Phyllochlorin Analogues Suitable for Use in Photodynamic Therapy - Patent application

Abstract

The present invention relates to phyllochlorin analogues and pharmaceutically acceptable salts thereof, as well as compositions comprising phyllochlorin analogues and pharmaceutically acceptable salts thereof. Phyllochlorin analogues and pharmaceutically acceptable salts thereof are suitable for use in photodynamic therapy, cytoluminescence therapy and photodynamic diagnosis, for example, for the treatment or detection of tumors or antiviral treatment. The present invention also relates to the use of phyllochlorin analogues and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic or photodiagnostic agents, as well as methods for photodynamic therapy, cytoluminescence therapy or photodynamic diagnosis, for example, for the treatment or detection of tumors or antiviral treatment. [Formula 1] JPEG2025539864000057.jpg68159

Description

[Technical Field]

[0001] The present invention relates to phyllochlorin analogues and pharmaceutically acceptable salts thereof, as well as compositions comprising phyllochlorin analogues and pharmaceutically acceptable salts thereof. Phyllochlorin analogues and their pharmaceutically acceptable salts are suitable for use in photodynamic therapy, cytoluminescence therapy and photodynamic diagnosis, for example, for the treatment or detection of tumors or for antiviral treatment. The present invention also relates to the use of phyllochlorin analogues and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic or photodiagnostic agents, as well as methods for photodynamic therapy, cytoluminescence therapy or photodynamic diagnosis, for example, for the treatment or detection of tumors or for antiviral treatment.

[0002] The structure of "phyllochlorin" is as follows: [ka] [Background technology]

[0003] Porphyrins and their analogues are known photosensitive chemical compounds that can absorb photons and emit them at higher wavelengths. These unique properties have many applications, one of which is photodynamic therapy (PDT).

[0004] There are currently two generations of photosensitizers for PDT: the first generation contains heme porphyrins (blood derivatives), and the second generation is mostly chlorophyll analogues, the latter compounds known as chlorins and bacteriochlorins.

[0005] Chlorin e4 has been shown to exhibit good photosensitizing activity. It has also been shown to have protective effects against indomethacin-induced gastric lesions in rats and TAA- or CCl4-induced acute liver injury in mice. Therefore, it has been suggested that chlorin e4 may be a promising new drug candidate for anti-gastroenteritis and liver damage protection. International Publication No. 2009 / 040411 suggests the use of chlorin e4 zinc complexes in photodynamic therapy, and International Publication No. 2014 / 091241 suggests the use of chlorin e4 disodium in photodynamic therapy. [ka]

[0006] However, there is a continuing need for better photosensitizers. There is a need for compounds with high singlet oxygen quantum yields, and preferably compounds with strong photosensitizing properties in organic and aqueous media. There is also a need for compounds with high fluorescence quantum yields. Furthermore, there is a need for compounds and / or compositions that have higher phototoxicity, lower dark toxicity, good stability, good solubility, and / or are easily purified. Summary of the Invention

[0007] A first aspect of the present invention relates to a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: (-R 1 Ha-CH2OR 2 , -CH2SR 2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CH2N(R 2 )2 or -R 2x Selected from; -R 2 are each independently -H, -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4, -C(O)-N(R 4 )2, -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-N(R 4 )2, -R α -H, -R β , -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O)2R β , -R α -NH2, -R α -NH(R β )、-R α -N(R β )2、-R α -N3、-R α -X、-R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y、-R α -[R 6 Y、-R α -[N(R 5 )2(R 5’ )]、-R α -[P(R 5 )2(R 5’ )] or -R α -[R 6’ and is selected from; -R 2x is -H, -R α -H, -R α -R β , -R α -OH, -R​​​​​​​​​​​​​​​​​​​​α -NH(R β ), -R α -N(R β )2, -R α -N3, -R α -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, -R α -[R 6 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or -R α -[R 6’ ] is selected from; -R 4 are independently -H, -R α -H, -R β , -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O)2R β , -R α -NH2, -R α -NH(R β ), -R α -N(R β )2, -R α -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, -R α -[R 6 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or -R α -[R 6’] is selected from; -R α - are each independently C1-C 42 alkylene groups, wherein the alkylene group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) C1-C4 alkyl, C1-C4 haloalkyl, or halo groups, and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms in the backbone of the alkylene group are optionally replaced with a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently saturated or unsaturated hydrocarbyl groups, which may be linear or branched or may be or include a cyclic group, which may be optionally substituted, and which may optionally include one or more (e.g., 1, 2, 3, 4, or 5) heteroatoms N, O, S, P, or Se in its carbon backbone; -R 5 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl, or C5-C6 heteroaryl, where phenyl or C5-C6 heteroaryl is optionally selected from one or more (e.g., 1, 2, 3, 4, or 5) C1-C6 alkyl, C1-C6 haloalkyl, O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CHO) n -H or -O-(CH2CH2O) n optionally substituted with -CH3 groups; -R 5’ is C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each selected from -CO2 -phenyl or C5-C6 heteroaryl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), halo, —CO2H, —CO2Z, —CO2NH2, —O—(CH2CHO) n -H or -O-(CH2CH2O) n may be further substituted with -CH3 groups; -R 6 optionally one or more (e.g., 1, 2, 3, 4, or 5) —C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), halo, —CO2H, —CO2Z, —CO2NH2, —O—(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 groups; -R 6’ is -CO2 - and optionally further substituted with one or more (e.g., 1, 2, 3, or 4) C-C alkyl, C-C haloalkyl, —O(C-C alkyl), —O(C-C haloalkyl), halo, —COH, —COZ, —CONH, —O—(CHCHO) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 groups; n is 1, 2, 3, 4, 5, or 6; X is a halo group; Y is a counter anion, Z is a counter cation, and M 2+ is a metal cation.

[0008] A second aspect of the invention provides a compound of formula (I) or a complex of formula (II) according to the first aspect of the invention for use in medicine.

[0009] In the context of this specification, a "hydrocarbyl" substituent or hydrocarbyl moiety in a substituent contains only carbon and hydrogen atoms, but does not include any heteroatoms such as N, O, S, P, or Se in its carbon skeleton, unless otherwise specified. Hydrocarbyl groups / moieties may be saturated or unsaturated (including aromatic), straight or branched chain, or may be or include cyclic groups, and unless otherwise specified, cyclic groups do not include heteroatoms such as N, O, S, P, or Se in its carbon skeleton. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl groups / moieties, and all combinations of these groups / moieties. Typically, hydrocarbyl groups are C1-C 60 Hydrocarbyl groups, more typically C1-C 40 Hydrocarbyl groups, more typically C1-C 20 More typically, the hydrocarbyl group is a C-C 12 More typically, the hydrocarbyl group is a C-C 10 A "hydrocarbylene" group is defined as a divalent hydrocarbyl group.

[0010] An "alkyl" substituent or alkyl moiety in a substituent can be linear (i.e., straight-chain) 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 otherwise specified, the term "alkyl" does not include "cycloalkyl." Typically, alkyl groups are C1-C 12 An alkyl group is a C1-C6 alkyl group. An "alkylene" group is defined similarly to a divalent alkyl group. Typically, an alkylene group is a C1-C6 alkyl group. 42 The alkylene group is preferably a C-C alkylene group. 32 Alkylene group, or C1-C 22 Alkylene group, or C1-C 12 It is an alkylene group.

[0011] An "alkenyl" substituent or alkenyl moiety in a substituent refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds. Examples of alkenyl groups / moieties include ethenyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and 1,4-hexadienyl groups / moieties. Unless otherwise specified, the term "alkenyl" does not include "cycloalkenyl." Typically, alkenyl groups are C2-C6 12 An alkenyl group is more typically a C2-C6 alkenyl group. An "alkenylene" group is defined similarly as a divalent alkenyl group.

[0012] An "alkynyl" substituent or alkynyl moiety in a substituent refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds. Examples of alkynyl groups / moieties include ethynyl, propargyl, but-1-ynyl, and but-2-ynyl. Typically, an alkynyl group is a C2-C 12 An alkynyl group is a C2-C6 alkynyl group. An "alkynylene" group is defined similarly as a divalent alkynyl group.

[0013] A "cyclic" substituent or cyclic moiety in a substituent refers to any hydrocarbyl ring, which may be saturated or unsaturated (including aromatic) and may contain one or more heteroatoms, such as N, O, S, P, or Se, in its carbon skeleton. Examples of cyclic groups include cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups, discussed below. Cyclic groups may be monocyclic, bicyclic (e.g., bridged, fused, or spiro), or polycyclic. Typically, cyclic groups are 3-12 membered cyclic groups, meaning they contain 3-12 ring atoms. More usually, cyclic groups are 3-7 membered monocyclic groups, meaning they contain 3-7 ring atoms.

[0014] A "heterocyclic" substituent or heterocyclic moiety in a substituent refers to a cyclic group or moiety that includes one or more carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms, such as N, O, S, P, or Se, in the ring structure. Examples of heterocyclic groups include the heteroaryl groups discussed below, as well as non-aromatic heterocyclic groups such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thietanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, thianyl, and dioxanyl groups.

[0015] A "cycloalkyl" substituent or cycloalkyl moiety in a substituent refers to a saturated hydrocarbyl ring containing, for example, 3-7 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, a cycloalkyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0016] A "cycloalkenyl" substituent or cycloalkenyl moiety in a substituent refers to a non-aromatic unsaturated hydrocarbyl ring having one or more carbon-carbon double bonds and containing, for example, 3-7 carbon atoms, examples of which include cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohexa-1,3-dien-1-yl. Unless otherwise specified, a cycloalkenyl substituent or moiety can include monocyclic, bicyclic, or polycyclic hydrocarbyl rings.

[0017] An "aryl" substituent or aryl moiety in a substituent refers to an aromatic hydrocarbyl ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused-ring aromatic hydrocarbons, in which all of the fused ring systems (excluding ring systems that are part of or formed by any substituent) are aromatic. Examples of aryl groups / moieties include phenyl, naphthyl, anthracenyl, and phenanthrenyl. Unless otherwise specified, the term "aryl" does not include "heteroaryl."

[0018] A "heteroaryl" substituent or heteroaryl moiety in a substituent refers to an aromatic heterocyclic group or moiety. The term "heteroaryl" includes monocyclic aromatic heterocycles and polycyclic fused-ring aromatic heterocycles, in which all of the fused ring systems (excluding ring systems that are part of or formed by any substituent) are aromatic. Examples of heteroaryl groups / moieties include: [ka]

[0019] For purposes of this specification, when a combination of moieties is referred to as a group, e.g., arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl, the last-mentioned moiety includes the atom by which the group is attached to the remainder of the molecule. An example of an arylalkyl group is benzyl.

[0020] For purposes of this specification, an optionally substituted group or moiety (—R β (like this): (i) Each hydrogen atom is optionally halo; -CN; -NO2; -N3; ​​-R x ;-OH;-OR x ;-R y -Haro;-R y -CN;-R y -NO2;-R y -N3;-R y -R x ;-R y -OH;-R y -OR x ;-SH;-SR x ;-SOR x ;-SO2H;-SO2R x ;-SO2NH2;-SO2NHR x ;-SO2N(R x )2;-R y -SH;-R y -SR x ;-R y -SOR x ;-Ry -SO2H;-R y -SO2R x ;-R y -SO2NH2;-R y -SO2NHR x ;-R y -SO2N(R x )2;-NH2;-NHR x ;-N(R x )2;-N + (R x )3;-R y -NH2;-R y -NHR x ;-R y -N(R x )2;-R y -N + (R x )3;-CHO;-COR x ;-COOH;-COOR x ;-OCOR x ;-R y -CHO;-R y -COR x ;-R y -COOH;-R y -COOR x ; or -R y -OCOR x and / or (ii) any two hydrogen atoms bonded to the same carbon atom are optionally oxo (=O), =S, =NH, or =NR x and / or (iii) Any two hydrogen atoms attached to the same or different atoms within the same optionally substituted group or moiety may optionally be replaced by —O—, —S—, —NH—, —N(R x )-, -N + (R x )2- or -R y - optionally substituted by a bridging substituent independently selected from: In that case, each -R y- is independently selected from an alkylene, alkenylene, or alkynylene group, wherein the alkylene, alkenylene, or alkynylene group contains 1 to 6 atoms in its backbone; one or more carbon atoms in the backbone of the alkylene, alkenylene, or alkynylene group may optionally be replaced by one or more heteroatoms N, O, or S; and the alkylene, alkenylene, or alkynylene group may optionally be replaced by one or more halo and / or -R x may be substituted with a group; and Each-R x are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C2-C6 cyclic groups, or any two or three -R attached to the same nitrogen atom x may be taken together with the nitrogen atom to which they are attached to form a C2-C7 cyclic group, where any -R x may be optionally substituted by one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -OH, -NH2, -CN, or oxo (=O) groups.

[0021] Typically, the substituents include 1, 2, 3 or 4 substituents, more typically 1, 2 or 3 substituents, more typically 1 or 2 substituents, more typically 1 substituent.

[0022] Unless otherwise specified, any divalent bridging substituent (e.g., —O—, —S—, —NH—, —N(R x )-, -N + (R x )2- or -R y -) or moiety must be attached only to the specified group or moiety and cannot be attached to a second group or moiety, even if the second group or moiety itself may be optionally substituted.

[0023] The term "halo" includes fluoro, chloro, bromo and iodo.

[0024] Unless otherwise specified, when a group is prefixed with the term "halo," such as a haloalkyl or halomethyl group, it is understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo, and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution in the corresponding group without the halo prefix. For example, a halomethyl group may contain one, two, or three halo substituents. A haloethyl or halophenyl group may contain one, two, three, four, or five halo substituents. Similarly, unless otherwise specified, when a group begins with a particular halo group, it is understood that the group in question is substituted with one or more of the specified halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted with one, two, or three fluoro groups.

[0025] Unless otherwise specified, when a group is referred to as "halo-substituted," it is understood that the group in question is substituted with one or more halo groups independently selected from fluoro, chloro, bromo, and iodo. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group referred to as halo-substituted. For example, a halo-substituted methyl group may contain one, two, or three halo substituents. A halo-substituted ethyl or halo-substituted phenyl group may contain one, two, three, four, or five halo substituents.

[0026] Unless otherwise specified, a reference to an element is considered to be a reference to all isotopes of that element, so for example, unless otherwise specified, a reference to hydrogen is considered to encompass all isotopes of hydrogen, including deuterium and tritium.

[0027] Unless otherwise stated, a reference to a compound or group should be understood to refer to all tautomeric forms of that compound or group.

[0028] When referring to a hydrocarbyl or other group that contains one or more heteroatoms N, O, S, P or Se in its carbon skeleton, or to a carbon atom of a hydrocarbyl or other group that is substituted by an N, O, S, P or Se atom, what is intended is: [ka] teeth, [ka] or [ka] is replaced by; -CH2- is replaced by -NH-, -PH-, -O-, -S- or -Se-; -CH3 is replaced by -NH2, -PH2, -OH, -SH, or -SeH; -CH= is replaced by -N= or -P=; -CH2- is replaced by -NH-, -PH-, -O-, -S- or -Se-; or CH≡ is replaced by N≡ or P≡; provided that the resulting group contains at least one carbon atom. For example, methoxy, dimethylamino, and aminoethyl groups are considered to be hydrocarbyl groups containing one or more heteroatoms N, O, S, P, or Se in their carbon skeleton.

[0029] In the context of this specification, unless otherwise stated, C x -C y A group is defined as a group containing xy carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing 1-4 carbon atoms. When calculating the total number of carbon atoms in a parent group, including any substituted and / or moieties, optional substituents and moieties are not taken into account. For the avoidance of doubt, substituted heteroatoms, such as N, O, S, P, or Se, are not included in the C x -C yWhen calculating the number of carbon atoms in a group, they should be counted as carbon atoms. For example, a morpholinyl group should be considered a C6 heterocyclic group, not a C4 heterocyclic group.

[0030] Because the pi electrons of the chlorin ring are delocalized, the chlorin ring can be represented by multiple resonance structures. Resonance structures are different ways of depicting the same compound. Two of the resonance structures of the chlorin ring are shown directly below: [ka]

[0031] Typically, a complex contains a central metal atom or ion, known as a coordination center, and a binding molecule or ion, known as a ligand. Typically, a complex contains a central metal atom or ion, known as a coordination center, and a binding molecule or ion, known as a ligand. Herein, the bond between the coordination center and the ligand is represented as shown in the complex below on the left (the attraction between the anionic ligand and the central metal cation is represented by four dashed lines), but equivalently, it can be represented as shown in the complex below on the right (the attraction between the ligand molecule and the central metal atom is represented by two covalent bonds and two dashed lines): [ka]

[0032] As used herein, -[NC5H5]Y refers to: [ka]

[0033] In one embodiment of the first or second aspect of the invention, X is a halo group selected from fluoro, chloro, bromo, or iodo. In one embodiment, X is chloro or bromo.

[0034] In one embodiment of the first or second aspect of the present invention, there is provided a compound of formula (I):

[0035] In one embodiment of the first or second aspect of the invention, Y is a halide (e.g., fluoride, chloride, bromide, or iodide) or other inorganic anion (e.g., bisulfate, hexafluorophosphate (PF6), nitrate, perchlorate, phosphate, or sulfate) or an organic anion (e.g., acetate, ascorbate, aspartate, benzoate, besylate (benzenesulfonate), bicarbonate, bis(trifluoromethanesulfonyl)imide (TFSI), tartrate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, decanoate, edetate, esylate (ethanesulfonate), fumarate, galactarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, β-hydroxybutyrate, 2-hydroxyethanesulfonate, hydroxypropyl methyl acrylate ... and the counter anion is selected from the group consisting of roximaleate, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate (methanesulfonate), methylsulfate, mucate, napsylate (naphthalene-2-sulfonate), octanoate, oleate, ornithine, pamoate, pantothenate, polygalacturonate, propanoate, propionate, salicylate, stearate, succinate, tartrate, teoclate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF), tetrakis(pentafluorophenyl)borate (F5-TPB), tetraphenylborate (TPB), tosylate (toluene-p-sulfonate), or triflate (trifluoromethanesulfonate).

[0036] In another embodiment of the first or second aspect of the invention, Y is a halide (e.g., fluoride, chloride, bromide, or iodide) or other inorganic anion (e.g., bisulfate, nitrate, perchlorate, phosphate, or sulfate) or an organic anion (e.g., acetate, aspartate, benzoate, besylate (benzenesulfonate), butyrate, camsylate (camphorsulfonate), citrate, esylate (ethanesulfonate), fumarate, galactarate, gluconate, or the like). , glutamate, glycolate, 2-hydroxyethanesulfonate, hydroxymaleate, lactate, malate, maleate, mandelate, mesylate (methanesulfonate), napsylate (naphthalene-2-sulfonate), ornithine, pamoate, pantothenate, propanoate, salicylate, succinate, tartrate, tosylate (toluene-p-sulfonate), or triflate (trifluoromethanesulfonate). In one embodiment, Y is fluoride, chloride, bromide, or iodide. In one embodiment, Y is chloride or bromide.

[0037] In one embodiment of the first or second aspect of the invention, Z is a counter cation selected from an inorganic cation (e.g., lithium, sodium, potassium, magnesium, calcium, or ammonium cation) or an organic cation (e.g., an amine cation (e.g., choline or meglumine cation) or an amino acid cation (e.g., arginine cation).

[0038] In one embodiment of the first or second aspect of the invention, M 2+ Zn 2+ , Cu 2+ , Fe 2+ , Pd 2+ or Pt 2+ In one embodiment, M 2+ is Zn 2+ is.

[0039] -R 1 Ha-CH2OR 2 , -CH2SR2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CH2N(R 2 )2, or -R 2x In one embodiment, -R 1 Ha-CH2OR 2 , -CH2SR 2 , -CH2N(R 2 )2, or -R 2x In one embodiment, -R 1 is -CH2OR 2 , -CH2SR 2 or -CHN(R 2 )2. In one embodiment, -R 1 is -CH2OR 2 or -CH2SR 2 In one embodiment, -R 1 Ha-CH2OR 2 In one embodiment, -R 1 Ha-R 2x and -R 2x Ha-R α -X.

[0040] In one embodiment of the first or second aspect of the invention, -R 2 or -R 2x -H, -R α -H, -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O)2R β , -R α -NH2, -R α -NH(R β ), -R α -N(R β )2, -R α -X, -R α -[N(R 5 )3]Y, -R α-[P(R 5 )3]Y, -R α -[R 6 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or -R α -[R 6’ In one embodiment, -R 2 or -R 2x -R α -H, -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O)2R β , -R α -NH2, -R α -NH(R β ), -R α -N(R β )2, -R α -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α In one embodiment, -R 2 or -R 2x -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β In one embodiment, -R 2 or -R 2x -R α -OR β , -R α -SR β , -R α-S(O)R β or -R α -S(O)2R β -R β is a saccharidyl group. In one embodiment, -R 2 or -R 2x -R α -OR β or -R α -SR β In one embodiment, -R 2 -R α -OR β or -R α -SR β -R β is a saccharidyl group.

[0041] In one embodiment of the first or second aspect of the invention, -R 2 is -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 )2, -C(S)-OR 4 , -C(S)-SR 4 or -C(S)-N(R 4 )2. In one embodiment, -R 2 is -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 )2 or -C(S)-N(R 4 )2. In one embodiment, -R 2 is -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 or -C(O)-N(R 4 )2 is selected.

[0042] In one embodiment of the first or second aspect of the invention, -R 2 is -C(O)-N(R 4 )(R 4’ ) and -R 4 -R α-OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β -R β is a saccharidyl group, and -R 4’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 2 is -C(O)-N(R 4 )(R 4’ ) and -R 4 -R α -OR β or -R α -SR β、 -R β is a saccharidyl group, and -R 4’ is H or C1-C4 alkyl (preferably methyl).

[0043] -R 4’ The group is another -R 4 -R bonded to the same atom as the group 4 -R refers to the group 4 and -R 4’ may be the same or different. Preferably, -R 4 and -R 4’ is different.

[0044] In one embodiment of the first or second aspect of the invention, -R 2 is -C(O)-N(R 4 )2. In one embodiment, -R 2 is -C(O)-N(C1-C4 alkyl)(R 4 In one embodiment, -R 2 is -C(O)-N(CH3)(R 4 )

[0045] In one embodiment of the first or second aspect of the invention, each -R α -Independently, C1-C 12 Alkylene group, -(CH2CH2O) m - group, -(CH2CH2S)m - group, -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CHCH- groups, all optionally substituted, and m is 1, 2, 3, or 4. In one embodiment, each -R α - is independent, C1-C 12 Alkylene group, -(CH2CH2O) m - group or -(CH2CH2S) m - groups, all optionally substituted, and m is 1, 2, 3, or 4. In one embodiment, each -R α - is independent, C1-C 12 Alkylene group or -(CH2CH2O) m - groups, both of which are optionally substituted, where m is 1, 2, 3, or 4. In one embodiment, each -R α - is independently an optionally substituted -(CH2CH2O) m - group, where m is 1, 2, 3 or 4.

[0046] In one embodiment of the first or second aspect of the invention, each -R α - is independently a C1-C8 alkylene group, or a C1-C6 alkylene group, or a C2-C4 alkylene group, all of which are optionally substituted.

[0047] In one embodiment of the first or second aspect of the invention, each -R α - is independently unsubstituted or substituted with one or more substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -R α - is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C4 alkyl, or C1-C4 haloalkyl. In one embodiment, each -R α - is unsubstituted.

[0048] In one embodiment of the first and second aspects of the invention, each -R βare independently saturated or unsaturated hydrocarbyl groups which may be linear or branched or which may be or contain cyclic groups, which may be optionally substituted, and which may optionally contain one or more heteroatoms N, O or S in its carbon skeleton.

[0049] In one embodiment of the first or second aspect of the invention, at least one -R β is independently a C1-C6 alkyl group, or a C1-C4 alkyl group, or a methyl group, all of which are optionally substituted. In one embodiment, each -R β is independently a C1-C6 alkyl group, or a C1-C4 alkyl group, or a methyl group, all of which are optionally substituted.

[0050] In one embodiment of the first or second aspect of the present invention, at least one -R β is independently a saccharidyl group. In one embodiment, each -R β are independently saccharidyl groups.

[0051] In one embodiment of the first or second aspect of the invention, each -R β is independently unsubstituted or substituted with one or more substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. In one embodiment, each -R β is independently unsubstituted or substituted with one or two substituents independently selected from halo, C-C alkyl, or C-C haloalkyl. In one embodiment, each -R β is non-substituted.

[0052] In one embodiment of the first or second aspect of the invention, each -R 4 are independent, -R α -H, -R β , -R α -R β , -R α -OH, -R α -OR β, -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O)2R β , -R α -NH2, -R α -NH(R β ), -R α -N(R β )2, -R α -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y or -R α -[NC5H5]Y. In one embodiment, each -R 4 are independent, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β In one embodiment, each -R 4 independently -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β -R β is a saccharidyl group. In one embodiment, each -R 4 -R α -OR β or -R α -SR β In one embodiment, each -R 4 independently -R α -OR β or -R α -SR β -R β is a saccharidyl group.

[0053] In one embodiment of the first or second aspect of the invention, -R 2 , -R 2x or -R 4 At least one of the following is independently -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β -R β is a saccharidyl group. In one embodiment, -R 2 , -R 2x or -R 4 At least one of the following is independently -R α -OR β or -R α -SR β -R β is a saccharidyl group.

[0054] For purposes of the present invention, a "saccharidyl group" is any group comprising at least one monosaccharide subunit, each of which may be optionally substituted and / or modified. Typically, a saccharidyl group consists of one or more monosaccharide subunits, each of which may be optionally substituted and / or modified.

[0055] Usually, the carbon atom of a single monosaccharide subunit of each saccharidyl group is directly attached to the remainder of the compound, most typically via a single bond.

[0056] For purposes of this specification, when a first atom or group is said to be "directly bonded" to a second atom or group, it is to be understood that the first atom or group is covalently bonded to the second atom or group and that there are no intervening atom(s) or group(s). For example, in the group -(C=O)N(CH), the carbon atom of each methyl group is directly bonded to the nitrogen atom and the carbon atom of the carbonyl group is directly bonded to the nitrogen atom, but the carbon atom of the carbonyl group is not directly bonded to the carbon atoms of either methyl group.

[0057] Typically, each saccharidyl group is derived from the corresponding saccharide by replacing a hydroxyl group of the saccharide with a group defined by the remainder of the compound.

[0058] The single bond between the anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond. A glycosidic group is attached to the anomeric carbon of a monosaccharide subunit by a glycosidic bond. The bond between the saccharidyl group and the rest of the compound can be a glycosidic or non-glycosidic bond. Typically, the bond between the saccharidyl group and the rest of the compound is a glycosidic bond, so the saccharidyl group is a glycosyl group. When the bond between the saccharidyl group and the rest of the compound is a glycosidic bond, the glycosidic bond can be in the α or β configuration. Typically, such glycosidic bonds are in the β configuration.

[0059] For purposes of the present invention, when a saccharidyl group "contains x monosaccharide subunits," this means that the saccharidyl group has x monosaccharide subunits and no more. In contrast, when a saccharidyl group "comprises x monosaccharide subunits," this means that the saccharidyl group has x or more monosaccharide subunits.

[0060] Each saccharidyl group can be independently selected from a monosaccharide, disaccharide, oligosaccharide, or polysaccharide group. As will be understood, a monosaccharide group contains a single monosaccharide subunit. Similarly, a disaccharide group contains two monosaccharide subunits. As used herein, an "oligosaccharide group" contains 2-9 monosaccharide subunits. Examples of oligosaccharide groups include trisaccharide, tetrasaccharide, pentasaccharide, hexasaccharide, heptasaccharide, octasaccharide, and nonasaccharide groups. As used herein, a "polysaccharide group" contains 10 or more monosaccharide subunits (such as 10-50, or 10-30, or 10-20, or 10-15 monosaccharide subunits).

[0061] Each monosaccharide subunit within a di-, oligo-, or polysaccharide group may be the same or different. Each monosaccharide subunit within a di-, oligo-, or polysaccharide group may be linked to another monosaccharide subunit within the group via a glycosidic or non-glycosidic bond. Typically, each monosaccharide subunit within a di-, oligo-, or polysaccharide group is connected to another monosaccharide subunit within the group via a glycosidic bond, which may be in the α- or β-configuration.

[0062] The oligosaccharidyl or polysaccharidyl groups may be linear, branched or macrocyclic, respectively. Typically, each oligosaccharidyl or polysaccharidyl group is a linear or branched oligosaccharidyl or polysaccharidyl group.

[0063] In one embodiment, at least one -R β is a monosaccharide or disaccharide group.

[0064] In a further embodiment, at least one -R β is a monosaccharidyl group. For example, at least one -R β can be a glycosyl group containing a single monosaccharide subunit, where the monosaccharide subunit can be optionally substituted and / or modified. Typically, at least one -R β is a glycosyl group containing a single monosaccharide subunit, where the monosaccharide subunit may be optionally substituted. Furthermore, typically, at least one -R β is a glycosyl group containing a single monosaccharide subunit, where the monosaccharide subunit is unsubstituted.

[0065] In one embodiment, at least one -R β is an aldosyl group, where the aldosyl group may be optionally substituted and / or modified. For example, at least one -R βmay be selected from a glycerosyl, aldotetrosyl (such as erythrosyl or threosyl), aldopentosyl (such as ribosyl, arabinosyl, xylosyl or lyxosyl) or aldohexosyl (such as allosyl, altrosyl, glucosyl, mannosyl, gulosyl, idosyl, galactosyl or talosyl) group, any of which may be optionally substituted and / or modified.

[0066] In another embodiment, at least one -R β is a ketosyl group, where the ketosyl group can be optionally substituted and / or modified. For example, at least one -R β may be selected from an erythrulosyl, ketopentosyl (such as ribulosyl or xylulosyl) or ketohexosyl (such as psicosyl, fructosyl, sorbosyl or tagatosyl) group, any of which may be optionally substituted and / or modified.

[0067] Each monosaccharide subunit can exist in a closed (cyclic) or open (acyclic) form. Typically, at least one -R β Each monosaccharide subunit in β can be a glycosyl group containing a single closed-ring monosaccharide subunit, where the monosaccharide subunit can be optionally substituted and / or modified. Typically, in such a scenario, at least one -R β is a pyranosyl or furanosyl group, such as an aldopyranosyl, aldofuranosyl, ketopyranosyl or ketofuranosyl group, any of which may be optionally substituted and / or modified. Furthermore, typically, at least one -R β is a pyranosyl group, such as an aldopyranosyl or ketopyranosyl group, either of which may be optionally substituted and / or modified.

[0068] In one embodiment, at least one -R βis selected from a ribopyranosyl, arabinopyranosyl, xylopyranosyl, lyxopyranosyl, allopyranosyl, altropyranosyl, glucopyranosyl, mannopyranosyl, gulopyranosyl, idopyranosyl, galactopyranosyl or talopyranosyl group, any of which may be optionally substituted and / or modified.

[0069] In a further embodiment, at least one -R β is a glucosyl group, such as a glucopyranosyl group, where the glucosyl or glucopyranosyl group may be optionally substituted and / or modified. Typically, at least one -R β is a glucosyl group, where the glucosyl group may be optionally substituted. Furthermore, typically, at least one -R β is an unsubstituted glucosyl group.

[0070] Each monosaccharide subunit can be in the D-configuration or the L-configuration. Typically, each monosaccharide subunit is present in the configuration most commonly found in nature.

[0071] In one embodiment, at least one -R β is a D-glucosyl group, such as a D-glucopyranosyl group, where the D-glucosyl or D-glucopyranosyl group may be optionally substituted and / or modified. Typically, at least one -R β is a D-glucosyl group, which may be optionally substituted. Furthermore, typically, at least one -R β is an unsubstituted D-glucosyl group.

[0072] For purposes of the present invention, the substituted monosaccharide group or monosaccharide subunit (a) one or more hydroxyl groups of a monosaccharide group or monosaccharide subunit may each independently be -H, -F, -Cl, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, -R b , -OR b , -SRb 、-R a -O-R b 、-R a -S-R b 、-SO-R b 、-SO2-R b 、-SO2-OR b 、-O-SO-R b 、-O-SO2-R b 、-O-SO2-OR b 、-NR b -SO-R b 、-NR b -SO2-R b 、-NR b -SO2-OR b 、-R a -SO-R b 、-R a -SO2-R b 、-R a -SO2-OR b 、-SO-N(R b )2、-SO2-N(R b )2、-O-SO-N(R b )2、-O-SO2-N(R b )2、-NR b -SO-N(R b )2、-NR b -SO2-N(R b )2、-R a -SO-N(R b )2、-R a -SO2-N(R b )2、-N(R b )2、-N(R b )3 + 、-R a -N(R b )2、-R a -N(R b )3 + 、-P(R b )2、-PO(R b )2、-OP(R b )2、-OPO(R b )2、-R a -P(R b )2、-R a -PO(R b )2、-OSi(R b )3、-R a-Si(R b )3, -CO-R b , -CO-OR b , -CO-N(R b )2, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, -NR b -CO-R b , -NR b -CO-OR b , -NR b -CO-N(R b )2, -R a -CO-R b , -R a -CO-OR b , or -R a -CO-N(R b )2; and / or (b) one, two, or three hydrogen atoms directly attached to a carbon atom of a monosaccharide group or monosaccharide subunit are each independently -F, -Cl, -Br, -I, -CF3, -CCl3, -CBr3, -CI3, -OH, -SH, -NH2, -N3, -NH=NH2, -CN, -NO2, -COOH, -R b , -OR b , -SR b , -R a -OR b , -R a -SR b , -SO-R b , -SO2-R b , -SO2-OR b , -O-SO-R b , -O-SO2-R b , -O-SO2-OR b , -NR b -SO-R b , -NR b -SO2-R b , -NR b -SO2-OR b , -R a -SO-R b , -R a -SO2-R b , -R a -SO2-OR b, -SO-N(R b )2, -SO2-N(R b )2, -O-SO-N(R b )2, -O-SO2-N(R b )2, -NR b -SO-N(R b )2, -NR b -SO2-N(R b )2, -R a -SO-N(R b )2, -R a -SO2-N(R b )2, -N(R b )2, -N(R b )3 + , -R a -N(R b )2, -R a -N(R b )3 + , -P(R b )2, -PO(R b )2, -OP(R b )2, -OPO(R b )2, -R a -P(R b )2, -R a -PO(R b )2, -OSi(R b )3, -R a -Si(R b )3, -CO-R b , -CO-OR b , -CO-N(R b )2, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, -NR b -CO-R b , -NR b -CO-OR b , -NR b -CO-N(R b )2, -R a -CO-R b , -R a -CO-OR b , or -R a -CO-N(R b )2; and / or (c) one or more of the hydroxyl groups of the saccharidyl group or monosaccharide subunit, together with the hydrogen bonded to the same carbon atom as the hydroxyl group, are each independently represented by ═O, ═S, or ═NR b , or =N(R b )2 + and / or is substituted with (d) Any two hydroxyl groups of a monosaccharide group or monosaccharide subunit together form -OR c -, -SR c -, -SO-R c -, -SO2-R c -or-NR b -R c -substituted with; At that time, Each-R a - is independently a substituted or unsubstituted alkylene, alkenylene, or alkynylene group, optionally containing one or more heteroatoms each independently selected from O, N, and S in its carbon skeleton, and preferably containing 1 to 10 carbon atoms; Each-R b - is independently hydrogen or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl group, optionally containing one or more heteroatoms each independently selected from O, N, and S in its carbon skeleton, and preferably containing 1 to 15 carbon atoms; Each-R c - is independently a chemical bond or a substituted or unsubstituted alkylene, alkenylene, or alkynylene group optionally containing one or more heteroatoms each independently selected from O, N, and S in its carbon skeleton, and preferably containing 1-10 carbon atoms; However, the monosaccharide group or monosaccharide subunit has at least one, preferably at least two or at least three, -OH, -OR b , -O-SO-R b , -O-SO2-R b , -O-SO2-OR b, -O-SO-N(R b )2, -O-SO2-N(R b )2, -OP(R b )2, -OPO(R b )2, -OSi(R b )3, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, or -OR c - is subject to inclusion.

[0073] Typically, the substituted monosaccharide group or monosaccharide subunit (a) one or more of the hydroxyl groups of the saccharidyl group or monosaccharide subunit is each independently -H, -F, -CF3, -SH, -NH2, -N3, -CN, -NO2, -COOH, -R b , -OR b , -SR b , -N(R b )2, -OPO(R b )2, -OSi(R b )3, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, -NR b -CO-R b , -NR b -CO-OR b , or -NR b -CO-N(R b )2; and / or (b) one or two of the hydrogen atoms directly attached to a carbon atom of the monosaccharide group or monosaccharide subunit are each independently -F, -CF3, -OH, -SH, -NH2, -N3, -CN, -NO2, -COOH, -R b , -OR b , -SR b , -N(R b )2, -OPO(R b )2, -OSi(R b )3, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, -NRb -CO-R b , -NR b -CO-OR b , or -NR b -CO-N(R b )2; and / or (c) one hydroxyl group of the monosaccharide group or monosaccharide subunit is replaced with =0, along with the hydrogen bonded to the same carbon atom as the hydroxyl group; and / or (d) Any two hydroxyl groups of a monosaccharide group or monosaccharide subunit together form -OR c -or-NR b -R c -substituted with; At that time, Each-R b - is independently hydrogen or a substituted or unsubstituted linear, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl group containing 1 to 8 carbon atoms and optionally containing in its carbon skeleton one, two, or three heteroatoms each independently selected from O and N; Each-R c - is independently a substituted or unsubstituted alkylene, alkenylene, or alkynylene group containing 1 to 8 carbon atoms and optionally containing in its carbon skeleton one, two, or three heteroatoms each independently selected from O and N; However, the monosaccharide group or monosaccharide subunit has at least two, preferably at least three, -OH, -OR b , -OPO(R b )2, -OSi(R b )3, -O-CO-R b , -O-CO-OR b , -O-CO-N(R b )2, or -OR c - is subject to inclusion.

[0074] In one embodiment, -R βis a saccharidyl group, and one or more hydroxyl groups of the saccharidyl group are each independently -O-CO-R b Each -R b is independently C1-C4 alkyl, preferably methyl. In one embodiment, -R β is a saccharidyl group, and all hydroxyl groups of the saccharidyl group are each independently -O-CO-R b Each -R b are independently C1-C4 alkyl, preferably methyl.

[0075] In modified monosaccharide groups or monosaccharide subunits, (a) the ring of the modified monosaccharide group or monosaccharide subunit, or what would be the ring in the closed ring form of the modified monosaccharide group or monosaccharide subunit, is partially unsaturated; and / or (b) The ring oxygen of the modified monosaccharide group or monosaccharide subunit, or what would be the ring oxygen in the closed ring form of the modified monosaccharide group or monosaccharide subunit, is replaced by -S- or -NR d -, where -R d are independently hydrogen or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, optionally containing one or more heteroatoms each independently selected from O, N and S in its carbon skeleton, and preferably containing 1 to 15 carbon atoms.

[0076] Alternatively, if the modified monosaccharide subunit forms part of a disaccharide, oligosaccharide, or polysaccharide group, -R dmay be a further monosaccharide subunit or subunits forming part of a di-, oligo- or polysaccharide group, and such further monosaccharide subunit or subunits may optionally be substituted and / or modified.

[0077] Typically, the modified monosaccharide group or monosaccharide subunit (a) the ring of the modified monosaccharide group or monosaccharide subunit, or what would be the ring in the closed form of the modified monosaccharide group or monosaccharide subunit, contains a single C=C; and / or (b) The ring oxygen of the modified monosaccharide group or monosaccharide subunit, or what would be the ring oxygen in the closed ring form of the modified monosaccharide group or monosaccharide subunit, is -NR d -, where -R d are independently hydrogen or a substituted or unsubstituted, linear, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl group containing from 1 to 8 carbon atoms, and optionally containing in its carbon skeleton one, two, or three heteroatoms each independently selected from O and N.

[0078] Typical examples of substituted and / or modified monosaccharide subunits include those corresponding to the following: (i) Deoxysugars such as deoxyribose, fucose, fuculose, and rhamnose, in which the monosaccharidyl group or the hydroxyl group of the monosaccharide subunit is replaced by -H; (ii) amino sugars, such as glucosamine and galactosamine, in which the monosaccharide group or the hydroxyl group of the monosaccharide subunit is replaced by -NH, most typically at the 2-position; and (iii) Sugar acids containing a -COOH group, such as aldonic acids (e.g., gluconic acid), urosonic acid, uronic acids (e.g., glucuronic acid), and aldaric acids (e.g., glucuronic acid or galactaric acid).

[0079] In one embodiment of the first or second aspect of the invention, at least one -R β teeth, [ka] is a monosaccharidyl group selected from:

[0080] Preferably, in the compound or complex according to the first or second aspect of the invention, at least one -R β teeth, [ka] is.

[0081] In one embodiment of the first or second aspect of the invention, -R 2 , -R 2x or -R 4 At least one of the following is independently -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β (preferably -R α -OR β or -R α -SR β -R β teeth, [ka] [ka] [ka] [ka] [ka] is selected from.

[0082] In one embodiment of the first or second aspect of the invention, -R 2 , -R 2x or -R 4 At least one of the following must be -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, -R α -[R 6 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )], or -R α -[R 6’ In one embodiment, -R 2 , -R 2x or -R 4 At least one of the following must be -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α -[R 6 ]Y. In one embodiment, -R 2 ,-R 2x or -R 4 At least one of [ka] is selected from.

[0083] In the first or second aspect of the present invention, each -R 5 may be the same or different. In a preferred embodiment, each -R 5 are identical.

[0084] In one embodiment of the first or second aspect of the invention, each -R5 is independently unsubstituted or substituted with one or two substituents. In one embodiment, each -R 5 is non-substituted.

[0085] In one embodiment of the first or second aspect of the invention, each -R 6 is independently unsubstituted or substituted with one or two substituents. 6 is non-substituted.

[0086] In one embodiment, -R 6 is not substituted by a halo group at the 4-position of the pyridine ring. 6 is not substituted at the 4-position of the pyridine ring. 6 is non-substituted.

[0087] In one embodiment of the first or second aspect of the invention, -R 1 contains 1 to 100 atoms other than hydrogen, preferably 1 to 80 atoms other than hydrogen, preferably 1 to 60 atoms other than hydrogen, preferably 1 to 50 atoms other than hydrogen, preferably 1 to 45 atoms other than hydrogen.

[0088] In a particularly preferred embodiment, the first or second aspect of the present invention relates to a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 Ha-CH2OR 2 , -CH2SR 2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CH2N(R 2 )(R 2’ , or -R 2x [preferably -R 1 is R 2x is]; -R 2 and -R 2xis -[(CH2) p Q] r -(CH2) s -[N(R 5 )3]Y, -[(CH2) p Q] r -(CH2) s -[P(R 5 )3]Y, -[(CH2) p Q] r -(CH2) s -[R 6 ]Y, -[(CH2) p Q] r -(CH2) s -[N(R 5 )2(R 5’ )], -[(CH2) p Q] r -(CH2) s -[P(R 5 )2(R 5’ )] or -[(CH2) p Q] r -(CH2) s -[R 6’ ] is selected from; -R 2’ is selected from hydrogen or C1-C6 alkyl [preferably, -R 2’ is selected from hydrogen or C1-C3 alkyl; more preferably, -R 2’ is selected from hydrogen or methyl]; -R 5 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n and —CH3, phenyl, or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl optionally comprises one or more (e.g., 1, 2, 3, 4, or 5) C1-C6 alkyl, C1-C6 haloalkyl, O(C1-C6 alkyl), —O(C1-C6 haloalkyl), halo, —CO2H, —CO2Z, —CO2NH2, —O—(CH2CHO) n -H or -O-(CH2CH2O) n may be substituted by -CH3 groups; -R 5’is C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each selected from -CO2 - wherein the phenyl or C5-C6 heteroaryl is optionally further substituted with one or more (e.g., 1, 2, 3, or 4) C1-C6 alkyl, C1-C6 haloalkyl, —O(C1-C6 alkyl), —O(C1-C6 haloalkyl), halo, —CO2H, —CO2Z, —CO2NH2, —O—(CH2CHO) n -H or -O-(CH2CH2O) n may be substituted by -CH3 groups; -R 6 optionally one or more (e.g., 1, 2, 3, 4, or 5) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted by -CH3 groups; -R 6’ is -CO2 - and optionally further substituted with one or more (e.g., 1, 2, 3, or 4) C-C alkyl, C-C haloalkyl, —O(C-C alkyl), —O(C-C haloalkyl), halo, —COH, —COZ, —CONH, —O—(CHCHO) n -H or -O-(CH2CH2O) n -[NC5H5] substituted by -CH3 groups; Q is O, S, NH, or NMe [preferably Q is O]; Y is a counteranion; Z is a countercation; M 2+ is a metal cation; n is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0089] In certain preferred embodiments, the first or second aspects of the invention relate to a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 Ha-R 2x and; -R 2x is -[(CH2) p Q] r -(CH2) s -[N(R 5 )3]Y, -[(CH2) p Q] r -(CH2) s -[P(R 5 )3]Y, -[(CH2) p Q] r -(CH2) s -[R 6 ]Y, -[(CH2) p Q] r -(CH2) s -[N(R 5 )2(R 5’ )], -[(CH2) p Q] r -(CH2) s -[P(R 5 )2(R 5’ )] or -[(CH2) p Q] r -(CH2) s -[R 6’ ] is selected from; -R 5 are each independently selected from C1-C3 alkyl or phenyl, wherein phenyl is optionally selected from C1-C6 alkyl, —O(C1-C6 alkyl), —CO2H, —CO2Z, —CO2NH2, —O—(CH2CH2O) n -H or -O-(CH2CH2O) noptionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —CH3; -R 5’ is -CO2 - C1-C3 alkyl substituted with -CO2 - wherein phenyl is optionally selected from C1-C6 alkyl, —O(C1-C6 alkyl), —CO2H, —CO2Z, —CO2NH2, —O—(CH2CH2O) n -H or -O-(CH2CH2O) n may be further substituted by 1, 2, 3, or 4 substituents independently selected from -CH3; -R 6 is C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from -CH3; -R 6’ is -CO2 - and optionally substituted with C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted by 1, 2, 3 or 4 substituents independently selected from -CH3; Q is O, S, NH or NMe (preferably O); Y is a counteranion; Z is a countercation; M 2+ is a metal cation; n is 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0090] In these two preferred embodiments of the previous paragraph, each -R 5 may be the same or different. Preferably, each -R 5 are identical.

[0091] In another preferred embodiment of the first or second aspect of the invention, the compound is a compound of formula (IA), (IB), (IC), (ID), (IE), (IF) or (IG): [ka] [ka] [ka] [ka] or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof, wherein: -R δ is selected from C1-C3 alkyl; -R ε is C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n - selected from CH3; Y is a counteranion; Z is a countercation; n is 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; t is 0, 1, 2, 3, 4 or 5; u is 0, 1, 2, 3 and 4.

[0092] The compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG) and their complexes and salts according to the first and second aspects of the present invention comprise a moiety -[(CH) p O] r -(CH2) s -including, p is 0, 1, 2, 3 or 4; r is 0, 1, 2, 3, 4, 5, or 6; s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0093] In one embodiment, p is 2, 3, or 4, r is 1, and s is 2, 3, or 4. In a preferred embodiment, 3-[(CH) p O] r -(CH2) s p is 3, r is 1 and s is 3 so that - is -(CH2)3-O-(CH2)3-.

[0094] In another embodiment, p is 2 or 3, r is 2 or 3, and s is 2 or 3. In a preferred embodiment, -[(CH) p O] r -(CH2) s p is 2, r is 2, and s is 2 so that - is -(CH2CH2O)2-(CH2)2-.

[0095] In yet another embodiment, -[(CH) p O] r -(CH2) s -ga-(CH2) 1-12 -, r is 0 and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0096] Preferably, in the compound or complex according to the first or second aspect of the present invention, the compound or complex is [ka] [ka] [ka] or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof, wherein -R 5 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n and -CH3, phenyl, or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl optionally comprises one or more of C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CHO) n -H or -O-(CH2CH2O) n may be substituted by -CH3 groups; -R 10 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 group; -R 9 each independently optionally represents one or more of C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n is phenyl substituted by a -CH3 group; n is 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3, or 4 (preferably q is 1); and Y is a counter anion.

[0097] Preferably, in the compound or complex according to the first or second aspect of the present invention, said compound or complex is [ka] [ka] [ka] [ka] [ka] or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the compound or complex according to the first or second aspect of the present invention is in the form of a pharmaceutically acceptable salt. In one embodiment, the compound or complex is in the form of an inorganic salt, such as a lithium, sodium, potassium, magnesium, calcium, or ammonium salt. In one embodiment, the compound or complex is in the form of a sodium or potassium salt. In one embodiment, the compound is in the form of a sodium salt. In another embodiment, the compound or complex is in the form of an organic salt, such as an amine salt (e.g., a choline or meglumine salt) or an amino acid salt (e.g., an arginine salt).

[0099] The compound or complex according to the first or second aspect of the invention has at least two chiral centres. The compound or complex of the first or second aspect of the invention is preferably substantially enantiomerically pure, meaning that the compound or complex contains less than 10% of other stereoisomers, preferably less than 5%, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, all by weight as measured by XRPD or SFC.

[0100] Preferably, the compound or complex according to the first or second aspect of the invention has an HPLC purity of greater than 97%, more preferably greater than 98%, more preferably greater than 99%, more preferably greater than 99.5%, more preferably greater than 99.8%, and most preferably greater than 99.9%. As used herein, % HPLC purity is measured by the area normalization method.

[0101] A third aspect of the invention provides a composition comprising a compound or complex according to the first or second aspect of the invention and a pharmaceutically acceptable carrier or diluent.

[0102] In one embodiment, the composition according to the third aspect of the present invention further comprises polyvinylpyrrolidone (PVP). In one embodiment, the composition comprises 0.01-10 wt% PVP as a percentage of the total weight of the composition, preferably 0.1-5 wt% PVP as a percentage of the total weight of the composition, preferably 0.5-5 wt% PVP as a percentage of the total weight of the composition. In one embodiment, the PVP is K30.

[0103] In one embodiment, the composition according to the third aspect of the present invention further comprises dimethyl sulfoxide (DMSO), hi one embodiment, the composition comprises 0.01 to 99 wt% DMSO by weight of the total composition, preferably 40 to 99 wt% DMSO by weight of the total composition, preferably 65 to 99 wt% DMSO by weight of the total composition.

[0104] In one embodiment, the composition according to the third aspect of the invention further comprises an immune checkpoint inhibitor. In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death-ligand 1), or CTLA4 (cytotoxic T-lymphocyte-associated protein 4). In one embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

[0105] Preferably, the compounds or complexes according to the first or second aspect of the invention and the pharmaceutical compositions according to the third aspect of the invention are suitable for use in photodynamic therapy or cytoluminescent therapy.

[0106] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are useful for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis. The compound is suitable for the treatment of: narrowing; intermittent claudication; dermatological conditions; acne; psoriasis; diseases characterized by areas of benign or malignant cell hyperproliferation or angiogenesis; benign or malignant tumors; early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0107] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are suitable for the treatment of diseases characterised by areas of benign or malignant cell hyperproliferation or angiogenesis.

[0108] Preferably, the compounds or complexes according to the first or second aspect of the invention and the pharmaceutical compositions according to the third aspect of the invention are suitable for the treatment of benign or malignant tumours.

[0109] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are suitable for the treatment of early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumours; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0110] Preferably, the compounds or complexes according to the first or second aspect of the invention and the pharmaceutical compositions according to the third aspect of the invention are suitable for use in photodynamic diagnosis.

[0111] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are useful for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis. ; intermittent claudication; dermatological conditions; acne; psoriasis; diseases characterized by areas of benign or malignant cellular hyperproliferation or angiogenesis; benign or malignant tumors; early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestines, colon, large intestine, rectum, bladder, ureters, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0112] Preferably, the compounds or complexes according to the first or second aspect of the invention and the pharmaceutical compositions according to the third aspect of the invention are suitable for the detection of areas affected by benign or malignant cell hyperproliferation or neovascularization.

[0113] Preferably, the compounds or complexes according to the first or second aspect of the invention and the pharmaceutical compositions according to the third aspect of the invention are suitable for the detection of benign or malignant tumours.

[0114] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are suitable for the detection of early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumours; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0115] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are suitable for the fluorescent or phosphorescent detection of the diseases listed above, preferably for the fluorescent or phosphorescent detection and quantification of said diseases.

[0116] Preferably, the compounds or complexes according to the first or second aspect of the invention, and the pharmaceutical compositions according to the third aspect of the invention, are suitable for administration simultaneously with or before the administration of radiation or sound, preferably before the administration of radiation.

[0117] Where the compounds or complexes according to the first or second aspect of the invention, or the pharmaceutical compositions according to the third aspect of the invention, are for use in photodynamic therapy or cytoluminescence therapy, then they are preferably suitable for administration 5 to 100 hours before irradiation, preferably 6 to 72 hours before irradiation, preferably 24 to 48 hours before irradiation.

[0118] When the compounds or complexes according to the first or second aspect of the invention, or the pharmaceutical compositions according to the third aspect of the invention, are for use in photodynamic diagnosis, then they are preferably suitable for administration 3 to 60 hours before irradiation, preferably 8 to 40 hours before irradiation.

[0119] Preferably, the radiation used in photodynamic therapy, cytoluminescence therapy, or photodynamic diagnosis is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm, preferably 550 nm to 750 nm, preferably 600 nm to 700 nm, and preferably 640 nm to 670 nm. The electromagnetic radiation may be administered at about 0.1 to 5 W, preferably about 1 W, for about 5 to 60 minutes, preferably about 15 to 20 minutes. In one embodiment of the present invention, two electromagnetic radiation sources (e.g., a laser light and an LED light) are used, both suitable for providing radiation in the wavelength range of 550 nm to 750 nm, preferably 600 nm to 700 nm, and preferably 640 nm to 670 nm. In another embodiment of the present invention, radiation may be provided by prostate, anal, vaginal, oral, or nasal devices for insertion into body cavities. In another embodiment of the present invention, radiation may be provided by mediated photoactivation, for example, by inserting a fiber-optic laser into the lung, liver, lymph nodes, or breast using a fine needle. In another embodiment of the invention, illumination may be provided by photoactivation of an endoscope, for example to deliver light to the lungs, stomach, colon, bladder or cervix.

[0120] The pharmaceutical composition according to the third aspect of the present invention may be in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraperitoneal, intracranial and epidural), transdermal, respiratory (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration. The pharmaceutical composition may also be in a form suitable for administration by enema or by injection into a tumor. Preferably, the pharmaceutical composition is in a form suitable for oral, parenteral (such as intravenous, intraperitoneal and intratumoral) or respiratory tract administration, preferably in a form suitable for oral or parenteral administration, preferably in a form suitable for oral administration.

[0121] In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration. Preferably, the pharmaceutical composition is provided in the form of tablets, capsules, hard or soft gelatin capsules, caplets, lozenges, or drops, as a powder or granules, or as an aqueous solution, suspension, or dispersion. More preferably, the pharmaceutical composition is provided in the form of an aqueous solution, suspension, or dispersion for oral administration, or in the form of a lyophilized powder that can be mixed with water before administration. Preferably, the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg / kg / day, preferably 0.1 to 2 mg / kg / day, preferably about 1 mg / kg / day, of the compound or complex according to the first or second aspect of the present invention.

[0122] In another preferred embodiment, the pharmaceutical composition is in a form suitable for parenteral administration. Preferably, the pharmaceutical composition is in a form suitable for intravenous administration. Preferably, the pharmaceutical composition is provided in the form of an aqueous solution for parenteral administration, or in the form of a lyophilized powder that can be mixed with water before administration. Preferably, the pharmaceutical composition is an aqueous solution or suspension having a pH of 6 to 8.5. Preferably, the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg / kg / day, preferably 0.1 to 2 mg / kg / day, preferably about 1 mg / kg / day, of a compound or complex according to the first or second aspect of the present invention.

[0123] In another preferred embodiment, the pharmaceutical composition is in a form suitable for administration to the respiratory tract. Preferably, the pharmaceutical composition is provided in the form of an aqueous solution, suspension, or dispersion for administration to the respiratory tract, or in the form of a lyophilized powder that can be mixed with water before administration to provide an aqueous solution, suspension, or dispersion for administration to the respiratory tract. Preferably, the pharmaceutical composition is in a form suitable for providing 0.01 to 10 mg / kg / day, preferably 0.1 to 2 mg / kg / day, preferably about 1 mg / kg / day, of a compound or complex according to the first or second aspect of the invention.

[0124] A fourth aspect of the present invention relates to a method for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; benign or malignant cell hyperproliferation or provides the use of a compound or complex according to the first or second aspect of the invention in the manufacture of a medicament for the treatment of a disease characterised by areas of angiogenesis; a benign or malignant tumour; early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0125] A fourth aspect of the present invention provides the use of a compound or complex according to the first or second aspect of the present invention in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescence therapy, or preferably the phototherapeutic agent is selected from the group consisting of atherosclerosis, multiple sclerosis, diabetes, diabetic retinopathy, arthritis, rheumatoid arthritis, fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections, HIV, AIDS, SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles infections, hepatitis, viral hepatitis, cardiovascular disease, coronary artery stenosis, carotid artery stenosis, intermittent claudication, dermatological conditions, acne, It is suitable for the treatment of psoriasis; diseases characterized by areas of benign or malignant cellular hyperproliferation or angiogenesis; benign or malignant tumors; early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestines, colon, large intestine, rectum, bladder, ureters, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0126] Preferably, the medicament or phototherapeutic agent of the fourth aspect of the invention is suitable for the treatment of diseases characterised by areas of benign or malignant cellular hyperproliferation or neovascularisation.

[0127] Preferably, the drug or phototherapeutic agent according to the fourth aspect of the invention is suitable for the treatment of benign or malignant tumours.

[0128] Preferably, the medicament or phototherapeutic agent according to the fourth aspect of the invention is suitable for the treatment of early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumour; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0129] The fourth aspect of the invention also provides the use of a compound or complex according to the first or second aspect of the invention in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.

[0130] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for use in treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; The test is suitable for detecting millet; psoriasis; diseases characterized by areas of benign or malignant cellular hyperproliferation or angiogenesis; benign or malignant tumors; early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestines, colon, large intestine, rectum, bladder, ureters, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0131] Preferably, the photodiagnostic agent according to the fourth aspect of the present invention is suitable for detecting areas affected by benign or malignant cell hyperproliferation or neovascularization.

[0132] Preferably, the photodiagnostic agent according to the fourth aspect of the present invention is suitable for detecting benign or malignant tumors.

[0133] Preferably, the photodiagnostic agent according to the fourth aspect of the present invention is suitable for the detection of early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumor; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0134] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for fluorescent or phosphorescent detection of said disease, preferably for fluorescent or phosphorescent detection and quantification of said disease.

[0135] Preferably, the drug, phototherapeutic agent or photodiagnostic agent is suitable for administration simultaneously with or before the administration of radiation or sound, preferably before the administration of radiation.

[0136] If the drug or phototherapeutic agent is for use in photodynamic therapy or cytoluminescence therapy, then it is preferably suitable for administration 5-100 hours before irradiation, preferably 6-72 hours before irradiation, preferably 24-48 hours before irradiation.

[0137] If the photodiagnostic agent is used for photodynamic diagnosis, then it is preferably suitable for administration 3-60 hours before irradiation, preferably 8-40 hours before irradiation.

[0138] Preferably, the radiation used in photodynamic therapy, cytoluminescence therapy, or photodynamic diagnosis is electromagnetic radiation having a wavelength in the range of 500-1000 nm, preferably 550-750 nm, preferably 600-700 nm, and preferably 640-670 nm. The electromagnetic radiation can be administered at about 0.1-5 W, preferably about 1 W, for about 5-60 minutes, preferably about 15-20 minutes. In one embodiment of the present invention, two electromagnetic radiation sources (e.g., a laser light and an LED light) are used, both radiation sources being suitable for providing radiation in the wavelength range of 550-750 nm, preferably 600-700 nm, and preferably 640-670 nm. In another embodiment of the present invention, the radiation can be provided by prostate, anal, vaginal, oral, or nasal devices for insertion into body cavities. In another embodiment of the present invention, the radiation can be provided by mediated photoactivation, for example, by inserting a fiber-optic laser into the lung, liver, lymph nodes, or breast using a fine needle. In another embodiment of the invention, illumination may be provided by photoactivation of an endoscope, for example to deliver light to the lungs, stomach, colon, bladder or cervix.

[0139] A fifth aspect of the present invention relates to a method for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis;

[0013] The present invention provides a method for treating diseases characterized by areas of hyperproliferation of benign or malignant cells or angiogenesis; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas. The method comprises administering a therapeutically effective amount of a compound or complex according to the first or second aspect of the invention to a human or animal in need thereof.

[0140] The fifth aspect of the present invention also provides a method for photodynamic or cytoluminescent therapy of a human or animal disease, the method comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound or complex according to the first or second aspect of the present invention. Preferably, the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infection; HIV; AIDS; SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; diseases characterized by areas of benign or malignant cell hyperproliferation or angiogenesis; benign or malignant tumors; early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0141] Preferably, the method of the fifth aspect of the invention is a method of treating areas of benign or malignant cellular hyperproliferation or neovascularization.

[0142] Preferably, the method of the fifth aspect of the invention is a method of treating a benign or malignant tumor.

[0143] Preferably, the method of the fifth aspect of the invention is a method of treating early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumor; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0144] The fifth aspect of the present invention also provides a method for photodynamic diagnosis of a human or animal disease, the method comprising administering to the human or animal a diagnostically effective amount of a compound or complex according to the first or second aspect of the present invention. Preferably, the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infection; HIV; AIDS; infection by SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or shingles; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; The disease may be acne, psoriasis, a disease characterized by areas of benign or malignant cell hyperproliferation or angiogenesis, a benign or malignant tumor, early cancer, cervical dysplasia, soft tissue sarcoma, germ cell tumor, retinoblastoma, age-related macular degeneration, lymphoma, Hodgkin's lymphoma, head and neck cancer, oral cancer, or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas. Preferably, the human or animal disease is characterized by areas of benign or malignant cell hyperproliferation or angiogenesis. Preferably, the human or animal disease is a benign or malignant tumor. Preferably, the human or animal disease is early stage cancer, cervical dysplasia, soft tissue sarcoma, germ cell tumor, retinoblastoma, age-related macular degeneration, lymphoma, Hodgkin's lymphoma, head and neck cancer, oral cancer, or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lung, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas. Preferably, the method of photodynamic diagnosis is suitable for fluorescent or phosphorescent detection of said disease, preferably fluorescent or phosphorescent detection and quantification of said disease.

[0145] In any of the methods of the fifth aspect of the invention, the human or animal is preferably further subjected to irradiation or sound simultaneously with or after administration of a compound or complex according to the first or second aspect of the invention. Preferably, the human or animal is subjected to irradiation after administration of a compound or complex according to the first or second aspect of the invention.

[0146] If the method is a photodynamic therapy or cytoluminescence therapy method, then the human or animal is preferably irradiated 5-100 hours, preferably 6-72 hours, preferably 24-48 hours after administration of the compound or complex according to the first or second aspect of the invention.

[0147] If the method is a method of photodynamic diagnosis, then the human or animal is preferably irradiated 3-60 hours, preferably 8-40 hours, after administration of the compound or complex according to the first or second aspect of the invention.

[0148] Preferably, the irradiation is electromagnetic radiation having a wavelength in the range of 500-1000 nm, preferably 550-750 nm, preferably 600-700 nm, preferably 640-670 nm. The electromagnetic radiation can be administered at about 0.1-5 W, preferably about 1 W, for about 5-60 minutes, preferably about 15-20 minutes. In one embodiment of the present invention, two electromagnetic radiation sources (e.g., a laser light and an LED light) are used, both radiation sources being suitable for providing irradiation in the wavelength range of 550-750 nm, preferably 600-700 nm, preferably 640-670 nm. In another embodiment of the present invention, the irradiation can be provided by prostate, anal, vaginal, oral, or nasal devices for insertion into body cavities. In another embodiment of the present invention, the irradiation can be provided by mediated photoactivation, for example, by inserting a fiber-optic laser into the lung, liver, lymph nodes, or breast using a fine needle. In another embodiment of the invention, illumination may be provided by photoactivation of an endoscope, for example to deliver light to the lungs, stomach, colon, bladder or cervix.

[0149] In any of the methods of the fifth aspect of the invention, preferably the human or animal is a human.

[0150] A sixth aspect of the present invention is (a) a compound or complex according to the first or second aspect of the present invention; (b) a pharmaceutical combination or kit comprising an immune checkpoint inhibitor.

[0151] In one embodiment, the immune checkpoint inhibitor is an inhibitor of PD-1 (programmed cell death protein 1), PD-L1 (programmed death-ligand 1), or CTLA4 (cytotoxic T-lymphocyte-associated protein 4). In one embodiment, the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

[0152] Preferably, the combination or kit of the sixth aspect is for use in treating a disease, disorder, or condition, wherein the disease, disorder, or condition is responsive to PD-1, PD-L1, or CTLA4 inhibition. Preferably, the combination or kit of the sixth aspect is for use in treating cancer. In one embodiment, the cancer is melanoma, lung cancer (e.g., non-small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin's lymphoma.

[0153] The sixth aspect also provides the use of a combination or kit of the sixth aspect of the invention in the manufacture of a medicament for treating a disease, disorder, or condition responsive to PD-1, PD-L1, or CTLA4 inhibition. The sixth aspect also provides the use of a combination or kit of the sixth aspect of the invention in the manufacture of a medicament for treating cancer. In one embodiment, the cancer is melanoma, lung cancer (e.g., non-small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin's lymphoma.

[0154] The sixth aspect of the present invention also provides a method for treating a disease, disorder, or condition responsive to PD-1, PD-L1, or CTLA4 inhibition, comprising administering a therapeutically effective amount of a combination or kit according to the sixth aspect of the present invention to a human or animal in need thereof. The sixth aspect of the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of a combination or kit according to the sixth aspect of the present invention to a human or animal in need thereof. In one embodiment, the cancer is melanoma, lung cancer (e.g., non-small cell lung cancer), kidney cancer, bladder cancer, head and neck cancer, or Hodgkin's lymphoma.

[0155] In the case of the combination or kit of the sixth aspect of the invention, the compound or complex according to the first or second aspect of the invention and the immune checkpoint inhibitor may be provided together in one pharmaceutical composition, or may be provided separately in two pharmaceutical compositions, which may be administered at the same time or at different times.

[0156] Preferably, the combination or kit of the sixth aspect is adapted for administration simultaneously with or prior to the administration of radiation or sound, preferably prior to the administration of radiation, hi one embodiment, the combination or kit of the sixth aspect is suitable for administration 5-100 hours prior to radiation, preferably 6-72 hours prior to radiation, preferably 24-48 hours prior to radiation.

[0157] Preferably, the radiation used in photodynamic therapy or cytoluminescence therapy is electromagnetic radiation having a wavelength in the range of 500-1000 nm, preferably 550-750 nm, preferably 600-700 nm, and preferably 640-670 nm. The electromagnetic radiation can be administered at about 0.1-5 W, preferably about 1 W, for about 5-60 minutes, preferably about 15-20 minutes. In one embodiment of the present invention, two electromagnetic radiation sources (e.g., a laser light and an LED light) are used, both radiation sources being suitable for providing radiation in the wavelength range of 550-750 nm, preferably 600-700 nm, and preferably 640-670 nm. In another embodiment of the present invention, the radiation can be provided by prostate, anal, vaginal, oral, or nasal devices for insertion into body cavities. In another embodiment of the present invention, the radiation can be provided by mediated photoactivation, for example, by inserting a fiber-optic laser into the lung, liver, lymph nodes, or breast using a fine needle. In another embodiment of the invention, illumination may be provided by photoactivation of an endoscope, for example to deliver light to the lungs, stomach, colon, bladder or cervix.

[0158] For the avoidance of doubt, insofar as is practicable, any embodiment of a given aspect of the invention may be practiced in combination with any other embodiment of the same aspect of the invention. Furthermore, it will be understood that insofar as is practicable, any preferred or optional embodiment of any aspect of the invention shall also be deemed to be a preferred or optional embodiment of any other aspect of the invention. [Example]

[0159] Details of the synthesis experiment Synthesis Example 1: Synthesis of 3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propan-1-ol (also known as phyllochlorin 3-hydroxypropyl) (Compound 1) [ka] Synthesis of phyllochlorin methyl ester [ka] To a single-port 100 mL RBF was added phyllochlorin (2.40 g, 4.72 mmol, 1 equiv.), potassium carbonate (0.78 g, 5.66 mmol, 1.2 equiv.), DMF (30 mL), and a small stir bar. The flask was placed under nitrogen and stirred at 300 rpm. Methyl iodide (382 μL, 6.13 mmol, 1.3 equiv.) was then added, and the flask was stirred at room temperature. HPLC analysis after 2 h and over the weekend confirmed the reaction was complete. The solution was diluted with DCM (30 mL), filtered through Celite® (1 cm depth), and washed with DCM until no color eluted. The solvent was removed under reduced pressure, yielding approximately 4 g of a blue solid. The crude material was dissolved in EtOAc (125 mL), washed with water (2 x 100 mL), dried (Na2SO4) and concentrated under reduced pressure to give the crude product as a dark blue / green solid (2.7 g). The crude material was purified by column chromatography (silica, 4 x 23 cm, solvent gradient from DCM to 3% MeOH / DCM) to give phyllochlorin methyl ester as a dark blue / green solid (1.60 g, 64.8%).

[0160] 1 H NMR(400MHz,CDCl3)δ-2.22(br,1H),-2.10(br,1H),1.72-1.80(m,6H),2.20 -2.10(m,1H),2.10-2.00(m,1H),2.48-2.62(m,2H),3.38(s,3H),3.53(s,3H) ,3.58(s,3H),3.64(s,3H),3.84(q,2H),3.98(s,3H),4.50(q,1H),4.56(d,1 H),6.13(dd,1H),6.37(dd,1H),8.16(dd,1H),8.83(brs,2H),9.71(brs,2H).

[0161] Reduction to 3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propan-1-ol [ka] To a two-neck 500 mL RBF was added lithium aluminum hydride (670 mg, 16.8 mmol, 5 equiv.) and THF (200 mL). The solution was stirred (350 rpm) and cooled under nitrogen using an ice / water bath for 10 minutes. Phyllochlorin methyl ester (1.75 g, 3.35 mmol, 1 equiv.) was added portionwise over 5 minutes. After 30 minutes, additional lithium aluminum hydride (670 mg, 16.8 mmol, 5 equiv.) was added, and stirring was continued for 90 minutes, during which time the reaction warmed slightly. TLC analysis indicated the reaction was complete. The flask was cooled (ice / water bath), and water (1.3 mL) was added, followed by 4 M NaOH (1.3 mL). After stirring for 10 minutes, additional water (4.0 mL) was added, and the solution was warmed to room temperature and stirred for 15 minutes. Sodium sulfate was added, and the mixture was stirred for 10 minutes before being filtered and rinsed with DCM until no further color eluted. The solvent was then removed under reduced pressure to give approximately 2.3 g of crude product (still containing some solvent). HPLC analysis at this stage indicated a purity of 97.3% for the crude product. The crude material was purified by column chromatography (silica, 4 x 11 cm, 2-4% MeOH / DCM) to give compound 1 as a dark blue / green solid (1.60 g, 97%) (HPLC purity: 97.6%).

[0162] 1 H NMR(400MHz,CDCl3)δ9.72(m,2H),8.88(s,1H),8.84(m,1H),8.16(dd,1H),6.48(dd,1H),6.14(dd,1H),4.51(m,2H),3.94(s,3H),3.85(q,2H),3.63 (s,3H),3.60-3.50(m,5H),3.38(s,3H),2.21-2.612(m,1H),1.85-1.72(m ,8H),1.52-1.40(m,2H),1.12-1.05(m,1H),-2.10(br,1H),-2.22(br,1H).

[0163] Synthesis Example 2: Synthesis of 3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propyl acetate (Compound 2) [ka] To a 25 mL RBF was added 3-hydroxypropyl phyllochlorin (compound 1) (100 mg, 0.202 mmol, 1 equiv.), pyridine (0.7 mL), acetic anhydride (0.2 mL, 2.11 mmol, 10 equiv.), and DMAP (0.5 mg). The solution was stirred at 30 °C for 1 h. Analysis by TLC and HPLC indicated the reaction was complete. Ethyl acetate (10 mL) and water (5 mL) were added, and the mixture was vigorously stirred for 10 min. The layers were separated, and the ethyl acetate layer was washed with 0.5 M HCl (3 × 5 mL), saturated NaHCO (3 × 5 mL), dried (NaSO), and concentrated to give compound 2 (78 mg, 72%) as a dark green, flaky solid (HPLC purity: 98.8%), which was not further purified by HPLC.

[0164] 1 H NMR(400MHz,CDCl3)δ9.72(m,2H),8.86(s,1H),8.84(m,1H),8.16(dd,1H),6.4 8(dd,1H),6.13(dd,1H),4.52(m,2H),4.06(t,2H),3.95(s,3H),3.85(q,2H),3 .65(s,3H),3.54(s,3H),3.37(s,3H),2.21-2.13(m,1H),1.96(s,3H),1.95-1. 80(m,2H),1.80-1.72(m,6H),1.62-1.50(m,2H),-2.10(br,1H),-2.22(br,1H).

[0165] Synthesis Example 3: Synthesis of (7S,8S)-8-(3-chloropropyl)-17-ethyl-3,7,10,13,18-pentamethyl-2-vinyl-7H,8H-porphyrin (also known as 3-chloropropyl phyllochlorin) (Compound 3) [ka] A single-neck 25 mL RBF was charged with 3-hydroxypropyl phyllochlorin (compound 1) (0.50 g, 1.01 mmol, 1 equiv.), dichloroethane (4 mL), and thionyl chloride (200 mg, 1.68 mmol, 1.65 equiv.). The resulting solution was cooled using an ice / water bath and stirred (350 rpm) under a nitrogen atmosphere. DMF (1 drop) was added, and the mixture was stirred at room temperature for 1 h and then at 40 °C for an additional 1 h, at which point HPLC analysis indicated the reaction was complete. The reaction was then cooled using an ice / water bath, and pH 7 phosphate buffer (10 mL) was added. The mixture was extracted with DCM (2 × 15 mL), dried (NaSO), and concentrated under reduced pressure to give the crude chloride. Column chromatography (3 × 10 cm silica) using 1% MeOH / DCM afforded compound 3 (450 mg, 87%) as a dark blue / green solid.

[0166] 1 H NMR(400MHz,CDCl3)δ9.71(m,2H),8.85(s,1H),8.84(m,1H),8.17(dd,1H),6.37(dd,1 H),6.13(dd,1H),4.51(m,2H),3.96(s,3H),3.84(q,2H),3.64(s,3H),3.53(s,3H),3.4 9-3.42(m,2H),3.38(s,3H),2.35-2.25(m,1H),2.08-1.95(m,1H),1.94-1.85(m,1H),1 .80-1.72(m,6H),1.71-1.60(m,1H),1.04-1.01(m,3H),-2.10(br,1H),-2.23(br,1H).

[0167] Synthesis Example 4: Synthesis of (2S,3R,4S,5S,6R)-2-((3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 4) [ka] Synthesis of (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-((3-mercaptopropyl)thio)tetrahydro-2H-pyran-3,4,5-triol [ka] Step 1: To a dry, three-neck, 250 mL RBF equipped with a stir bar and stopper was added 1,3-propanedithiol (11.9 g, 110 mmol, 2 equiv.). The flask was fitted with a reflux condenser equipped with a gas inlet and bubbler and then placed under nitrogen. Chloroform (30 mL) was added, and the solution was stirred at room temperature under nitrogen. 1,2,3,4,6-penta-O-acetyl-β-D-glucose (21.5 g, 55.0 mmol, 1 equiv.) was added using a funnel and washed with additional chloroform (10 mL). Finally, indium bromide (0.58 g, 1.64 mmol, 0.03 equiv.) was added, and the mixture was placed in a preheated oil bath (90 °C) and stirred under nitrogen for 2.5 h. The reaction mixture was cooled to room temperature and loaded directly onto a silica gel column (250 × 50 mm) composed of 100% DCM. The column was eluted with 100% DCM, then 30% EtOAc in hexanes, 60% EtOAc in hexanes, and finally 100% EtOAc, collecting 30 × 125 mL fractions. The most intense fractions (11–19), as evidenced by TLC, were combined and evaporated to give a colorless, viscous oil (10.33 g), which crystallized on standing. H NMR indicated this was the desired product, but contained 4% EtOAc and 5% acetic acid. Therefore, the material was dissolved in DCM (150 mL), washed with 1 M sodium bicarbonate solution (200 mL), and the washes were back-extracted with DCM (50 mL). The combined organic phases were washed with water (150 mL), dried (NaSO), and evaporated to give a viscous, colorless oil, which rapidly crystallized on standing. The material was triturated with 1:1 hexane / diethyl ether (approximately 30 mL) and larger crystals were crushed with a glass rod. After stirring for 1 hour, the suspension was filtered and the solid was dried overnight in a vacuum oven at 25°C (7.50 g).

[0168] 1H NMR(400MHz,CDCl3)δ5.21(dd,J=9.8,9.8Hz,1H),5.08(dd,J=9.8,9.8Hz,1H),5.03(dd,J=9.8,9.8Hz,1H),4 .49(d,J=9.8Hz,1H),4.23(dd,J=12.3,4.9Hz,1H),4.14(dd,J=12.3,2.4Hz,1H),3.71(ddd,J=9.8,4.9,2.4Hz ,1H),2.85(ddd,J=12.7,7.0,7.0Hz,1H),2.76(ddd,J=12.7,7.0,7.0Hz,1H),2.63(app.ddd,J=8.1,7.0,7.0H z,2H),2.08(s,3H),2.06(s,3H),2.02(s,3H),2.00(s,3H),1.90(app.p,J=7.0Hz,2H),1.37(t,J=8.1Hz,1H).

[0169] Step 2: (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((3-thiopropyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.50 g, 5.7 mmol, 1 equiv.) was weighed into a 100 mL dry, single-neck RBF, and the flask was equipped with a stir bar and a three-way tap. The flask was placed under nitrogen, and anhydrous MeOH (20 mL) was added via syringe through the three-way tap, while the flask was maintained under nitrogen. Methanolic ammonia (4.8 mL, approximately 57 mmol, 10 equiv.) was added using a graduated pipette, after which the flask was sealed and stirred at room temperature overnight. After 21 hours, the solvent was removed to give (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-((3-mercaptopropyl)thio)tetrahydro-2H-pyran-3,4,5-triol (1.74 g) as a clear, pale maroon oil, which was used without further purification.

[0170] 1H NMR (400MHz, d4-MeOH) δ1.92 (quintet, overlapping acetamide), 2.04 (quintet, 2H (major isomer)), 2.63 (t, 0.6H (minor isomer)), 2.73-2.94 (m, 4 .4H),3.19(m,1.3H),3.25-3.38(m,overlapping-NMR solvent),3.62-3.69(m,1.3H),3.83-3.89(m,1.3H),4.34-4.39(m,1.3H).

[0171] Synthesis of (2S,3R,4S,5S,6R)-2-((3-((3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 4) [ka] A 10 mL RBF was charged with 3-chloropropyl phyllochlorin (compound 3) (100 mg, 0.195 mmol, 1 equiv.), potassium carbonate (54 mg, 0.390 mmol, 2 equiv.), sodium bromide (2 mg, 0.020 mmol, 0.1 equiv.), and DMF (1 mL). (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-((3-mercaptopropyl)thio)tetrahydro-2H-pyran-3,4,5-triol (58 mg, 0.215 mmol, 1.1 equiv.) was added, and the resulting solution was stirred at 30 °C under nitrogen. After 3 h, TLC indicated the presence of only starting material, and the flask was then heated at 70 °C overnight. HPLC indicated approximately 50% consumption of the starting material and the formation of two products. The solvent was removed under reduced pressure. The residual blue solid was purified by column chromatography using 1.5-10% MeOH / DCM to elute compound 4 (9 mg, 6%).

[0172] Synthesis Example 5: (2S,3R,4S,5S,6R)-2-((3-((3-((7S,8S)-18-ethyl-2,5,8,12,17-pentamethyl-13-vinyl-7H,8H-porphyrin-7-yl)propyl)thio)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound 5) [ka] To a 5 mL RBF containing a stir bar, 3-chloropropyl phyllochlorin (compound 3) (71 mg, 0.1384 mmol, 1 equiv.) was added (partially dissolved), followed by a solution of β-D-thioglucose sodium salt (31 mg, 0.1421 mmol, 1.03 equiv.) in 1.4 mL of methanol. The resulting mixture was stirred (420 rpm) for 3 h, but no reaction was evident, so potassium iodide (approximately 2 mg) was added. Further stirring at ambient temperature was unsuccessful, so the reaction mixture was heated at 75 °C (external) overnight, at which point the reaction had progressed to 50% as monitored by HPLC and TLC. Further heating had no effect, so the reaction mixture was dissolved in 1:1 MeOH / DCM and passed through a 5 cm pad of silica (in a glass pipette). The solvent was removed to give a black film. The crude product was purified by Biotage automated column chromatography to give compound 5 as a black solid (10.4 mg, 11%).

[0173] 1H NMR(400MHz,d6-DMSO)δ9.76(s,1H),9.74(s,1H),9.12(d,J=2.5Hz,1H),9.07(d,J=1.7Hz,1H),8.34(dd,J=17.8,11.6Hz,1H),6. 45(dd,J=17.8,1.6Hz,1H),6.17(dd,J=11.6,1.5Hz,1H),5.19-4.85(m,3H),4.64(q,J=7.2Hz,1H),4.58-4.44(m,2H),4.25(d,J=9 .6Hz,1H),3.93(d,J=2.4Hz,3H),3.82(q,J=7.6Hz,2H),3.70-3.59(m,4H),3.55(s,3H),3.49-3.38(m,2H),3.18-3.00(m,2H),3.0 0-2.92(m,1H),2.76-2.64(m,2H),2.27-2.13(m,1H),2.05-1.91(m,1H),1.79-1.61(m,8H),-2.27(s,1H),-2.44(d,J=2.3Hz,1H).

[0174] Synthesis Example 6: Synthesis of phyllochlorin 3-azidopropyl (Compound 6) [ka] To a 100 mL RBF was added 3-chloropropyl phyllochlorin (compound 3) (3.14 g, 6.12 mmol, 1 equiv.) and DMF (30 mL). Sodium azide (477 mg, 7.34 mmol, 1.2 equiv.) was then added, and the resulting mixture was stirred at 60 °C overnight. An additional portion of sodium azide (119 mg, 1.84 mmol, 0.3 equiv.) was added, and the reaction was stirred at 60 °C for an additional 3 h, at which point the reaction was complete as monitored by HPLC. The solvent was removed by rotary evaporation to give the crude product as a dark residue. The crude product was purified by column chromatography using a step column (40 / 57 mm), 35 cm silica height, and a mobile phase of 0–5% MeOH in DCM. The product-containing fractions were combined to give compound 6 as a blue / black solid (878 mg, 28%).

[0175] 1H NMR(400MHz,CDCl3)δ9.73(d,J=2.8Hz,2H),8.87(s,1H),8.84(s,1H),8.16(dd,J=17.8,11.5Hz,1H),6 .37(dd,J=17.8,1.5Hz,1H),6.14(dd,J=11.6,1.5Hz,1H),4.57-4.48(m,2H),3.96(s,3H),3.85(q,J=7. 6Hz,2H),3.65(d,J=1.0Hz,3H),3.54(s,3H),3.37(s,3H),3.21(t,J=6.5Hz,2H),2.27-2.16(m,1H),1. 90-1.81(m,1H),1.79(d,J=7.3Hz,3H),1.75(t,J=7.6Hz,3H),1.52(s,2H),-2.11(s,1H),-2.22(s,1H).

[0176] Synthesis Example 7: Synthesis of phyllochlorin 3-aminopropyl (Compound 7) [ka] A 10 mL RBF was charged with 3-azidopropyl phyllochlorin (compound 6) (628 mg, 1.21 mmol, 1 equiv.), THF (2 mL), and water (0.4 mL). Triphenylphosphine (380 mg, 1.45 mmol, 1.2 equiv.) was then added in one portion, and the resulting mixture was stirred for 3 h, at which point the reaction was complete as monitored by TLC. The solvent was removed by rotary evaporation. The residue was dissolved in DCM (10 mL), dried over Na2SO4, filtered, and concentrated to a dark residue, which was purified by column chromatography using a step column (27 / 40 mm), 30 cm silica height, and a gradient of 10% to 60% MeOH / DCM. The major product fractions were combined to give compound 7 (393 mg, 66%) as a blue / black solid.

[0177] 1H NMR(400MHz,d6-DMSO)δ9.76(d,J=8.4Hz,2H),9.12(s,1H),9.09(d,J=1.8Hz,1H),8.36(dd,J=17.9, 11.6Hz,1H),7.10(s,2H),6.46(dd,J=17.8,1.6Hz,1H),6.19(dd,J=11.6,1.5Hz,1H),4.59(d,J=7.6 Hz,3H),3.94(s,3H),3.83(q,J=7.6Hz,2H),3.64(s,3H),3.56(s,3H),2.75(s,1H),2.70-2.58(m,1H) ),2.19-2.06(m,1H),1.87-1.64(m,9H),1.23(d,J=9.5Hz,1H),-2.27(s,1H),-2.43(d,J=2.2Hz,1H).

[0178] Synthesis Example 8 - Synthesis of phyllochlorin 3-aminopropyl-valinamide hydrochloride (Compound 8) [ka] Step 1: A 10 mL RBF was charged with Boc-L-valine (96.8 mg, 0.4456 mmol, 1.1 equiv.), PyBOP (252.98 mg, 0.4861 mmol, 1.2 equiv.), DCM (1 mL), and triethylamine (73 μL, 0.5266 mol, 1.3 equiv.). The resulting mixture was stirred (420 rpm) at ambient temperature for 5 min and then added to a 10 mL RBF containing a solution of 3-aminopropyl phyllochlorin (compound 7) (200 mg, 0.4051 mmol, 1 equiv.) in DCM (2 mL), using additional DCM (1 mL) for quantitative transfer. The resulting mixture was stirred for 45 min, at which point the reaction was complete as monitored by TLC. The solvent was removed on a rotary evaporator to give a black residue which was purified by Biotage automated column chromatography to give phyllochlorin 3-aminopropyl(Boc)-valinamide as a dark purple solid (273 mg, 97%).

[0179] Step 2: In a 10 mL RBF, phyllochlorin 3-aminopropyl(Boc)-valinamide was dissolved in DCM (1 mL). A solution of 4 M HCl / dioxane (0.97 mL, 3.8964 mmol, 10 equiv.) was then added, and the resulting mixture was stirred for 1 h, at which point the reaction was complete as monitored by HPLC. The solvent was removed by rotary evaporation to give a black residue, which was dissolved in minimal DMSO (2 mL) and purified by Biotage automated column chromatography using a C-18 column (0.1 M HCl / acetonitrile). Fractions were analyzed by HPLC, and the product-containing fractions were combined to give compound 8 (25 mg, 9%) as a black solid (HPLC purity: 91.9%).

[0180] 1 H NMR(400MHz,d6-DMSO)δ10.18(d,J=6.3Hz,2H),9.51(s,1H),9.34(s,1H),8.65(t,J=5.6Hz,1H),8.47(dd,J=17.8,11.7Hz,1H),8.19(d,J=5.4Hz,3H), 6.51(dd,J=17.8,1.4Hz,1H),6.29(d,J=11.7Hz,1H),4.76(q,J=7.2Hz,1H) ,4.68(dd,J=9.6,2.8Hz,1H),4.04(s,3H),3.98(q,J=7.6Hz,1H),3.71(s,3 H),3.60(s,3H),3.49(dd,J=7.6,3.8Hz,1H),3.44(s,3H),3.24(dq,J=13.0 ,6.5Hz,1H),3.07(dq,J=12.7,6.4Hz,1H),2.25-2.13(m,1H),2.00(h,J=6. 8Hz,1H),1.81(d,J=7.2Hz,4H),1.72-1.63(m,1H),1.60(t,J=7.5Hz,3H),1 .55-1.48(m,2H),0.83(dd,J=6.9,2.8Hz,6H),-3.02(s,1H),-3.24(s,1H).

[0181] Synthesis Example 9: Synthesis of phyllochlorin 3-pyridinium propyl iodide (Compound 9) [ka] Step 1: To a 50 mL RBF equipped with a reflux condenser and stir bar containing 3-chloropropyl phyllochlorin (compound 3) (300 mg, 0.585 mmol, 1 equiv.) was added acetone (15 mL) and NaI (263 mg, 1.754 mmol, 3 equiv.). The solution was heated at 65 °C under nitrogen with HPLC monitoring. After 4 h, an additional portion of NaI (263 mg, 1.754 mmol, 3 equiv.) was added, and heating was continued for a total of 30 h. The mixture was cooled, and the acetone was removed by rotary evaporation. The residue was diluted with DCM (25 mL), washed with water (25 mL), dried (NaSO), and concentrated by rotary evaporation to give the crude product as a dark green oil. The residue was purified by column chromatography (3 × 20 cm) using a gradient of 0–0.5% MeOH / DCM. The major dark green spot (R in DCM) f =0.50) were combined to give phyllochlorin 3-propyl iodide as a dark green solid (270 mg, 76%) (HPLC purity: 93.3%), which was used directly in the next step.

[0182] Step 2: To a sealed tube (2.5 x 20 cm, Teflon screw cap) containing 3-propyl phyllochlorin iodide (120 mg, 0.198 mmol, 1 equiv.) and a stir bar, MeCN (5 mL) and pyridine (157 mg, 1.985 mmol, 10 equiv.) were added. After flushing the tube with nitrogen and sealing it, the dark green mixture was stirred (300 rpm) at 90 °C for 20 h. The mixture was cooled, transferred to a RBF, and the solvent was removed by rotary evaporation to remove MeCN and most of the pyridine, yielding the crude product as a dark green oil. The residue was purified by column chromatography (3 x 13 cm) using 8–11% MeOH / DCM. Fractions containing the major dark green spot (Rf = 0.2 in 10% MeOH / DCM) were combined to give compound 9 (90 mg, 66%) as a dark green solid.

[0183] 1H NMR(400MHz,CDCl3)δ9.68(s,1H),9.58(s,1H),8.80(m,2H),7.97(dd,1H),7.41(m,2H),7 .12(m,1H),6.47(m,2H),6.24(dd,1H),6.00(dd,1H),4.39(m,1H),4.27(m,1H),3.80(q,2 H),3.74(s,3H),3.61(s,3H),3.44(s,3H),3.30(s,3H),3.25(m,1H),2.73(m,1H),1.71(m ,4H),1.63-1.55(m,7H),1.52-1.35(m,2H),1.00(m,1H),-2.47(brs,1H),-2.53(brs,1H).

[0184] Synthesis Example 10: Synthesis of phyllochlorin 3-triphenylphosphonium propyl iodide (Compound 10) [ka] To a sealed tube (2.5 x 20 cm, Teflon screw cap) containing 3-propyl phyllochlorin iodide (120 mg, 0.198 mmol, 1 equiv.) and a stir bar, MeCN (7 mL) and PPh3 (57 mg, 0.218 mmol, 1.1 equiv.) were added. After flushing the tube with nitrogen and sealing it, the dark green mixture was stirred (300 rpm) at 90 °C for 20 h. The mixture was cooled, transferred to a RBF, and the solvent was removed by rotary evaporation to remove MeCN, yielding the crude product as a dark green oil. The residue was purified by column chromatography (3 x 13 cm) using 2–4% MeOH / DCM. Fractions containing the major dark green spot (Rf = 0.15 in 5% MeOH / DCM) were combined to give compound 10 (120 mg, 70%) as a dark green solid (HPLC purity: 97.6%).

[0185] 1H NMR(400MHz,CDCl3)δ9.73(m,2H),8.82(s,1H),8.69(s,1H),8.18(dd,1H),7.02(m,3H),6. 60(m,6H),6.40(m,7H),6.19(d,1H),4.72(m,1H),4.50(m,1H),3.94(s,3H),3.88(q,2H),3 .68(s,3H),3.48(s,3H),3.39(s,3H),3.20(m,1H),2.72(m,1H),2.61(m,1H),2.08(m,1H), 1.80-1.71(m,6H),1.25-1.10(m,1H),0.40-0.30(m,1H),-2.25(brs,1H),-2.35(brs,1H).

[0186] Biological experiment details Example 1: Determination of the solubility of phyllochlorin analogues The absorbance maxima were used as a proxy measure of solubility. The corresponding phyllochlorin analogs were diluted to 50 μM in PBS (phosphate buffered saline) solutions containing decreasing amounts of DMSO ranging from 100% to 0%.

[0187] Where necessary, polyvinylpyrrolidone (K30) was added to a final concentration of 1% w / v. Absorbance was measured using a Cytation 3 Multimode Plate Reader (Biotek) in spectral scanning mode, capturing spectra between 500 and 800 nm in 2 nm increments. An equivalent volume of blank solution was also measured and subtracted accordingly. Each spectrum was normalized to have a minimum signal of 0 and a maximum signal in 100% pure DMSO solution (the most soluble state).

[0188] Example 2: Cytotoxicity, Phototoxicity and Therapeutic Index Preparation of photosensitizer stock solution Photosensitizers (e.g., phyllochlorin analogs, chlorin e4 disodium (provided by Advanced Molecular Technologies, Scoresby) or talaporfin sodium (purchased from Focus Bioscience, catalog number HY-16477-5MG)) were resuspended in 100% dimethyl sulfoxide (DMSO) at a concentration of 5.5 mM. Samples were stored at 4°C protected from light.

[0189] Preparation of photosensitizers for in vitro testing For in vitro experiments, photosensitizer (stock solution, 5.5 mM in 100% DMSO) was diluted 1:100 in concentrated excipient solution (10% w / v Kollidon-12, 42.4% w / v polysorbate 80, 0.6% w / v anhydrous citric acid, 40% w / v ethanol, 1.0% DMSO, final concentration of 55 μM photosensitizer). Serial dilutions were prepared at a fixed dilution ratio of 1:55 in cell culture medium (Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12 (DMEM / F-12)) supplemented with 10% v / v fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin, and the same excipient solution.

[0190] cell culture The human ovarian cancer cell line SKOV3 (ATCC #HTB-77) was maintained in Dulbecco's modified Eagle's medium / nutrient mixture F-12 (DMEM / F-12) supplemented with 10% v / v fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. Monolayer cultures were grown in a humidified incubator at 37°C with 5% CO. When cells reached approximately 80% confluence, spent medium was replaced with medium containing the photosensitizer at the required concentration, and the cells were incubated for the desired period to allow for uptake of the photosensitizer.

[0191] statistical analysis All data were analyzed using GraphPad PRISM v8.3.1(549) (GraphPad Software, CA). Spectral absorbance and viability measurements were normalized to a range of 0-100%, and the minimum and maximum values ​​were determined from the data set. Dose-response was determined using sigmoidal four-point nonlinear regression with variable slope, and IC10 or IC90 was calculated for each compound. All data are presented as mean ± SD (where applicable).

[0192] cytotoxicity SKOV3 cells were seeded into 96-well black-walled plates (Greiner #655090) at a density of 5000 cells per well in 100 μl of medium. Upon reaching approximately 60% confluence, the medium was aspirated and replaced with fresh medium containing 0-100 μM of the relevant phyllochlorin analogue in DMSO. Cells were incubated for an additional 24 hours to allow for uptake of the phyllochlorin analogue.

[0193] To examine the intrinsic cytotoxicity (i.e., "dark toxicity") of phyllochlorin analogs, the culture medium was replaced with fresh medium containing 10% (v / v) AlamarBlue Cell Viability Reagent (ThermoFisher) after 24 hours, and the cells were incubated at 37°C for 6 hours. Untreated cells were used as a control. Fluorescence (Ex 555 nm / Em 596 nm) was measured using a Cytation 3 Cell Imaging Multi-Mode Reader (Biotek), and cytotoxicity was assessed by the percentage of viable cells remaining. All measurements were performed in quadruplicate.

[0194] phototoxicity SKOV3 cells were seeded into 96-well black-walled plates (Greiner #655090) at a density of 5000 cells per well in 100 μl of medium. Upon reaching approximately 60% confluence, the medium was aspirated and replaced with fresh medium containing 0-100 μM of the relevant phyllochlorin analogue in DMSO. Cells were incubated for an additional 24 hours to allow for uptake of the phyllochlorin analogue.

[0195] To investigate phototoxicity, cells were incubated with phyllochlorin analogues (0–10 μM in DMSO) for 24 h, followed by a medium change (as above) and subsequent irradiation with a laser at a density of 50 mW / cm. 2 The specimen was exposed to a 652 nm laser (Invion) ​​for 5 minutes (total 15 J / cm 2 After activation, cells were cultured for an additional 24 hours. The medium was then replaced with fresh medium containing AlamarBlue, and the survival rate of viable cells was assessed as described above. Controls included cells treated with phyllochlorin analogs but not activated by laser light, cells not treated with phyllochlorin analogs but treated with laser light, and an untreated control. All measurements were performed in quadruplicate.

[0196] Toxicity profiles of phyllochlorin analogues We previously evaluated the phototoxicity and intrinsic cytotoxicity (i.e., "dark toxicity") of several phyllochlorin analogs using SKOV3 ovarian cancer cells. For comparative purposes, phyllochlorin analogs were compared with chlorin e4 disodium and talaporfin sodium, a clinically approved photosensitizer used in the photodynamic therapy of lung cancer. Phototoxicity IC90 and dark toxicity IC10 values ​​were calculated using log[inhibitor]-vs. normalized response dose curves with varying slopes, using the equation Y = 100 / (1 + (IC90 / X)^HillSlope(phototoxicity IC90)) or Y = 100 / (1 + (IC10 / X)^HillSlope(dark toxicity IC10)).

[0197] Chlorin e4 disodium and talaporfin sodium were significantly less phototoxic in vitro than all phyllochlorin analogs tested, with IC values ​​in the μM range (versus the nM range for phyllochlorin analogs). Compounds 4, 5, 7, and 8 were more phototoxic than all other species tested, all with apparent IC values ​​below 100 nM. Thus, the phyllochlorin analog species exhibited approximately 450-fold increased phototoxicity compared to the clinically approved photosensitizer, talaporfin sodium.

[0198] Therapeutic index of phyllochlorin analogues To assess the therapeutic potential of phyllochlorin analogs, the therapeutic index (TI) was calculated. TI provides a quantitative measure of relative drug safety by comparing the drug concentration required to achieve the desired effect with the drug concentration that results in undesired off-target toxicity. TI was calculated using the phototoxicity IC90 compared to the dark toxicity IC10.

[0199] The TI values ​​are shown in Table 1. Talaporfin sodium has the lowest therapeutic index (TI = 0.49), and chlorin e4 disodium is only slightly better (TI = 1.89), indicating that they have low relative cytotoxicity but a narrow potential therapeutic window for use. The phyllochlorin analogs of the present invention have significantly improved TI and significantly higher phototoxicity (Table 1).

[0200] Therefore, the phyllochlorin analogs of the present invention have a desirable therapeutic index superior to that of clinically applied photosensitizers. Furthermore, the greater phototoxicity of phyllochlorin analogs suggests the possibility of using them at significantly reduced doses in vivo. Therefore, phyllochlorin analogs have a therapeutic profile suitable for clinical application.

[0201] [Table 1]

[0202] It will be understood that the present invention has been described by way of example only and that 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 solely by the claims that follow.

Claims

1. A compound of formula (I) or a complex of formula (II), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, -R １ is -CH ２ OR ２ 、-CH ２ SR ２ 、-CH ２ S(O)R ２ 、-CH ２ S(O) ２ R ２ 、-CH ２ N(R ２ ) ２ or -R ２ｘ selected from; -R ２ is each independently, -H, -C(O)R ４ -C(O)-OR ４ -C(O)-SR ４ -C(O)-N(R ４ ) ２ -C(S)-OR ４ -C(S)-SR ４ -C(S)-N(R ４ ) ２ -R α -H, -R β -R α -R β -R α -OH, -R α -OR β -R α -SH, -R α -SR β -R α -S(O)R β -R α -S(O) ２ R β -R α -NH ２ -R α -NH(R β )、-R α -N(R β ) ２ -R α -N ３ -R[[ID=6j]] α -X, -R α -[N(R ５ ) ３ Y、-R α -[P(R ５ ) ３ Y、-R α -[R ６ Y、-R α -[N(R ５ ) ２ (R ５’ )]、-R α -[P(R ５ ) ２ (R ５’ )]または-R α -[R ６’ から選択され; -R ２ｘ is -H, -R α -H, -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O) ２ R β , -R α -NH ２ , -R α -NH(R β ), -R α -N(R β ) ２ , -R α -N ３ , -R α -X, -R α -[N(R ５ ) ３ Y, -R α -[P(R ５ ) ３ Y, -R α -[R ６ Y, -R α -[N(R ５ ) ２ (R ５’ )], -R α -[P(R ５ ) ２ (R ５’ )] or -R α -[R ６’ and is selected from; -R ４ These are independently -H and -R α -H, -R β , -R α -R β , -R α -OH, -R α -OR β , -R α -SH, -R α -SR β , -R α -S(O)R β , -R α -S(O) ２ R β , -R α -NH ２ , -R α -NH(R) β ), -R α -N(R) β ) ２ , -R α -X, -R α -[N(R ５ ) ３ ]Y, -R α - [P(R ５ ) ３ ]Y, -R α - [R ６ ]Y, -R α -[N(R ５ ) ２ (R ５’ ) ], -R α - [P(R ５ ) ２ (R ５’ ) ] or -R α - [R ６’ Selected from ]; -R α - are independent of each other, C １ -C ４２ Selected from alkylene groups, the alkylene group comprises one or more C １ -C ４ Alkyl, C １ -C ４ The alkylene group may be optionally substituted with a haloalkyl or halo group, and one or more carbon atoms in the skeleton of the alkylene group may be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe; -R β Each of these is independently a saturated or unsaturated hydrocarbyl group, the hydrocarbyl group may be linear or branched, or a cyclic group, or may contain a cyclic group, the hydrocarbyl group may optionally be substituted, and the hydrocarbyl group may optionally contain one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R ５ Each is independent of C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -(CH ２ CH ２ O) ｎ -H, -(CH ２ CH ２ O) ｎ -CH ３ , phenyl or C ５ -C ６ Selected from heteroaryls, the phenyl or C ５ -C ６ A heteroaryl can optionally contain one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ It may be substituted with the base; -R ５’ C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, -(CH ２ CH ２ O) ｎ -H, -(CH ２ CH ２ O) ｎ -CH ３ , phenyl or C ５ -C ６ Selected from heteroaryls, each being -CO ２ － It is substituted with the phenyl or C ５ -C ６ Heteroaryls also have one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ It may be substituted with the base; -R ６ , optionally 1 or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ Substituted with the base - [NC ５ H ５ ] and; -R ６’ is, -CO ２ － Substituted with, and optionally one or more more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Haloalkyl), Halo, -CO ２ H, -CO ２ Z, -CO ２ NH ２ , -O-(CH ２ CH ２ O) ｎ -H or -O- (CH ２ CH ２ O) ｎ -CH ３ Substituted with the basis of -[NC ５ H ５ ] and; n is 1, 2, 3, 4, 5, or 6. X is a halo group, Y is the anti-anion, Z is a countercation, and M ２＋ It is a metal cation. The aforementioned compound or complex, or a pharmaceutically acceptable salt thereof.

2. Each -R α - becomes independent C １ -C ６ A compound or complex according to claim 1, selected from alkylenes.

3. -R ２ , -R ２ｘ and -R ４ At least one of them is -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β Selected from, -R β The compound or complex according to claim 1, wherein is a saccharidyl group.

4. -R β but, 【Chemistry 2】 The compound or complex according to claim 3, wherein the saccharidyl group is selected from the above.

5. The aforementioned saccharidyl group 【Transformation 3】 The compound or complex according to claim 4.

6. -R β but, 【Chemistry 4】 A saccharidyl group selected from the following, where -R ７ is C １ -C ４ A compound or complex according to claim 3, selected from alkyl groups.

7. -R ７ The compound or complex according to claim 6, wherein is methyl.

8. -R １ ga-CH ２ OR ２ or -CH ２ SR ２ Selected from, in the formula, -R ２ -H, -C(O)R ４ , -R α -H, -R β , -R α -R β , -R α -OR β or -R α -SR β Selected from, -R β This is a saccharidyl group, -R ４ is C １ -C ４ The compound or complex according to claim 1, wherein it is alkyl.

9. The compound or the complex 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 The compound or complex according to claim 1, which is a metal cation complex thereof, or a pharmaceutically acceptable salt thereof.

10. (a) for use in drugs; and / or (b) for use in photodynamic therapy or cell bioluminescence therapy; and / or (c) Atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacteria or parasitic infections; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or herpes zoster infections; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; benign or malignant Diseases characterized by areas of excessive proliferation or angiogenesis of sex cells; benign or malignant tumors; early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cancer; or for use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas; and / or (d) For use in the treatment of diseases characterized by areas of benign or malignant cell overgrowth or angiogenesis; and / or (e) for use in the treatment of benign or malignant tumors; and / or (f) For use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile ducts, intestines, colon, large intestine, rectum, bladder, ureters, kidneys, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas; and / or (g) for use in photodynamic diagnostics; and / or (h) The compound is suitable for administration before the administration of radiation; and / or (i) The compound is suitable for administration before radiation exposure, and the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm; The compound or complex according to claim 1.

11. A pharmaceutical composition comprising a compound or complex according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent.

12. (a) further comprising polyvinylpyrrolidone; and / or (b) further comprising an immune checkpoint inhibitor; and / or (c) further comprising an immune checkpoint inhibitor, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, semiprimab, atezolizumab, avelumab, durvalumab, or ipilimumab; and / or (d) for use in photodynamic therapy or cell bioluminescence therapy; and / or (e) Atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacteria or parasitic infections; HIV; AIDS; infections by SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; benign or Diseases characterized by areas of excessive proliferation or angiogenesis of malignant cells; benign or malignant tumors; early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cancer; or for use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas; and / or (f) For use in the treatment of diseases characterized by areas of benign or malignant cell overgrowth or angiogenesis; and / or (g) for use in the treatment of benign or malignant tumors; and / or (h) For use in the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile ducts, intestines, colon, large intestine, rectum, bladder, ureters, kidneys, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas; and / or (i) for use in photodynamic diagnostics; and / or (j) The pharmaceutical composition is suitable for administration before the administration of radiation; and / or (k) The pharmaceutical composition is suitable for administration before radiation therapy, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm; and / or (l) The pharmaceutical composition is in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraabdominal, intracranial and epidural), transdermal, respiratory (aerosol), rectal, vaginal or topical (including cheek, mucous membrane and sublingual) administration; and / or (m) The pharmaceutical composition is in a form suitable for oral or parenteral administration; The pharmaceutical composition according to claim 11.

13. Atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacteria or parasitic infections; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or herpes zoster infections; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; hyperproliferation of benign or malignant cells or Use of the compound or complex according to claim 1 in the manufacture of a drug for the treatment of cancers of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

14. Use of the compound or complex according to claim 1 in the manufacture of a phototherapy agent for use in photodynamic therapy or cell luminescence therapy.

15. The phototherapy agent is used to treat atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infections; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (avian) influenza virus, dengue virus, herpes simplex or herpes zoster; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; benign or malignant The use according to claim 14, for the treatment of diseases characterized by areas of excessive proliferation or angiogenesis of sex cells; benign or malignant tumors; early cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

16. The use according to any one of claims 13 to 15, wherein the drug or phototherapy agent is for the treatment of a disease characterized by areas of benign or malignant cell overgrowth or angiogenesis.

17. The use according to any one of claims 13 to 15, wherein the drug or phototherapy agent is for the treatment of a benign or malignant tumor.

18. The use according to any one of claims 13 to 15, wherein the drug or phototherapy agent is for the treatment of early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumor; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchi, bronchioles, lungs, hollow organs, esophagus, stomach, bile duct, intestine, colon, large intestine, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

19. Use of the compound or complex according to claim 1 in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.

20. The use according to any one of claims 13 to 15 and 19, wherein the drug, the phototherapy agent, or the photodiagnostic agent is suitable for administration before the administration of radiation.

21. The use according to claim 20, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm.

22. (a) A compound or complex according to any one of claims 1 to 10, (b) Immune checkpoint inhibitors, A kit that includes this.

23. The kit according to claim 22, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, semiprimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

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