96 well plate as the tested compounds.

Table 4.

Table 5.

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

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 derivatives were effective at reducing the toxic effects of Glutamate when tested at a concentration that was not in itself toxic for the cells as shown in Table 6. 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 6. Neuroprotective activity of various SND derivatives against oxidative stress induced by Glutamate. Numbers represent fold increase in viability over the cells treated with Glu.

Example 4. Metal chelating properties of SND derivatives

The metal chelating properties of molecules with polyphenolic structures suggest they may play a role in metal-overload diseases and in all oxidative stress conditions involving a transition metal ion [Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings KR. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002 Nov;36(ii):ii99-2o8] Exp erimental Method

The test compounds were evaluated for the ability to form complexes with Al, Fe, Cu and Zu ions by using a spectrophotometric method. Different salts of these metals were dissolved in MeOH to concentrations of 50 and 200 mM and added to 50 mM compound or blank wells; wavelength between 200 - 600 nm was recorded. Morin was used as a positive control.

Results

As expected, morin was able to form a complex with all four ions, whereas SND derivatives showed a certain degree of selectively in ion chelating potential. 7,8 DHF was used as a comparator in this experiment as shown in Table 7.

Table 7. 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;

Example 5. 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 8.

Table 8. Antioxidant activity of SND derivatives expressed as TEAC values (pM Trolox equivalents).

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 subject-matter disclosed herein is further defined in the following clauses:

1. A compound of formula (I):

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; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; wherein at least two of R¹ , R², R⁴, and R⁵ are independently selected from –OH, -O-C_1-4 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; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; each -R^β is independently selected from a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C3-C14 cyclic group, and wherein any -R^β 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, C_1-6 alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R¹⁰, when not H, is independently optionally substituted with 1 or 2 -R^β; 110100PCT1 R¹¹ and R¹² are independently selected from H, C_1-6-alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R¹¹ and R¹², when is not H, are independently optionally substituted with 1 or 2 -R^β; or R¹¹ and R¹² together form a 5- or 6-membered heterocycle optionally having an additional heteroatom selected from N 5 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, C_3-14 cyclic group, halo, -NO₂, -CN, -OH, -NH₂, mercapto, formyl, carboxy, carbamoyl, C_1-6 alkoxy, C_1-6 alkylthio, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, C_1-6 alkylsulfinyl, 10 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, C_3-14 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, 15 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,20 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, 25 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. 30 2. A compound as defined in clause 1, wherein R¹ , R², R⁴, and R⁵, independently, are selected from –OH, and -O-C_1-4 alkyl, or from H; halo; -CN; -NO₂; -R^β; -OH; -OR^β; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β, wherein at least two of R¹ , R², R⁴, and R⁵ are independently selected from –OH, and -O-C1-4 35 alkyl 89 110100PCT1 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; -R^β; -OH; -OR^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β; wherein at least two of R¹ , R², R⁴, and R⁵ are independently selected from –OH, and -OCH₃. 5 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; -R^β; -OH; 10 -OR^β; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; and -OCOR^β. 6. A compound as defined in any preceding clause, wherein R³, R⁶, R⁷, R⁸, and R⁹ are H. 15 7. A compound as defined in any preceding clause, wherein -R^β is independently selected from a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₁₄ cyclic group, and wherein any -R^β may optionally be substituted with one or more halo, -OH, -NH2, -CN, -NO2, -C≡CH, -CHO, -CON(CH3)2 or oxo (=O) groups. 20 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; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1- 25 3 -R^β. 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. 30 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; -R^β; -OH, -OR^β; -SH; -SR^β; 90 -SOR^β; -SO₂H; -SO₂R^β; -SO₂NH₂; -SO₂NHR^β; -SO₂N(R^β)₂; -NH₂; -NHR^β; -N(R^β)₂; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1- 3 -R^β. 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-C_1-4 alkyl, e.g. –OH and –OCH₃; and R³, R⁴, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO₂; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β. 13. A compound as defined in clause 1; wherein R¹, R² and R⁵, independently, are selected from –OH and –O-C_1-4 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 C_1-4 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 C_1-4 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 C -₄ alkyl. 18. A compound as defined in any one or more of the preceding clauses; wherein Z is -

NR^HR¹² 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-NR^UR¹²; 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-NR^uR¹²; and q is independently selected from 1-4.

21. A compound as defined in clause 1, wherein the compound is selected from the following:

22. A pharmaceutically acceptable salt, multi-salt, solvate or prodrug of a compound as defined in any one of claims l to 21. 23. A pharmaceutical composition comprising a compound as defined in any one of clauses 1 to 21, or a pharmaceutically acceptable salt, 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 salt, 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 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: –NR¹¹R¹²; –N(R¹⁰)-(CH2)p–NR¹¹R¹²; and –N(R¹⁰)-(CH2)q–N(R¹⁰)-(CH2)q–NR¹¹R¹²; R¹ , R², and R⁵, independently, are selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, –OC(O)N(R¹³)₂; R⁴ is selected from –OH, -O-C1-4 alkyl, -OC(O)R13, -OC(O)NHR¹³, – OC(O)N(R¹³)2, or from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; R³, R⁶, R⁷, R⁸, and R⁹, independently, are selected from H; halo; -CN; -NO2; -R^β; -OH, -OR^β; -SH; -SR^β; -SOR^β; -SO2H; -SO2R^β; -SO2NH2; -SO2NHR^β; -SO2N(R^β)2; -NH2; -NHR^β; -N(R^β)2; -CHO; -COR^β; -COOH; -COOR^β; -OCOR^β; and benzyl optionally substituted with 1-3 -R^β; each -R^β is independently selected from a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C14 cyclic group, and wherein any -R^β 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, C_1-6 alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C3-10 cycloalkyl, and benzyl, wherein each R¹⁰, when not H, is independently optionally substituted with 1 or 2 -R^β; R¹¹ and R¹² are independently selected from H, C_1-6-alkyl, C₂-C₆ alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, benzyl, and benzyl substituted with –O(C_1-4 alkyl); wherein each R¹¹ and R¹², when is not H, are independently optionally substituted with 1 or 2 - R^β; 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 C_1-4 alkyl or with benzyl; 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, C_1-6 alkoxy, C_1-6 alkylthio, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, C_1-6 alkylsulfinyl, C_1-6 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, C_3-14 cyclic group, halo, -NO₂, -CN, -OH, -NH₂, mercapto, formyl, carboxy, carbamoyl, C_1-6 alkoxy, C_1-6 alkylthio, -NH(C_1-6 alkyl), -N(C_1-6 alkyl)₂, C_1-6 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 for use as claimed in claim 1, wherein R¹ , R², and R⁵, independently, are selected from –OH, and -O-C1-4 alkyl.

3. A compound for use as claimed in claim 2, wherein R¹ , R², and R⁵, independently, are selected from -OH, and -0-CH₃.

4. A compound for use as claimed in any preceding claim, wherein R⁴ is selected from -OH and -O-C_1-4 alkyl.

5. A compound for use as claimed in claim 4, wherein R⁴ is selected from -OH and -OCH₃.

6. A compound as claimed in any of claims 1 to 3, wherein R⁴ is H.

7. A compound for use as claimed in any preceding claim, wherein R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -N0₂; -RP; -OH; -ORP; -NH₂; -NHRP; -N(RP)₂; -CHO; -CORP; -COOH; -COORP; and -OCORP.

8. A compound for use as claimed in claim 7, wherein R³, R⁶, R⁷, R⁸ and R⁹ are independently selected from H; halo; -CN; -N0₂; and -NH₂.

9. A compound for use as claimed in any preceding claim, wherein R³, R⁶, R⁷, R⁸ and R⁹ are H.

10. A compound for use as claimed in any preceding claim, wherein R¹¹ and R¹² are independently selected from H, C -₂ alkyl, and benzyl substituted with -0(C -₄ alkyl).

11. A compound for use as claimed in any of claims 1 to 9, wherein R¹¹ and R¹² together form a 5- or 6-membered heterocycle optionally having one additional heteroatom selected from N and O; wherein the 5- or 6-membered heterocycle is optionally substituted with a C -₂ alkyl or with benzyl.

12. A compound for use as claimed in any preceding claim, wherein n is an integer from 1 to 4.

13. A compound for use as claimed in any of claims 1 to 11, wherein n is o.

14· A compound for use as claimed in any preceding claim, wherein Z is -NR^UR¹².

15. A compound for use as claimed in any of claims 1 to 13, wherein Z is -N(R¹⁰)- (CH₂)_P-NR”R¹².

16. A compound for use as claimed in claim 15, wherein p is 2, 3, or 4.

17. A compound for use as claimed in any of claims 1 to 13, wherein Z is -N(R¹⁰)- (CH₂)_q-N(R¹⁰)-(CH₂)_q-NR¹¹R¹².

18. A compound for use as claimed in claim 17, wherein each q is independently 3 or 4.

19. A compound for use as claimed in any of claims 1 to 13, wherein Z is -N(R¹⁰)- (CH₂)_r-N(R¹⁰)-(CH₂)_r-N(R¹⁰)-(CH₂)_r-NR^uR¹².

20. A compound for use as claimed in claim 19, wherein each r is independently 3 or

4

21. A compound for use as claimed in any preceding claim, wherein each R¹⁰ is independently selected from H and -CH₃.

22. 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.