Porphyrin and phosphonium-porphyrin based compounds for photodynamic therapy and diagnostics

Abstract

The present invention relates to chlorin e6 analogs and pharmaceutically acceptable salts thereof, as well as compositions comprising the chlorin e6 analogs and pharmaceutically acceptable salts thereof. The chlorin e6 analogs 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 chlorin e6 analogs and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic or photodiagnostic agents, and methods of photodynamic therapy, cytoluminescence therapy, or photodynamic diagnosis, for example, for the treatment or detection of tumors or antiviral treatment. JPEG2025538650000109.jpg61159

Description

[Technical Field]

[0001] The present invention relates to chlorin e6 analogs and pharmaceutically acceptable salts thereof, as well as compositions comprising the chlorin e6 analogs and pharmaceutically acceptable salts thereof. The chlorin e6 analogs 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 chlorin e6 analogs and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic or photodiagnostic agents, and methods of photodynamic therapy, cytoluminescence therapy, or photodynamic diagnosis, for example, for the treatment or detection of tumors or antiviral treatment.

[0002] The structure of "chlorin e6" is shown below. [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] Conjugation of molecules to triphenylphosphonium cations has been shown to enhance mitochondrial delivery, but this is not always guaranteed, as demonstrated in a recent paper by Gilson et al. (Bioconjugate Chemistry, 2019, vol. 30(5), pages 1451-1458). Addition of one triphenylphosphonium cation to the known photodynamic agent chlorin e6 resulted in lysosome accumulation, whereas addition of two triphenylphosphonium cations resulted in distribution to both lysosomes and mitochondria. The authors concluded that "mitochondrially localized PS did not improve cell killing in this study," and the unconjugated parent chlorin e6 exhibited better photodynamic (cell killing) activity than the two triphenylphosphonium-conjugated derivatives.

[0007] 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

[0008] 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 is -CH2OR 2 , -CH2SR 2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CHN(R 2 )2, -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2 (preferably, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2 is selected); -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 -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, -R α -[R 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ] is selected from; -R 3 and -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 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -Rα -[P(R 5 )2(R 5’ )] or R α -[R 8’ ] is selected from; -R α - are each independently C1-C 42 alkylene groups, which may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo groups, and one or more backbone carbon atoms of the alkylene group may be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group which may be linear or branched or may be or contain a cyclic group which may be optionally substituted and which may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -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-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 may be 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 of which is -CO2 -and the phenyl or C5-C6 heteroaryl is optionally substituted with one or more of 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 may be further substituted with -CH3 groups; -R 6 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2 is selected; -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2 is selected; -R 8 is one or more of 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] optionally substituted with -CH3 groups; -R 8’ is -CO2 - and substituted with one or more of 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] optionally further substituted with -CH3 groups; -R 9 -OR 2 , -N(R2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , or -X; 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.

[0009] A second aspect of the present invention provides a compound of formula (I) or a complex of formula (II) according to the first aspect of the present invention for use in medicine.

[0010] In one embodiment of the first or second aspect of the invention, -R 1 , -R 7 and -R 9 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 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )], -R α -[R 8’ ], or containing a saccharidyl group.

[0011] In one embodiment of the first or second aspect of the invention, -R 9 is -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , or -X.

[0012] In the context of this specification, a "hydrocarbyl" substituent or hydrocarbyl moiety in a substituent contains only carbon and hydrogen atoms, but does not contain any heteroatoms such as N, O, S, P, or Se in its carbon skeleton, unless otherwise specified. Hydrocarbyl groups / moieties can be saturated or unsaturated (including aromatic), straight-chain or branched, or can be or contain cyclic groups, and unless otherwise specified, cyclic groups do not contain 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.

[0013] 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. More typically, the alkyl group is a C1-C6 alkyl group. An "alkylene" group is defined similarly as a divalent alkyl group. Usually, an alkylene group is a C1-C6 alkyl group. 42 More typically, the alkylene group is a C-C 32 Alkylene group, or C1-C 22 Alkylene group, or C1-C 12 It is an alkylene group.

[0014] 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. More typically, the alkenyl group is a C2-C6 alkenyl group. An "alkenylene" group is defined similarly as a divalent alkenyl group.

[0015] 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 It is an alkynyl group. More typically, the alkynyl group is a C2-C6 alkynyl group. An "alkynylene" group is defined similarly as a divalent alkynyl group.

[0016] 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- to 12-membered cyclic groups, meaning they contain 3 to 12 ring atoms. More typically, cyclic groups are 3- to 7-membered monocyclic groups, meaning they contain 3 to 7 ring atoms.

[0017] 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.

[0018] A "cycloalkyl" substituent or cycloalkyl moiety in a substituent refers to a saturated hydrocarbyl ring containing, for example, 3 to 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.

[0019] 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 to 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.

[0020] 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."

[0021] 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] where G=O, S or NH.

[0022] 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 atoms of the remainder of the molecule to which the group is attached. An example of an arylalkyl group is benzyl.

[0023] For purposes of this specification, an optionally substituted group or moiety (—R β etc.): (i) each hydrogen atom is optionally replaced by halo; -CN; -NO; -N; -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 -SORx ;-R y -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 may be substituted with monovalent substituents independently selected from (ii) Any two hydrogen atoms attached to the same carbon atom are oxo (=O), =S, =NH, or =NR x and / or (iii) Any two hydrogen atoms bonded to the same or different atoms within the same optionally substituted group or moiety may be replaced by —O—, —S—, —NH—, —N(R x )-, -N + (R x )2- or -R y -, and optionally substituted with a bridging substituent independently selected from where each -R y- is independently selected from an alkylene, alkenylene, or alkynylene group which contains 1 to 6 atoms in its backbone; one or more carbon atoms in the backbone of an alkylene, alkenylene, or alkynylene group can optionally be replaced with one or more heteroatoms N, O, or S; and the alkylene, alkenylene, or alkynylene group can optionally contain one or more halo and / or -R x groups; 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 form a C2-C7 cyclic group together with the nitrogen atom to which they are attached, and any -R x can be optionally substituted with 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.

[0024] 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.

[0025] Unless otherwise specified, any divalent bridging substituent (e.g., —O—, —S—, —NH—, —N(R x )-, -N + (R x )2- or -R y The -) must be attached only to the specified group or moiety, and cannot be attached to a second group or moiety, even if that second group or moiety itself may be optionally substituted.

[0026] The term "halo" includes fluoro, chloro, bromo and iodo.

[0027] 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.

[0028] 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 in 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.

[0029] 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.

[0030] Unless otherwise stated, a reference to a compound or group should be understood to refer to all tautomeric forms of that compound or group.

[0031] 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] 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.

[0032] In the context of this specification, unless otherwise stated, C x -C y A group is defined as a group containing x to y carbon atoms. For example, a C1-C4 alkyl group is defined as an alkyl group containing 1 to 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, e.g., N, O, S, P, or Se, are not included in the C x -C y When 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.

[0033] 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]

[0034] 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]

[0035] As used herein, -[NC5H5]Y refers to: [ka]

[0036] 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.

[0037] In one embodiment of the first or second aspect of the present invention, there is provided a compound of formula (I):

[0038] 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, sulfate, bisulfate, or phosphate) or an organic anion (e.g., acetate, ascorbate, aspartate, benzoate, besylate (benzenesulfonate), bicarbonate, bis(trifluoromethanesulfonyl)imide (TFSI), acid tartrate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, decanoate, edetate, esylate (ethanesulfonate), fumarate, galactarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, β-hydroxybutyrate, 2-hydroxyethanesulfonate, and the counteranion is selected from hydroxymaleate, 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).

[0039] 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.

[0040] 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)).

[0041] 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.

[0042] In one embodiment of the first or second aspect of the invention, -R 1is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2. In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2 or -C(S)-N(R 3 )2. In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2 is selected.

[0043] In one embodiment of the first or second aspect of the invention, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2 or -C(S)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR3 and -R 3 is C1-C4 alkyl (preferably methyl).

[0044] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ), where -R 2 or -R 3 -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 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) and -R 3 -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β and -R β is a saccharidyl group, and -R 3’is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 -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 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) and -R 3 -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 3’ is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 -R α -OR β or -R α -SRβ -R β is a saccharidyl group, and -R 3’ is C1-C4 alkyl (preferably methyl). Typically, in these embodiments, -R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe. Alternatively, in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0045] -R 3’ The group is another -R 3 -R bonded to the same atom as the group 3 -R refers to the group 3 and -R 3’ may be the same or different. Preferably, -R 3 and -R 3’ is different.

[0046] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ) and -R 2 or -R 3 -R α -Rβ or -R β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) and -R 3 -R α -R β or -R β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 -R α -R β or -R β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). Typically, in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m - group or -(CH2CH2S) m - groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0047] In any of the embodiments of the previous three paragraphs, the saccharidyl group may optionally be replaced with a protecting group, such as, for example, acetyl, or a natural amino acid, such as valine. The amino acid may be attached to the saccharidyl group, for example, by forming an ester between the carboxylic acid group of the amino acid and the hydroxyl group of the saccharidyl group.

[0048] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ -R 2 or -R 3 -R α -R β or -R β -R β is a C1-C8 alkyl group optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) —OH or —OAc; —R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) wherein -R 3 -R α -R β or -R β -R β is a C1-C8 alkyl group optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) hydroxyl groups, and -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 Ha-R α -R β or -Rβ -R β is a C1-C8 alkyl group optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) hydroxyl groups, and -R 3’ is H or C1-C4 alkyl (preferably methyl). Typically, in these embodiments, -R α - is an unsubstituted C1 to C6 alkylene group, or an unsubstituted C1 to C4 alkylene group, or an unsubstituted C1 to C2 alkylene group.

[0049] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or C(S)-N(R 3 )(R 3’ ), where -R 2 or -R 3 -R α -H or -R α -OH; -R α - is C1-C 12 alkylene groups, which may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo groups, and one or more carbon atoms in the backbone of the alkylene group may be optionally substituted with one or more heteroatoms O or S; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) where -R 3-R α -H or -R α -OH; -R α - is C1-C 12 alkylene groups, which may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo groups, and one or more carbon atoms in the backbone of the alkylene group may be optionally substituted with one or more heteroatoms O or S; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 -R α -H or -R α -OH, -R α - is C1-C 12 alkylene groups, wherein one or more carbon atoms in the backbone of the alkylene group can be optionally replaced by one or more heteroatoms O or S; 3’ is H or C1-C4 alkyl (preferably methyl).

[0050] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ) where -R 2 or -R 3 Ha-R β and;-R β Halo, -CN, -NO2, -N3, -OH, -OR x , -SH, -SR x , -SOR x , -SO2H, -SO2Rx , -SO2NH2, -SO2NHR x , -SO2N(R x )2, -NH2, -NHR x , -N(R x )2, -N + (R x )3, -CHO, -COR x , -COOH, -COOR x , -OCOR x or -NH-CO-CR z C1-C optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from —NH2 12 Alkyl or C2-C 12 alkenyl group; each -R x is independently selected from C1-C4 alkyl; -R z is the side chain of a natural amino acid; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), where -R 3 Ha-R β and;-R β Halo, -CN, -NO2, -N3, -OH, -OR x , -SH, -SR x , -SOR x , -SO2H, -SO2R x , -SO2NH2, -SO2NHR x , -SO2N(R x )2, -NH2, -NHR x , -N(R x )2, -N + (R x )3, -CHO, -COR x , -COOH, -COOR x , -OCOR x or -NH-CO-CR zC1-C optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents independently selected from —NH2 12 is an alkyl group; each -R x is independently selected from C1-C4 alkyl; -R z is the side chain of a natural amino acid; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 Ha-R β and -R β are independently halo, -CN, -NO2, -N3, -OH, -OR x , -SH, -SR x , -SOR x , -SO2H, -SO2R x , -SO2NH2, -SO2NHR x , -SO2N(R x )2, -NH2, -NHR x , -N(R x )2, -N + (R x )3, -CHO, -COR x , -COOH, -COOR x , -OCOR x or -NH-CO-CR z -NH2, wherein each -R x are independently selected from C1-C4 alkyl, -R z is the side chain of a natural amino acid, and -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0051] In one embodiment of the first or second aspect of the invention, -R 1 is -CO-(NR zz -CHR z -CO) v -N(R zz )2 and -CO-(NR zz -CHRz -CO) v -OR zz where each -R z are independently selected from the side chains of natural amino acids; each -R zz is independently selected from hydrogen and C1-C4 alkyl (preferably methyl); and v is 1, 2, 3, 4, 5, 6, 7 or 8.

[0052] In one embodiment of the first or second aspect of the invention, -R 1 is R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or C(S)-N(R 3 )(R 3’ where -R 2 or -R 3 Ha-R β and;-R β is C1-C 20 alkyl groups, wherein the alkyl group is optionally substituted with 1, 2, 3, or 4 halo groups, and wherein 1, 2, 3, 4, 5, or 6 carbon atoms in the backbone of the alkyl group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe; -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0053] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3, -C(S)-N(R 3 )2 or C(S)-N(R 3 )(R 3’ ) are selected from;-R 3’ is H or C1-C4 alkyl (preferably methyl); -R 2 or -R 3 -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y or -R α -[R 8 ]Y. In one embodiment, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) are selected from;-R 3’ is H or C1-C4 alkyl (preferably methyl); -R 2 or -R 3 -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y; each -R 5 is independently selected from C1-C4 alkyl or phenyl, wherein phenyl is optionally substituted with 1, 2, or 3 C1-C4 alkyl or C1-C4 alkoxy groups; -R 8 is —[NC5H5] optionally substituted with 1, 2, or 3 C1-C4 alkyl or C1-C4 alkoxy groups; —R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH, or NMe; and Y is a counterion (preferably a halide).

[0054] In one embodiment of the first or second aspect of the invention, -R 1 -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or C(S)-N(R 3 )(R 3’ ) where -R 2 or -R 3 Ha-R α -[P(R 5 ) 3] Y; each -R 5 is independently selected from phenyl or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl is optionally selected from 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 n is 1, 2, 3, or 4; Y is fluoride, chloride, bromide, or iodide; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) where -R 3 Ha-R α -[P(R 5 ) 3] Y; each -R 5is independently selected from phenyl or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl is optionally selected from 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 n is 1, 2, 3, or 4; Y is fluoride, chloride, bromide, or iodide; -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is -C(O)-N(R 3 )(R 3’ ) where -R 3 is -R α -[P(R 5 )3]Y, and each -R 5 is independently selected from phenyl or C5-C6 heteroaryl, and the 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 -CH3 groups, n is 1, 2, 3 or 4, Y is fluoride, chloride, bromide or iodide, -R 3’ is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, where m is 1, 2, 3, or 4.

[0055] In one embodiment of the first or second aspect of the invention, -R 1 is -C(O)-OR 3 and -R3 is selected from hydrogen, C1-C4 alkyl (preferably methyl), or a cation (e.g., lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (e.g., choline or meglumine), or a cation of an amino acid (e.g., arginine)). In one embodiment, -R 1 -C(O)-OR 3 and -R 3 is selected from C1-C4 alkyl (preferably methyl), or a cation (e.g., lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (such as choline or meglumine) or amino acid (such as arginine) cation, etc.).

[0056] In one embodiment of the first or second aspect of the invention, -R 1 is -C(O)-N(R 3 )2. In one embodiment, -R 1 is -C(O)-N(C1-C4 alkyl)(R 3 ) or -C(O)-NHR 3 In one embodiment, -R 1 is -C(O)-N(CH3)(R 3 ) or -C(O)-NHR 3 In one embodiment, -R 1 is -C(O)-N(C1-C4 alkyl)(R 3 In one embodiment, -R 1 is -C(O)-N(CH3)(R 3 )

[0057] In one embodiment of the first or second aspect of the invention, -R 1 is -CH2OR 2 , -CH2SR 2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CHN(R 2 )2 or -R 2 In one embodiment, -R 1 is -CH2OR 2 , -CH2SR 2, -CHN(R 2 )2 or -R 2 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 is -CH2OR 2 In one embodiment, -R 1 Ha-R 2 and -R 2 Ha-R α -X.

[0058] In one embodiment of the first or second aspect of the invention, -R 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 -X, -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y or -R α In one embodiment, -R 2 -R α -OR β , -R α -SR β , -R α -S(O)Rβ or -R α -S(O)2R β In one embodiment, each -R 2 -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 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.

[0059] 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.

[0060] 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). In one embodiment, -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 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 -Rα -SR β -R β is a saccharidyl group, and -R 4’ is C1-C4 alkyl (preferably methyl).

[0061] -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.

[0062] 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 )

[0063] In one embodiment of the first or second aspect of the invention, -R 6 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl, and preferably each -R 3 is methyl. In one embodiment, -R 6 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl, and preferably each -R 3 is methyl. In one embodiment, -R 6-C(O)-OR 3 and -R 3 is C1-C4 alkyl, preferably -R 3 is methyl.

[0064] In one embodiment of the first or second aspect of the invention, -R 6 -C(O)-OR 3 and -R 3 is selected from hydrogen, C1-C4 alkyl (preferably methyl), or a cation (e.g., lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (e.g., choline or meglumine), or an amino acid (e.g., arginine) cation).

[0065] In one embodiment of the first or second aspect of the invention, -R 6 is C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ) and -R 3 Ha-R β and -R β is C1-C 20 alkyl groups, wherein the alkyl group is optionally substituted with 1, 2, 3, or 4 halo groups, and wherein 1, 2, 3, 4, 5, or 6 carbon atoms in the backbone of the alkyl group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe; -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0066] In one embodiment of the first or second aspect of the invention, -R 6 is C(O)-OR 3 , -C(O)-SR 3, -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2, each of which is selected from -R 3 -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 6 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, each of which is selected from -R 3 -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 6 is -C(O)-OR 3 or -C(O)-SR 3 -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group. Typically in these embodiments, -R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe. Alternatively, in these embodiments, -R α - is C1-C 12an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0067] In one embodiment of the first or second aspect of the invention, -R 6 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ), where -R 3 -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 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 6 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 -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 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 6 is -C(O)-OR 3, -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). Typically, in these embodiments, -R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe. Alternatively, in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0068] -R 3’ The group is another -R 3 -R bonded to the same atom as the group 3 -R refers to the group 3 and -R 3’ may be the same or different. Preferably, -R 3 and -R 3’ is different.

[0069] In one embodiment of the first or second aspect of the invention, -R 6 is -C(O)-N(R 3 )2. In one embodiment, -R 6 is -C(O)-N(C1-C4 alkyl)(R 3 ) or -C(O)-NHR 3 In one embodiment, -R 6is -C(O)-N(CH3)(R 3 ) or -C(O)-NHR 3 is.

[0070] In one embodiment of the first or second aspect of the invention, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl, and preferably each -R 3 is methyl. In one embodiment, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, each of which is selected from -R 3 is C1-C4 alkyl, and preferably each -R 3 is methyl. In one embodiment, -R 7 -C(O)-OR 3 and -R 3 is C1-C4 alkyl, preferably -R 3 is methyl.

[0071] In one embodiment of the first or second aspect of the invention, -R 7 -C(O)-OR 3 and -R 3 is selected from hydrogen, C1-C4 alkyl (preferably methyl), or a cation (e.g., lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (e.g., choline or meglumine), or an amino acid (e.g., arginine) cation).

[0072] In one embodiment of the first or second aspect of the invention, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3)2, -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 , -C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ) and -R 3 Ha-R β and -R β is C1-C 20 alkyl groups, wherein the alkyl group is optionally substituted with 1, 2, 3, or 4 halo groups, and wherein 1, 2, 3, 4, 5, or 6 carbon atoms in the backbone of the alkyl group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe; -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0073] In one embodiment of the first or second aspect of the invention, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )2, -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )2, each of which is selected from -R 3 -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 7 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, each of which is selected from -R 3 -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 7 is -C(O)-OR 3 or -C(O)-SR 3 -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group. Typically in these embodiments, -R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe. Alternatively, in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0074] In one embodiment of the first or second aspect of the invention, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ) and -R 3 -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2Rβ -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ) and -R 3 -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 3’ is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 7 is -C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ) and -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl (preferably methyl). Typically, in these embodiments, -R α - is C1-C 12 alkylene groups, wherein 1, 2, 3, or 4 carbon atoms in the backbone of the alkylene group are optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe. Alternatively, in these embodiments, -R α - is C1-C 12 an alkylene group (preferably a C1-C8 alkylene group or a C1-C6 alkylene group), —(CH2CH2O) m -CH2CH2- group or -(CH2CH2S)m -CH2CH2- groups, all of which are optionally substituted, where m is 1, 2, 3, or 4.

[0075] -R 3’ The group is another -R 3 -R bonded to the same atom as the group 3 -R refers to the group 3 and -R 3’ may be the same or different. Preferably, -R 3 and -R 3’ is different.

[0076] In one embodiment of the first or second aspect of the invention, -R 7 is -C(O)-N(R 3 )2. In one embodiment, -R 7 is -C(O)-N(C1-C4 alkyl)(R 3 ) or -C(O)-NHR 3 In one embodiment, -R 7 is -C(O)-N(CH3)(R 3 ) or -C(O)-NHR 3 is.

[0077] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 or -S(O)2R 2 In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2. In one embodiment, -R 9 -OR 2 or -SR 2 In one embodiment, -R 9 -OR 2 is.

[0078] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 -H, -C(O)R 4 , -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 In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 -H, -C(O)R 4 , -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 , -Rα -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 9 -OR 2 or -SR 2 -R 2 -H, -C(O)R 4 , -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.

[0079] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2or -S(O)2R 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β and optionally -R β is a saccharidyl group. In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β and optionally -R β is a succadyl group. In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 -R α -OR β or -R α -SR β and optionally -R β is a succadyl group. In one embodiment, -R 9 -OR 2 or -SR 2 -R 2 -R α -OR β , -R α -SR β , -R α -S(O)R β or -Rα -S(O)2R β and optionally -R β is a succadyl group. In one embodiment, -R 9 -OR 2 or -SR 2 -R 2 -R α -OR β or -R α -SR β and optionally -R β is a succadiyl group.

[0080] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 is -C(O)R 4 In one embodiment, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 is -C(O)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 βis a succadyl group. In one embodiment, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 -C(O)R 4 and -R 4 -R α -OR β or -R α -SR β Selected from -R β is a succadiyl group.

[0081] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 is -C(O)R 4 In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 is -C(O)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 succadyl group. In one embodiment, -R 9 -OR 2 , -SR 2 , -S(O)R 2or -S(O)2R 2 -R 2 is -C(O)R 4 and -R 4 -R α -OR β or -R α -SR β -R β is a succadiyl group.

[0082] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 or -SR 2 -R 2 is -C(O)R 4 In one embodiment, -R 9 -OR 2 or -SR 2 -R 2 is -C(O)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. In one embodiment, -R 9 -OR 2 or -SR 2 -R 2 is -C(O)R 4 and -R 4 -R α -OR β or -R α -SR β -R β is a succadiyl group.

[0083] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -N(R 2)(R 2’ ), -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 -R β , -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 succadyl group, -R α - is C1-C 12 In one embodiment, -R is selected from alkylene groups, wherein 1, 2, 3, or 4 carbon atoms of the backbone of the alkylene group can be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe. 9 -OR 2 , -N(R 2 )(R 2’ ) or -SR 2 -R 2’ is selected from hydrogen or C1-C4 alkyl (preferably hydrogen or methyl), -R 2 -R β , -R α -OR β or -R α -SR β -R β is a succadyl group, -R α - is C1-C 12 It is an alkylene group, in which 1, 2, 3, or 4 carbon atoms of the backbone of the alkylene group can be optionally replaced with a heteroatom or group independently selected from O, S, NH, or NMe.

[0084] In any of the embodiments of the previous five paragraphs, the saccharidyl group may optionally be replaced with a protecting group, e.g., acetyl, or a natural amino acid, such as valine. The amino acid may be attached to the saccharidyl group, e.g., by forming an ester between the carboxylic acid group of the amino acid and the hydroxyl group of the saccharidyl group.

[0085] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S. (O)R 2 or -S(O)2R 2 and -R2 ’ is hydrogen, C1 - C4 Alkyl, or -CO2( C1 - C4 alkyl), and -R 2 is -C(O)R 4 , -C(O) -OR4 , -C(O)-N( R4 )(R4 ’ ), - Rα- [N(R 5 )3]Y, -Rα- [P( R5 )3]Y, or -Rα- [ R8 ]Y, -R4 ’ is selected from hydrogen or C1-C4 alkyl, -R 4 -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y. In one embodiment, -R 9 -OR 2 ,-N(R 2 )(R 2’ ),-SR 2 ,-S(O)R 2 or -S(O)2R 2 -R 2’is selected from hydrogen, C1-C4 alkyl, or —CO2(C1-C4 alkyl), and —R 2 is -C(O)R 4 ,-C(O)-OR 4 ,-C(O)-N(R 4 )(R 4’ ),-R α -[N(R 5 )3]Y,-R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y is selected from -R 4’ is selected from hydrogen or C1-C4 alkyl, -R 4 -R α -[N(R 5 )3]Y,-R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y, each -R 5 is independently selected from C1-C4 alkyl or phenyl, where phenyl is optionally substituted with one, two, or three C1-C4 alkyl or C1-C4 alkoxy groups; -R 7 is —[NC5H5] optionally substituted with one, two, or three C1-C4 alkyl or C1-C4 alkoxy groups, and —R α- - is C1-C 12 In one embodiment, -R is selected from alkylene groups, wherein one, two, three, or four carbon atoms of the backbone of the alkylene group may be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe, and Y is a counterion (preferably a halide). 9 -OR 2 or -N(R 2 )(R 2’ ) and -R 2’ is selected from hydrogen, C1-C4 alkyl, or —CO2(C1-C4 alkyl), and —R 2 is -C(O)R 4 , -C(O)-OR 4 , -C(O)-N(R 4 )(R 4’ ), -Rα -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y is selected from -R 4’ is selected from hydrogen or C1-C4 alkyl, -R 4 -R α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, or -R α -[R 8 ]Y, each -R 5 is independently selected from C1-C4 alkyl or phenyl, where phenyl is optionally substituted with one, two, or three C1-C4 alkyl or C1-C4 alkoxy groups; -R 8 is —[NC5H5] optionally substituted with one, two, or three 1-C4 alkyl or C1-C4 alkoxy groups, and —R α - is C1-C 12 is selected from an alkylene group, wherein one, two, three, or four carbon atoms of the backbone of the alkylene group may optionally be replaced by a heteroatom or group independently selected from O, S, NH, or NMe, and Y is a counterion (preferably a halide).

[0086] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 or -S(O)2R 2 -R 2 is selected from hydrogen, C1-C4 alkyl, —CO(C1-C4 alkyl), or —CO2(C1-C4 alkyl). In one embodiment, —R 9 -OR 2 or -N(R 2 )2, and -R 2is selected from hydrogen, C1-C4 alkyl, —CO(C1-C4 alkyl) or —CO2(C1-C4 alkyl).

[0087] In one embodiment of the first or second aspect of the invention, -R 9 -OR 2 , -N(R 2 )2, -N(R 2 )(R 2’ ), -SR 2 , -S(O)R 2 or -S(O)2R 2 ;-R 2’ selected from hydrogen or C1-C4 alkyl; -R 2 -R 4 , -C(O)R 4 , -C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ ) and -R 4’ is selected from hydrogen or C1-C4 alkyl, -R 4 is C1-C 12 In one embodiment, -R is selected from alkyl groups, which may be optionally substituted with one, two, three, or four halo groups, and one, two, three, or four carbon atoms of the backbone of the alkyl group may be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe. 9 -OR 2 or -N(R 2 )(R 2’ );-R 2’ is selected from hydrogen, or C1-C4 alkyl, -R 2 -R 4 , -C(O)R 4 , -C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ ) and -R 4’ is selected from hydrogen, or C1-C4 alkyl, -R 4 is C1-C 12alkyl groups, which may be optionally substituted with one, two, three, or four halo groups, and one, two, three, or four backbone carbon atoms of the alkyl group may optionally be replaced by a heteroatom or group independently selected from O, S, NH, or NMe.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] In one embodiment of the first and second aspects of the invention, each -R β are independently saturated or unsaturated hydrocarbyl groups which may be linear or branched or which may be or include cyclic groups, which may be optionally substituted, and which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

[0092] 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 optionally substituted.

[0093] 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.

[0094] 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 βis 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.

[0095] In one embodiment of the first and second aspects of the invention, each -R 3 independently, -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 3 independently, -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 3 independently, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O)2R β -Rβ is a saccharidyl group. In one embodiment, each -R 3 independently, -R α -OR β or -R α -SR β In one embodiment, each -R 3 independently, -R α -OR β or -R α -SR β -R β is a saccharidyl group.

[0096] In one embodiment of the first and second aspects of the invention, each -R 4 independently, -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 independently, -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 4independently -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.

[0097] In one embodiment of the first or second aspect of the invention, -R 2 , -R 3 or -R 4 At least one of the following may be 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 3 or -R 4 At least one of the following may be independently -R α -OR β or -R α -SR β -R β is a saccharidyl group.

[0098] 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 is composed of one or more monosaccharide subunits, each of which may be optionally substituted and / or modified.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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, and 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 bond is in the β configuration.

[0103] 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.

[0104] 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 two to nine 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 to 50, or 10 to 30, or 10 to 20, or 10 to 15 monosaccharide subunits).

[0105] Each monosaccharide subunit within a disaccharide, oligosaccharide, or polysaccharide group can be the same or different. Each monosaccharide subunit within a disaccharide, oligosaccharide, or polysaccharide group can be linked to another monosaccharide subunit within the group via a glycosidic or non-glycosidic bond. Typically, each monosaccharide subunit within a disaccharide, oligosaccharide, or polysaccharide group is linked to another monosaccharide subunit within the group via a glycosidic bond, which can be in the α or β configuration.

[0106] Each oligosaccharidyl or polysaccharidyl group may be a linear, branched or macrocyclic oligosaccharidyl or polysaccharidyl group. Typically, each oligosaccharidyl or polysaccharidyl group is a linear or branched oligosaccharidyl or polysaccharidyl group.

[0107] In one embodiment, at least one -R β is a monosaccharide or disaccharide group.

[0108] 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 can be optionally substituted. More typically, at least one -R β is a glycosyl group containing a single monosaccharide subunit, where the monosaccharide subunit is unsubstituted.

[0109] In one embodiment, at least one -R β is an aldosyl group, where the aldosyl group can be optionally substituted and / or modified. For example, at least one -R β may 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.

[0110] 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.

[0111] 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. More typically, at least one -R β is a pyranosyl group, such as an aldopyranosyl or ketopyranosyl group, either of which can be optionally substituted and / or modified.

[0112] In one embodiment, at least one -R β is 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.

[0113] 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 can be optionally substituted. More typically, at least one -R β is an unsubstituted glucosyl group.

[0114] 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.

[0115] 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, where the D-glucosyl group can be optionally substituted. More typically, at least one -R β is an unsubstituted D-glucosyl group.

[0116] For purposes of the present invention, in 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 , -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 (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; where: Each-R a- is independently a substituted or unsubstituted alkylene, alkenylene, or alkynylene group which optionally contains one or more heteroatoms each independently selected from O, N, and S in its carbon skeleton and which preferably contains 1 to 10 carbon atoms; Each-R b - is independently hydrogen or a substituted or unsubstituted straight-chain, branched, or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl, or alkynylaryl group optionally containing in its carbon skeleton one or more heteroatoms each independently selected from O, N, and S 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 to 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.

[0117] Typically, in substituted monosaccharide groups or monosaccharide subunits, (a) one or more of the hydroxyl groups of the saccharidyl group or monosaccharide subunits are 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, -NR b -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, together 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; where: Each-R b - is independently hydrogen or a substituted or unsubstituted straight-chain, 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 optionally containing in its carbon skeleton one, two, or three heteroatoms each independently selected from O and N, and containing from 1 to 8 carbon atoms; 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.

[0118] In one embodiment, -R β is a saccharidyl group, and one or more hydroxyl groups of the saccharidyl group are each independently -O-CO-R b are substituted with -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 are substituted with -R b are independently C1-C4 alkyl, preferably methyl.

[0119] In 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 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.

[0120] Alternatively, if the modified monosaccharide subunit forms part of a disaccharide, oligosaccharide, or polysaccharide group, -R d may be a further monosaccharide subunit or subunits forming part of a disaccharide, oligosaccharide or polysaccharide group, and such further monosaccharide subunits or subunits may optionally be substituted and / or modified.

[0121] Typically, 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 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.

[0122] 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 substituted with —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., gulanic or galactaric acid).

[0123] In one embodiment of the first or second aspect of the invention, at least one -R β is a saccharidyl group selected from: [ka]

[0124] Preferably, in the compound or complex according to the first or second aspect of the invention, at least one -R β teeth, [ka]

[0125] In one embodiment of the first or second aspect of the invention, -R2 , -R 3 or -R 4 At least one of the following must be -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 ) are independently selected from -R β is selected from the following: [ka] JPEG2025538650000013.jpg184159

[0126] In one embodiment of the first or second aspect of the invention, -R 2 , -R 3 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 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )], or -R α -[R 8’ In one embodiment, -R 2 , -R 3 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 8 ]Y. In one embodiment, -R 2, -R 3 or -R 4 at least one of which is independently selected from the following: [ka]

[0127] 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 is the same.

[0128] In one embodiment of the first or second aspect of the invention, each -R 5 is independently unsubstituted or substituted with one or two substituents. In one embodiment, each -R 5 is non-substituted.

[0129] In one embodiment of the first or second aspect of the invention, -R 8 is unsubstituted or substituted with one or two substituents. In one embodiment, -R 8 is non-substituted.

[0130] In one embodiment, -R 8 is not substituted with a halo group at the 4-position of the pyridine ring. 8 is unsubstituted at the 4-position of the pyridine ring. 8 is non-substituted.

[0131] In one embodiment of the first or second aspect of the invention, -R 1 , -R 6 , -R 7 and -R 9 each independently 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.

[0132] In certain preferred embodiments, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 is as follows: (a)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 are each independently C1-C4 alkyl, preferably -R 1 -C(O)-OR 3 and -R 3 is C1-C4 alkyl; or (b)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ) and -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl; -R 6 is as follows: (a)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 are each independently C1-C4 alkyl, preferably -R 6 -C(O)-OR 3 and -R 3 is C1-C4 alkyl; or (b)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ) and -R3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl; -R 7 is as follows: (a)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 are each independently C1-C4 alkyl, preferably -R 7 -C(O)-OR 3 and -R 3 is C1-C4 alkyl; or (b)-C(O)-OR 3 , -C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ) and -R 3 -R α -OR β or -R α -SR β -R β is a saccharidyl group, and -R 3’ is H or C1-C4 alkyl; -R 9 -OR 2 or -SR 2 -R 2 -R α -OR β or -R α -SR β and -R β is a succadiyl group, -R α - is C1-C 12alkylene groups, which may be substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl or halo groups, and one or more carbon atoms in the backbone of the alkylene group may be substituted with one or more heteroatoms O or S; M 2+ is a metal cation.

[0133] In certain preferred embodiments, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 is -CH2OR 2 , -CH2SR 2 , -CH2S(O)R 2 , -CH2S(O)2R 2 , -CHN(R 2 )(R 2’ ), -R 2 , -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably, -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ), more preferably selected from -R 1 is -C(O)-N(R 3 )(R 3’ ) is]; -R 2 are each independently -H, -C(O)R4 、-C(O)-OR 4 、-C(O)-SR 4 、-C(O)-N(R 4 )(R 4’ )、-C(S)-OR 4 、-C(S)-SR 4 、-C(S)-N(R 4 )(R 4’ )、-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、-[(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 8 ]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’ )]または-[(CH2) p Q] r -(CH2) s -[R8’ ] is selected from -R 3 and -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, -[(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 8 ]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 8’ ] is selected from; -R 2 , -R 3 , and -R 4 At least one of the -[(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 8 ]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 8’ ] is selected from; -R 2’ , -R 3’ , and -R 4’ are each independently selected from hydrogen or C1-C6 alkyl, preferably -R 2’ , -R 3’ , and -R 4’ are each independently selected from hydrogen or C1-C3 alkyl, more preferably -R 2’ , -R 3’ , and -R 4’ are each independently selected from hydrogen or methyl; -R α - are each independently C1-C 42 alkylene groups, which may be 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 may be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group 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 skeleton; -R 5 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n and selected from —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—(CH2CH2O) n -H or -O-(CH2CH2O) n may be 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 of which is -CO2 - and the 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 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 6 is -C(O)-N(R 3 )(R 3’ ) is]; -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 7 is -C(O)-N(R 3 )(R 3’ ) is]; -R 8 is 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] optionally substituted with -CH3 groups; -R 8’ is -CO2 - and optionally 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] further substituted with -CH3 groups; -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2, or -X; Q is O, S, NH, or NMe [preferably Q is O]; X is a halo group; Y is a counter anion; 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.

[0134] In certain preferred embodiments, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 1 is -C(O)-N(R 3 )(R 3’ ) is]; -R 2 are each independently -H, -C(O)R 4 , -C(O)-OR 4 , -C(O)-SR 4 , -C(O)-N(R 4 )(R 4’ ), -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-N(R 4 )(R 4’ ), -Rα -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, -[(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 8 ]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 8’ ] is selected from -R 3 and -R 4 are independently -H, -R α -H, -R β , -R α -R β , -R α -OH, -R α -ORβ , 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, -[(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 8 ]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 8’ ] is selected from; -R 2 , -R 3 , and -R 4 At least one of the -[(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 8 ]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 8’ ] is selected from; -R 3’ and -R 4’ are each independently hydrogen or C1-C3 alkyl [preferably -R 3’ and -R 4’ are each independently selected from hydrogen or methyl; -R α - are each independently C1-C 42 alkylene groups, which can be optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) C-C alkyl, C-C 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 can be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group 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 skeleton; -R 5are each independently selected from C1-C3 alkyl or phenyl, where phenyl is optionally selected from 1-C6 alkyl, —O(C1-C6 alkyl), —CO2H, —CO2Z, —CO2NH2, —O—(CH2CH2O) n -H or -O-(CH2CH2O) n may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from -CH3; -R 5’ is -CO2 - C1-C3 alkyl substituted with -CO2 - phenyl optionally substituted with C1-C6 alkyl, —O(C1-C6 alkyl), —CO2H, —CO2Z, —CO2NH2, —O—(CH2CH2O) n -H or -O-(CH2CH2O) n may be further substituted with 1, 2, 3, or 4 substituents independently selected from -CH3; -R 6 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 6 is -C(O)-N(R 3 )(R 3’ ) is]; -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [preferably -R 7 is -C(O)-N(R 3 )(R 3’ ) is]; -R8 is C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from -CH3; -R 8’ is -CO2 - Substituted with C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] optionally further substituted with 1, 2, 3, or 4 substituents independently selected from -CH3; -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , or -X; Q is O, S, NH, or NMe [preferably Q is O]; X is a halo group; Y is a counter anion; 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.

[0135] In these two preferred embodiments of the previous paragraph, each -R 5 may be the same or different. Preferably, each -R 5 is the same.

[0136] In another preferred form of one embodiment of the first or second aspect of the invention, the compound is a compound of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB) or (ICC): [ka] JPEG2025538650000019.jpg220159JPEG2025538650000020.jpg168159JPEG2025538650 000021.jpg190159JPEG2025538650000022.jpg206159JPEG2025538650000023.jpg93159 or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof, wherein: -R 1 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) are 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 )(R 4’ ), -C(S)-OR 4 , -C(S)-SR 4 , -C(S)-N(R 4 )(R 4’ ), -R α -H, -R β , -R α -R β , -R α -OH, -R α -ORβ , -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, or -R α -X is selected from -R 3 and -R 4 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)2R β , -R α -NH2, -R α -NH(R β ), -R α -N(R β )2, or -R α -X is selected from -R 3’ and -R 4’ are each independently hydrogen or C1-C3 alkyl [preferably -R 3’ and -R 4’ are each independently selected from hydrogen or methyl; -R 6 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R3’ ) are selected from; -R 7 is -C(O)-OR 3 , -C(O)-SR 3 , -C(O)-N(R 3 )(R 3’ ), -C(S)-OR 3 , -C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) are selected from; -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , or -X; -R α - are each independently C1-C 12 alkylene groups, which may be 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, or 6) carbon atoms in the backbone of the alkylene group may be optionally replaced with a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group 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 skeleton; -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; X is a halo group; Y is a counter anion; 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.

[0137] The compounds of formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (IM), (IN), (IO), (IP), (IQ), (IR), (IS), (IT), (IU), (IV), (IW), (IX), (IY), (IZ), (IAA), (IBB), (ICC) and complexes and salts thereof according to the first and second aspects of the present invention comprise the moiety -[(CH2) p O] r -(CH2) s -, wherein 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.

[0138] 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-.

[0139] 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) sp is 2, r is 2, and s is 2 so that - is -(CH2CH2O)2-(CH2)2-.

[0140] 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.

[0141] In certain preferred embodiments, the first or second aspect of the present invention provides a compound of formula (I') or a complex of formula (II'): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 9 -OR 2 , -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 , or -X; -R 10 , -R 11 and -R 12 are each independently -OR 3 , -SR 3 or -N(R 3 )2 is selected; -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 , -Rα -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 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ] is selected from; -R 3 and -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 8 ]Y, -Rα -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )] or R α -[R 8’ ] is selected from; -R α - are each independently C1-C 42 alkylene groups, which may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo groups, and one or more backbone carbon atoms of the alkylene group may be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group which may be linear or branched or may be or contain a cyclic group which may be optionally substituted and which may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -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-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 may be 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 of which is -CO2 -and the phenyl or C5-C6 heteroaryl is optionally substituted with one or more of 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 may be further substituted with -CH3 groups; -R 8 is one or more of 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] optionally substituted with -CH3 groups; -R 8’ is -CO2 - and substituted with one or more of 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] optionally further 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; However, it is one of the following: (i)-R 9 , -R 10 and -R 11 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 8 ]Y, -R α -[N(R 5 )2(R5’ )], -R α -[P(R 5 )2(R 5’ )], -R α -[R 8’ ], or containing a saccharidyl group; or (ii)-R 9 is -N(R 2 )2, -SR 2 , -S(O)R 2 , -S(O)2R 2 or -X.

[0142] In another particularly preferred embodiment, the first or second aspect of the invention provides a compound of formula (I″) or a complex of formula (II″): [ka] or a pharmaceutically acceptable salt thereof, wherein: -U- is -O-, -N(R u )- or -S-; -V- is -CH2-, -O-, -N(R v )- or -S-; -W-, -R α -[N(R 5 )3]Y,-R α -[P(R 5 )3]Y,-R α -[R 8 ]Y,-R α -[N(R 5 )2(R 5’ )],-R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ] and -R 10 , -R 11 and -R 12 are each independently selected from —OH or —O—(C1-C4 alkyl); -R α - is C1-C 12alkylene groups, which can be optionally substituted with one or more (e.g., one, two, three, or four) C-C alkyl, C-C haloalkyl, or halo groups; and one or more (e.g., one, two, three, or four) carbon atoms in the backbone of the alkylene group can be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe; -R 5 are each independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl, or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl optionally includes one or more of 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 may be substituted with a -CH3 group, -R 5’ is C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl, or C5-C6 heteroaryl, each of which is -CO2 - and the phenyl or C5-C6 heteroaryl is optionally substituted with one or more of 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 may be further substituted with -CH3 groups; -R 8 is one or more of 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] optionally substituted with -CH3 groups; -R 8’ is -CO2 - and substituted with one or more of 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] optionally further substituted with -CH3 groups; -R u is hydrogen or C1-C4 alkyl, -R v is hydrogen or C1-C4 alkyl, n is 1, 2, 3, 4, 5 or 6; Y is a counter anion; Z is a counter cation; and M 2+ is a metal cation.

[0143] In another particularly preferred embodiment, the first or second aspect of the invention provides a compound of formula (I″) or a complex of formula (II″): [ka] or a pharmaceutically acceptable salt thereof, wherein: -U- is -O-, -N(R u )- or -S-; -V- is -CH2-, -O-, -N(R v )- or -S-; -W- is -Rα- [N( R5 )3]Y, -Rα- [P( R5 )3]Y, or -Rα- [ R8 ]Y, -R 10 , -R 11 and -R 12 are each independently selected from —OH or —O—(C1-C4 alkyl); -Rα - is C1-C 12 alkylene groups (preferably C1-C9 alkylene groups, preferably C2-C6 alkylene groups), in which one or more (e.g., 1, 2, 3, or 4, preferably 1 or 2) carbon atoms in the backbone of the alkylene group can be optionally replaced by a heteroatom or group independently selected from O, S, NH, or NMe (preferably, O, NH, or NMe, preferably O); -R 5 are independently C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl, or C5-C6 heteroaryl, wherein phenyl or C5-C6 heteroaryl can be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), or -O(C1-C4 haloalkyl); -R 8 is —[NC5H5] optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, —O(C1-C4 alkyl) or —O(C1-C4 haloalkyl); -R u is hydrogen or C1-C4 alkyl, -R v is hydrogen or C1-C4 alkyl, n is 1, 2, 3, 4, 5 or 6; Y is a counter anion, and M 2+ is a metal cation.

[0144] The first aspect of the present invention further provides a compound of formula (III) or a complex of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein: -R 1 is -CO2H or -C(O)-R 14 -R 15 Selected from; -R6 is -CO2H or -CO2R 13 Selected from; -R 7 is -CO2H or -C(O)-R 14 -R 15 Selected from; -R 13 is selected from C1-C3 alkyl; -R 14 - is selected from NH, NMe, O or S; -R 15 is C1-C 20 alkyl, wherein one or more carbon atoms of the alkyl group can be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe, and the alkyl group can be optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) —OH or —NH groups; M 2+ is a metal cation; However, -R 1 , -R 6 and -R 7 must not also be -CO2Me.

[0145] In one embodiment, -R 1 -CO2H, -C(O)-R 14 -(CH2) x -Me, -C(O)-R 14 -(CH2) x -OH, -C(O)-R 14 -(CH2CH2O) y -Me or -C(O)-R 14 -(CH2CH2O) y -H, where x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R 1 -CO2H, -C(O)-R 14 -(CH2) x -Me or -C(O)-R 14 -(CH2CH2O) yIn one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably, x is 3, 4, 5, 6, 7, 8, 9, 10, or 11. In one embodiment, y is 1, 2, 3, 4, 5, or 6, preferably, y is 1, 2, 3, or 4.

[0146] In one embodiment, -R 7 -CO2H, -C(O)-R 14 -(CH2) x -Me, -C(O)-R 14 -(CH2) x -OH, -C(O)-R 14 -(CH2CH2O) y -Me or -C(O)-R 14 -(CH2CH2O) y -H, where x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R 7 -CO2H, -C(O)-R 14 -(CH2) x -Me or -C(O)-R 14 -(CH2CH2O) y In one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably, x is 3, 4, 5, 6, 7, 8, 9, 10, or 11. In one embodiment, y is 1, 2, 3, 4, 5, or 6, preferably, y is 1, 2, 3, or 4.

[0147] In one embodiment, -R 13 is methyl or ethyl.

[0148] In one embodiment, -R 14 - is NH or NMe. Preferably, -R 14 - is NMe.

[0149] In one embodiment, -R 15 is -(CH2) x -Me, -(CH2) x-OH, -(CH2CH2O) y -Me or -(CH2CH2O) y -H, where x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and y is 0, 1, 2, 3, 4, 5 or 6. Preferably, -R 15 is -(CH2) x -Me or -(CH2CH2O) y In one embodiment, x is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, preferably, x is 3, 4, 5, 6, 7, 8, 9, 10, or 11. In one embodiment, y is 1, 2, 3, 4, 5, or 6, preferably, y is 1, 2, 3, or 4.

[0150] In one embodiment, M 2+ Zn 2+ , Cu 2+ , Fe 2+ , Pd 2+ or Pt 2+ In one embodiment, M 2+ is Zn 2+ is.

[0151] In one embodiment, the compound of formula (III) or the complex of formula (IV) is in the form of a pharmaceutically acceptable salt, for example, lithium, sodium, potassium, magnesium, calcium, ammonium, amine (such as choline or meglumine), or amino acid (such as arginine) salt.Preferably, the pharmaceutically acceptable salt is lithium, sodium, potassium, magnesium, calcium, ammonium, choline, meglumine, arginine salt, or a combination thereof.Preferably, the pharmaceutically acceptable salt is lithium, sodium, potassium, or meglumine salt, or a combination thereof.Preferably, the pharmaceutically acceptable salt is sodium or meglumine salt, or a combination thereof.

[0152] In one embodiment, the pharmaceutically acceptable salt is a monosodium salt. In another embodiment, the pharmaceutically acceptable salt is a disodium salt. In another embodiment, the pharmaceutically acceptable salt is a monomeglumine salt. In another embodiment, the pharmaceutically acceptable salt is a dimeglumine salt. In another embodiment, the pharmaceutically acceptable salt is a mixed salt of monosodium and monomeglumine.

[0153] Preferably, in the compound or complex according to the first or second aspect of the invention, the compound or complex comprises: [ka] JPEG2025538650000029.jpg172159JPEG2025538650000030.jpg185159JPEG202553865000003 1.jpg186159JPEG2025538650000032.jpg190159JPEG2025538650000033.jpg189159JPEG2025 538650000034.jpg203159JPEG2025538650000035.jpg227159JPEG2025538650000036.jpg200 159JPEG2025538650000037.jpg213159JPEG2025538650000038.jpg206159JPEG2025538650000 039.jpg214159JPEG2025538650000040.jpg209159JPEG2025538650000041.jpg227159JPEG20 25538650000042.jpg229159JPEG2025538650000043.jpg192159JPEG2025538650000044.jpg2 22159JPEG2025538650000045.jpg213159JPEG2025538650000046.jpg229159JPEG2025538650000047.jpg182159JPEG2025538650000048.jpg108159, or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof.

[0154] 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).

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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 to 10 wt% PVP as a percentage of the total weight of the composition, preferably 0.1 to 5 wt% PVP as a percentage of the total weight of the composition, preferably 0.5 to 5 wt% PVP as a percentage of the total weight of the composition. In one embodiment, the PVP is K30.

[0159] 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 as a percentage of the total weight of the composition, preferably 40 to 99 wt% DMSO as a percentage of the total weight of the composition, preferably 65 to 99 wt% DMSO as a percentage of the total weight of the composition.

[0160] 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.

[0161] 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.

[0162] 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; interstitial pneumonia; Suitable for the treatment of: 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0163] 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.

[0164] 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.

[0165] 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0166] 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.

[0167] 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; interstitial pneumonia; Suitable for detecting 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, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0168] 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 detecting areas affected by benign or malignant cell hyperproliferation or neovascularization.

[0169] 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.

[0170] 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0171] 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 the aforementioned diseases.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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 can 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 of which are 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, 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.

[0176] 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.

[0177] In one 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.

[0178] 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.

[0179] 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.

[0180] 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 cellular hyperproliferation or vascular There is provided 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 neoplasia; a benign or malignant tumour; an early stage cancer; cervical dysplasia; soft tissue sarcoma; a 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0181] 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. Preferably, the phototherapeutic agent is a compound or complex according to the first or second aspect of the present invention for ... 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; It is suitable for the treatment of diseases characterized by areas of hyperproliferation of benign or malignant cells or angiogenesis; benign or malignant tumors; early stage cancers; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0182] 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.

[0183] Preferably, the drug or phototherapeutic agent according to the fourth aspect of the invention is suitable for the treatment of benign or malignant tumours.

[0184] 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0185] A 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.

[0186] Preferably, the photodiagnostic agent according to 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; 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, intestine, colon, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0187] 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.

[0188] Preferably, the photodiagnostic agent according to the fourth aspect of the present invention is suitable for detecting benign or malignant tumors.

[0189] 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 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0190] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for the fluorescent or phosphorescent detection of the aforementioned diseases, preferably for the fluorescent or phosphorescent detection and quantification of the aforementioned diseases.

[0191] 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.

[0192] If the drug or phototherapeutic agent is for use in photodynamic therapy or cytoluminescence therapy, then it is preferably suitable for administration 5 to 100 hours before irradiation, preferably 6 to 72 hours before irradiation, preferably 24 to 48 hours before irradiation.

[0193] If the photodiagnostic agent is used for photodynamic diagnosis, then it is preferably suitable for administration 3 to 60 hours before irradiation, preferably 8 to 40 hours before irradiation.

[0194] 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 can 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 of which are 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, 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.

[0195] A fifth aspect of the present invention provides 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

[0013] The present invention provides a method for treating a disease characterized by areas of hyperproliferation of malignant cells or angiogenesis; a benign or malignant tumor; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas, which method comprises 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 invention.

[0196] 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; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; or acne. ; psoriasis; a disease characterized by areas of benign or malignant cell hyperproliferation or angiogenesis; benign or malignant tumor; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0197] Preferably, the method of the fifth aspect of the invention is a method of treating areas of benign or malignant cellular hyperproliferation or neovascularization.

[0198] Preferably, the method of the fifth aspect of the invention is a method of treating a benign or malignant tumor.

[0199] 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 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

[0200] The fifth aspect of the 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 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; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas. Preferably, the human or animal disease is characterized by benign or malignant cell hyperproliferation or by areas of 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 organ, esophagus, stomach, bile duct, intestine, colon, colorectum, 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 the aforementioned diseases, preferably for fluorescent or phosphorescent detection and quantification of the aforementioned diseases.

[0201] 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.

[0202] If the method is a photodynamic therapy or cytoluminescence therapy method, then the human or animal is preferably irradiated 5 to 100 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 6 to 72 hours, preferably 24 to 48 hours after administration.

[0203] If the method is a method of photodynamic diagnosis, then the human or animal is preferably irradiated 3 to 60 hours, preferably 8 to 40 hours, after administration of the compound or complex according to the first or second aspect of the invention.

[0204] Preferably, the irradiation 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 can 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 radiation sources being suitable for providing irradiation at wavelengths in the 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, irradiation can be provided by prostate, anal, vaginal, oral, or nasal devices for insertion into body cavities. In another embodiment of the present invention, 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.

[0205] In any of the methods of the fifth aspect of the invention, preferably the human or animal is a human.

[0206] A sixth aspect of the present invention is (a) a compound or complex according to the first or second aspect of the present invention, and (b) Providing a drug combination or kit comprising an immune checkpoint inhibitor.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] Preferably, the combination or kit of the sixth aspect is adapted for administration simultaneously with or prior to the administration of irradiation or sound, preferably prior to the administration of irradiation. In one embodiment, the combination or kit of the sixth aspect is suitable for administration 5 to 100 hours prior to irradiation, preferably 6 to 72 hours prior to irradiation, preferably 24 to 48 hours prior to irradiation.

[0213] Preferably, the radiation used in photodynamic therapy or cytoluminescence therapy 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 can 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 radiation sources being 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, 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.

[0214] 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.

[0215] Details of the synthesis experiment Synthesis Example 1 (Comparative Example) - Synthesis of Chlorin e6 13-hydroxymethyltrimethyl ester (Compound 1) [ka] Step 1: To a 100 mL RBF was added chlorin e6 trimethyl ester (1.00 g, 1.566 mmol, 1 equiv.), THF (40 mL), osmium tetroxide (4 mg, 0.016 mmol, 0.01 equiv.), deionized water (3 mL), AcOH (3 mL), and sodium periodate (0.737 g, 3.444 mmol, 2.2 equiv.). The resulting mixture was stirred under nitrogen in the dark at ambient temperature for 19 h. Additional sodium periodate (0.068 g, 0.313 mmol, 0.2 equiv.) was added, and the solution was stirred for an additional 8 h. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (60 mL), transferred to a separatory funnel, washed with brine (30 mL), saturated aqueous NaHCO (30 mL), and water (50 mL), before being dried (NaSO) and concentrated by rotary evaporation to give chlorin e6 13-formyltrimethyl ester as a reddish-brown solid (1.0 g, quantitative).

[0216] 1 H NMR (400 MHz, CDCl3) δ 11.52 (s, 1H), 10.25 (s, 1H), 9.68 (s, 1H), 8.95 (s, 1H), 4.56 (m, 1H), 5.40 (d, 1H), 5.28 (d, 1H), 4.51-4.42 (m, 2H), 4.29 (s, 3H), 3.80-3.72 (m, 8H), 3.67 (s, 3H), 3.59 (s, 3H), 3.31 (s, 3H), 2.67-2.58 (m, 1H), 2.30-2.18 (m, 2H), 1.78-1.69 (m, 7H), -1.31 (brs, 1H), -1.80 (brs, 1H).

[0217] Step 2: To a 250 mL RBF was added chlorin e6 13-formyltrimethyl ester (850 mg, 1.327 mmol, 1 equiv.), MeOH (30 mL), DCM (15 mL), and sodium borohydride (100 mg, 2.653 mmol, 2 equiv.). The resulting mixture was stirred under nitrogen at ambient temperature for 1 h. The reaction mixture was diluted with water (60 mL) and stirred for 10 min. The mixture was then extracted with DCM (2 × 30 mL). The combined DCM layers were washed with water (50 mL), then dried (NaSO), and concentrated by rotary evaporation to give a dark red solid. The crude product was redissolved in DCM (25 mL) and washed with dilute aqueous NaHCO (10 mL), followed by pH = 7 phosphate buffer (10 mL), then dried (NaSO), and concentrated by rotary evaporation to give compound 1 as a dark red solid (0.81 g, 94%).

[0218] 1 H NMR (400 MHz, CDCl3) δ 9.70 (brs, 1H), 9.56 (br s, 1H), 8.74 (brs, 1H), 5.90 (m, 2H), 5.36 (d, 1H), 5.23 (d, 1H), 4.40 (m, 4H), 4.25 (s, 3H), 3.78 (m, 7H), 3.70 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H), 3.60 (s, 3H), 3.45 (m, 3H), 3.29 (m, 3H), 2.80-2.75 (m, 2H), 2.60-2.50 (m, 5H), 1.78-1.68 (m, 12H), -1.43 (br, 1H), -1.63 (br, 1H).

[0219] Synthesis Example 2 - Synthesis of chlorin e6 trimethyl ester 13-(6-triphenylphosphonium bromide)hexyl)carbamate (compound 2) [ka] Step 1: To a 50 mL RBF was added (6-((tert-butoxycarbonyl)amino)hexyl)triphenylphosphonium bromide (676 mg, 1.246 mmol, 8 equiv), DCM (7 mL), and TFA (1.5 mL). The resulting solution was stirred at ambient temperature for 1 h and then concentrated by rotary evaporation. The residue was resuspended and concentrated twice from chloroform (2 × 40 mL) to give 6-aminohexyltriphenylphosphonium bromide TFA as a viscous oil (0.995 g), which was then dissolved in DCM (2 mL) for the next coupling reaction.

[0220] Step 2: To a 50 mL RBF was added chlorin e6 13-hydroxymethyltrimethyl ester (compound 1) (100 mg, 0.156 mmol, 1 equiv.), carbonyldiimidazole (76 mg, 0.467 mmol, 3 equiv.), DCM (5 mL), and 4-dimethylaminopyridine (DMAP) (25 mg, 0.205 mmol, 1.3 equiv.). The resulting mixture was stirred under nitrogen for 3 h with TLC monitoring. TEA (455 mg, 4.496 mmol, 29 equiv.) was added, followed by 6-aminohexyltriphenylphosphonium bromide (0.995 g in 2 mL of DCM (containing approximately 0.444 g of TFA)), and stirring was continued for 4 days. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel, washed with 1 M HCl (2 x 15 mL) and pH = 7 phosphate buffer (20 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 5-8% MeOH / DCM. The major dark green spot (R in 5% MeOH / DCM) f =0.10) were combined to give compound 2 as a dark green solid (53 mg, 31% over two steps).

[0221] 1H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 9.61 (s, 1H), 8.74 (s, 1H), 7.60-7.50 (m, 9H), 7.50-7.35 (m, 7H), 6.36 (m, 2H), 5.86 (m, 1H), 5.36 (d, 1H), 5.24 (d, 1H), 4.48-4.37 (m, 2H), 4.26 (s, 3H), 3.78 (s, 3H), 3.71 (q, 2H), 3.63 (s, 3H), 3.50-3.40 (m, 5H), 3.30-3.20 (m, 5H), 2.62-2.52 (m, 1H), 2.24-2.14 (m, 2H), 2.06-1.85 (brm, 3H), 1.75-1.70 (m, 4H), 1.70-1.62 (m, 4H), 1.58-1.20 (m, 12H), -1.46 (brs, 1H), -1.66 (brs, 1H).

[0222] Synthesis Example 3 - Synthesis of chlorin e6 trimethyl ester 13-(N-(3-(3-triphenylphosphoniumpropoxy)propyl)chloride)carbamate (Compound 3) [ka] Step 1: A 500 mL three-necked RBF equipped with a 3 cm stir bar was charged with bis(3-chloropropyl)ether (20.00 g, 70.15 mmol, 1.66 equiv), triphenylphosphine (18.40 g, 70.15 mmol, 1 equiv), sodium iodide (7.01 g, 46.77 mmol, 0.66 equiv), and acetonitrile (340 mL). The RBF was placed in an oil bath, fitted with an air-cooled condenser, and stirring (500 rpm) was initiated under N at an external temperature of 90 °C. The mixture was stirred for 72 h. At this point, the reaction flask was cooled to room temperature, and the suspension was filtered through a 2 cm plug of Celite®, washing with acetonitrile (250 mL). The pale yellow solution was then evaporated to dryness to give a dark yellow oil (44.40 g) which was subjected to column chromatography (silica gel, 9 x 12 cm) using 6% MeOH in DCM as eluent. f Fractions with a RI = 0.35 were combined and concentrated by rotary evaporation. The resulting residue was further purified by column chromatography (silica gel, 9 x 7 cm). DCM was used as the eluent until triphenylphosphine was no longer observed by TLC, after which the eluent was changed to 10% MeOH in DCM to remove the product from the column. The R was visualized by UV in 6% MeOH / DCM. f Fractions with HCl = 0.35 were combined and concentrated by rotary evaporation to give (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride as a pale red solid (18.74 g, 62%).

[0223] 1 H NMR (400 MHz, CDCl3) δ 7.87-7.76 (m, 9H), 7.75-7.63 (m, 6H), 3.93-3.80 (m, 2H), 3.75 (td, J = 5.7, 1.3 Hz, 2H), 3.58 (q, J = 6.3 Hz, 4H), 2.05-1.88 (m, 4H).

[0224] Step 2: To a 50 mL RBF was added (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride (4.0 g, 9.23 mmol, 1 equiv.), NaN3 (11.08 g, 1.2 equiv.), NaBr (38 mg, 0.04 equiv.), tetrapropylammonium bromide (49 mg, 0.02 equiv.), and water (10 mL). After connecting a water-cooled condenser, the flask was heated at 110 °C with stirring for 44 h. The mixture was then cooled, and EtOAc (50 mL) was added. The mixture was transferred to a separatory funnel and washed with water (3 × 30 mL) and brine (30 mL). The combined aqueous layers were extracted with DCM (3 × 20 mL). The combined organic layers were then dried (MgSO4), filtered, and concentrated to give (3-(3-azidopropoxy)propyl)triphenylphosphonium chloride as a pale yellow solid (3.20 g, 79%).

[0225] 1 H NMR (400 MHz, CDCl3) δ 7.86-7.77 (m, 9H), 7.73-7.66 (m, 6H), 3.90-3.80 (m, 2H), 3.75 (t, 2H), 3.53 (t, 2H), 3.33 (t, 2H), 1.99-1.89 (m, 2H), 1.82 (p, 2H).

[0226] Step 3: A three-necked 100 mL RBF was charged with (3-(3-azidopropoxy)propyl)triphenylphosphonium chloride (1.00 g, 2.273 mmol, 1 equiv.), 10% Pd / C (20 mg), methanol (10 mL), and a stir bar. A hydrogen balloon was connected to the center connection of the flask via a short, air-cooled condenser, and the side arm was connected to a three-way stopcock. The apparatus was evacuated and then back-filled with nitrogen (three times), evacuated, and back-filled with hydrogen (twice). The resulting solution was then stirred (550 rpm) under a hydrogen atmosphere at 35 °C for 2 h. The solution was then filtered through Celite® (0.5×3 cm), washed with chloroform (2×10 mL), and the solvent removed under reduced pressure to give (3-(3-aminopropoxy)propyl)triphenylphosphonium chloride as a viscous oil that solidified on standing (1.05 g, quantitative).

[0227] 1 H NMR (400 MHz, CDCl3) δ 7.86-7.76 (m, 9H), 7.73-7.66 (m, 6H), 3.88-3.79 (m, 2H), 3.73 (t, 2H), 3.51 (t, 2H), 2.75 (t, 2H), 1.99-1.87 (m, 2H), 1.68 (p, 2H), 1.41 (brs, 2H).

[0228] Step 4: To a 25 mL RBF was added chlorin e6 13-hydroxymethyltrimethyl ester (compound 1) (60 mg, 0.0934 mmol, 1 equiv.), carbonyldiimidazole (30 mg, 0.1867 mmol, 2 equiv.), DCM (4 mL), and DMAP (5 mg, 0.0409 mmol, 0.4 equiv.). The resulting mixture was stirred under nitrogen for 3 h with TLC monitoring. (3-(3-aminopropoxy)propyl)triphenylphosphonium chloride (193 mg, 0.4668 mmol, 5 equiv.) dissolved in DCM (1 mL) was added, and stirring was continued for 4 days. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel, and washed with 1 M HCl (2 × 20 mL), pH 7 phosphate buffer (30 mL), then dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography (3x12cm) using 3-5% MeOH / DCM. The major dark green spot (R in 5% MeOH / DCM) f =0.20) were combined to give compound 3 as a dark green solid (33 mg, 33%).

[0229] 1 H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 7.61-7.50 (m, 6H), 7.48-7.36 (m, 9H), 6.33 (m, 2H), 5.53 (m, 1H), 5.36 (d, 1H), 5.25 (d, 1H), 4.48-4.38 (m, 2H), 4.27 (s, 3H), 3.79 (s, 3H), 3.74 (q, 2H), 3.63 (s, 3H), 3.61-3.50 (m, 7H), 3.49-3.43 (m, 5H), 3.40-3.33 (m, 2H), 3.26 (s, 3H), 2.62-2.52 (m, 1H), 2.25-2.15 (m, 2H), 1.80-1.60 (m, 14H), 0.90-0.80 (m, 1H), -1.47 (brs, 1H), -1.68 (brs, 1H).

[0230] Synthesis Example 4 - Synthesis of chlorin e6 trimethyl ester 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate (compound 4) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyltrimethyl ester (compound 1) (100 mg, 0.156 mmol, 1 equiv.), carbonyldiimidazole (50 mg, 0.311 mmol, 2 equiv.), DCM (4 mL), and DMAP (5 mg, 0.0409 mmol, 0.25 equiv.). The resulting mixture was stirred under nitrogen at 25 °C for 3 h. (3-Aminopropyl)triphenylphosphonium bromide (311 mg, 0.778 mmol, 5 equiv.) was added, and stirring was continued at 25 °C overnight. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel, and washed with 1 M HCl (2 × 10 mL) and pH = 7 phosphate buffer (25 mL), then dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 5-9% MeOH / DCM. The major dark green spot (R in 5% MeOH / DCM) f =0.15) were combined to give compound 4 as a dark green solid (125 mg, 75%).

[0231] 1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 9.67 (s, 1H), 8.75 (s, 1H), 9.79 (t, 1H), 7.42-7.33 (m, 6H), 7.19-7.08 (m, 9H), 6.95-6.86 (m, 1H), 6.75-6.62 (m, 1H), 6.37 (m, 2H), 5.37 (d, 1H), 5.26 (d, 1H), 4.48-4.37 (m, 2H), 4.37 (s, 3H), 3.80 (s, 3H), 3.71 (q, 2H), 3.63 (m, 4H), 3.58 (m, 4H), 3.51 (m, 5H), 3.45 (s, 2H), 3.30 (s, 3H), 2.62-2.53 (m, 1H), 2.26-2.17 (m, 2H), 2.00-1.87 (m, 3H), 1.80-1.60 (m, 10H), -1.45 (brs, 1H), -1.60 (brs, 1H).

[0232] Synthesis Example 5 - Synthesis of chlorin e6 trimethyl ester 13-(N-(2-triphenylphosphoniummethyl) bromide) carbamate (compound 5) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyltrimethyl ester (compound 1) (90 mg, 0.140 mmol, 1 equiv.), carbonyldiimidazole (45 mg, 0.280 mmol, 2 equiv.), DCM (4 mL), and DMAP (5 mg, 0.0409 mmol, 0.3 equiv.). The resulting mixture was stirred under nitrogen at 22 °C for 3 h. (2-Aminoethyl)triphenylphosphonium bromide (270 mg, 0.700 mmol, 5 equiv.) was added, and stirring was continued at 22 °C overnight. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel, and washed with 1 M HCl (2 × 10 mL) and pH = 7 phosphate buffer (25 mL), then dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-6% MeOH / DCM. The major dark green spot (R in 5% MeOH / DCM) f =0.10) were combined to give compound 5 as a dark green solid (38 mg, 26%).

[0233] 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.61 (s, 1H), 8.77 (s, 1H), 7.71 (t, 1H), 7.66-7.57 (m, 6H), 7.43-7.35 (m, 8H), 6.24 (m, 2H), 5.37 (d, 1H), 5.24 (d, 1H), 4.48-4.38 (m, 2H), 4.26 (s, 3H), 3.88-3.70 (m, 9H), 3.52 (s, 3H), 3.48 (s, 3H), 3.46 (s, 3H), 3.30 (s, 3H), 2.64-2.52 (m, 1H), 2.26-2.17 (m, 2H), 1.90-1.80 (m, 4H), 1.78-1.68 (m, 8H), -1.46 (brs, 1H), -1.64 (brs, 1H).

[0234] Synthesis Example 6 - Synthesis of chlorin e6 13-(N-methylamino)methyl trimethyl ester (compound 6) [ka] To a 25 mL RBF was added chlorin e6 13-formyltrimethyl ester (50 mg, 0.078 mmol, 1 equiv.), DCM (1 mL), methanol (3 mL), TEA (32 mg, 0.312 mmol, 4 equiv.), and methylamine hydrochloride (11 mg, 0.156 mmol, 2 equiv.). The resulting mixture was stirred under nitrogen in the dark for 1 h, and then additional portions of methylamine hydrochloride (11 mg, 0.156 mmol, 2 equiv.) and TEA (32 mg, 0.312 mmol, 4 equiv.) were added, and stirring was continued for an additional 1 h. NaBH4 (15 mg, 0.390 mmol, 5 equiv.) was added, and stirring was continued for 30 min. The reaction was acidified with 2 M HCl (1 mL) and stirred for 10 min. Phosphate buffer pH=7 (15 mL) was added, and the mixture was extracted with DCM (2×5 mL), then dried (NaSO) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-7% MeOH / DCM. The major dark green spot (R in 10% MeOH / DCM) f =0.30) were combined to give compound 6 as a dark green solid (27 mg, 53%).

[0235] 1 H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 9.46 (s, 1H), 8.65 (s, 1H), 5.34 (d, 1H), 5.21 (d, 1H), 4.87 (brm, 2H), 4.42-4.34 (m, 2H), 4.25 (s, 3H), 3.77 (m, 4H), 3.70-3.62 (m, 6H), 3.47 (s, 3H), 3.30 (s, 3H), 3.25 (s, 3H), 2.59 (s, 3H), 2.58-2.48 (m, 1H), 2.21-2.09 (m, 2H), 1.77-1.69 (m, 5H), 1.67-1.61 (m, 4H), -1.47 (brs, 1H), -1.70 (brs, 1H).

[0236] Synthesis Example 7 - Synthesis of Chlorin e6 13-(N-methyl-5-triphenylphosphonium bromide pentanamide) trimethyl ester (Compound 7) [ka] To a 25 mL RBF was added chlorin e6 13-(N-methylamino)methyl trimethyl ester (compound 6) (20 mg, 0.0305 mmol, 1 equiv.), 4-(carboxybutyl)triphenylphosphonium bromide (18 mg, 0.0640 mmol, 2.1 equiv.), DCM (1 mL), and DMTMM (18 mg, 0.0640 mmol, 2.1 equiv.). The resulting mixture was stirred under nitrogen in the dark at ambient temperature for 2 h. The reaction mixture was transferred to a separatory funnel, diluted with DCM (15 mL), and washed with 0.5 M HCl (10 mL). The aqueous layer was re-extracted with DCM (2 × 5 mL), and the combined organics were washed with pH = 7 phosphate buffer (10 mL) followed by 1 M aqueous NaHCO (10 mL). The organic phase was dried (NaSO) and concentrated by rotary evaporation to give a blue-black film. The residue was purified by column chromatography using 3-7% MeOH / DCM. The major dark green spot (R in 10% MeOH / DCM) f =0.30) were combined to give compound 7 as a dark green solid (10 mg, 30%).

[0237] 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.65 (s, 1H), 8.71 (s, 1H), 7.75-7.67 (m, 7H), 7.57-7.46 (m, 9H), 5.85 (m, 2H), 5.37-5.20 (m, 2H), 4.48-4.37 (m, 2H), 4.26 (s, 3H), 3.88-3.70 (m, 8H), 3.63 (s, 3H), 3.57 (s, 3H), 3.40 (s, 3H), 3.19 (s, 3H), 3.14 (s, 3H), 2.78 (m, 2H), 2.62-2.52 (m, 1H), 2.23-2.12 (m, 4H), 1.90-1.65 (m, 18H), -1.44 (brs, 1H), -1.56 (brs, 1H).

[0238] Synthesis Example 8 - Synthesis of chlorin e6 trimethyl ester 13-(N-methyl-(3-triphenylphosphoniumpropoxy)chloride)carbamate (Compound 8) [ka] To a 25 mL RBF was added chlorin e6 13-(N-methylamino)methyl trimethyl ester (compound 6) (100 mg, 0.152 mmol, 1 equiv.), carbonyldiimidazole (49 mg, 0.304 mmol, 1.5 equiv.), and DCM (4 mL). The resulting mixture was stirred under nitrogen for 1 h. (3-Hydroxypropyl)triphenylphosphonium chloride (108 mg, 0.304 mmol, 1.5 equiv.) in DCM (2 mL) was added, and stirring was continued overnight at 23 °C in the dark. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel, washed with water (15 mL), extracted with DCM (2 × 5 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3-8% MeOH / DCM. The major dark green spot (R in 7% MeOH / DCM) f =0.25) were combined to give compound 8 as a dark green solid (56 mg, 35%).

[0239] 1 H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 9.55 (s, 1H), 8.72 (s, 1H), 7.75-7.60 (m, 5H), 7.55-7.45 (m, 2H), 7.42-7.30 (m, 8H), 5.72-5.68 (m, 2H), 5.40-5.20 (m, 4H), 4.62 (m, 2H), 4.41 (m, 2H), 4.25 (s, 3H), 4.05-3.90 (m, 2H), 3.75 (m, 6H), 3.62 (s, 3H), 3.55 (s, 3H), 3.40 (m, 3H), 3.1 (m, 3H), 2.95 (m, 2H), 2.62-2.50 (m, 1H), 2.25-2.00 (m, 4H), 1.80-1.65 (m, 8H), -1.45 (brs, 1H), -1.58 (brs, 1H).

[0240] Synthesis Example 9 - Synthesis of chlorin e6 (2-methoxyethyl)methylamine dimethyl ester 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate (compound 9) [ka] Step 1: A single-neck 250 mL RBF was charged with chlorin e6 (0.5 g, 1 equiv.), di-tert-butyl dicarbonate ((Boc)O) (188 mg, 1.03 equiv.), and DCM (60 mL). DMAP (8 mg, 0.08 equiv.) was added, and the resulting solution was stirred at 40 °C under a nitrogen atmosphere for 2 h. The resulting black solution was filtered using a cotton plug, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane (2 × 10 mL) and dried to give chlorin e6 anhydride as a black solid (475 mg, 98%), which was used in the next step without further purification.

[0241] 1H NMR (400 MHz, CDCl3) δ 9.52 (m, 2H), 9.22 (m, 1H), 8.45 (m, 1H), 7.82 (m, 1H), 6.34 (m, 1H), 6.14 (m, 1H), 5.40 (m, 2H), 4.60-4.30 (m, 2H), 3.55 (m, 5H), 3.32 (s, 3H), 3.16 (m, 4H), 2.75-2.50 (m, 2H), 2.35 (m, 2H), 1.95 (m, 1H), 1.75-1.60 (m, 6H), 1.15 (t, 2H), -0.5 (brs, 2H).

[0242] Step 2: A single-neck 250 mL RBF was charged with chlorin e6 anhydride (470 mg, 1 equiv.), (2-methoxyethyl)methylamine (108 mg, 1.5 equiv.), and DCM (30 mL). The resulting solution was stirred overnight at 35 °C under a nitrogen atmosphere. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered and washed with diethyl ether (2 × 10 mL). The remaining black solid was purified by column chromatography using 10–50% MeOH / DCM. Fractions containing the first dark band to elute were combined to afford chlorin e6 (2-methoxyethyl)methylamine as a blue-green solid (320 mg, 59% yield, 95.33% purity by HPLC).

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.42 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.20 (m, 1H), 4.50 (m, 1H), 4.30-4.10 (m, 2H), 3.85 (m, 3H), 3.65-3.30 (m, 10H), 3.20 (m, 2H), 2.85 (m, 1H), 2.15 (m, 1H), 1.15 (t, 2H), -2.0 (brs, 1H), -2.68 (brs, 1H).

[0244] Step 3: A single-neck 250 mL RBF was charged with chlorin e6 (2-methoxyethyl)methylamine (310 g, 1 equiv.), potassium carbonate (192 mg, 3 equiv.), DMF (10 mL), and a stir bar. The flask was placed under nitrogen and stirred at 300 rpm with an air-cooled condenser attached. Methyl iodide (0.072 mL, 3 equiv.) was then added. The solution was stirred at 25 °C over the weekend. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude product was dissolved in DCM (30 mL), washed with water (2 × 10 mL), dried (NaSO), and concentrated under reduced pressure to give the crude product as a dark blue / green solid (350 mg). At this point, HPLC analysis indicated approximately 96% purity. The remaining black / green solid was purified by column chromatography using 1–5% MeOH / DCM, and the fractions containing the first dark band to elute were combined to give chlorin e6 (2-methoxyethyl)methylamine dimethyl ester as a blue-green solid (310 mg, 98% yield, 98.69% purity by HPLC).

[0245] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (m, 1H), 8.72 (m, 1H), 8.10-8.00 (m, 2H), 6.44 (d, 1H), 6.14 (d, 1H), 5.50-5.20 (m, 2H), 4.50 (m, 2H), 4.30-4.10 (m, 2H), 3.90-3.65 (m, 5H), 3.65 (s, 3H), 3.60 (m, 6H), 3.45 (m, 6H), 3.30 (s, 3H), 2.95 (s, 3H), 2.85 (s, 3H), 2.60 (m, 1H), 2.20 (m, 2H), 1.75-1.55 (m, 7H), -1.30 (brs, 1H), -1.45 (brs, 1H).

[0246] Step 4: To a 250 mL RBF was added chlorin e6 (2-methoxyethyl)methylamine dimethyl ester (310 mg, 1 equiv.), THF (10 mL), osmium tetroxide (approximately 1 mg, 0.01 equiv.), deionized water (0.8 mL), AcOH (0.8 mL), and sodium periodate (247 mg, 2.6 equiv.). The resulting mixture was stirred overnight at ambient temperature under nitrogen in the dark. The reaction mixture was concentrated using a rotary evaporator to remove the THF, then redissolved in DCM (20 mL), transferred to a separatory funnel, washed with brine (10 mL), saturated NaHCO3 (10 mL), water (10 mL), dried (Na2SO4), and concentrated by rotary evaporation to give a reddish-brown powdery solid (approximately 2.5 g). The remaining dark solid was purified by column chromatography using 1-2% MeOH / DCM, and the fractions containing the first dark band to elute were combined to give chlorin e6 13-formyl(2-methoxyethyl)methylamine dimethyl ester as a reddish-brown powdery solid (210 mg, 68% yield, 93.43% purity by HPLC).

[0247] 1 H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.35 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 8.00 (s, 1H), 5.60-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.90-3.40 (m, 14 H), 3.55 (m, 7 H), 3.42 (s, 3H), 3.32 (s, 3H), 2.93 (s, 3H), 2.85 (s, 3H), 2.70-2.60 (m, 2H), 2.50-2.40 (m, 2H), 1.70 (m, 7H), -1.20 (brs, 1H), -1.75 (brs, 1H).

[0248] Step 5: To a 100 mL RBF was added chlorin e6 13-formyl(2-methoxyethyl)methylamine dimethyl ester (210 mg, 1 equiv.), MeOH (5 mL), DCM (2 mL), and sodium borohydride (22 mg, 2 equiv.). The resulting mixture was stirred under nitrogen at ambient temperature for 1 h. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4), and concentrated by rotary evaporation to give a dark green solid (approximately 200 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted with a gradient of 1% MeOH / DCM (300 mL), then 2% MeOH / DCM (200 mL), then 3% MeOH / DCM (200 mL). Fractions of approximately 20 mL in size were collected when the first color began to elute. Fractions 6, 7, and 8, containing the product (major dark green spot, R in 5% MeOH / DCM), were f = ca. 0.7) were combined to give chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine dimethyl ester (compound 9A) as a blue / green solid (110 mg, 52% yield, 97.34% purity by HPLC).

[0249] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.60 (m, 1H), 8.78 (m, 1H), 5.90 (s, 2H), 5.50-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.70-3.16 (m, 8H), 3.55 (m, 7H), 3.42 (s, 3H), 3.30 (s, 3H), 3.15 (s, 1H), 2.64-2.50 (m, 1H), 2.50-2.35 (m, 1H), 2.20 (m, 3H), 1.80 (m, 7H), 1.68 (m, 4H), -1.60 (brs, 1H), -1.70 (brs, 1H).

[0250] Step 6: To a 25 mL RBF was added chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine dimethyl ester (compound 9A) (70 mg, 1 equiv.), carbonyldiimidazole (32 mg, 2 equiv.), DCM (3 mL), and DMAP (2 mg). The resulting mixture was stirred under nitrogen for 3 h. (3-Aminopropyl)triphenylphosphonium bromide (200 mg, 5 equiv.) was added, and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel, washed with water (15 mL), dried (Na2SO4), and concentrated by rotary evaporation to give a dark green residue (approximately 100 mg). The residue was purified by column chromatography (3 x 12 cm) using 0-6% MeOH / DCM as the loading eluent. The major dark green band (R in 5% MeOH / DCM) f =0.15) was concentrated to give compound 9 as a dark green solid (65 mg, 58% yield, 97.25% purity by HPLC).

[0251] 1 H NMR (400 MHz, CDCl3) δ 9.78 (m, 1H), 9.65 (m, 1H), 8.75 (m, 1H), 7.48 (t, 1H), 7.25 (m, 9H), 7.00 (m, 9 H), 6.70 (m, 1H), 6.65-6.50 (m, 1H), 6.35 (m, 2H), 5.50-5.30 (m, 2H), 4.45-4.15 (m, 5H), 3.80-3.65 (m, 8H), 3.60-3.40 (m, 18H), 3.32 (s, 3H), 2.70-2.40 (m, 1H), 2.30-2.00 (m, 2H), 1.80-1.60 (m, 8H) -1.40 (m, 1H), -1.60 (m, 1H).

[0252] Synthesis Example 10-Chlorin e6 Synthesis of N-methylbutylamine dimethyl ester 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate (Compound 10) [ka] Step 1: A single-neck 250 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 equiv.), N-methylbutylamine (108 mg, 1.5 equiv.), and DCM (30 mL). The resulting solution was stirred overnight at 35° C. under a nitrogen atmosphere. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2×10 mL), and dried on a rotavapor to afford chlorin e6 N-methylbutylamine as a blue-green solid (670 mg, quantitative yield, 85.80% purity by HPLC). The crude product was used in the next step without further purification.

[0253] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.70 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.70 (m, 1H), 5.30 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 3.85 (m, 3H), 3.65-3.40 (m, 10H), 2.85 (m, 1H), 2.40-2.10 (m, 5H), 1.70 (t, 3H), 1.80-1.50 (m, 10H), 1.25 (m, 4H), 1.00 (t, 2H), 0.90 (t, 4H), 0.80 (t, 1H), -1.90 (brs, 1H), -2.35 (brs, 1H).

[0254] Step 2: A single-neck 250 mL RBF was charged with chlorin e6 N-methylbutylamine (650 g, 1 equiv.), potassium carbonate (404 mg, 3 equiv.), DMF (10 mL), and a stir bar. The flask was placed under nitrogen. Methyl iodide (0.150 mL, 2.5 equiv.) was then added. The solution was stirred at 25 °C overnight. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude product was dissolved in DCM (30 mL), washed with water (2 × 10 mL), dried (NaSO), and concentrated under reduced pressure to give chlorin e6 N-methylbutylamine dimethyl ester as a dark blue / green solid (700 mg, quantitative yield, 86.64% purity by HPLC). The crude product was used in the next step without further purification.

[0255] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (m, 1H), 8.72 (m, 1H), 8.10-8.00 (m, 2H), 6.44 (d, 1H), 6.14 (d, 1H), 5.50-5.20 (m, 2H), 4.50 (m, 2H), 4.20 (m, 3H), 3.90-3.60 (m, 6H), 3.65 (s, 3H), 3.55 (m, 4H), 3.45 (m, 6H), 3.30 (s, 3H), 2.95 (s, 3H), 2.85 (s, 3H), 2.60 (m, 1H), 2.20 (m, 2H), 1.75-1.55 (m, 9H), 1.40 (m, 1H), 1.10 (t, 1H), 0.90 (t, 3H), -1.30 (brs, 1H), -1.45 (brs, 1H).

[0256] Step 3: To a 250 mL RBF was added chlorin e6 N-methylbutylamine dimethyl ester (700 mg, 1 equiv.), THF (10 mL), osmium tetroxide (approximately 2 mg, 0.01 equiv.), deionized water (0.8 mL), AcOH (0.8 mL), and sodium periodate (561 mg, 2.6 equiv.). The resulting mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (20 mL), transferred to a separatory funnel, washed with brine (10 mL), saturated NaHCO (10 mL), water (10 mL), dried (NaSO), and concentrated by rotary evaporation to give chlorin e6 13-formyl N-methylbutylamine dimethyl ester as a reddish-brown powdery solid (670 mg, quantitative yield, 85.31% purity by HPLC). The crude product was used in the next step without further purification.

[0257] 1 H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.25 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 8.00 (s, 1H), 5.60-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.25-4.15 (m, 3H), 3.80-3.40 (m, 17 H), 3.42 (s, 3H), 3.32 (s, 3H), 2.93 (s, 3H), 1.85 (m, 3H), 2.70-2.60 (m, 2H), 1.70 (m, 7H), 1.40 (m, 2H), 1.20 (t, 2H), 1.00 (t, 2H), -1.80 (brs, 1H).

[0258] Step 4: To a 100 mL RBF was added chlorin e6 13-formyl N-methylbutylamine dimethyl ester (650 mg, 1 equiv.), MeOH (15 mL), DCM (4 mL), and sodium borohydride (70 mg, 2 equiv.). The resulting mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (Na2SO4), and concentrated by rotary evaporation to give a dark green solid (approximately 300 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted with a gradient of 1% MeOH / DCM (300 mL), then 2% MeOH / DCM (300 mL), then 3% MeOH / DCM (300 mL). Fractions of approximately 20 mL in size were collected when the first color began to elute. Fractions 6, 7, and 8 contained the product (major dark green spot, R in 5% MeOH / DCM). f = ca. 0.7) were combined to give chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (compound 10A) as a blue / green solid (230 mg, 36% yield, 98.49% purity by HPLC).

[0259] 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.52 (m, 1H), 8.70 (m, 1H), 5.90 (s, 2H), 5.50-5.30 (m, 2H), 4.50-4.30 (m, 2H), 4.20-4.15 (m, 3H), 3.70-3.60 (m, 3H), 3.65 (s, 3 H), 3.55 (m, 4H), 3.45 (m, 6H), 3.30 (s, 3H), 3.05 (s, 1H), 2.64-2.50 (m, 1H), 2.70-2.45 (m, 2H), 2.20 (m, 3H), 1.80 (m, 7H), 1.38 (m, 2H), 1.10 (t, 1H), 0.90 (t, 2H), -1.40 (brs, 1H), -1.70 (brs, 1H).

[0260] Step 5: To a 100 mL RBF was added chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (compound 10A) (140 mg, 1 equiv.), carbonyldiimidazole (64 mg, 2 equiv.), DCM (6 mL), and DMAP (2 mg). The resulting mixture was stirred under nitrogen for 3 h. (3-Aminopropyl)triphenylphosphonium bromide (400 mg, 5 equiv.) was added, and stirring was continued at ambient temperature overnight. After overnight, additional carbonyldiimidazole (32 mg) was added, and the reaction was then heated (heat block) at 30 °C for an additional 3 h. At this stage, the reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel, washed with water (2 × 10 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. To this residue was added additional carbonyldiimidazole (64 mg), DCM (6 mL), and DMAP (2 mg). The resulting mixture was stirred under nitrogen at 30°C (external) for 3 hours. Additional (3-aminopropyl)triphenylphosphonium bromide (400 mg, 5 equiv.) was added, and stirring was continued at 30°C overnight. The reaction mixture was then diluted with DCM (20 mL), transferred to a separatory funnel, washed with water (20 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green residue (approximately 150 mg). The residue was purified by column chromatography using 0-6% MeOH / DCM and loaded as a solution to the eluent. The major dark green band (R in 5% MeOH / DCM) was f =0.15) was concentrated to give compound 10 as a dark green solid (62 mg, 28% yield, 98.08% purity by HPLC).

[0261] 1H NMR (400 MHz, CDCl3) δ 9.70 (m, 1H), 9.55 (m, 1H), 8.65 (m, 1H), 7.38 (t, 1H), 7.15 (m, 5H), 6.90 (m, 8H), 6.70 (m, 1H), 6.65-6.50 (m, 1H), 6.35 (m, 2H), 5.50-5.30 (m, 2H), 4.45-4.10 (m, 5H), 3.80-3.55 (m, 5H), 3.53-3.35 (m, 13H), 3.25 (s, 3H), 2.70-2.40 (m, 1H), 2.30-2.00 (m, 2H), 1.80-1.60 (m, 8H), 1.40 (m, 1H), 1.00 (t, 2H), 0.90 (t, 2H), -1.50 (m, 1H), -1.65 (m, 1H).

[0262] Synthesis Example 11-Chlorin e6 Synthesis of 13-hydroxymethyl N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester (Compound 11) [ka] Step 1: A single-neck 100 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 equiv.), (3-(methylamino)propyl)triphenylphosphonium bromide hydrobromide (641 mg, 1.5 equiv.), and DCM (30 mL). The resulting solution was stirred overnight at 35 °C under a nitrogen atmosphere. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2 × 10 mL), and dried on a rotavapor to afford chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide as a blue / green solid (1.20 mg, quantitative yield, 72.47% purity by HPLC). The crude product was used in the next step without further purification.

[0263] 1H NMR (400 MHz, DMSO-d6) δ 9.75 (m, 1H), 9.10 (m, 1H), 9.10 (s, 1H), 8.35 (m, 1H), 8.00-7.75 (m, 11H), 7.65 (m, 3H), 6.44 (d, 1H), 6.14 (d, 1H), 4.60 (m, 1H), 3.85 (m, 3H), 3.65-3.40 (m, 10H), 2.90 (m, 1H), 2.20-2.15 (m, 2H), 1.80-1.50 (m, 6H), 1.00 (t, 2H), -1.90 (brm, 1H), -2.40 (brm, 1H).

[0264] Step 2: A single-neck 250 mL RBF was charged with chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide (1.0 gm, 1 eq.), potassium carbonate (415 mg, 3 eq.), DMF (10 mL), and a stir bar. The flask was placed under nitrogen and stirred at 300 rpm with an air-cooled condenser attached. Methyl iodide (0.150 mL, 2.5 eq.) was then added. The solution was stirred overnight at 30°C. The solvent was removed under reduced pressure at 60°C to give a dark green solid. The crude product was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (NaSO), and concentrated under reduced pressure to give the crude product as a dark blue / green solid (700 mg). At this point, HPLC analysis indicated approximately 75% purity. The remaining blue / green solid was purified by column chromatography using 2–3% MeOH / DCM, and the fractions containing the first dark band to elute were combined to give chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester as a blue / green solid (440 mg, quantitative yield, 99.69% purity by HPLC).

[0265] 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.50 (s, 1H), 8.70 (s, 1H), 8.10-8.00 (dd, 1H), 7.65 (m, 6H), 7.55 (m, 3H), 7.40 (m, 6H), 6.44 (d, 1H), 6.14 (d, 1H), 5.20 (m, 2H), 4.30 (m, 2H), 4.00-3.90 (m, 5H), 3.70 (m, 3H), 3.65 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H), 3.30 (s, 3H), 3.20 (s, 3H), 2.60 (m, 1H), 2.20 (m, 4H), 1.70-1.55 (m, 6H), 1.40 (m, 1H), 1.20 (m, 1H), -1.40 (brs, 1H), -1.52 (brs, 1H).

[0266] Step 3: To a 250 mL RBF was added chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester (200 mg, 1 equiv.), THF (10 mL), osmium tetroxide (approximately 1 mg, 0.01 equiv.), deionized water (0.8 mL), AcOH (0.8 mL), and sodium periodate (247 mg, 2.6 equiv.). The resulting mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (20 mL), transferred to a separatory funnel, washed with brine (10 mL), saturated NaHCO (10 mL), water (10 mL), dried (NaSO), and concentrated by rotary evaporation to give chlorin e6 13-formyl N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester as a reddish-brown powdery solid (220 mg, quantitative yield, 72.47% purity by HPLC). The crude product was used in the next step without further purification.

[0267] 1H NMR (400 MHz, CDCl3) δ 11.50 (s, 1H), 10.20 (s, 1H), 9.60 (s, 1H), 9.50 (s, 1H), 8.90 (s, 1H), 7.65 (m, 12H), 7.40 (m, 3H), 5.20 (m, 2H), 4.30 (m, 2H), 4.00-3.90 (m, 5H), 3.70 (m, 8H), 3.65 (s, 3H), 3.55 (s, 3H), 3.40 (s, 3H), 3.30 (s, 3H), 3.25 (s, 3H), 2.60 (m, 4H), 2.20 (m, 4H), 1.70-1.55 (m, 6H), 1.40 (m, 2H), -1.40 (brs, 1H), -1.80 (brs, 1H).

[0268] Step 4: To a 100 mL RBF was added chlorin e6 13-formyl N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester (210 mg, 1 equiv.), MeOH (15 mL), DCM (4 mL), and sodium borohydride (15 mg, 2 equiv.). The resulting mixture was stirred under nitrogen at ambient temperature for 2 hours. The reaction mixture was concentrated using a rotavapor. The mixture was then diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green solid (approximately 200 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted with a gradient of 1% MeOH / DCM (300 mL), then 2% MeOH / DCM (300 mL), then 3% MeOH / DCM (300 mL). Fractions of approximately 20 mL in size were collected when the first color began to elute. The product (major dark green spot, R in 5% MeOH / DCM) f Fractions 6, 7 and 8 containing 11 (approximately 0.7%) were combined to give compound 11 as a green solid (45 mg, 21% yield, 90.77% purity by HPLC).

[0269] 1H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 9.40 (m, 1H), 8.65 (s, 1H), 7.80-7.50 (m, 12 H), 7.40 (m, 5H), 5.65 (s, 2H), 5.20 (m, 2H), 4.40-4.20 (m, 2H), 4.05 (m, 4H), 3.70-3.65 (m, 3H), 3.60 (s, 3H), 3.55 (m, 4H), 3.35 (m, 3H), 3.30 (s, 3H), 3.10 (s, 1H), 2.60-2.50 (m, 1H), 2.15 (m, 4H), 1.70 (m, 11H), 1.38 (m, 2H), 0.90 (m, 3H), -1.50 (brs, 1H), -1.65 (brs, 1H).

[0270] Synthesis Example 12-Chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex 13-hydroxymethyldimethyl ester (compound 12) [ka] Step 1: To a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.612 g, 1.14 mmol, 1.4 equiv) in DCM (5 mL) was added TFA (1 mL). The resulting solution was stirred at ambient temperature (420 rpm) for 1 h and then concentrated by rotary evaporation. The residue was resuspended and concentrated twice from chloroform (2 × 10 mL) to give (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-methylamino)propyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate TFA salt as a viscous oil.

[0271] Step 2: A single-neck 250 mL RBF was charged with chlorin e6 anhydride (2.0 g, 1 equiv.), (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(((3-methylamino)propyl)thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate TFA salt (2.84 g, 1.5 equiv.), sodium bicarbonate (435 mg, 1.5 equiv.), and DCM (30 mL). The resulting solution was stirred overnight at 30° C. under a nitrogen atmosphere. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2×10 mL), and dried on a rotavapor. The remaining black solid was purified by column chromatography using 2–10% MeOH / DCM, and the fractions containing the first dark band to elute were combined and concentrated to give chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex diacid as a blue-green solid (1.2 g, 34% yield, 96.19% purity by HPLC).

[0272] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.70 (s, 1H), 9.10 (s, 1H), 8.35 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.70 (m, 1H), 5.30 (m, 1H), 5.00-4.70 (m, 2H), 4.60 (m, 1H), 4.40 (m, 1H), 4.10-3.85 (m, 5H), 3.55 (m, 10H), 2.75 (m, 2H), 2.40-2.10 (m, 5H), 2.00-1.50 (m, 12H), 1.70 (t, 3H), 1.55 (m, 2H), -1.80 (m, 1H), -2.25 (brs, 1H).

[0273] Step 3: A single-neck 250 mL RBF was charged with chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex diacid (1.0 gm, 1 eq.), potassium carbonate (490 mg, 3 eq.), DMF (10 mL), and a stir bar. The flask was placed under nitrogen and stirred at 300 rpm with an air-cooled condenser attached. Methyl iodide (0.218 mL, 2.5 eq.) was then added. The solution was stirred overnight at 30 °C. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude product was dissolved in DCM (30 mL), washed with water (2 × 10 mL), dried (NaSO), and concentrated under reduced pressure to give the crude product as a dark blue / green solid (approximately 1.2 g). HPLC analysis at this point indicated approximately 65% ​​purity. The remaining blue / green solid was purified by column chromatography using 2–4% MeOH / DCM, and the fractions containing the first dark band to elute were combined and concentrated to give chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex dimethyl ester as a blue / green solid (700 mg, 69% yield, 85.89% purity by HPLC).

[0274] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.70 (s, 1H), 8.10-8.00 (dd, 1H), 6.44 (d, 1H), 6.14 (d, 1H), 5.30-5.00 (m, 3H), 4.50-4.00 (m, 8H), 3.80-3.10 (m, 10H), 3.55 (s, 3H), 3.45 (s, 3H), 3.30 (s, 3H), 2.20-2.00 (m, 15H), 1.80 (m, 5H), -1.20-1.52 (m, 2H).

[0275] Step 4: To a 250 mL RBF was added chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex dimethyl ester (700 mg, 1 equiv.), THF (25 mL), osmium tetroxide (approximately 2 mg, 0.01 equiv.), deionized water (2.5 mL), AcOH (2.5 mL), and sodium periodate (373 mg, 2.6 equiv.). The resulting mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature overnight and at 30 °C for 1 h. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (20 mL), transferred to a separatory funnel, washed with water (10 mL), dried (NaSO), and concentrated by rotary evaporation to give chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex 13-formyldimethyl ester as a reddish-brown powdery solid (700 mg, quantitative yield, 47.93% purity by HPLC). The crude product was used in the next step without further purification.

[0276] 1 H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.20 (s, 1H), 9.65 (m, 1H), 8.95 (m, 1H), 5.50-5.00 (m, 8H), 4.50-4.00 (m, 12H), 3.90-3.40 (m, 24 H), 3.32 (s, 3H), 2.70-2.60 (m, 2H), 2.30-2.10 (m, 6H), 2.00 (m, 16 H), 1.70 (m, 8H), -1.75 (brs, 1H).

[0277] Step 5: To a 100 mL RBF was added chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex 13-formyldimethyl ester (700 mg, 1 equiv.), MeOH (20 mL), DCM (8 mL), and sodium borohydride (19 mg, 0.72 equiv.). The resulting mixture was stirred under nitrogen at ambient temperature for 1 h. The reaction mixture was concentrated using a rotavapor to give a dark green solid (approximately 800 mg), which was redissolved in MeOH (10 mL) and concentrated using a rotavapor at approximately 65 °C and 700 mbar (three cycles). Finally, the solvent MeOH was completely evaporated to give the crude product (approximately 700 mg). The residue was subjected to column chromatography. The crude product was dissolved in DCM and eluted with a gradient of 1% MeOH / DCM (300 mL), then 2% MeOH / DCM (200 mL), and then 3% MeOH / DCM (200 mL). Fractions of approximately 20 mL size were collected when the first color began to elute. The product (major dark green spot, R in 5% MeOH / DCM) f Fractions 6, 7 and 8 containing 1H 2 O (=approximately 0.7) were combined and concentrated to give compound 12 as a blue / green solid (410 mg, 59% yield, 39.06% purity by HPLC).

[0278] 1 H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 9.50 (m, 1H), 8.70 (m, 1H), 5.80 (s, 2H), 5.50-4.80 (m, 8H), 4.50-4.00 (m, 12H), 3.70-3.40 (m, 20H), 3.45 (s, 3H), 3.20 (s, 3H), 2.64-2.50 (m, 2H), 2.30-2.10 (m, 6H), 2.00 (m, 20H), 1.80 (m, 7H), 1.62 (m, 6H), -1.50 - -1.70 (brm, 2H).

[0279] Synthesis Example 13-Chlorin e6 Synthesis of β-D-1-thioglucose-N-methylpropylamide complex 13-hydroxymethyldimethyl ester (compound 13) [ka] Step 2: To a solution of chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex 13-hydroxymethyldimethyl ester (compound 12) (120 mg, 0.095 mmol, 1 equiv.) in MeOH (3 mL) and DCM (3 mL), NaOMe (4.6 M in MeOH, 0.020 mL, 0.095 mmol, 1 equiv.) was added, and the mixture was stirred (420 rpm) under nitrogen for 1 h. HPLC analysis after 45 min showed conversion to the deacetylated product. The reaction mixture was concentrated by rotary evaporation to give a black film. The residue was purified by column chromatography. The crude product was dissolved in 5% MeOH / DCM and diluted with 5-7% MeOH / DCM (high R). f The column was eluted with a gradient of 7% to 12% MeOH / DCM (to elute the first dark band). Fractions were collected when the first dark band began to elute. Fractions 6–14 were combined and concentrated to give compound 13 as a dark green solid (52 mg, 62% yield, 98.34% purity by HPLC).

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (m, 2H), 9.00 (m, 1H), 5.80 (s, 2H), 5.40-5.30 (m, 2H), 5.20-4.90 (m, 2H), 4.45-4.30 (m, 6H), 4.20 (m, 3H), 3.85-3.70 (m, 3H), 3.65 (m, 3H), 3.60-3.40 (m, 12H), 3.30 (s, 3H), 3.20 (d, 3H), 2.70-2.45 (m, 2H), 1.60-1.40 (m, 6H), -1.60 (m, 1H), -1.80 (m, 1H).

[0281] Synthesis Example 14-Chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex Synthesis of 13-(3-(triphenylphosphoniumpropyl) bromide) carbamate dimethyl ester (compound 14) [ka] To a 50 mL RBF was added chlorin e6 tetraacetic acid β-D-1-thioglucose-N-methylpropylamide complex 13-hydroxymethyldimethyl ester (compound 12) (300 mg, 1 eq.), carbonyldiimidazole (92 mg, 2 eq.), DCM (6 mL), and DMAP (5 mg). The resulting mixture was stirred under nitrogen for 3 hours. (3-Aminopropyl)triphenylphosphonium bromide (573 mg, 5 eq.) was added, and stirring was continued overnight at ambient temperature. The reaction mixture was concentrated, redissolved in 5 mL of 3% MeOH in DCM, and loaded directly onto the column. The residue was purified by column chromatography using 0-6% MeOH / DCM and loaded as a 3% MeOH in DCM solution. The major dark green band (R in 5% MeOH / DCM) was f =0.15) fractions were concentrated to give compound 14 as a dark green solid (80 mg, 19% yield, 77.81% purity by HPLC).

[0282] 1 H NMR (400 MHz, CDCl3) δ 9.60 (m, 2H), 8.55 (m, 1H), 7.25 (m, 2H), 7.20-7.10 (m, 5H), 7.15-6.85 (m, 8H), 6.25 (s, 2H), 5.40-5.30 (m, 2H), 5.20-4.90 (m, 2H), 4.45-4.00 (m, 6H), 3.70-3.55 (m, 7H), 3.53-3.35 (m, 13H), 3.22 (s, 3H), 2.70-2.40 (m, 2H), 2.25-2.00 (m, 2H), 2.00-1.85 (m, 15 H), 1.60-1.40 (m, 12H), 0.80 (m, 6H) -1.40 -1.80 (m, 2H).

[0283] Synthesis Example 15-Chlorin e6 Synthesis of N-methylbutylamine 13-N-methylaminodimethyl ester (Compound 15) [ka] To a 50 mL RBF was added chlorin e6 13-formyl N-methylbutylamine dimethyl ester (327 mg, 0.470 mmol, 1 equiv.), DCM (5 mL), methanol (20 mL), triethylamine (119 mg, 1.18 mmol, 2.5 equiv.), and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 equiv.). The resulting mixture was stirred in the dark under nitrogen for 2.5 h. Additional triethylamine (119 mg, 1.18 mmol, 2.5 equiv.) and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 equiv.) were then added, and the reaction was stirred for an additional 1.5 h. NaBH4 (178 mg, 4.70 mmol, 10 equiv.) was added, and stirring was continued for 16 h. The reaction was acidified with 2 M HCl (approximately 4 mL) and stirred for 10 min. Phosphate buffer pH=7 (20 mL) was added, and the mixture was extracted with DCM (3×20 mL), then dried (NaSO) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 4-6% MeOH / DCM, loaded as a solution in the eluent. The main fraction (R in 10% MeOH / DCM) f =0.30) was concentrated by rotary evaporation to give compound 15 as a dark blue solid (304 mg, 91%).

[0284] 1H NMR (400 MHz, chloroform-d) δ 9.56 (s, 1H), 9.36 (d, J = 2.7 Hz, 1H), 8.62 (d, J = 4.7 Hz, 1H), 5.46-5.24 (m, 2H), 4.73 (s, 2H), 4.43-4.25 (m, 2H), 4.18 (d, J = 6.1 Hz, 3H), 3.83-3.72 (m, 1H), 3.70-3.61 (m, 4H), 3.57 (s, 1H), 3.48 (s, 3H), 3.45 (s, 3H), 3.27 (d, J = 2.2Hz, 3H), 3.20 (s, 3H), 3.09 (s, 1H), 2.66-2.54 (m, 1H), 2.52 (s, 3H), 2.27-2.11 (m, 2H), 1.93-1.79 (m, 1H), 1.76-1.59 (m, 6H), 1.59-1.48 (m, 1H), 1.43-1.35 (m, 1H), 1.08 (t, J = 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 2H), -1.38 - -1.75 (m, 2H).

[0285] Synthesis Example 16-Chlorin e6 Synthesis of N-methylbutylamine 13-(N-methyl-5-triphenylphosphonium bromide pentanamide) dimethyl ester (Compound 16) [ka] To a 25 mL RBF was added chlorin e6 N-methylbutylamine 13-N-methylaminodimethyl ester (compound 15) (100 mg, 0.141 mmol, 1 equiv.), 4-(carboxybutyl)triphenylphosphonium bromide (125 mg, 0.282 mmol, 2.2 equiv.), DCM (6 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) (83 mg, 0.282 mmol, 2.2 equiv.). The resulting mixture was stirred under nitrogen in the dark at ambient temperature for 16 h. The reaction progress was monitored by HPLC. The reaction mixture was transferred to a separatory funnel, diluted with DCM (30 mL), and washed with 0.5 M HCl (20 mL). The aqueous layer was re-extracted with DCM (10 mL), and the combined organics were washed with pH 7 phosphate buffer (20 mL) followed by 1 M NaHCO (20 mL). The organic phase was dried (Na SO ) and concentrated by rotary evaporation to give a dark green film. The dark green film was dissolved in 4% MeOH / DCM and subjected to column chromatography by eluting with a gradient of 4-10% MeOH / DCM. Fractions of 25 mL in size were collected when the first color began to elute. The product (major dark green spot, R in 10% MeOH / DCM) was f =0.3) were combined to give compound 16 (76 mg, 48%) as a dark green solid (97.98% purity by HPLC).

[0286] 1H NMR (400 MHz, クロロホルム-d) δ 9.77 (s, 1H), 9.66 (s, 1H), 8.73 (d, J = 8.9 Hz, 1H), 7.63 (dq, J = 13.2, 7.6 Hz, 6H), 7.50-7.34 (m, 8H), 5.85 (s, 2H), 5.45-5.16 (m, 2H), 4.47-4.26 (m, 2H), 4.17 (d, J = 6.4 Hz, 3H), 3.85-3.71 (m, 4H), 3.67 (s, 2H), 3.56 (d, J = 7.3 Hz, 4H), 3.46 (d, J = 3.3 Hz, 3H), 3.41 (d, J = 2.8 Hz, 3H), 3.20 (d, J = 2.8 Hz, 3H), 3.16 (s, 3H), 3.09 (s, 1H), 2.76 (t, J = 6.7 Hz, 2H), 2.69-2.45 (m, 1H), 2.33-2.08 (m, 5H), 1.88 (d, J = 7.8 Hz, 1H), 1.82-1.50 (m, 17H), 1.40 (q, J = 7.5 Hz, 1H), 1.33 (s, 1H), 1.22 (d, J = 6.6 Hz, 1H), 1.09 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.53 ​​(d, J = 31.5 Hz, 1H).

[0287] Synthesis Example 17-クロリンe6 13-ヒドロキシメチルトリエチルエステル (Compound 17)

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[0288] 1 H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 9.57 (s, 1H), 8.76 (s, 1H), 8.06 (dd, 1H), 6.34 (d, 1H), 6.13 (d, 1H), 5.38 (d, 1H), 5.25 (d, 1H), 4.89-4.81 (m, 1H), 4.78-4.69 (m, 1H), 4.50-4.41 (m, 2H), 4.30-4.18 (m, 2H), 4.16-4.04 (m, 2H), 3.79 (q, 2H), 3.60 (s, 3H), 3.48 (s, 3H), 3.30 (s, 3H), 2.58-2.48 (m, 1H), 2.30-2.12 (m, 2H), 1.85-1.70 (m, 7H), 1.66 (t, 3H), 1.22-1.15 (m, 6H), -1.35 (brs, 1H), -1.52 (brs, 1H).

[0289] Step 2: To a 250 mL RBF was added chlorin e6 triethyl ester (2.01 g, 2.95 mmol, 1 equiv.), THF (75 mL), osmium tetroxide (7.5 mg, 0.0295 mmol, 0.01 equiv.), deionized water (6 mL), AcOH (6 mL), and sodium periodate (1.64 g, 7.67 mmol, 2.6 equiv.). The resulting mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 3 days. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (90 mL), transferred to a separatory funnel, washed with brine (60 mL), saturated NaHCO (60 mL), and water (75 mL), then dried (Na SO ) and concentrated by rotary evaporation to give the crude product as a dark blue solid (2.09 g). The crude product was purified by column chromatography using 2% MeOH in DCM as eluent. R was dissolved in 5% MeOH in DCM. f Fractions containing a red spot at 0.85 were combined and concentrated by rotary evaporation to give chlorin e6 13-formyltriethyl ester as a dark blue solid (1.05 g, 52%).

[0290] 1H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 10.27 (s, 1H), 9.68 (s, 1H), 8.96 (s, 1H), 5.42 (d, J = 18.8 Hz, 1H), 5.27 (d, J = 18.8 Hz, 1H), 4.87 (dq, J = 10.7, 7.1 Hz, 1H), 4.74 (dq, J = 10.8, 7.1 Hz, 1H), 4.54-4.43 (m, 2H), 4.25 (dtt, J = 18.1, 11.0, 7.2 Hz, 2H), 4.17-4.02 (m, 2H), 3.80 (s, 3H), 3.79-3.74 (m, 2H), 3.59 (s, 3H), 3.33 (s, 3H), 2.64-2.53 (m, 1H), 2.31-2.17 (m, 2H), 1.76 (d, J = 7.3 Hz, 3H), 1.72 (t, J = 7.6 Hz, 3H), 1.66 (t, J = 7.2 Hz, 3H), 1.20 (q, J = 7.0 Hz, 7H), -1.32 (s, 1H), -1.82 (s, 1H).

[0291] Step 3: To a 250 mL RBF was added chlorin e6 13-formyl triethyl ester (850 mg, 1.24 mmol, 1 equiv.), MeOH (20 mL), DCM (10 mL), and sodium borohydride (94 mg, 2.48 mmol, 2 equiv.). The resulting mixture was stirred (600 rpm) under nitrogen at ambient temperature for 10 minutes. The reaction mixture was diluted with water (15 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 × 30 mL). The combined DCM layers were washed with water (50 mL), then dried (NaSO), and concentrated by rotary evaporation to give the crude product as a dark green solid. The crude product was purified by silica chromatography (4 × 20 cm) eluting with 2% MeOH / DCM. The R f The fractions containing the spot at 0.7 were combined and concentrated by rotary evaporation to give compound 17 as a dark green solid (628 mg, 74%).

[0292] 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 9.48 (s, 1H), 8.76 (s, 1H), 5.76 (s, 2H), 5.40 (d, 1H), 5.28 (d, 1H), 4.90-4.81 (m, 1H), 4.78-4.70 (m, 1H), 4.51-4.43 (m, 2H), 4.31-4.19 (m, 2H), 4.15-4.05 (m, 2H), 3.74 (q, 2H), 3.59 (s, 3H), 3.39 (s, 3H), 3.25 (s, 3H), 2.59-2.50 (m, 1H), 2.30-2.21 (m, 1H), 2.20-2.11 (m, 1H), 1.85-1.63 (m, 11H), 1.23-1.16 (m, 7H), -1.49 (brs, 1H), -1.67 (brs, 1H).

[0293] Synthesis Example 18-Chlorin e6 Synthesis of 13-(oxopentyl)triphenylphosphonium bromide triethyl ester (compound 18) [ka] To a 50 mL RBF was added chlorin e6 13-hydroxymethyl triethyl ester (compound 17) (200 mg, 0.292 mmol, 1 equiv.), 4-(carboxybutyl)triphenylphosphonium bromide (259 mg, 0.584 mmol, 2 equiv.), EDC.HCl (112 mg, 0.584 mmol, 2 equiv.), DMAP (71 mg, 0.584 mmol, 2 equiv.), and DCM (15 mL). The resulting mixture was stirred (600 rpm) under nitrogen at ambient temperature in the dark. The reaction progress was monitored by TLC. After 1 h, the solvent was removed by rotary evaporation to leave a green oil. The green oil was dissolved in 3% MeOH / DCM and subjected to column chromatography by eluting with a gradient of 3–5% MeOH / DCM. The product (major dark green spot, R in 5% MeOH / DCM) was isolated. f =0.15) were combined to give compound 18 as a dark green solid (290 mg, 90%).

[0294] 1 H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 9.57 (s, 1H), 8.78 (s, 1H), 7.31-7.26 (m, 3H), 7.24 (dd, J = 7.1, 1.5 Hz, 3H), 7.20-7.13 (m, 3H), 7.05 (td, J = 7.8, 3.4 Hz, 7H), 6.35 (s, 2H), 5.40 (d, J = 18.8 Hz, 1H), 5.26 (d, J = 18.7 Hz, 1H), 4.85 (dq, J = 10.9, 7.1 Hz, 1H), 4.74 (dq, J = 10.9, 7.2 Hz, 1H), 4.53-4.42 (m, 2H), 4.34-4.18 (m, 2H), 4.16-4.03 (m, 2H), 3.76 (q, J = 7.6 Hz, 2H), 3.72-3.60 (m, 1H), 3.58 (s, 3H), 3.45 (s, 3H), 3.30 (s, 3H), 2.66-2.43 (m, 3H), 2.31-2.05 (m, 4H), 1.76 (d, J = 7.3 Hz, 4H), 1.67 (dt, J = 10.0, 7.4 Hz, 8H), 1.44-1.28 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H), -1.60 (s, 1H), -1.78 (s, 1H).

[0295] Synthesis Example 19-クロリンe6トリエチルエステル13-(N-(3-トリフェSynthesis of ニルホスホニウムプロピル)ブロミド)カルバメート (Compound 19)

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[0296] 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.67 (s, 1H), 8.76 (s, 1H), 7.44 (t, 1H), 7.37-7.29 (m, 6H), 7.15-7.04 (m, 9H), 6.90-6.81 (m, 1H), 6.72-6.57 (m, 1H), 6.37 (m, 2H), 5.39 (d, 1H), 5.26 (d, 1H), 4.89-4.80 (m, 1H), 4.78-4.69 (m, 1H), 4.48-4.39 (m, 2H), 4.30-4.18 (m, 2H), 4.14-4.05 (m, 2H), 3.72 (q, 2H), 3.59 (m, 4H), 3.51 (m, 7H), 3.30 (s, 3H), 2.60-2.51 (m, 1H), 2.29-2.15 (m, 2H), 1.80-1.60 (m, 18H), 1.28-1.16 (m, 9H), -1.47 (brs, 1H), -1.66 (brs, 1H).

[0297] Synthesis Example 20-Chlorin e6 Synthesis of 13-hydroxymethyl N-methylbutylamine diethyl ester (Compound 20) [ka] Step 1: A single-neck 100 mL RBF was charged with chlorin e6 N-methylbutylamine (761 mg, 1.14 mmol, 1 equiv), potassium carbonate (788 mg, 5.70 mmol, 5 equiv), DMF (15 mL), and a stir bar. The flask was placed under nitrogen and stirred at 400 rpm with an air-cooled condenser attached. Ethyl iodide (445 mg, 2.85 mmol, 2.5 equiv) was then added. The solution was stirred at 25 °C for 3 days. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 60 °C to give a dark green solid. The crude product was dissolved in DCM (50 mL), washed with water (2 × 20 mL), dried (NaSO), and concentrated under reduced pressure to give the crude product as a dark blue solid. The crude product was purified by silica gel column chromatography using 1% MeOH in DCM as eluent. R in 1% MeOH / DCM was added. f The fractions at 0.5 were combined and concentrated by rotary evaporation to give chlorin e6 N-methylbutylamine diethyl ester as a dark blue solid (400 mg, 49%).

[0298] 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.4 Hz, 1H), 9.56 (d, J = 6.2 Hz, 1H), 8.73 (d, J = 5.5 Hz, 1H), 8.07 (ddd, J = 17.9, 11.5, 3.6 Hz, 1H), 6.34 (dd, J = 17.8, 1.6 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.54-5.25 (m, 2H), 4.78-4.57 (m, 2H), 4.47-4.30 (m, 2H), 4.20-3.96 (m, 2H), 3.84-3.75 (m, 2H), 3.74-3.60 (m, 1H), 3.57 (d, J = 2.0 Hz, 3H), 3.47 (d, J = 2.3 Hz, 3H), 3.44 (s, 2H), 3.30 (d, J = 2.2 Hz, 3H), 3.08 (s, 1H), 2.64-2.42 (m, 1H), 2.30-2.11 (m, 2H), 1.93-1.80 (m, 1H), 1.78-1.69 (m, 6H), 1.69 (s, 1H), 1.60 (td, J = 7.2, 2.8 Hz, 2H), 1.39 (q, J = 7.4 Hz, 1H), 1.22 (t, J = 7.1 Hz, 2H), 1.14 (t, J = 7.2 Hz, 1H), 1.06 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.18 - -1.63 (m, 2H).

[0299] Step 2: To a 25 mL RBF was added chlorin e6 N-methylbutylamine diethyl ester (390 mg, 0.540 mmol, 1 equiv.), THF (6 mL), osmium tetroxide (1.4 mg, 0.0054 mmol, 0.01 equiv.), deionized water (0.5 mL), AcOH (0.5 mL), and sodium periodate (299 mg, 1.40 mmol, 2.6 equiv.). The resulting mixture was stirred (420 rpm) under nitrogen in the dark at ambient temperature for 18 h. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (30 mL), transferred to a separatory funnel, washed with brine (20 mL), saturated NaHCO (20 mL), and water (20 mL), then dried (NaSO), and concentrated by rotary evaporation to give a red-blue solid. The red-blue solid was purified by column chromatography using 1-2% MeOH in DCM as eluent. f The fractions with a spot at 0.4 were combined and concentrated by rotary evaporation to give chlorin e6 13-formyl N-methylbutylamine diethyl ester as a dark blue solid (310 mg, 79%).

[0300] 1H NMR (400 MHz, CDCl3) δ 11.55 (d, J = 2.2 Hz, 1H), 10.27 (s, 1H), 9.66 (s, 1H), 8.95 (s, 1H), 5.57-5.31 (m, 2H), 4.80-4.56 (m, 2H), 4.51-4.34 (m, 2H), 4.24-3.97 (m, 2H), 3.85-3.74 (m, 5H), 3.74-3.61 (m, 1H), 3.57 (s, 3H), 3.47 (s, 2H), 3.45-3.37 (m, 1H), 3.34 (d, J = 1.6 Hz, 3H), 3.09 (s, 1H), 2.72-2.46 (m, 1H), 2.35-2.15 (m, 2H), 1.95-1.83 (m, 1H), 1.80-1.69 (m, 6H), 1.63-1.52 (m, 8H), 1.41 (p, J = 7.4 Hz, 1H), 1.24 (t, J = 7.1 Hz, 2H), 1.13 (dt, J = 21.3, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 4H), -1.08 - -1.55 (m, 1H), -1.75 (d, J = 16.9 Hz, 1H).

[0301] Step 3: To a 50 mL RBF was added chlorin e6 13-formyl N-methylbutylamine diethyl ester (240 mg, 0.332 mmol, 1 equiv), MeOH (9 mL), DCM (3 mL), and sodium borohydride (25 mg, 0.664 mmol, 2 equiv). The resulting mixture was stirred (400 rpm) under nitrogen at 25° C. for 2 h. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (20 mL) and washed with water (20 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (10 mL). The combined DCM layers were washed with brine (20 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green solid (346 mg). The dark green solid was dissolved in DCM and subjected to column chromatography by eluting with 2% MeOH / DCM. The major dark green spot (R in 5% MeOH / DCM) was f= approximately 0.6) were combined to give compound 20 as a dark blue solid (119 mg, 49%).

[0302] 1 H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 7.4 Hz, 1H), 9.47 (d, J = 3.4 Hz, 1H), 8.73 (d, J = 6.5 Hz, 1H), 5.77 (s, 2H), 5.55-5.29 (m, 2H), 4.81-4.56 (m, 2H), 4.47-4.30 (m, 2H), 4.21-3.98 (m, 2H), 3.78-3.60 (m, 2H), 3.55 (s, 3H), 3.45 (s, 2H), 3.39 (d, J = 0.9 Hz, 3H), 3.25 (d, J = 1.7 Hz, 3H), 3.08 (s, 1H), 2.67-2.41 (m, 1H), 2.32-2.07 (m, 2H), 1.96-1.81 (m, 1H), 1.77 (d, J = 7.2 Hz, 3H), 1.71-1.63 (m, 3H), 1.60 (td, J = 7.2, 3.2 Hz, 3H), 1.45-1.32 (m, 1H), 1.22 (t, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 1H), 1.07 (t, J = 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 2H), -1.69 (d, J = 39.4 Hz, 2H).

[0303] Synthesis Example 21-Chlorin e6 Synthesis of N-methylbutylamine diethyl ester 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate (Compound 21) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl N-methylbutylamine diethyl ester (compound 20) (55 mg, 0.0757 mmol, 1 equiv.), carbonyldiimidazole (24 mg, 0.151 mmol, 2 equiv.), DCM (4 mL), and DMAP (2 mg). The resulting mixture was stirred (400 rpm) under nitrogen for 3 h. The reaction progress was monitored by TLC. (3-Aminopropyl)triphenylphosphonium bromide (152 mg, 0.379 mmol, 5 equiv.) was added, and stirring was continued at 30 °C for 27 h. The reaction progress was monitored by HPLC. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel, washed with water (20 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green residue (103 mg). The residue was purified by column chromatography using 5-8% MeOH / DCM, loaded as a solution in eluent. The major dark green band (R in 10% MeOH / DCM) f =0.4) were combined and concentrated by rotary evaporation to give compound 21 as a dark green solid (31 mg, 36%).

[0304] 1H NMR (400 MHz, CDCl3) δ 9.77 (d, J = 7.8 Hz, 1H), 9.65 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 57.2 Hz, 1H), 7.24-7.13 (m, 5H), 7.06-6.88 (m, 7H), 6.75 (s, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 6.37 (t, J = 2.9 Hz, 2H), 5.53-5.31 (m, 2H), 4.80-4.58 (m, 1H), 4.50-4.28 (m, 2H), 4.20-3.98 (m, 1H), 3.73 (q, J = 7.4 Hz, 2H), 3.56 (s, 3H), 3.51 (s, 3H), 3.46 (s, 2H), 3.45-3.37 (m, 1H), 3.31 (s, 3H), 3.21 (s, 1H), 3.07 (s, 1H), 2.72-2.44 (m, 1H), 2.34-2.13 (m, 1H), 1.94-1.83 (m, 1H), 1.83-1.48 (m, 26H), 1.46-1.31 (m, 1H), 1.31-1.19 (m, 4H), 1.14 (t, J = 7.1 Hz, 1H), 1.09 (t, J = 7.3 Hz, 1H), 0.94 (t, J = 7.3 Hz, 2H), 0.90-0.78 (m, 1H), -1.33 - -1.90 (m, 2H).

[0305] Synthesis Example 22-Chlorin e6 Synthesis of N-methylbutylamine diethyl ester 13-(oxopentyl)triphenylphosphonium bromide (Compound 22) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl N-methylbutylamine diethyl ester (compound 20) (55 mg, 0.0757 mmol, 1 equiv.), 4-(carboxybutyl)triphenylphosphonium bromide (67 mg, 0.151 mmol, 2 equiv.), EDC.HCl (29 mg, 0.151 mmol, 2 equiv.), DMAP (18 mg, 0.145 mmol, 2 equiv.), and DCM (5 mL). The resulting mixture was stirred (600 rpm) under nitrogen at 25 °C. The reaction progress was monitored by TLC. After 2 h, the solvent was removed by rotary evaporation to leave a dark green residue. The residue was dissolved in 5% MeOH / DCM and subjected to column chromatography by eluting with a gradient of 5–7% MeOH / DCM. The product (major dark green spot, R in 5% MeOH / DCM) was isolated. f =0.3) were combined to give compound 22 as a dark green solid (65 mg, 75%).

[0306] 1H NMR (400 MHz, CDCl3) δ 9.71-9.47 (m, 2H), 8.78 (d, J = 7.0 Hz, 1H), 7.18-6.99 (m, 10H), 6.97-6.80 (m, 6H), 6.35 (d, J = 2.6 Hz, 2H), 5.58-5.30 (m, 2H), 4.81-4.57 (m, 2H), 4.52-4.30 (m, 2H), 4.22-3.95 (m, 2H), 3.77 (q, J = 8.3 Hz, 3H), 3.57 (s, 3H), 3.48 (s, 2H), 3.45 (s, 3H), 3.31 (s, 3H), 3.09 (s, 1H), 2.70-2.44 (m, 3H), 2.34-2.19 (m, 1H), 2.18-2.08 (m, 2H), 1.91 (t, J = 7.9 Hz, 1H), 1.77 (d, J = 7.1 Hz, 3H), 1.72-1.64 (m, 6H), 1.61 (td, J = 7.1, 2.6 Hz, 3H), 1.39 (q, J = 7.4 Hz, 1H), 1.25 (d, J = 7.1 Hz, 5H), 1.18-1.09 (m, 2H), 0.95 (t, J = 7.3 Hz, 2H), -1.76 (d, J = 29.4 Hz, 1H).

[0307] Synthesis Example 23-Chlorin e6 Synthesis of N-methylbutylamine dimethyl ester 13-(oxopentyl)triphenylphosphonium bromide (Compound 23) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (60 mg, 0.0859 mmol, 1 equiv.), 4-(carboxybutyl)triphenylphosphonium bromide (76 mg, 0.172 mmol, 2 equiv.), EDC.HCl (33 mg, 0.172 mmol, 2 equiv.), DMAP (21 mg, 0.172 mmol, 2 equiv.), and DCM (5 mL). The resulting mixture was stirred (400 rpm) under nitrogen at 25 °C. The reaction progress was monitored by TLC. After 2 h, the solvent was removed by rotary evaporation to leave a dark green residue. The residue was dissolved in 5% MeOH / DCM and subjected to column chromatography by eluting with a gradient of 5–10% MeOH / DCM. The product (major dark green spot, R in 5% MeOH / DCM) was isolated. f =0.2) were combined and concentrated by rotary evaporation to give compound 23 as a dark green solid (80 mg, 83%).

[0308] 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 9.56 (d, J = 6.7 Hz, 1H), 8.76 (d, J = 7.1 Hz, 1H), 7.17-7.00 (m, 9H), 6.97-6.86 (m, 6H), 6.34 (d, J = 3.0 Hz, 2H), 5.54-5.32 (m, 2H), 4.49-4.31 (m, 2H), 4.20 (d, J = 6.3 Hz, 3H), 3.76 (q, J = 8.2 Hz, 2H), 3.68 (s, 2H), 3.58 (s, 1H), 3.56 (d, J = 2.3 Hz, 3H), 3.50 (s, 2H), 3.46-3.41 (m, 3H), 3.30 (s, 3H), 3.10 (s, 1H), 2.72-2.45 (m, 2H), 2.34-2.06 (m, 3H), 1.93 (p, J = 7.9 Hz, 1H), 1.81-1.74 (m, 3H), 1.74-1.52 (m, 8H), 1.40 (h, J = 7.4 Hz, 1H), 1.12 (t, J = 7.3 Hz, 1H), 0.96 (t, J = 7.3 Hz, 2H), -1.51 - -1.84 (m, 1H).

[0309] Synthesis Example 24-Chlorin e6 Synthesis of 13-hydroxymethyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (Compound 24) [ka] Step 1: A single-neck, 1 L RBF was charged with e6 chlorin anhydride (6.90 g, 11.9 mmol, 1 equiv.), N-methyl-3,6,9,12-tetraoxatridecan-1-amine (3.96 g, 17.9 mmol, 1.5 equiv.), and DCM (400 mL). The resulting solution was stirred (400 rpm) at 35 °C under a nitrogen atmosphere for 18 h. The resulting dark green solution was concentrated under reduced pressure until approximately 10 mL of DCM remained. Diethyl ether (100 mL) was then added, and the mixture was manually swirled in the RBF. The solvent was decanted, leaving a sticky, dark green paste. The paste was further washed with diethyl ether (2 × 100 mL) until a sticky, dark blue solid remained. Residual solvent was removed from the solid by rotary evaporation to give chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amineamide as a dark blue solid (7.34 g, 77%).

[0310] 1 H NMR (400 MHz, DMSO-d6) δ 9.77-9.67 (m, 2H), 9.10 (d, J = 1.7 Hz, 1H), 8.33 (dd, J = 17.8, 11.7 Hz, 1H), 6.44 (dd, J = 17.7, 1.6 Hz, 1H), 6.16 (dd, J = 11.6, 1.4 Hz, 1H), 5.90-5.70 (m, 1H), 5.56-5.34 (m, 1H), 4.58 (q, J = 7.4 Hz, 1H), 4.36 (d, J = 10.5 Hz, 1H), 4.08-3.91 (m, 1H), 3.86-3.78 (m, 2H), 3.78-3.73 (m, 0H), 3.65-3.43 (m, 66H), 3.43-3.34 (m, 7H), 3.23-3.16 (m, 5H), 3.01-2.96 (m, 1H), 2.96-2.91 (m, 2H), 2.71-2.53 (m, 1H), 2.45 (s, 2H), 2.32 (d, J = 4.5 Hz, 1H), 2.25-2.12 (m, 1H), 1.72-1.57 (m, 6H), -1.75 - -2.03 (m, 1H), -2.28 (s, 1H).

[0311] Step 2: A single-neck 500 mL RBF was charged with chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amineamide (5.50 g, 6.88 mmol, 1 equiv.), potassium carbonate (4.75 g, 34.4 mmol, 5 equiv.), DMF (180 mL), and a stir bar. The flask was placed under nitrogen and stirred at 400 rpm with an air-cooled condenser attached. Methyl iodide (2.44 g, 17.2 mmol, 2.5 equiv.) was then added. The solution was stirred at 25 °C for 18 h. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 70 °C to give the crude product as a dark green solid. The crude product was dissolved in EtOAc (125 mL), washed with water (2 x 150 mL), dried (Na2SO4), and concentrated under reduced pressure to give the crude product as a dark blue solid (5.82 g). The blue solid was purified by column chromatography using 2-4% MeOH / DCM as eluent. R f Fractions containing the major band at 0.4 were combined and concentrated by rotary evaporation to give chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide as a dark blue solid (3.10 g, 53%).

[0312] 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 3.0 Hz, 1H), 9.54 (d, J = 6.9 Hz, 1H), 8.72 (d, J = 6.9 Hz, 1H), 8.11-8.02 (m, 1H), 6.34 (dd, J = 17.8, 1.5 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.47-5.23 (m, 2H), 4.45-4.31 (m, 2H), 4.23 (s, 2H), 4.18 (s, 1H), 4.04-3.91 (m, 1H), 3.78 (ttd, J = 9.2, 4.8, 2.7 Hz, 5H), 3.73-3.65 (m, 7H), 3.64 (s, 3H), 3.59-3.52 (m, 8H), 3.46 (d, J = 2.4 Hz, 3H), 3.38 (s, 3H), 3.29 (d, 3H), 3.16 (s, 1H), 2.64-2.38 (m, 1H), 2.26-2.01 (m, 2H), 1.76 (dd, J = 7.2, 3.4 Hz, 3H), 1.74-1.68 (m, 3H), -1.28 (d, J = 25.8 Hz, 1H), -1.44 (d, J = 25.4 Hz, 1H).

[0313] Step 3: To a 500 mL RBF was added chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethylesteramide (3.00 g, 3.62 mmol, 1 equiv.), THF (120 mL), osmium tetroxide (9.2 mg, 0.0362 mmol, 0.01 equiv.), deionized water (12 mL), AcOH (12 mL), and sodium periodate (2.01 g, 9.41 mmol, 2.6 equiv.). The resulting mixture was stirred (420 rpm) in the dark under nitrogen at 25 °C for 16 h. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (250 mL), transferred to a separatory funnel, washed with brine (120 mL), saturated NaHCO (120 mL), and water (120 mL), then dried (NaSO), and concentrated by rotary evaporation to give the crude product as a dark blue solid (3.53 g). The crude product was purified by column chromatography using 2-2.5% MeOH / DCM to remove the first dark band eluting (R in 5% MeOH / DCM). f =0.5) were combined and concentrated by rotary evaporation to give chlorin e6 13-formyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide as a dark blue solid (2.01 g, 67%).

[0314] 1H NMR (400 MHz, CDCl3) δ 11.53 (d, J = 2.0 Hz, 1H), 10.23 (d, J = 4.4 Hz, 1H), 9.64 (s, 1H), 8.92 (d, J = 4.7 Hz, 1H), 5.54-5.31 (m, 2H), 4.44 (q, J = 6.8, 6.4 Hz, 1H), 4.39-4.33 (m, 1H), 4.25 (s, 2H), 4.20 (s, 1H), 4.08-3.94 (m, 1H), 3.88-3.73 (m, 8H), 3.73-3.68 (m, 5H), 3.66 (d, J = 7.1 Hz, 4H), 3.59 (s, 2H), 3.56 (d, J = 2.4 Hz, 6H), 3.38 (s, 3H), 3.32 (d, J = 1.2 Hz, 3H), 3.17 (s, 1H), 2.69-2.43 (m, 1H), 2.30-2.04 (m, 2H), 1.81-1.68 (m, 6H), -1.28 (s, 1H), -1.75 (d, J = 17.5 Hz, 1H).

[0315] Step 4: To a 100 mL RBF was added chlorin e6 13-formyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (1.00 g, 1.20 mmol, 1 equiv.), MeOH (30 mL), DCM (15 mL), and sodium borohydride (91 mg, 2.40 mmol, 2 equiv.). The resulting mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (40 mL). The combined DCM layers were washed with brine (80 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green solid. The dark green solid was dissolved in 2% MeOH in DCM and subjected to column chromatography by eluting with a gradient of 2-5% MeOH in DCM. fThe fractions with the major dark green spot at 0.4 were combined and concentrated by rotary evaporation to give compound 24 as a dark green solid (802 mg, 80%).

[0316] 1 H NMR (400 MHz, CDCl3) δ 9.66 (d, J = 2.6 Hz, 1H), 9.43 (d, J = 4.0 Hz, 1H), 8.70 (d, J = 6.2 Hz, 1H), 5.71 (s, 2H), 5.52-5.20 (m, 2H), 4.45-4.31 (m, 2H), 4.22 (s, 2H), 4.18 (s, 1H), 4.06-3.90 (m, 1H), 3.83-3.71 (m, 4H), 3.71-3.65 (m, 5H), 3.63 (d, J = 1.9 Hz, 3H), 3.58-3.52 (m, 8H), 3.38 (d, J = 1.1 Hz, 3H), 3.35 (s, 3H), 3.25 (d, J = 1.5 Hz, 3H), 3.15 (s, 1H), 2.64-2.38 (m, 1H), 2.26-2.13 (m, 1H), 2.13-1.99 (m, 1H), 1.77 (dd, J = 7.2, 3.6 Hz, 3H), 1.69 (t, J = 7.6 Hz, 3H), -1.30 - -1.73 (m, 2H).

[0317] Synthesis Example 25-Chlorin e6 Synthesis of 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (Compound 25) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl-15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (compound 24) (100 mg, 0.120 mmol, 1 equiv.), carbonyldiimidazole (39 mg, 0.240 mmol, 2 equiv.), DCM (4 mL), and DMAP (3 mg). The resulting mixture was stirred (600 rpm) under nitrogen at 30°C for 3 h. The reaction progress was monitored by TLC. (3-Aminopropyl)triphenylphosphonium bromide (240 mg, 0.600 mmol, 5 equiv.) was added, and stirring was continued at 30°C for 18 h. The reaction was monitored by HPLC. The reaction mixture was diluted with DCM (30 mL), transferred to a separatory funnel, washed with water (30 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 5-9% MeOH / DCM, loaded as a solution to the eluent. R f The fractions with the major dark green spot at 0.60 were combined and concentrated to give compound 25 as a dark green solid (89 mg, 59%).

[0318] 1H NMR (400 MHz, CDCl3) δ 9.72 (d, J = 6.0 Hz, 1H), 9.62 (d, J = 3.5 Hz, 1H), 8.71 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 6.3 Hz, 1H), 7.24-7.17 (m, 4H), 7.06-6.91 (m, 7H), 6.82-6.47 (m, 2H), 6.41-6.27 (m, 2H), 5.49-5.25 (m, 2H), 4.46-4.28 (m, 2H), 4.22 (s, 2H), 4.18 (s, 1H), 4.07-3.90 (m, 1H), 3.84-3.65 (m, 8H), 3.64 (s, 2H), 3.59-3.53 (m, 5H), 3.50 (d, J = 2.5 Hz, 3H), 3.46-3.38 (m, 1H), 3.36 (d, J = 9.6 Hz, 2H), 3.30 (s, 2H), 3.15 (s, 1H), 2.69-2.37 (m, 1H), 2.33-2.12 (m, 1H), 1.77 (s, 1H), 1.71 (dd, J = 7.4, 2.2 Hz, 2H), 1.69-1.61 (m, 2H), -1.37 - -1.92 (m, 1H).

[0319] Synthesis Example 26-Chlorin e6 Synthesis of 13-hydroxymethyl 15-N-methyl-1-dodecanamine dimethyl ester amide (Compound 26) [ka] Step 1: A single-neck, 1 L RBF was charged with e6 chlorin anhydride (7.00 g, 12.1 mmol, 1 equiv.), N-methyl-1-dodecanamine (4.03 g, 18.2 mmol, 1.5 equiv.), and DCM (400 mL). The resulting solution was stirred (400 rpm) under a nitrogen atmosphere at 35 °C for 16 h. The resulting dark green solution was concentrated under reduced pressure until approximately 10 mL of DCM remained. Then, hexane (100 mL) was added, and the mixture was manually swirled in the RBF. The solvent was decanted, leaving a sticky dark green paste. The paste was further washed with hexane (2 × 100 mL) until a dark green solid remained. Residual solvent was removed from the solid by rotary evaporation to give chlorin e6 15-N-methyl-1-dodecanamine amide as a dark green solid (9.16 g, 97%).

[0320] 1H NMR (400 MHz, メタノール-d4) δ 9.66 (s, 1H), 9.42 (d, J = 5.2 Hz, 1H), 8.98 (d, J = 4.7 Hz, 1H), 7.86 (ddd, J = 17.8, 11.6, 3.3 Hz, 1H), 6.16-6.04 (m, 1H), 5.94 (dd, J = 19.7, 13.5 Hz, 2H), 4.61-4.52 (m, 1H), 4.40-4.29 (m, 1H), 3.92-3.80 (m, 1H), 3.72-3.62 (m, 2H), 3.57 (d, J = 10.7 Hz, 5H), 3.08 (s, 3H), 3.02 (s, 1H), 2.74 (ddd, J = 22.8, 11.1, 6.4 Hz, 1H), 2.66-2.51 (m, 1H), 2.44-2.33 (m, 1H), 2.33-2.20 (m, 2H), 2.13 (s, 1H), 2.00 (s, 3H), 1.87-1.74 (m, 2H), 1.74-1.56 (m, 7H), 1.43-1.03 (m, 25H), 1.01-0.91 (m, 2H), 0.85 (t, J = 7.1 Hz, 6H), 0.76 (p, J = 7.2 Hz, 2H), 0.52-0.34 (m, 4H), 0.29-0.15 (m, 2H), 0.08 - -0.09 (m, 4H).

[0321] Step 2: A single-neck 500 mL RBF was charged with chlorin e6 15-N-methyl-1-dodecanamine amide (7.00 g, 9.00 mmol, 1 equiv.), potassium carbonate (6.21 g, 45.0 mmol, 5 equiv.), DMF (220 mL), and a stir bar. The flask was placed under nitrogen and stirred at 400 rpm with an air-cooled condenser attached. Methyl iodide (3.19 g, 22.5 mmol, 2.5 equiv.) was then added. The solution was stirred at 25 °C for 18 h. The reaction progress was monitored by HPLC. The solvent was removed under reduced pressure at 70 °C to give the crude product as a dark green solid. The crude product was dissolved in EtOAc (125 mL), washed with water (2 × 150 mL), dried (NaSO), and concentrated under reduced pressure to give the crude product as a dark blue / green solid (10.03 g). The dark blue / green solid was purified by column chromatography using 2-5% MeOH / DCM as eluent. f Two fractions containing the major band at R = 0.4 were collected and concentrated by rotary evaporation to give the product as a dark blue solid. The second product fraction from the first column was re-purified by column chromatography using 3% MeOH / DCM as the eluent. R was purified by column chromatography in 5% MeOH / DCM. f The first pure fraction containing the major band at RI = 0.4 was combined with the first fraction from the first column and concentrated by rotary evaporation to give chlorin e6 15-N-methyl-1-dodecanamine dimethyl ester amide as a dark green solid (3.45 g, 48%).

[0322] 1H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.7 Hz, 1H), 9.55 (d, J = 6.9 Hz, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.06 (ddd, J = 17.9, 11.5, 4.1 Hz, 1H), 6.34 (dd, J = 17.8, 1.6 Hz, 1H), 6.12 (dd, J = 11.5, 1.5 Hz, 1H), 5.47-5.18 (m, 2H), 4.48-4.27 (m, 2H), 4.20 (d, J = 4.0 Hz, 3H), 3.79 (q, J = 7.7, 2.2 Hz, 2H), 3.67 (s, 3H), 3.59-3.54 (m, 4H), 3.46 (d, J = 2.7 Hz, 5H), 3.30 (d, J = 2.6 Hz, 3H), 3.09 (s, 1H), 2.71-2.46 (m, 1H), 2.33-2.10 (m, 2H), 1.85-1.61 (m, 8H), 1.45-1.21 (m, 19H), 0.95-0.84 (m, 3H), -1.27 (d, J = 27.7 Hz, 1H), -1.43 (d, J = 28.5 Hz, 1H).

[0323] Step 3: To a 500 mL RBF was added chlorin e6 15-N-methyl-1-dodecanamine dimethylesteramide (3.40 g, 4.22 mmol, 1 equiv.), THF (140 mL), osmium tetroxide (approximately 10.7 mg, 0.0422 mmol, 0.01 equiv.), deionized water (14 mL), AcOH (14 mL), and sodium periodate (2.35 g, 11.0 mmol, 2.6 equiv.). The resulting mixture was stirred (420 rpm) in the dark under nitrogen at 25 °C for 16 h. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (250 mL), transferred to a separatory funnel, washed with brine (120 mL), saturated NaHCO (120 mL), and water (120 mL), then dried (NaSO) and concentrated by rotary evaporation to give the crude product as a dark blue solid. The crude product was purified by column chromatography using 2% MeOH / DCM to remove the first dark band eluting (R in 5% MeOH / DCM). f =0.5) were combined to give chlorin e6 13-formyl 15-N-methyl-1-dodecanamine dimethyl ester amide as a dark blue solid (1.88 g, 55%).

[0324] 1H NMR (400 MHz, CDCl3) δ 11.53 (d, J = 2.8 Hz, 1H), 10.22 (d, J = 2.2 Hz, 1H), 9.63 (d, J = 2.9 Hz, 1H), 8.91 (d, J = 2.7 Hz, 1H), 5.56-5.18 (m, 2H), 4.52-4.28 (m, 2H), 4.19 (d, J = 3.6 Hz, 3H), 3.81-3.72 (m, 5H), 3.68 (s, 2H), 3.56 (d, J = 4.0 Hz, 4H), 3.47 (s, 2H), 3.45-3.36 (m, 1H), 3.31 (d, J = 1.3 Hz, 3H), 3.08 (s, 1H), 2.72-2.44 (m, 1H), 2.34-2.12 (m, 2H), 1.91-1.79 (m, 1H), 1.78-1.62 (m, 6H), 1.46-1.15 (m, 18H), 0.92-0.80 (m, 3H), -1.28 (d, J = 16.7 Hz, 1H), -1.76 (d, J = 18.5 Hz, 1H).

[0325] Step 4: To a 100 mL RBF was added chlorin e6 13-formyl 15-N-methyl-1-dodecanamine dimethyl ester amide (920 mg, 1.14 mmol, 1 equiv.), MeOH (30 mL), DCM (15 mL), and sodium borohydride (86 mg, 2.28 mmol, 2 equiv.). The resulting mixture was stirred (600 rpm) under nitrogen at ambient temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated by rotary evaporation. The mixture was diluted with DCM (80 mL) and washed with water (80 mL). The DCM layer was collected, and the aqueous layer was further extracted with DCM (40 mL). The combined DCM layers were washed with brine (80 mL), dried (Na2SO4), and concentrated by rotary evaporation to give a dark green solid. The dark green solid was dissolved in 2% MeOH in DCM and subjected to column chromatography by eluting with a gradient of 2% MeOH in DCM. The major dark green spot (R in 5% MeOH / DCM) f= ca. 0.4) were combined to give compound 26 as a dark blue solid (688 mg, 72%).

[0326] 1 H NMR (400 MHz, CDCl3) δ 9.67 (d, J = 1.2 Hz, 1H), 9.41 (d, J = 3.1 Hz, 1H), 8.69 (d, J = 5.0 Hz, 1H), 5.67 (d, J = 2.9 Hz, 2H), 5.51-5.22 (m, 2H), 4.48-4.30 (m, 2H), 4.19 (d, J = 4.2 Hz, 3H), 3.81-3.71 (m, 2H), 3.67 (s, 2H), 3.59-3.54 (m, 4H), 3.46 (s, 2H), 3.33 (s, 3H), 3.25 (d, J = 2.1 Hz, 3H), 3.09 (s, 1H), 2.69-2.44 (m, 1H), 2.32-2.09 (m, 2H), 1.99 (s, 1H), 1.77 (dd, J = 7.2, 3.3 Hz, 3H), 1.70 (q, J = 6.9, 6.2 Hz, 4H), 1.44-1.20 (m, 18H), 0.94-0.83 (m, 3H), -1.26 - -1.77 (m, 2H).

[0327] Synthesis Example 27 - Synthesis of chlorin e6 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate 15-N-methyl-1-dodecanamine dimethyl ester amide (compound 27) [ka] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl-15-N-methyl-1-dodecanamine dimethyl ester amide (compound 26) (100 mg, 0.1234 mmol, 1 equiv.), carbonyldiimidazole (40 mg, 0.2469 mmol, 2 equiv.), DCM (4 mL), and DMAP (3 mg). The resulting mixture was stirred under nitrogen at 30 °C for 3 h. (3-Aminopropyl)triphenylphosphonium bromide (247 mg, 0.6172 mmol, 5 equiv.) was added, and stirring was continued at 30 °C for 18 h. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel, washed with water (20 mL), dried (NaSO), and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a 3-7% MeOH / DCM gradient. The major dark green spot (R in 7% MeOH / DCM) f =0.40) were combined to give compound 27 as a dark green solid (123 mg, 80%).

[0328] 1 H NMR (400 MHz, CDCl3) δ 9.75 (m, 1H), 9.63 (s, 1H), 8.72 (m, 1H), 7.47 (m, 1H), 7.24-7.17 (m, 6H), 7.06-6.91 (m, 9H), 6.81-6.47 (m, 2H), 6.37 (m, 2H), 5.47-5.27 (m, 2H), 4.50-4.30 (m, 2H), 4.22-4.18 (m, 3H), 3.78-3.66 (m, 6H), 3.59-3.53 (m, 5H), 3.52-3.50 (m, 5H), 3.50-3.48 (m, 3H), 3.47-3.39 (m, 3H), 3.31 (s, 3H), 2.70-2.47 (m, 1H), 2.31-2.12 (m, 2H), 1.92-1.82 (m, 1H), 1.75-1.55 (m, 17H), 1.38-1.20 (m, 22H), -1.35 - -1.73 (m, 2H).

[0329] Synthesis Example 28-Chlorin e6 Synthesis of 13-hydroxymethyl(2-methoxyethyl)methylamine (Compound 28) [ka] To a 50 mL RBF was added chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine dimethyl ester (159 mg, 0.227 mmol, 1 equiv.), lithium hydroxide monohydrate (29 mg, 0.681 mmol, 3 equiv.), THF (9 mL), and water (3 mL). The mixture was stirred at 25 °C for 2 h. The progress of the reaction was monitored by HPLC. The reaction mixture was diluted with EtOAc (50 mL), transferred to a separatory funnel, and then 1 M HCl solution (25 mL) was added. After shaking the separatory funnel for approximately 1 min, pH 7 buffer (40 mL) was added, and the funnel was shaken for approximately 1 min. The organic layer was then separated, dried over MgSO4, and concentrated by rotary evaporation to give compound 28 as a dark blue solid (140 mg, 92% yield, 98.12% purity by HPLC).

[0330] 1 H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H), 9.42-9.32 (m, 1H), 8.67 (s, 1H), 5.73-5.57 (m, 2H), 5.36-5.02 (m, 1H), 4.96 (s, 1H), 4.45-4.26 (m, 2H), 4.20-3.97 (m, 4H), 3.92-3.83 (m, 0H), 3.83-3.62 (m, 2H), 3.60 (s, 1H), 3.57 (s, 2H), 3.54 (s, 1H), 3.52 (s, 2H), 3.39 (s, 2H), 3.31 (d, J = 2.3 Hz, 3H), 3.24-3.18 (m, 3H), 3.08 (s, 1H), 2.53 (s, 1H), 2.03 (s, 1H), 1.99-1.83 (m, 1H), 1.77-1.62 (m, 6H), 1.59-1.38 (m, 1H), 1.23-1.20 (m, 1H), -1.65 (s, 1H).

[0331] Synthesis Example 29 - Synthesis of chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine bis(N-methyl-D-glucamine) salt (compound 29) [ka] Chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine (compound 28) (60 mg, 0.0893 mmol, 1 equiv.) was weighed into a 25 mL RBF, followed by the addition of distilled deionized water (5 mL) using a stir bar. Meglumine (35 mg, 0.179 mmol, 2 equiv.) was added, and the mixture was then stirred with heating at 40 °C for 1 h. The solution was allowed to cool to ambient temperature, diluted with water (20 mL), and then filtered through a porosity 3 filter (3 cm diameter) into a 250 mL RBF equipped with a side-arm adapter. The reaction flask was rinsed with deionized water (approximately 10 mL), which was passed through the filter to complete the transfer. The filtrate was then lyophilized for 17 h to afford compound 29 as a dark brown fluffy solid (86 mg, 91% yield, 97.76% purity by HPLC).

[0332] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (dd, J = 7.0, 2.8 Hz, 2H), 8.99 (d, J = 4.5 Hz, 1H), 5.77 (s, 2H), 5.47-5.26 (m, 2H), 4.53 (q, J = 7.2 Hz, 1H), 4.31 (dd, J = 20.9, 10.1 Hz, 1H), 4.14 (s, 1H), 3.80 (q, J = 8.0, 6.0 Hz, 2H), 3.72 (q, J = 5.2 Hz, 3H), 3.64 (d, J = 5.3 Hz, 2H), 3.61-3.57 (m, 3H), 3.52 (s, 4H), 3.51-3.49 (m, 3H), 3.45-3.34 (m, 7H), 3.30 (d, J = 7.2 Hz, 5H), 2.95 (s, 1H), 2.72-2.61 (m, 5H), 2.32 (s, 7H), 2.24-1.99 (m, 2H), 1.82 (s, 1H), 1.73-1.58 (m, 6H), -1.63 (d, J = 14.9 Hz, 1H), -1.83 (d, J = 13.0 Hz, 1H).

[0333] Synthesis Example 30-Chlorin e6 Synthesis of 13-hydroxymethyl(2-methoxyethyl)methylamine disodium salt (compound 30) [ka] Chlorin e6 13-hydroxymethyl(2-methoxyethyl)methylamine (compound 28) (60 mg, 0.0893 mmol, 1 equiv.) was weighed into a 100 mL RBF, followed by the addition of distilled, deionized water (5 mL) using a stir bar. 0.1 M sodium hydroxide solution (1.70 mL, 0.170 mmol, 1.9 equiv.) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was then lyophilized overnight (16 h) to afford compound 30 as a dark green, fluffy solid (64 mg, quantitative yield, 94.43% purity by HPLC).

[0334] 1H NMR (400 MHz, DMSO-d6) δ 9.77-9.66 (m, 2H), 9.00 (d, J = 7.2 Hz, 1H), 5.86 (d, J = 16.0 Hz, 1H), 5.76 (d, J = 4.9 Hz, 2H), 5.65 (d, J = 18.4 Hz, 1H), 5.51-5.34 (m, 1H), 4.50 (q, J = 6.9 Hz, 1H), 4.30 (dd, J = 24.4, 10.5 Hz, 1H), 4.20 (s, 2H), 4.15 (s, 1H), 4.03 (t, J = 5.2 Hz, 1H), 3.92-3.74 (m, 3H), 3.52 (d, J = 2.4 Hz, 6H), 3.44 (d, J = 2.3 Hz, 3H), 3.33 (s, 2H), 3.29 (d, J = 3.7 Hz, 3H), 2.97 (s, 1H), 2.43-2.22 (m, 1H), 2.15-1.92 (m, 1H), 1.68 (td, J = 7.6, 1.7 Hz, 3H), 1.60 (d, J = 6.5 Hz, 4H), 1.47-1.19 (m, 1H), -1.65 (d, J = 26.0 Hz, 1H), -1.85 (d, J = 25.8 Hz, 1H).

[0335] Biological experiment details Example 1 - Determination of the Solubility of Chlorin e6 Analogues The absorbance maximum was used as a surrogate measure of solubility. The relevant chlorin e6 analogs were diluted to 50 μM in PBS (phosphate-buffered saline) solutions containing decreasing amounts of DMSO from 100% to 0%.

[0336] 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, with spectra captured from 500 to 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).

[0337] Example 2 - Cytotoxicity, Phototoxicity and Therapeutic Index Preparation of photosensitizer stock solutions Photosensitizers (e.g., chlorin e6 analog, 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.

[0338] Preparation of photosensitizers for in vitro testing For in vitro testing, 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 in cell culture medium (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, 100 μg / mL streptomycin, and the same excipient solution at a constant 1:55 dilution.

[0339] 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.

[0340] 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 the IC10 or IC90 was calculated for each compound. All data are presented as mean ± SD (where applicable).

[0341] cytotoxicity SKOV3 cells were seeded into 96-well black-walled plates (Greiner #655090) at a cell 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 chlorin e6 analog in DMSO. Cells were incubated for an additional 24 h to allow for uptake of the chlorin e6 analog.

[0342] To test the intrinsic cytotoxicity (i.e., "dark toxicity") of chlorin e6 analogs, the culture medium was replaced with fresh medium containing 10% (v / v) AlamarBlue cell viability reagent (ThermoFisher) after 24 h, and the cells were incubated at 37 °C for 6 h. Untreated cells were used as a control. Fluorescence emission (Ex 555 nm / Em 596 nm) was measured using a Cytation 3 cell imaging multimode reader (Biotek), and cytotoxicity was assessed by the percentage of viable cells remaining. All measurements were performed in quadruplicate.

[0343] phototoxicity SKOV3 cells were seeded into 96-well black-walled plates (Greiner #655090) at a cell 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 chlorin e6 analog in DMSO. Cells were incubated for an additional 24 h to allow for uptake of the chlorin e6 analog.

[0344] To test for phototoxicity, cells incubated with chlorin e6 analogs (0–10 μM in DMSO) were exposed to 50 mW / cm light after 24 h with a medium change (as above). 2 The samples were exposed to a 660 nm laser (Invion) ​​or a light-emitting diode (LED) panel (Invion) ​​for 5 min at a light power density of 15 J / cm (total 15 J / cm ). 2 ). Exposure to laser and LED induces comparable responses in terms of phototoxicity. 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 chlorin e6 analogs but not activated by laser light, cells not treated with chlorin e6 analogs but irradiated with laser light, and an untreated control. All measurements were performed in quadruplicate.

[0345] Toxicity profiles of chlorin e6 analogues The phototoxicity and intrinsic cytotoxicity (i.e., "dark toxicity") of chlorin e6 analogs were evaluated using SKOV3 ovarian cancer cells as previously described. For comparison purposes, chlorin e6 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 the log[inhibitor]-versus-normalized dose-response curve and variable slope according to the formula Y = 100 / (1 + (IC90 / X)^HillSlope(phototoxicity IC90)) or Y = 100 / (1 + (IC10 / X)^HillSlope(dark toxicity IC10)).

[0346] Phototoxicity and dark toxicity values ​​are shown in Table 1. The phototoxicity IC90 values ​​of most chlorin e6 analogs were less than 10 nM (Table 1). These were substantially better than those of chlorin e4 disodium (IC90 21.32 μM) or talaporfin sodium (IC90 22.83 μM). In fact, the best-performing compound (compound 3) achieved phototoxicity four orders of magnitude greater than that of talaporfin sodium. Thus, chlorin e6 analogs achieved up to approximately 10,000-fold increase in phototoxicity compared to talaporfin sodium, a clinically approved photosensitizer.

[0347] Significant variation in dark toxicity of the chlorin e6 analogs of the present invention was observed (Table 1). However, the high phototoxicity of the chlorin e6 analogs of the present invention is expected to offset any dark toxicity issues by reducing the required doses during use.

[0348] Therapeutic index of chlorin e6 analogues To assess the therapeutic potential of chlorin e6 analogs, the therapeutic index (TI) was calculated. TI provides a quantitative measure that describes relative drug safety by comparing the drug concentration required for the desired effect with the concentration that results in undesired off-target toxicity. TI was calculated using the phototoxicity IC90 versus the dark toxicity IC10.

[0349] The TI values ​​are shown in Table 1. Talaporfin sodium has a low 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 small potential therapeutic window of use. The chlorin e6 analogs of the present invention had a significantly improved TI with substantially greater phototoxicity (Table 1).

[0350] Therefore, the chlorin e6 analogs of the present invention have a desirable therapeutic index that is better than that of clinically applied photosensitizers. Furthermore, the greater phototoxicity of chlorin e6 analogs suggests the possibility of their use at significantly reduced doses in vivo. Therefore, the chlorin e6 analogs have an acceptable therapeutic profile for clinical application.

[0351] Additionally, chlorin e6 analogs of the present invention having an ammonium group, a phosphonium group, a pyridinium group, or a saccharidyl group (e.g., R as defined in the detailed description and claims) can be used. α -[N(R 5 )3]Y, -R α -[P(R 5 )3]Y, -R α -[R 8 ]Y, -R α -[N(R 5 )2(R 5’ )], -R α -[P(R 5 )2(R 5’ )], -R α -[R 8’ ] or saccharidyl group) are particularly preferred because they have better phototoxicity properties compared to similar compounds that do not have such groups. This can be seen, for example, when comparing: Compound 1 and Compounds 2-5 Compound 6 and Compounds 7-8 Compound 15 and Compound 16 Compound 17 and Compounds 18-19 Compound 20 and Compounds 21-22 Compound 24 and Compound 25 Of course, compounds that do not have such groups can be used as intermediates to prepare compounds that do have such groups. Table 1. Toxicity profile and therapeutic index of chlorin e6 analogues: * indicates phototoxicity measured with LED [Table 1]

[0352] Example 3 - Stability study of chlorin e6 analogue salts in aqueous solution procedure Reaction solutions were prepared by dissolving 2-3 mg of each chlorin e6 analog salt in 5 mL of distilled, deionized water in a 50 mL test tube with a lid. The solution was stirred in the test tube at 30 °C. Air (oxygen) and ambient light were not excluded. HPLC analysis of the samples was performed at 0.5, 4, or 66 hours (unless otherwise indicated). The purpose was to examine degradation over time. The test results are summarized in Table 2 below. [Table 2]

[0353] The structures of photoron and photodithiazine are as follows: [ka]

[0354] HPLC method Column and instrument details Equipment: Waters Alignment HPLC equipped with a Waters e2695 separation module and a Waters 2998 PDA detector. Column: YMC-Pack Pro C18 / S-3μm / 12nm 150 x 4.6mml. DS / N: 112YB00270 Guard column: Phenomenex Security Guard Cartridge C18 4 x 3.0 mm IDPRD-281272 HPLC method [Table 3] Mobile phase: A = 0.05 w / v% phosphoric acid in distilled water, B = acetonitrile Injection volume: 5 μL HPLC run length: 35 min Detection wavelength: 406 nm Column temperature: 40℃

[0355] conclusion As can be seen from the experimental results, -R 7 an ester or amide group (e.g., —COR as defined in the detailed description and claims); 13 or -C(O)-R 14 -R 15 ) are more stable in aqueous solution than compounds without such groups.

[0356] It will be understood that the present invention has been described above 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, -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 , -R ２ , —C(O)—OR ３ , —C(O)—SR ３ , -C(O)-N(R ３ ) ２ , -C(S)-OR ３ , -C(S)-SR ３ or -C(S)-N(R ３ ) ２ Selected from: -R ２ is, independently of each other, 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 -X, -R α -[N(R ５ ), ３ Y, -R α -[P(R ５ ), ３ Y, -R α -[R ８ , -R α -[N(R ５ ), ２ (R ５’ ), -R α -[P(R ５ ), ２ (R ５’ ), or -R α -[R ８’ and is selected from; -R ３ and -R ４ are each 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) 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 ８ ] Y, -R α -[N(R ５ ) ２ (R ５’ ) ], -R α -[P(R ５ ) ２ (R ５’ ) or R α - [R ８’ ] is selected from; -R α - are each independently C １ -C ４２ alkylene groups, said alkylene groups optionally being selected from one or more C １ -C ４ Alkyl, C １ -C ４ It may be substituted with a haloalkyl or halo group, and one or more carbon atoms in the backbone of the alkylene group may optionally be replaced with a heteroatom or group independently selected from O, S, NH, or NMe; -R β are each independently a saturated or unsaturated hydrocarbyl group 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 heteroatoms N, O, S, P or Se in its carbon skeleton; -R ５ are each independently 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 heteroaryl, wherein said phenyl or C ５ -C ６ Heteroaryl optionally includes 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 may be substituted with a group; -R ５’ is 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 heteroaryl, each of which is —CO ２ － and substituted with said phenyl or C ５ -C ６ Heteroaryl optionally includes 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 may be further substituted with groups; -R ６ is -C(O)-OR ３ , —C(O)—SR ３ , -C(O)-N(R ３ ) ２ , -C(S)-OR ３ , -C(S)-SR ３ or -C(S)-N(R ３ ) ２ Selected from: -R ７ is -C(O)-OR ３ , —C(O)—SR ３ , -C(O)-N(R ３ ) ２ , -C(S)-OR ３ , -C(S)-SR ３ or -C(S)-N(R ３ ) ２ Selected from: -R ８ is 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 -[NC optionally substituted with a group ５ H ５ ] and -R ８’ is -CO ２ － and 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 -[NC] optionally further substituted with a group ５ H ５ ] and -R ９ is -OR ２ , -N(R ２ ) ２ , -SR ２ , -S(O)R ２ , -S(O) ２ R ２ or -X; 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; However, it must be one of the following: (i)-R １ , -R ７ and -R ９ At least one of the groups is -R α -[N(R ５ ) ３ ] Y, -R α -[P(R ５ ) ３ ] Y, -R α - [R ８ ] Y, -R α -[N(R ５ ) ２ (R ５’ ) ], -R α -[P(R ５ ) ２ (R ５’ ) ], -R α - [R ８’ ], or containing a saccharidyl group; or (ii)-R ９ is -N(R ２ ) ２ , -SR ２ , -S(O)R ２ , -S(O) ２ R ２ or -X).

2. Each -R α - but independently, C １ -C ６ 2. The compound or complex of claim 1, wherein the alkylene is selected from the group consisting of alkylenes.

3. -R ２ , -R ３ and -R ４ At least one of the groups is -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β -R β 10. A compound or complex according to any preceding claim, wherein is a saccharidyl group.

4. -R β is a saccharidyl group selected from: 【Chemistry 2】

5. 5. The compound or complex of claim 4, wherein the saccharidyl group is: 【Transformation 3】

6. -R β is a saccharidyl group selected from: 【Chemistry 4】 (In the formula, -R １１ is C １ -C ４ alkyl).

7. -R １１ 7. The compound or complex of claim 6, wherein is methyl.

8. -R １ is -C(O)-OR ３ and R ３ But, -R β and -R β But C １ -C ４ 10. A compound or complex according to any preceding claim, which is an alkyl group.

9. -R １ is -C(O)-OR ３ , —C(O)—SR ３ or —C(O)—N(R ３ ) (R ３’ ) selected from -R ３ But, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β -R β is a saccharidyl group, and -R ３’ is H or C １ -C ４ The compound or complex according to any one of claims 1 to 7, wherein the compound or complex is alkyl.

10. -R ６ is -C(O)-OR ３ and -R ３ But C １ -C ４ 10. A compound or complex according to any preceding claim, wherein the compound or complex is alkyl.

11. -R ６ is -C(O)-OR ３ , —C(O)—SR ３ or —C(O)—N(R ３ ) (R ３’ ) selected from -R ３ But, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β -R β is a saccharidyl group, and -R ３’ is H or C １ -C ４ The compound or complex according to any one of claims 1 to 9, which is alkyl.

12. -R ７ is -C(O)-OR ３ and -R ３ But C １ -C ４ 10. A compound or complex according to any preceding claim, wherein the compound or complex is alkyl.

13. -R ７ is -C(O)-OR ３ , —C(O)—SR ３ or —C(O)—N(R ３ ) (R ３’ ) selected from -R ３ But, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β -R β is a saccharidyl group, and -R ３’ is H or C １ -C ４ The compound or complex according to any one of claims 1 to 11, which is alkyl.

14. -R ９ But, -OR ２ or -SR ２ -R ２ But, -R α -OR β , -R α -SR β , -R α -S(O)R β or -R α -S(O) ２ R β -R β 10. A compound or complex according to any preceding claim, wherein is a saccharidyl group.

15. a compound of formula (III) or a complex of formula (IV), 【Transformation 5】 or a pharmaceutically acceptable salt thereof, -R １ is -CO ２ H or -C(O)-R １４ -R １５ Selected from: -R ６ is -CO ２ H or -CO ２ R １３ Selected from: -R ７ is -CO ２ H or -C(O)-R １４ -R １５ Selected from: -R １３ is C １ -C ３ alkyl; -R １４ - is selected from NH, NMe, O or S; -R １５ is C １ -C ２０ alkyl, wherein one or more carbon atoms of said alkyl group may be optionally substituted with a heteroatom or group independently selected from O, S, NH, or NMe, and said alkyl group may contain one or more (e.g., 1, 2, 3, 4, 5, 6, 7, or 8) —OH or —NH ２ may be optionally substituted with a group; M ２＋ is a metal cation; However, -R １ , -R ６ and -R ７ At the same time, -CO ２ (Provided that the person is not a Me.)

16. The compound or the complex is 【Transformation 6】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 or a metal cation complex thereof, or a pharmaceutically acceptable salt thereof.

17. 10. A compound or complex according to any preceding claim for use in medicine.

18. 10. A compound or complex according to any preceding claim for use in photodynamic therapy or cytoluminescent therapy.

19. 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 (Chicken) 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 cell hyperproliferation or 10. A compound or complex as claimed in any preceding claim for use in the treatment of diseases characterised by areas of angiogenesis; benign or malignant tumours; early stage cancers; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

20. 10. A compound or complex according to any preceding claim for use in the treatment of a disease characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.

21. 10. A compound or complex according to any preceding claim for use in the treatment of benign or malignant tumors.

22. 10. A compound or complex as claimed in any preceding claim for use in the treatment 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

23. 10. A compound or complex according to any preceding claim for use in photodynamic diagnosis.

24. 10. A compound or complex according to any preceding claim, wherein the compound is suitable for administration prior to the administration of radiation.

25. 25. The compound or complex of claim 24, wherein the irradiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm.

26. A pharmaceutical composition comprising a compound or complex according to any preceding claim and a pharmaceutically acceptable carrier or diluent.

27. 27. The pharmaceutical composition of claim 26, further comprising polyvinylpyrrolidone.

28. 28. The pharmaceutical composition of claim 26 or 27, further comprising an immune checkpoint inhibitor.

29. 29. The pharmaceutical composition of claim 28, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

30. A pharmaceutical composition according to any one of claims 26 to 29 for use in photodynamic therapy or cytoluminescence therapy.

31. 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 (Chicken) 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 cell hyperproliferation or blood 31. The pharmaceutical composition of any one of claims 26 to 30 for use in treating a disease characterized by areas of neovascularization; a benign or malignant tumor; an early stage cancer; cervical dysplasia; soft tissue sarcoma; a 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

32. A pharmaceutical composition according to any one of claims 26 to 31 for use in the treatment of diseases characterised by benign or malignant cellular hyperproliferation or by areas of neovascularisation.

33. A pharmaceutical composition according to any one of claims 26 to 32 for use in the treatment of benign or malignant tumors.

34. 34. The pharmaceutical composition of any one of claims 26 to 33 for use in the treatment 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

35. 28. The pharmaceutical composition of claim 26 or 27 for use in photodynamic diagnosis.

36. The pharmaceutical composition according to any one of claims 26 to 35, wherein the pharmaceutical composition is suitable for administration before the administration of radiation.

37. 37. The pharmaceutical composition of claim 36, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm.

38. 38. The pharmaceutical composition according to any one of claims 26 to 37, wherein the pharmaceutical composition is in a form suitable for oral, parenteral (including intravenous, subcutaneous, intramuscular, intradermal, intratracheal, intraperitoneal, intratumoral, intraarticular, intraperitoneal, intracranial and epidural), transdermal, airway (aerosol), rectal, vaginal or topical (including buccal, mucosal and sublingual) administration.

39. 39. The pharmaceutical composition of claim 38, wherein the pharmaceutical composition is in a form suitable for oral or parenteral administration.

40. atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection with 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 cell hyperproliferation or areas of angiogenesis 26. Use of a compound or complex according to any one of claims 1 to 25 in the manufacture of a medicament for the treatment of diseases characterized by uterine 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

41. 26. Use of a compound or complex according to any one of claims 1 to 25 in the manufacture of a phototherapeutic agent for use in photodynamic therapy or cytoluminescence therapy.

42. The phototherapeutic agent may be used to treat 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 herpes zoster; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; dermatological conditions; acne; psoriasis; benign or malignant 42. The use according to claim 41 for the treatment of diseases characterized by areas of hyperproliferation of cells or angiogenesis; benign or malignant tumors; early stage cancers; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

43. The use according to any one of claims 40 to 42, wherein the drug or phototherapeutic agent is intended for the treatment of a disease characterized by benign or malignant cellular hyperproliferation or by areas of neovascularization.

44. The use according to any one of claims 40 to 43, wherein the drug or phototherapeutic agent is intended for the treatment of benign or malignant tumors.

45. 45. The use of any one of claims 40 to 44, 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'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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas.

46. Use of a compound or complex according to any one of claims 1 to 25 in the manufacture of a photodiagnostic agent for use in photodynamic diagnosis.

47. The use according to any one of claims 40 to 46, wherein the drug, phototherapeutic agent or photodiagnostic agent is suitable for administration before the administration of radiation.

48. 48. The use according to claim 47, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm.

49. atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infections; HIV; AIDS; infection with SARS virus (preferably Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)), Asian (Chicken) 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; diseases characterized by areas of benign or malignant cellular hyperproliferation or angiogenesis; benign or malignant diseases 26. A method for treating a 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin or pancreas, said method comprising administering to a human or animal in need thereof a therapeutically effective amount of a compound or complex according to any one of claims 1 to 25.

50. 26. A method for photodynamic or cytoluminescent therapy of a disease in a human or animal, said method comprising administering to a human or animal in need of treatment a therapeutically effective amount of a compound or complex according to any one of claims 1 to 25.

51. The human or animal disease may be atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; a fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infection; HIV; AIDS; infection with 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; a dermatological condition; acne; psoriasis; benign or a disease characterized by areas of malignant cell hyperproliferation or angiogenesis; a benign or malignant tumor; 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

52. 52. The method of any one of claims 49 to 51, wherein the human or animal disease is characterized by benign or malignant cellular hyperproliferation or by areas of neovascularization.

53. The method according to any one of claims 49 to 52, wherein the human or animal disease is a benign or malignant tumor.

54. 54. The method of any one of claims 49 to 53, wherein 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, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

55. 26. A method for the photodynamic diagnosis of disease in humans or animals, said method comprising administering to a human or animal a diagnostically effective amount of a compound or complex according to any one of claims 1 to 25.

56. 56. The method of any one of claims 49 to 55, wherein after administration of a compound or complex according to any one of claims 1 to 25, the human or animal is subjected to irradiation.

57. 57. The method of claim 56, wherein the radiation is electromagnetic radiation having a wavelength in the range of 500 nm to 1000 nm.

58. (a) a compound or complex according to any one of claims 1 to 25; (b) a co-drug that is an immune checkpoint inhibitor.

59. 59. The pharmaceutical combination or kit of claim 58, wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, or ipilimumab.

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