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

Abstract

The invention relates to a dihydroporphin e6 analogue and a pharmaceutically acceptable salt thereof, and a composition containing the dihydroporphin e6 analogue and the pharmaceutically acceptable salt 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 for antiviral therapy. The invention also relates to the use of dihydroporphin e6 analogs and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic or photodiagnostic agents, and to methods of photodynamic therapy, cytoluminescence therapy or photodynamic diagnosis, for example for the treatment or detection of tumors or for antiviral therapy. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to dihydrochlorin e6 analogs and pharmaceutically acceptable salts thereof, as well as compositions comprising dihydrochlorin e6 analogs and pharmaceutically acceptable salts thereof. Dihydrochlorin e6 analogs and pharmaceutically acceptable salts thereof are suitable for use in photodynamic therapy, cell luminescence therapy and photodynamic diagnosis, for example, for treating or detecting tumors or for antiviral treatment. The present invention also relates to the use of dihydrochlorin e6 analogs and pharmaceutically acceptable salts thereof in the manufacture of phototherapeutic agents or photodiagnostic agents, and to methods for photodynamic therapy, cell luminescence therapy or photodynamic diagnosis, for example, for treating or detecting tumors or for antiviral treatment.

[0002] The structure of "dihydrochlorin e6" is shown below:

[0003] Background Art

[0004] Porphyrins and their analogs are known as photosensitive chemical compounds that can absorb visible light photons and emit them at higher wavelengths. This unique property has many applications, and PDT (photodynamic therapy) is one of them.

[0005] Currently, there are two generations of photosensitizers for PDT. The first generation includes heme porphyrins (blood derivatives), and the second generation is mainly chlorophyll analogs. Later compounds are called dihydrochlorins and bacteriochlorins.

[0006] Chlorin e4 has been shown to exhibit good photosensitizing activity. Chlorin e4 has been shown to have protective effects against indomethacin-induced gastric lesions in rats and acute liver injury induced by TAA or CCl4 in mice. Therefore, chlorin e4 has been suggested as a promising new drug candidate for gastric ulcer protection and liver damage protection. WO 2009 / 040411 proposes the use of chlorin e4 zinc complexes in photodynamic therapy, and WO 2014 / 091241 proposes the use of chlorin e4 disodium in photodynamic therapy.

[0007]

[0008] Although it is known in the literature that conjugation of molecules to triphenylphosphonium cations enhances delivery to mitochondria, this is not always guaranteed, as demonstrated in a recent paper by Gilson et al. (Bioconjugate Chemistry, 2019, Vol. 30(5), pp. 1451-1458). Adding one triphenylphosphonium cation to the known photodynamic agent chlorin e6 resulted in the derivative accumulating in lysosomes, while adding two triphenylphosphonium cations resulted in distribution to lysosomes and mitochondria. The authors concluded that "mitochondrial localization of PS did not improve cell killing in this study" and that the unconjugated parent chlorin e6 showed better photodynamic (cell killing) activity than the two triphenylphosphonium-conjugated derivatives.

[0009] There is a continuing need for better photosensitizers. Compounds with high singlet oxygen quantum yields, preferably in organic and aqueous media, and compounds with strong photosensitizing capabilities are needed. Compounds with high fluorescence quantum yields are also needed. Furthermore, compounds and / or compositions with higher phototoxicity, lower dark toxicity, good stability, and / or ease of purification are needed. Summary of the Invention

[0010] The first aspect of the present invention provides a compound of formula (I) or a complex of formula (II):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, wherein:

[0013] -R 1 Selected from -CH2OR 2 、-CH2SR 2 、-CH2S(O)R 2 、-CH2S(O)2R 2 、-CH2N(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 Selected from -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(R3 )2);

[0014] -R 2 Each independently selected from -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’ ];

[0015] -R 3 and -R 4 Each independently selected from -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’ )]、-R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ];

[0016] -R α - each independently selected from C1-C 42 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe;

[0017] -R β each independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton;

[0018] -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally replaced by one or more 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 -CH3 group substitution;

[0019] -R 5’ Selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each of which is replaced by -CO2 - Substituted, wherein the phenyl or C5-C6 heteroaryl may be optionally further substituted by one or more 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 -CH3 group substitution;

[0020] -R 6 Selected from -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;

[0021] -R 7 Selected from -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;

[0022] -R 8 is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O)n -[NC5H5] substituted with -CH3 group;

[0023] -R 8’ is -[NC5H5], which is replaced by -CO2 - and optionally further substituted with one or more 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 -CH3 group substitution;

[0024] -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X;

[0025] n is 1, 2, 3, 4, 5, or 6;

[0026] X is a halogen group;

[0027] Y is a counter anion;

[0028] Z is a counter cation; and

[0029] M 2+ It is a metal cation.

[0030] 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.

[0031] In one embodiment of the first or second aspect of the present invention, -R 1 、-R 7 and -R 9 At least one of them contains -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 sugar group.

[0032] In one embodiment of the first or second aspect of the present invention, -R 9 Selected from -N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X.

[0033] In the context of this specification, a "hydrocarbyl" substituent or a hydrocarbyl moiety in a substituent includes only carbon and hydrogen atoms, but does not include any heteroatoms, such as N, O, S, P, or Se, in its carbon skeleton unless otherwise stated. The hydrocarbyl group / moiety can be saturated or unsaturated (including aromatics), and can be straight or branched, or can be or include a cyclic group, wherein the cyclic group does not include any heteroatoms, such as N, O, S, P, or Se, in its carbon skeleton unless otherwise stated. Examples of hydrocarbyl groups include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aryl groups / moieties, and combinations of all of these groups / moieties. Typically, a hydrocarbyl group is C1-C 60 Hydrocarbyl, more typically C1-C 40 Hydrocarbyl, more typically C1-C 20 More typically, the hydrocarbyl group is C1-C 12 More typically, the hydrocarbyl group is C1-C 10 "Hydrocarbylene" is similarly defined as a divalent hydrocarbon radical.

[0034] An "alkyl" substituent or alkyl moiety in a substituent may be linear (i.e., straight-chained) or branched. Examples of alkyl groups / moieties include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and n-pentyl groups / moieties. Unless otherwise indicated, the term "alkyl" does not include "cycloalkyl." Typically, an alkyl group is C1-C 12 Alkyl. More typically, an alkyl group is a C1-C6 alkyl group. "Alkylene" is defined in a similar manner as a divalent alkyl group. Typically, an alkylene group is a C1-C6 alkyl group. 42 More typically, an alkylene group is C1-C 32 Alkylene, or C1-C 22 Alkylene, or C1-C 12 Alkylene.

[0035] 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 indicated, the term "alkenyl" does not include "cycloalkenyl". Typically, alkenyl is a C2-C 12 Alkenyl. More typically, an alkenyl is a C2-C6 alkenyl. "Alkenylene" is similarly defined as a divalent alkenyl group.

[0036] An "alkynyl" substituent or alkynyl moiety of 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 C2-C 12 Alkynyl. More typically, the alkynyl group is a C2-C6 alkynyl group. "Alkynylene" is defined in a similar manner as a divalent alkynyl group.

[0037] The cyclic moiety in " cyclic " substituent or substituent refers to any hydrocarbyl ring, wherein the hydrocarbyl ring can be saturated or unsaturated (including aromatic), and can include one or more heteroatoms, such as N, O, S, P or Se in its carbon skeleton. The example of cyclic group includes cycloalkyl, cycloalkenyl, heterocycle, aryl and heteroaryl as discussed below. Cyclic group can be monocycle, dicycle (such as bridging, condensation or spirocycle) or polycycle. Usually, cyclic group is 3 to 12 yuan of cyclic groups, which means that it contains 3 to 12 ring atoms. More usually, cyclic group is 3 to 7 yuan of monocyclic groups, which means that it contains 3 to 7 ring atoms.

[0038] 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 (such as one, two, three or four) heteroatoms (e.g., N, O, S, P or Se) in the ring structure. Examples of heterocyclic groups include heteroaryl and non-aromatic heterocyclic groups as discussed below, such as azetidinyl, azetinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrophenylthio, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxetanyl, thietanyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, thianyl and dioxanyl.

[0039] A "cycloalkyl" substituent or cycloalkyl moiety in a substituent refers to a saturated hydrocarbon 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 may include a monocyclic, bicyclic, or polycyclic hydrocarbon ring.

[0040] A "cycloalkenyl" substituent or cycloalkenyl moiety of a substituent refers to a non-aromatic, unsaturated hydrocarbon 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 hydrocarbon rings.

[0041] The aryl moiety in an "aryl" substituent or substituent refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic condensed-ring aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system formed as a part of an optional substituent or by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term "aryl" does not include "heteroaryl".

[0042] A "heteroaryl" substituent or heteroaryl moiety of 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 fused ring systems (excluding any ring systems that are part of or formed by optional substituents) are aromatic. Examples of heteroaryl groups / moieties include the following:

[0043]

[0044]

[0045] wherein G=O, S or NH.

[0046] For the purposes of this specification, when a combination of moieties is referred to as a group, for example arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl, the last-mentioned moiety contains the atoms through which the group is attached to the rest of the molecule. An example of an arylalkyl group is benzyl.

[0047] For the purposes of this specification, an optionally substituted group or moiety (such as -R β )middle:

[0048] (i) Each hydrogen atom may be optionally replaced by a monovalent substituent independently selected from the group consisting of: halo; -CN; -NO2; -N3; -R x ;-OH;-OR x ;-R y -halogen; -R y -CN;-R y -NO2; -R y -N3; -R y -R x ;-R y-OH; -R y -OR x ;-SH;-SR x ;-SOR x ;-SO2H;-SO2R x ;-SO2NH2;-SO2NHR x ;-SO2N(R x )2;-R y -SH; -R y -SR x ;-R y -SOR x ;-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

[0049] (ii) Any two hydrogen atoms attached to the same carbon atom may optionally be independently selected from oxo (=O), =S, =NH or =NR x substituted with a π-bonded substituent; and / or

[0050] (iii) Any two hydrogen atoms attached to the same or different atoms within the same optionally substituted group or moiety may optionally be independently selected from -O-, -S-, -NH-, -N(R x )-、-N + (R x )2-or-R y - is replaced by a bridging substituent;

[0051] Each of these -R y - is independently selected from alkylene, alkenylene or alkynylene, wherein the alkylene, alkenylene or alkynylene group contains 1 to 6 atoms in its main chain, wherein one or more carbon atoms in the main chain of the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more heteroatoms N, O or S, and wherein the alkylene, alkenylene or alkynylene group may be optionally replaced by one or more halo and / or -R x group substitution; and

[0052] Each of these -R x independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C2-C6 cyclic group, or any two or three -R x Together with the nitrogen atom to which they are attached, they can form a C2-C7 cyclic group, and any -R x It may 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.

[0053] Typically, a substituted group contains 1, 2, 3, or 4 substituents, more typically 1, 2, or 3 substituents, more typically 1 or 2 substituents, and more typically 1 substituent.

[0054] Unless otherwise indicated, any divalent bridging substituent (e.g., -O-, -S-, -NH-, -N(R)-) of an optionally substituted group or moiety is x )-、-N + (R x )2-or-R y -) must be attached only to the designated group or moiety and may not be attached to a second group or moiety, even if the second group or moiety may itself be optionally substituted.

[0055] The term "halo" includes fluorine, chlorine, bromine and iodine.

[0056] Unless otherwise stated, when a group is prefixed with the term "halo", such as haloalkyl or halomethyl, it should be understood that the group under discussion is replaced by one or more halo groups independently selected from fluorine, chlorine, bromine and iodine. Generally, the maximum number of halo substituents is only limited by the number of hydrogen atoms that can be used for replacement on the corresponding group without the halo prefix. For example, halomethyl can contain one, two or three halo substituents. Haloethyl or halophenyl can contain one, two, three, four or five halo substituents. Similarly, unless otherwise stated, when a group is prefixed with a specific halo, it should be understood that the group under discussion is replaced by one or more specific halo groups. For example, the term "fluoromethyl" refers to a methyl group substituted by one, two or three fluoro groups.

[0057] Unless otherwise indicated, 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 fluorine, chlorine, bromine, and iodine. Typically, the maximum number of halo substituents is limited only by the number of hydrogen atoms available for substitution on the group referred to as halo-substituted. For example, a halo-substituted methyl group may contain one, two, or three halo substituents. A halo-substituted ethyl group or a halo-substituted phenyl group may contain one, two, three, four, or five halo substituents.

[0058] Unless otherwise stated, any reference to an element should be taken to include all isotopes of that element. Thus, for example, any reference to hydrogen should be taken to include all isotopes of hydrogen, including deuterium and tritium, unless otherwise stated.

[0059] Unless otherwise stated, any reference to a compound or group is to be considered as a reference to all tautomers of said compound or group.

[0060] When referring to a hydrocarbyl or other group containing one or more heteroatoms N, O, S, P or Se in its carbon skeleton, or when referring to a hydrocarbyl or other group having carbon atoms replaced by N, O, S, P or Se atoms, it is intended that:

[0061] quilt Replacement;

[0062] -CH2- is replaced by -NH-, -PH-, -O-, -S- or -Se-;

[0063] -CH3 is replaced by -NH2, -PH2, -OH, -SH or -SeH;

[0064] -CH= is replaced by -N= or -P=;

[0065] CH2= is replaced by NH=, PH=, O=, S= or Se=; or

[0066] CH≡ is replaced by N≡ or P≡;

[0067] The proviso is that the resulting radical contains at least one carbon atom. For example, methoxy, dimethylamino and aminoethyl are considered to be hydrocarbon radicals containing one or more heteroatoms N, O, S, P or Se in their carbon skeleton.

[0068] In the context of this specification, unless otherwise stated, C x -C y A radical is defined as a radical containing from x to y carbon atoms. For example, a C1-C4 alkyl radical is defined as an alkyl radical containing from 1 to 4 carbon atoms. When calculating the total number of carbon atoms in a parent radical substituted with optional substituents and / or containing optional moieties, the optional substituents and moieties are not taken into account. For the avoidance of doubt, when calculating the total number of carbon atoms in a parent radical substituted with optional substituents and / or containing optional moieties, the optional substituents and moieties are not taken into account. x -C y When counting the number of carbon atoms in a group, replacing heteroatoms (such as N, O, S, P or Se) are not counted as carbon atoms. For example, morpholinyl is considered a C6 heterocyclic group rather than a C4 heterocyclic group.

[0069] The pi electrons of the chlorin ring are delocalized, and therefore the chlorin ring can be depicted by more than one resonance structure. Resonance structures are different ways of drawing the same compound. Two resonance structures of the chlorin ring are depicted directly below:

[0070]

[0071] Typically, a complex comprises a central metal atom or ion, known as a coordination center, and a bound molecule or ion, known as a ligand. In this specification, the bond between the coordination center and the ligand is depicted as shown in the complex at the bottom left (where the attractive force between the anionic ligand and the central metal cation is represented by four dashed lines), but equivalently it can be depicted as shown in the complex at the bottom right (where the attractive force between the ligand molecule and the central metal atom is represented by two covalent bonds and two dashed lines):

[0072]

[0073] As used herein, -[NC5H5]Y refers to:

[0074]

[0075] In one embodiment of the first or second aspect of the present invention, X is a halide selected from fluoro, chloro, bromo or iodo. In one embodiment, X is chloro or bromo.

[0076] In one embodiment of the first or second aspect of the present invention, there is provided a compound of formula (I).

[0077] In one embodiment of the first or second aspects of the invention, Y is a counter anion selected from the group consisting of: halide (e.g., fluoride, chloride, bromide, or iodide) or other inorganic anion (e.g., bisulfate, hexafluorophosphate (PF6), nitrate, perchlorate, phosphate, or sulfate) or an organic anion (e.g., acetate, ascorbate, aspartate, benzoate, besylate (benzenesulfonate), bicarbonate, bis(trifluoromethanesulfonyl)imide (TFSI), bitartrate, butyrate, camsylate (camphorsulfonate), carbonate, citrate, decanoate, edetate, ethanesulfonate (ethanesulfonate), fumarate, galactonate, glucoheptonate, gluconate, glutathione ... sulfonate, octanoate, oleate, ornithine, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, succinate, tartrate, teoclate, tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF), tetrakis(pentafluorophenyl)borate (F5-TPB), tetraphenylborate (TPB), toluenesulfonate (p-toluenesulfonate), or trifluoromethanesulfonate (trifluoromethanesulfonate).

[0078] In another embodiment of the first or second aspects of the invention, Y is a counter anion selected from the group consisting of 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), benzoate, ... In one embodiment, Y is fluoride, chloride, bromide, or iodide. In one embodiment, Y is chloride or bromide.

[0079] In one embodiment of the first or second aspect of the invention, Z is a counter cation selected from an inorganic cation such as a lithium, sodium, potassium, magnesium, calcium or ammonium cation or an organic cation such as an amine cation such as a choline or meglumine cation or an amino acid cation such as an arginine cation.

[0080] In one embodiment of the first or second aspect of the present invention, M 2+ is selected from Zn 2+ 、Cu 2+ 、Fe 2+ 、Pd 2+ or Pt 2+ In one embodiment, M 2+ It is Zn 2+ .

[0081] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Selected from -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 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2.

[0082] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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, and each -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -C(O)-OR 3 、-C(O)-SR 3 、-C(O)-N(R 3 )2 or -C(S)-N(R 3 )2, and each -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and each -R 3 is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 is-C(O)-OR 3 , and -R 3 It is a C1-C4 alkyl group (preferably a methyl group).

[0083] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -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 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α-OR β or -R α -SR β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ is C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α -OR β or -R α -SR β , and -R β is a sugar group, and -R 3’ Is C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0084] -R 3' A group is a group that is connected to another -R 3 Groups attached to the same atom -R 3 Group. -R 3 and -R 3’ Can be the same or different. Preferably, -R 3 and -R3’ different.

[0085] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Selected from -R α -R β or -R β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -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 Selected from -R α -R β or -R β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α -R β or -R β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m- group or -(CH2CH2S) m - groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0086] In any of the embodiments of the three preceding paragraphs, the glycosyl group can be optionally substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine. The amino acid can be attached to the glycosyl group, for example, by forming an ester between the carboxylic acid group of the amino acid and the hydroxyl group of the glycosyl group.

[0087] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Selected from -R α -R β or -R β , and -R β is C1-C8 alkyl optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -OAc groups, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -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 Selected from -R α -R β or -R β , and -R β is a C1-C8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxy groups, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1Yes -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α -R β or -R β , and -R β is a C1-C8 alkyl group optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) hydroxy groups, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α - is an unsubstituted C1-C6 alkylene group, or an unsubstituted C1-C4 alkylene group, or an unsubstituted C1-C2 alkylene group.

[0088] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Selected from -R α -H or -R α -OH; -R α -Selected from C1-C 12 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with one or more heteroatoms O or S; and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -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 Selected from -R α -H or -R α-OH; -R α -Selected from C1-C 12 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with one or more heteroatoms O or S; and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ); where -R 3 Selected from -R α -H or -R α -OH; -R α -Selected from C1-C 12 Alkylene, wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced by one or more heteroatoms O or S; and -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0089] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Yes-R β ;-R β It is C1-C 12 Alkyl or C2-C 12 Alkenyl, which is optionally substituted by one or more (such as one, two, three, four or five) independently selected from 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 is substituted by a substituent; each -R x 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). In one embodiment, -R 1 Selected from -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 Yes-R β ;-R β It is C1-C 12 Alkyl, which is optionally substituted by one or more (such as one, two, three, four or five) independently selected from 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 is substituted by a substituent; each -R x 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). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ); where -R 3 Yes-Rβ ;-R β is C1-C8 alkyl, which is optionally substituted by one or more (such as one, two or three) independently selected from 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 is substituted by a substituent; each -R x 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).

[0090] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -CO-(NR zz -CHR z -CO) v -N(R zz )2 and -CO-(NR zz -CHR z -CO) v -OR zz ; Each -R z are independently selected from the side chains of natural amino acids; each -R zz are independently selected from hydrogen and C1-C4 alkyl (preferably methyl); and v is 1, 2, 3, 4, 5, 6, 7 or 8.

[0091] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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)-SR3 、-C(S)-N(R 3 )2 or -C(S)-N(R 3 )(R 3’ ); where -R 2 or -R 3 Yes-R β ;-R β Selected from C1-C 20 alkyl, wherein the alkyl may be optionally substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe; and -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0092] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 3’ is H or C1-C4 alkyl (preferably methyl); and -R 2 or -R 3 Selected from -R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 In one embodiment, -R 1 Selected from -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’ );-R 3’ is H or C1-C4 alkyl (preferably methyl); -R 2 or -R 3 Selected from -Rα -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 ]Y; each-R 5 independently selected from C1-C4 alkyl or phenyl, wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R 8 is -[NC5H5] optionally substituted by one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe; and Y is a counterion (preferably a halide).

[0093] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -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 Yes-R α -[P(R 5 )3]Y; each -R 5 independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 group substituted; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Selected from -C(O)-OR 3 、-C(O)-SR3 、-C(O)-N(R 3 )(R 3’ ) or -C(S)-N(R 3 )(R 3’ ); where -R 3 Yes-R α -[P(R 5 )3]Y; each -R 5 independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 group substituted; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R 3' Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 1 Yes -C(O)-N(R 3 )(R 3’ ); where -R 3 Yes-R α -[P(R 5 )3]Y; each -R 5 independently selected from phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl), -O(C1-C4 haloalkyl), halo, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 group substituted; n is 1, 2, 3 or 4; Y is fluoride, chloride, bromide or iodide; and -R 3' Is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0094] In one embodiment of the first or second aspect of the present invention, -R 1 YES-C(O)-OR 3 , where -R 3is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation (such as lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (such as choline or meglumine) or an amino acid (such as arginine) cation). In one embodiment, -R 1 is-C(O)-OR 3 , where -R 3 is selected from C1-C4 alkyl (preferably methyl) or a cation such as lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (such as choline or meglumine) or an amino acid (such as arginine) cation.

[0095] In one embodiment of the first or second aspect of the present invention, -R 1 Yes -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 ).

[0096] In one embodiment of the first or second aspect of the present invention, -R 1 Selected from -CH2OR 2 、-CH2SR 2 、-CH2S(O)R 2 、-CH2S(O)2R 2 、-CH2N(R 2 )2 or -R 2 In one embodiment, -R 1 Selected from -CH2OR 2 、-CH2SR 2 、-CH2N(R 2 )2 or -R 2 In one embodiment, -R 1 Selected from -CH2OR 2 、-CH2SR 2 or -CH2N(R 2 )2. In one embodiment, -R 1 Selected from -CH2OR 2 or -CH2SR 2In one embodiment, -R 1 Yes-CH2OR 2 In one embodiment, -R 1 Yes-R 2 , and -R 2 Yes-R α -X.

[0097] In one embodiment of the first or second aspect of the present invention, -R 2 Selected from -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, -R 2 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β In one embodiment, -R 2 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 2Selected from -R α -OR β or -R α -SR β In one embodiment, -R 2 Selected from -R α -OR β or -R α -SR β , and -R β It's a sugar group.

[0098] In one embodiment of the first or second aspect of the present invention, -R 2 Selected from -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 Selected from -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 Selected from -C(O)R 4 、-C(O)-OR 4 、-C(O)-SR 4 or -C(O)-N(R 4 )2.

[0099] In one embodiment of the first or second aspect of the present invention, -R 2 Yes -C(O)-N(R 4 )(R 4’ ), where -R 4 Selected from -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 sugar group, and -R 4’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 2 Yes -C(O)-N(R4 )(R 4’ ), where -R 4 Selected from -R α -OR β or -R α -SR β , and -R β is a sugar group, and -R 4’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 2 Yes -C(O)-N(R 4 )(R 4’ ), where -R 4 Selected from -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 sugar group, and -R 4’ is C1-C4 alkyl (preferably methyl). In one embodiment, -R 2 Yes -C(O)-N(R 4 )(R 4’ ), where -R 4 Selected from -R α -OR β or -R α -SR β , and -R β is a sugar group, and -R 4’ It is a C1-C4 alkyl group (preferably a methyl group).

[0100] -R 4' A group is a group that is connected to another -R 4 Groups attached to the same atom -R 4 Group. -R 4 and -R 4’ Can be the same or different. Preferably, -R 4 and -R 4’ different.

[0101] In one embodiment of the first or second aspect of the present invention, -R 2 Yes -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)(R4 ).

[0102] In one embodiment of the first or second aspect of the present invention, -R 6 Selected from -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, and each -R 3 is a C1-C4 alkyl group, preferably each -R 3 In one embodiment, -R 6 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and each -R 3 is a C1-C4 alkyl group, preferably each -R 3 In one embodiment, -R 6 is-C(O)-OR 3 , and -R 3 is C1-C4 alkyl, preferably -R 3 It's methyl.

[0103] In one embodiment of the first or second aspect of the present invention, -R 6 is-C(O)-OR 3 , where -R 3 is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation such as lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (such as choline or meglumine) or an amino acid (such as arginine) cation.

[0104] In one embodiment of the first or second aspect of the present invention, -R 6 Selected from -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 3 Yes-R β ;-Rβ Selected from C1-C 20 alkyl, wherein the alkyl may be optionally substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe; and -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0105] In one embodiment of the first or second aspect of the present invention, -R 6 Selected from -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, and each -R 3 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 6 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and each -R 3 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 6 Selected from -C(O)-OR 3 or -C(O)-SR 3 , and -R 3 Selected from -R α -OR β or -R α -SR β , and -R β Is a glycosyl group. Typically in these embodiments, -Rα -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0106] In one embodiment of the first or second aspect of the present invention, -R 6 Selected from -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 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 6 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 6Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α -OR β or -R α -SR β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0107] -R 3' A group is a group that is connected to another -R 3 Groups attached to the same atom -R 3 Group. -R 3 and -R 3’ Can be the same or different. Preferably, -R 3 and -R 3’ different.

[0108] In one embodiment of the first or second aspect of the present invention, -R 6 Yes -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 6 is -C(O)-N(CH3)(R 3 ) or -C(O)-NHR 3 .

[0109] In one embodiment of the first or second aspect of the present invention, -R 7 Selected from -C(O)-OR 3 、-C(O)-SR3 、-C(O)-N(R 3 )2. -C(S)-OR 3 、-C(S)-SR 3 or -C(S)-N(R 3 )2, and each -R 3 is a C1-C4 alkyl group, preferably each -R 3 In one embodiment, -R 7 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and each -R 3 is a C1-C4 alkyl group, preferably each -R 3 In one embodiment, -R 7 is-C(O)-OR 3 , and -R 3 is C1-C4 alkyl, preferably -R 3 It's methyl.

[0110] In one embodiment of the first or second aspect of the present invention, -R 7 is-C(O)-OR 3 , where -R 3 is selected from hydrogen, C1-C4 alkyl (preferably methyl) or a cation such as lithium, sodium, potassium, magnesium, calcium, ammonium, an amine (such as choline or meglumine) or an amino acid (such as arginine) cation.

[0111] In one embodiment of the first or second aspect of the present invention, -R 7 Selected from -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 3 Yes-R β ;-R β Selected from C1-C 20alkyl, wherein the alkyl may be optionally substituted with one, two, three or four halo groups, and wherein one, two, three, four, five or six carbon atoms in the backbone of the alkyl may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe; and -R 3’ is H or C1-C4 alkyl (preferably methyl).

[0112] In one embodiment of the first or second aspect of the present invention, -R 7 Selected from -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, and each -R 3 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 7 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and each -R 3 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 7 Selected from -C(O)-OR 3 or -C(O)-SR 3 , and -R 3 Selected from -R α -OR β or -R α -SR β , and -R β Is a glycosyl group. Typically in these embodiments, -R α -Selected from C1-C 12Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0113] In one embodiment of the first or second aspect of the present invention, -R 7 Selected from -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 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 7 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). In one embodiment, -R 7 Selected from -C(O)-OR 3 、-C(O)-SR3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -R α -OR β or -R α -SR β , and -R β is a sugar group, and -R 3’ Is H or C1-C4 alkyl (preferably methyl). Typically in these embodiments, -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. Alternatively, in these embodiments, -R α -It is C1-C 12 Alkylene (preferably C1-C8 alkylene, or C1-C6 alkylene), -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4.

[0114] -R 3' A group is a group that is connected to another -R 3 Groups attached to the same atom -R 3 Group. -R 3 and -R 3’ Can be the same or different. Preferably, -R 3 and -R 3’ different.

[0115] In one embodiment of the first or second aspect of the present invention, -R 7 Yes -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 .

[0116] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R2 or -S(O)2R 2 In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 In one embodiment, -R 9 Select from -OR 2 or -SR 2 In one embodiment, -R 9 Yes-OR 2 .

[0117] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Selected from -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. In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2Selected from -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. In one embodiment, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Selected from -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 -Rα -[NC5H5]Y.

[0118] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -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 Selected from -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 In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Selected from -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 In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Selected from -R α -OR β or -R α -SR β , and optionally, -R β In one embodiment, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Selected from -Rα -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and optionally, -R β In one embodiment, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Selected from -R α -OR β or -R α -SR β , and optionally, -R β It's a sugar group.

[0119] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -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); and -R 2 Yes-C(O)R 4 In one embodiment, -R 9 Select from -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 Yes-C(O)R 4 ;-R 4 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β ; and -R βIn one embodiment, -R 9 Select from -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 Yes-C(O)R 4 ;-R 4 Selected from -R α -OR β or -R α -SR β ; and -R β It's a sugar group.

[0120] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Yes-C(O)R 4 In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Yes-C(O)R 4 , and -R 4 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 9 Select from -OR 2 、-SR 2 、-S(O)R 2 or -S(O)2R 2 , and -R 2 Yes-C(O)R 4 , and -R 4 Selected from -R α -ORβ or -R α -SR β , and -R β It's a sugar group.

[0121] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Yes-C(O)R 4 In one embodiment, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Yes-C(O)R 4 , and -R 4 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, -R 9 Select from -OR 2 or -SR 2 , and -R 2 Yes-C(O)R 4 , and -R 4 Selected from -R α -OR β or -R α -SR β , and -R β It's a sugar group.

[0122] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -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 Selected from -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 glycosyl group; and -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe. In one embodiment, -R 9 Select from -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 Selected from -R β 、-R α -OR β or -R α -SR β ;-R β is a glycosyl group; and -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe.

[0123] In any of the embodiments in the five preceding paragraphs, the glycosyl group can be optionally substituted, for example, with a protecting group such as acetyl or a natural amino acid such as valine. The amino acid can be attached to the glycosyl group, for example, by forming an ester between the carboxylic acid group of the amino acid and the hydroxyl group of the glycosyl group.

[0124] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -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, C1-C4 alkyl or -CO2(C1-C4 alkyl); -R 2 Selected from -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;-R 4’ is selected from hydrogen or C1-C4 alkyl; and -R 4 Selected from -R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 In one embodiment, -R 9 Select from -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); -R 2 Selected from -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;-R 4’ Selected from hydrogen or C1-C4 alkyl; -R 4 Selected from -R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 ]Y; each -R 5 independently selected from C1-C4 alkyl or phenyl, wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R 8 is -[NC5H5] optionally substituted by one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R α -Selected from C1-C 12wherein one, two, three or four carbon atoms in the backbone of the alkylene group may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe; and Y is a counterion (preferably a halide). In one embodiment, -R 9 Select from -OR 2 or -N(R 2 )(R 2’ );-R 2’ is selected from hydrogen, C1-C4 alkyl or -CO2(C1-C4 alkyl); -R 2 Selected from -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;-R 4’ Selected from hydrogen or C1-C4 alkyl; -R 4 Selected from -R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 ]Y; each-R 5 independently selected from C1-C4 alkyl or phenyl, wherein the phenyl is optionally substituted with one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R 8 is -[NC5H5] optionally substituted by one, two or three C1-C4 alkyl or C1-C4 alkoxy groups; -R α -Selected from C1-C 12 Alkylene, wherein one, two, three or four carbon atoms in the backbone of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe; and Y is a counterion (preferably a halide).

[0125] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 or -S(O)2R 2 ; and -R 2is selected from hydrogen, C1-C4 alkyl, -CO(C1-C4 alkyl) or -CO2(C1-C4 alkyl). In one embodiment, -R 9 Select from -OR 2 or -N(R 2 )2; and -R 2 Selected from hydrogen, C1-C4 alkyl, -CO(C1-C4 alkyl) or -CO2(C1-C4 alkyl).

[0126] In one embodiment of the first or second aspect of the present invention, -R 9 Select from -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 Selected from -R 4 、-C(O)R 4 、-C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ );-R 4’ is selected from hydrogen or C1-C4 alkyl; and -R 4 Selected from C1-C 12 wherein the alkyl group is optionally substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl group are optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe. 9 Select from -OR 2 or -N(R 2 )(R 2’ );-R 2’ Selected from hydrogen or C1-C4 alkyl; -R 2 Selected from -R 4 、-C(O)R 4 、-C(O)-OR 4 or -C(O)-N(R 4 )(R 4’ );-R 4’ is selected from hydrogen or C1-C4 alkyl; and -R 4 Selected from C1-C 12Alkyl, wherein the alkyl may be optionally substituted with one, two, three or four halo groups, and wherein one, two, three or four carbon atoms in the backbone of the alkyl may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe.

[0127] In one embodiment of the first or second aspect of the invention, each -R α - independently C1-C 12 Alkylene, -(CH2CH2O) m -group, -(CH2CH2S) m -group, -(CH2CH2O) m -CH2CH2- group or -(CH2CH2S) m -CH2CH2- groups, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -R α - independently C1-C 12 Alkylene, -(CH2CH2O) m - group or -(CH2CH2S) m - groups, all optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -R α - independently C1-C 12 Alkylene or -(CH2CH2O) m - groups, both optionally substituted, wherein m is 1, 2, 3 or 4. In one embodiment, each -R α - is independently optionally substituted -(CH2CH2O) m - group, wherein m is 1, 2, 3 or 4.

[0128] In one embodiment of the first or second aspect of the invention, each -R α - is independently C1-C8 alkylene, or C1-C6 alkylene, or C2-C4 alkylene, all optionally substituted.

[0129] 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 -Not superseded.

[0130] In one embodiment of the first or second aspect of the invention, each -Rβ is independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more heteroatoms N, O or S in its carbon skeleton.

[0131] In one embodiment of the first or second aspect of the present invention, at least one -R β is independently C1-C6 alkyl, or C1-C4 alkyl, or methyl, all optionally substituted. β are independently C1-C6 alkyl, or C1-C4 alkyl, or methyl, all optionally substituted.

[0132] In one embodiment of the first or second aspect of the present invention, at least one -R β In one embodiment, each -R β are independently glycosyl.

[0133] 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, C1-C4 alkyl or C1-C4 haloalkyl. β is independently unsubstituted or substituted with one or two substituents independently selected from halo, C1-C4 alkyl or C1-C4 haloalkyl. β Not replaced.

[0134] In one embodiment of the first or second aspect of the invention, each -R 3 Independently selected from -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, -Rα -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[NC5H5]Y. In one embodiment, each -R 3 Independently selected from -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 selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, each -R 3 Independently selected from -R α -OR β or -R α -SR β In one embodiment, each -R 3 Independently selected from -R α -OR β or -R α -SR β , and -R β It's a sugar group.

[0135] In one embodiment of the first or second aspect of the invention, each -R 4 Independently selected from -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 selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β In one embodiment, each -R 4 Independently selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β In one embodiment, each -R 4 Independently selected from -R α -OR β or -R α -SR β In one embodiment, each -R 4 Independently selected from -R α -OR β or -R α -SR β , and -R β It's a sugar group.

[0136] In one embodiment of the first or second aspect of the present invention, -R 2 、-R 3 or -R 4 At least one of -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R βIn one embodiment, -R 2 、-R 3 or -R 4 At least one of -R α -OR β or -R α -SR β , and -R β It's a sugar group.

[0137] For the purposes of the present invention, a "glycosyl" is any group comprising at least one monosaccharide subunit, wherein each monosaccharide subunit may be optionally substituted and / or modified. Typically, a glycosyl group is composed of one or more monosaccharide subunits, wherein each monosaccharide subunit may be optionally substituted and / or modified.

[0138] Typically, a carbon atom of a single monosaccharide subunit of each glycosyl group is directly linked (most often via a single bond) to the rest of the compound.

[0139] For the purposes of this specification, when it is stated that a first atom or group is "directly attached" to a second atom or group, it is understood that the first atom or group is covalently bonded to the second atom or group without one or more intervening atoms or groups. For example, for the group -(C=O)N(CH3)2, the carbon atom of each methyl group is directly attached to the nitrogen atom and the carbon atom of the carbonyl group is directly attached to the nitrogen atom, but the carbon atom of the carbonyl group is not directly attached to the carbon atom of any methyl group.

[0140] Typically, each sugar group is derived from the corresponding sugar by replacing a hydroxyl group of the sugar with a group defined by the remainder of the compound.

[0141] The single bond between the anomeric carbon of a monosaccharide subunit and a substituent is called a glycosidic bond. The glycosidic group is connected to the anomeric carbon of the monosaccharide subunit via a glycosidic bond. The bond between the glycosyl and the rest of the compound can be a glycosidic bond or a non-glycosidic bond. Typically, the bond between the glycosyl and the rest of the compound is a glycosidic bond, such that the saccharidyl group is a glycosyl group. When the bond between the glycosyl and the rest of the compound is a glycosidic bond, the glycosidic bond can be in α or β configuration. Typically, this glycosidic bond is in β configuration.

[0142] For the purposes of the present invention, when a glycosyl group "contains x monosaccharide subunits," this means that the glycosyl group has only x monosaccharide subunits. In contrast, when a glycosyl group "comprises x monosaccharide subunits," this means that the glycosyl group has x or more monosaccharide subunits.

[0143] Each saccharide group can be independently selected from a monosaccharide group, a disaccharide group, an oligosaccharide group or a polysaccharide group. As will be understood, a monosaccharide group contains a single monosaccharide subunit. Similarly, a disaccharide group contains two monosaccharide subunits. As used herein, an "oligosaccharide group" contains 2 to 9 monosaccharide subunits. Examples of oligosaccharides include trisaccharides, tetrasaccharides, pentasaccharides, hexasaccharides, heptasaccharides, octasaccharides and nonasaccharides. As used herein, a "polysaccharide group" contains 10 or more monosaccharide subunits (such as 10-50, or 10-30, or 10-20, or 10-15 monosaccharide subunits).

[0144] Each monosaccharide subunit within a disaccharide, oligosaccharide, or polysaccharide group may be the same or different. Each monosaccharide subunit within a disaccharide, oligosaccharide, or polysaccharide group may be linked to another monosaccharide subunit within the group via a glycosidic bond or a 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, and the glycosidic bond may be in an α or β configuration.

[0145] Each oligosaccharide group or polysaccharide group may be a linear, branched or macrocyclic oligosaccharide group or polysaccharide group. Typically, each oligosaccharide group or polysaccharide group is a linear or branched oligosaccharide group or polysaccharide group.

[0146] In one embodiment, at least one -R β It is a monosaccharide or a disaccharide.

[0147] In another embodiment, at least one -R β Is a monosaccharide group. For example, at least one -R β It can be a saccharide group containing a single monosaccharide subunit, wherein 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, wherein the monosaccharide subunit may be optionally substituted. More typically, at least one -R β A sugar moiety containing a single monosaccharide subunit, wherein the monosaccharide subunit is unsubstituted.

[0148] In one embodiment, at least one -R β is an aldose group, wherein the aldose group may be optionally substituted and / or modified. For example, at least one -R β It can be selected from a glycerosyl group, an aldotrosyl group (such as an erythrosyl group or a threosyl group), an aldopentosyl group (such as a ribosyl group, an arabinosyl group, a xylosyl group or a lyxosyl group) or an aldohexosyl group (such as an allosyl group, an altrosyl group, a glucosyl group, a mannosyl group, a gulosyl group, an idosyl group, a galactosyl group or a talosyl group), any of which can be optionally substituted and / or modified.

[0149] In another embodiment, at least one -R β is a ketose group, wherein the ketose group may be optionally substituted and / or modified. For example, at least one -Rβ It may be selected from erythrosyl, ketopentosyl (such as ribulosyl or xylulosyl) or hexokosyl (such as psicosyl, fructosyl, sorbosyl or tagatosyl), any of which may be optionally substituted and / or modified.

[0150] Each monosaccharide subunit can exist in a closed ring (cyclic) or open chain (acyclic) form. β Each monosaccharide subunit in the present invention exists in a closed ring (cyclic) form. For example, at least one -R β It may be a glycosyl group containing a single closed-ring monosaccharide subunit, wherein the monosaccharide subunit may be optionally substituted and / or modified. Typically in this case, at least one -R β is a pyranosyl or furanosyl group, such as pyranosyl, furanosyl, pyranonosyl or furanonosyl, 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 group or a pyranonosyl group, either of which may be optionally substituted and / or modified.

[0151] In one embodiment, at least one -R β is selected from ribopyranosyl, arabinopyranosyl, xylopyranosyl, lyxopyranosyl, allopyranosyl, altropyranosyl, glucopyranosyl, mannopyranosyl, gulopyranosyl, idopyranosyl, galactopyranosyl or talopyranosyl, any of which may be optionally substituted and / or modified.

[0152] In another embodiment, at least one -R β is a glucosyl group, such as a glucopyranosyl group, wherein the glucosyl group or the glucopyranosyl group may be optionally substituted and / or modified. Typically, at least one -R β is a glucosyl group, wherein the glucosyl group is optionally substituted. More typically, at least one -R β It is an unsubstituted glucose group.

[0153] Each monosaccharide subunit can exist in the D- or L-configuration. Typically, each monosaccharide subunit exists in the configuration most commonly found in nature.

[0154] In one embodiment, at least one -R β Is a D-glucose group, such as a D-glucopyranosyl group, wherein the D-glucose group or the D-glucopyranosyl group may be optionally substituted and / or modified. Typically, at least one -R β is a D-glucose group, wherein the D-glucose group is optionally substituted. More typically, at least one -R β It is an unsubstituted D-glucose group.

[0155] For the purposes of the present invention, in a substituted monosaccharide group or monosaccharide subunit:

[0156] (a) one or more hydroxyl groups of a monosaccharide group or a monosaccharide subunit are each independently replaced by -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(Rb )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 replacement; and / or

[0157] (b) one, two or three hydrogen atoms directly attached to a carbon atom of a monosaccharide group or a monosaccharide subunit are each independently replaced by -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-Rb 、-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、-Ra -CO-R b 、-R a -CO-OR b or -R a -CO-N(R b )2 replacement; and / or

[0158] (c) one or more hydroxyl groups of a monosaccharide group or monosaccharide subunit, together with the hydrogen atoms attached to the same carbon atoms as the hydroxyl groups, are each independently replaced by ═O, ═S, ═NR b or =N(R b )2 + Replacement; and / or

[0159] (d) Any two hydroxyl groups of a monosaccharide group or a monosaccharide subunit are combined with -OR c -、-SR c -、-SO-R c -、-SO2-R c -or-NR b -R c - Substitution;

[0160] in:

[0161] Each -R a - independently substituted or unsubstituted alkylene, alkenylene or alkynylene, which optionally includes in its carbon skeleton one or more heteroatoms each independently selected from O, N and S and preferably contains 1 to 10 carbon atoms;

[0162] Each -R b is independently hydrogen, or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon backbone and preferably contains 1-15 carbon atoms; and

[0163] Each -R c - is independently a chemical bond, or a substituted or unsubstituted alkylene, alkenylene or alkynylene group, which optionally includes one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably contains 1 to 10 carbon atoms;

[0164] Provided that the monosaccharide group or monosaccharide subunit contains 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 )2OR-OR c -.

[0165] Typically, in a substituted monosaccharide group or monosaccharide subunit:

[0166] (a) one or more hydroxyl groups of a monosaccharide group or a monosaccharide subunit are each independently replaced by -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 replacement; and / or

[0167] (b) one or two hydrogen atoms directly attached to a carbon atom of a monosaccharide group or a monosaccharide subunit are each independently replaced by -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(Rb )2 replacement; and / or

[0168] (c) one hydroxyl group of a monosaccharide group or a monosaccharide subunit, together with the hydrogen bonded to the same carbon atom as the hydroxyl group, is replaced by =0; and / or

[0169] (d) Any two hydroxyl groups of a monosaccharide group or a monosaccharide subunit are combined with -OR c -or-NR b -R c - Substitution;

[0170] in:

[0171] Each -R b is independently hydrogen, or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, which optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon backbone and contains 1-8 carbon atoms; and

[0172] Each -R c - is independently substituted or unsubstituted alkylene, alkenylene or alkynylene, which optionally includes one, two or three heteroatoms each independently selected from O and N in its carbon skeleton and contains 1-8 carbon atoms;

[0173] Provided that the monosaccharide group or monosaccharide subunit contains 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 )2OR-OR c -.

[0174] In one embodiment, -R β is a glycosyl group and one or more hydroxyl groups of the glycosyl group are each independently replaced by -O-CO-R b Substitute, where each -R b are independently C1-C4 alkyl, preferably methyl. In one embodiment, -R β is a glycosyl group and all hydroxyl groups of the glycosyl group are independently substituted by -O-CO-R b Substitute, where each -R b are independently C1-C4 alkyl, preferably methyl.

[0175] In the modified monosaccharide group or monosaccharide subunit:

[0176] (a) the ring of the modified monosaccharide group or monosaccharide subunit or the ring in the closed ring form of the modified monosaccharide group or monosaccharide subunit is partially unsaturated; and / or

[0177] (b) the epoxy group of the modified monosaccharide group or monosaccharide subunit or the epoxy group in the closed ring form of the modified monosaccharide group or monosaccharide subunit is replaced by -S- or -NR d -Substitution, where -R d is independently hydrogen, or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, optionally including one or more heteroatoms each independently selected from O, N and S in its carbon skeleton and preferably containing 1 to 15 carbon atoms.

[0178] Alternatively, where the modified monosaccharide subunit forms part of a disaccharide, oligosaccharide or polysaccharide group, -R d There may be additional monosaccharide subunit(s) forming part of a di-, oligo- or polysaccharide group, wherein any such additional monosaccharide subunit(s) may optionally be substituted and / or modified.

[0179] Typically, in the modified monosaccharide group or monosaccharide subunit:

[0180] (a) the ring of the modified monosaccharide group or monosaccharide subunit, or the ring in the closed ring form of the modified monosaccharide group or monosaccharide subunit, contains a single C=C; and / or

[0181] (b) the epoxy group of the modified monosaccharide group or monosaccharide subunit or the epoxy group in the closed ring form of the modified monosaccharide group or monosaccharide subunit is replaced by -NR d -Substitution, where -R d is independently hydrogen, or a substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, optionally including one, two or three heteroatoms each independently selected from O and N in its carbon skeleton and containing 1-8 carbon atoms.

[0182] Representative examples of substituted and / or modified monosaccharide subunits include those corresponding to:

[0183] (i) deoxysugars, such as deoxyribose, fucose, fucose, and rhamnose, in which the hydroxyl group of a monosaccharide group or a monosaccharide subunit has been replaced by -H;

[0184] (ii) amino sugars, such as glucosamine and galactosamine, in which the hydroxyl group of a monosaccharide group or monosaccharide subunit has been replaced by -NH2, most commonly at the 2-position; and

[0185] (iii) Sugar acids containing a -COOH group, such as aldonic acid (eg gluconic acid), ketonic acid, uronic acid (eg glucuronic acid) and aldaric acid (eg gularic or galactaric acid).

[0186] In one embodiment of the first or second aspect of the present invention, at least one -R β is a monosaccharide group selected from the group consisting of:

[0187]

[0188] Preferably, in the compound or complex according to the first or second aspect of the present invention, at least one -R β yes:

[0189]

[0190] In one embodiment of the first or second aspect of the present invention, -R 2 、-R 3 or -R 4 At least one of -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β (preferably selected from -R α -OR β or -R α -SR β ), and -R β Selected from:

[0191]

[0192]

[0193] In one embodiment of the first or second aspect of the present invention, -R 2 、-R 3 or -R 4 At least one of -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(R5 )2(R 5’ )] or -R α -[R 8’ In one embodiment, -R 2 、-R 3 or -R 4 At least one of -R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 In one embodiment, -R 2 、-R 3 or -R 4 At least one of is independently selected from:

[0194]

[0195] In the first or second aspect of the present invention, each -R 5 Can be the same or different. In a preferred embodiment, each -R 5 same.

[0196] In one embodiment of the first or second aspect of the invention, each -R 5 In one embodiment, each -R 5 Not replaced.

[0197] In one embodiment of the first or second aspect of the present invention, -R 8 is unsubstituted or substituted with one or two substituents. In one embodiment, -R 8 Not replaced.

[0198] In one embodiment, -R 8 The 4-position of the pyridine ring is not substituted by a halo group. 8 The 4-position of the pyridine ring is unsubstituted. In one embodiment, -R 8 Not replaced.

[0199] In one embodiment of the first or second aspect of the present 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, and preferably 1 to 45 atoms other than hydrogen.

[0200] In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):

[0201]

[0202] or a pharmaceutically acceptable salt thereof, wherein:

[0203] -R 1 Selected from:

[0204] (a)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 Each independently is a C1-C4 alkyl group; preferably -R 1 is-C(O)-OR 3 And -R 3 is C1-C4 alkyl; or

[0205] (b)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ );-R 3 Selected from -R α -OR β or -R α -SR β ;-R β is a glycosyl group; and -R 3’ is H or C1-C4 alkyl;

[0206] -R 6 Selected from:

[0207] (a)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 Each independently is a C1-C4 alkyl group; preferably -R 6 is-C(O)-OR 3 And -R 3 is C1-C4 alkyl; or

[0208] (b)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ );-R 3Selected from -R α -OR β or -R α -SR β ;-R β is a glycosyl group; and -R 3’ is H or C1-C4 alkyl;

[0209] -R 7 Selected from:

[0210] (a)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )2, and -R 3 Each independently is a C1-C4 alkyl group; preferably -R 7 is-C(O)-OR 3 And -R 3 is C1-C4 alkyl; or

[0211] (b)-C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ );-R 3 Selected from -R α -OR β or -R α -SR β ;-R β is a glycosyl group; and -R 3’ is H or C1-C4 alkyl;

[0212] -R 9 Select from -OR 2 or -SR 2 , and -R 2 Selected from -R α -OR β or -R α -SR β , and -R β It is a sugar group;

[0213] -R α -Selected from C1-C 12 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with one or more heteroatoms O or S; and

[0214] M 2+ It is a metal cation.

[0215] In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):

[0216]

[0217] or a pharmaceutically acceptable salt thereof, wherein:

[0218] -R 1 Selected from -CH2OR 2 、-CH2SR 2 、-CH2S(O)R 2 、-CH2S(O)2R 2 、-CH2N(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 Selected from -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, -R 1 Yes -C(O)-N(R 3 )(R 3’ )];

[0219] -R 2 Each independently selected from -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 -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’ ];

[0220] -R 3 and -R 4 Each independently selected from -H, -R α -H, -R β 、-R α -R β 、-R α -OH, -R α -OR β 、-R α -SH, -Rα -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’ ];

[0221] Where -R 2 、-R 3 and -R 4 At least one selected from -[(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’ ];

[0222] -R 2’ 、-R 3’ and -R 4’ 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];

[0223] -R α - each independently selected from C1-C 42 Alkylene, wherein the alkylene may be optionally substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo, and wherein one or more (such as one, two, three, four, five, six, seven, eight, nine or ten) carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe;

[0224] -R β each independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton;

[0225] -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n-CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally replaced by one or more (such as one, two, three, four or five) 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 -CH3 group substitution;

[0226] -R 5’ Selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each of which is replaced by -CO2 - Substituted, wherein the phenyl or C5-C6 heteroaryl may be optionally further substituted by one or more (such as one, two, three or four) 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 -CH3 group substitution;

[0227] -R 6 Selected from -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 Yes -C(O)-N(R 3 )(R 3’ )];

[0228] -R 7 Selected from -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, -R7 Yes -C(O)-N(R 3 )(R 3’ )];

[0229] -R 8 is optionally substituted by one or more (such as one, two, three, four or five) C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 group;

[0230] -R 8’ is -[NC5H5], which is -CO2 - and optionally further substituted by one or more (such as one, two, three or four) 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 -CH3 group substitution;

[0231] -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X;

[0232] Q is O, S, NH or NMe [preferably, Q is O];

[0233] X is a halogen group;

[0234] Y is a counter anion;

[0235] Z is a counter cation;

[0236] M 2+ It is a metal cation;

[0237] n is 1, 2, 3, 4, 5, or 6;

[0238] p is 0, 1, 2, 3, or 4;

[0239] r is 0, 1, 2, 3, 4, 5, or 6; and

[0240] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0241] In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II):

[0242]

[0243] or a pharmaceutically acceptable salt thereof, wherein:

[0244] -R 1 Selected from -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 Yes -C(O)-N(R 3 )(R 3’ )];

[0245] -R 2 Each independently selected from -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 -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’ ];

[0246] -R 3 and -R 4 Each independently selected from -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(R5 )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’ ];

[0247] Where -R 2 、-R 3 and -R 4 At least one selected from -[(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’ ];

[0248] -R 3’ and -R 4’ Each independently selected from hydrogen or C1-C3 alkyl [preferably, -R 3’ and -R 4’ are each independently selected from hydrogen or methyl];

[0249] -R α - each independently selected from C1-C 42 Alkylene, wherein the alkylene may be optionally substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo, and wherein one or more (such as one, two, three, four, five, six, seven, eight, nine or ten) carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe;

[0250] -R β each independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton;

[0251] -R 5 Each independently selected from C1-C3 alkyl or phenyl, wherein the phenyl group may be optionally independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 is substituted with one, two, three, four or five substituents;

[0252] -R 5’ Selected from -CO2 - Substituted C1-C3 alkyl or -CO2 - Substituted phenyl, wherein the phenyl group may be further independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 is substituted with one, two, three or four substituents;

[0253] -R 6 Selected from -C(O)-OR 3 、-C(O)-SR 3 、-C(O)-N(R3 )(R 3’ ),-C(S)-OR 3 、-C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ ) [Preferably, -R 6 Yes -C(O)-N(R 3 )(R 3’ )];

[0254] -R 7 Selected from -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 Yes -C(O)-N(R 3 )(R 3’ )];

[0255] -R 8 is optionally independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with one, two, three, four or five substituents of -CH3;

[0256] -R 8’ is -[NC5H5], which is -CO2 - substituted and optionally further independently selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3 is substituted with one, two, three or four substituents;

[0257] -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X;

[0258] Q is O, S, NH or NMe [preferably, Q is O];

[0259] X is a halogen group;

[0260] Y is a counter anion;

[0261] Z is a counter cation;

[0262] M 2+ It is a metal cation;

[0263] n is 1, 2, 3, 4, 5, or 6;

[0264] p is 0, 1, 2, 3, or 4;

[0265] r is 0, 1, 2, 3, 4, 5, or 6; and

[0266] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0267] In the two preferred embodiments of the preceding paragraphs, each -R 5 Can be the same or different; preferably, each -R 5 same.

[0268] In another preferred embodiment of the first or second aspect of the invention, the compound is 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):

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] or a metal cation complex thereof or a pharmaceutically acceptable salt thereof; wherein:

[0276] -R 1 Selected from -C(O)-OR 3 、-C(O)-SR3 、-C(O)-N(R 3 )(R 3’ )、-C(S)-OR 3 、-C(S)-SR 3 or -C(S)-N(R 3 )(R 3’ );

[0277] -R 2 Each independently selected from -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 -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;

[0278] -R 3 and -R 4 Each independently selected from -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 、-Rα -S(O)2R β 、-R α -NH2、-R α -NH(R β ),-R α -N(R β )2 or -R α -X;

[0279] -R 3’ and -R 4’ Each independently selected from hydrogen or C1-C3 alkyl [preferably, -R 3’ and -R 4’ are each independently selected from hydrogen or methyl];

[0280] -R 6 Selected from -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’ );

[0281] -R 7 Selected from -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’ );

[0282] -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X;

[0283] -R α - each independently selected from C1-C 12Alkylene, wherein the alkylene may be optionally substituted with one or more (such as one, two, three, four or five) C1-C4 alkyl, C1-C4 haloalkyl or halo, and wherein one or more (such as one, two, three, four, five or six) carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe;

[0284] -R β each independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more (such as one, two, three, four or five) heteroatoms N, O, S, P or Se in its carbon skeleton;

[0285] -R δ Selected from C1-C3 alkyl;

[0286] -R ε Selected from C1-C6 alkyl, -O(C1-C6 alkyl), -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -CH3;

[0287] X is a halogen group;

[0288] Y is a counter anion;

[0289] Z is a counter cation;

[0290] n is 1, 2, 3, or 4;

[0291] p is 0, 1, 2, 3, or 4;

[0292] r is 0, 1, 2, 3, 4, 5, or 6;

[0293] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0294] t is 0, 1, 2, 3, 4, or 5; and

[0295] u is 0, 1, 2, 3, and 4.

[0296] 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 their complexes and salts according to the first and second aspects of the present invention comprise the moiety -[(CH p O] r -(CH2) s -,in

[0297] p is 0, 1, 2, 3, or 4;

[0298] r is 0, 1, 2, 3, 4, 5, or 6; and

[0299] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

[0300] In one embodiment, p is 2, 3, or 4; r is 1; and s is 2, 3, or 4. In a preferred embodiment, p is 3; r is 1; and s is 3; such that -[(CH2) p O] r -(CH2) s -is -(CH2)3-O-(CH2)3-.

[0301] In another embodiment, p is 2 or 3; r is 2 or 3; and s is 2 or 3. In a preferred embodiment, p is 2; r is 2; and s is 2; such that -[(CH2) p O] r -(CH2) s -is -(CH2CH2O)2-(CH2)2-.

[0302] In another embodiment, r is 0; and s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; such that -[(CH2) p O] r -(CH2) s -Yes-(CH2) 1-12 -.

[0303] In a particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I) or a complex of formula (II'):

[0304]

[0305] or a pharmaceutically acceptable salt thereof, wherein:

[0306] -R 9 Select from -OR 2 、-N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X;

[0307] -R 10 、-R 11 and -R 12 Each independently selected from -OR 3 、-SR 3 or -N(R 3 )2;

[0308] -R 2 Each independently selected from -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’ )]、-Rα -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ];

[0309] -R 3 and -R 4 Each independently selected from -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’ )]、-R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ];

[0310] -R α - each independently selected from C1-C 42 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe;

[0311] -R βeach independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton;

[0312] -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally replaced by one or more 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 -CH3 group substitution;

[0313] -R 5’ Selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each of which is replaced by -CO2 - Substituted, wherein the phenyl or C5-C6 heteroaryl may be optionally further substituted by one or more 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 -CH3 group substitution;

[0314] -R 8 is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 group;

[0315] -R 8’ is -[NC5H5], which is replaced by -CO2 -and optionally further substituted with one or more 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 -CH3 group substitution;

[0316] n is 1, 2, 3, 4, 5, or 6;

[0317] X is a halogen group;

[0318] Y is a counter anion;

[0319] Z is a counter cation; and

[0320] M 2+ It is a metal cation;

[0321] The conditions are:

[0322] (i)-R 9 、-R 10 and -R 11 At least one of them contains -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 a sugar group; or

[0323] (ii)-R 9 Selected from -N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X.

[0324] In another particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I") or a complex of formula (II"):

[0325]

[0326] or a pharmaceutically acceptable salt thereof, wherein:

[0327] -U- is -O-, -N(R u )-or-S-;

[0328] -V- is -CH2-, -O-, -N(R v )-or-S-;

[0329] -W-Yes-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’ ];

[0330] -R 10 、-R 11 and -R 12 Each independently selected from -OH or -O-(C1-C4 alkyl);

[0331] -R α -Selected from C1-C 12 Alkylene, wherein the alkylene may be optionally substituted with one or more (such as one, two, three or four) C1-C4 alkyl, C1-C4 haloalkyl or halo; and wherein one or more (such as one, two, three or four) carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH or NMe;

[0332] -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally replaced by one or more 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 -CH3 group substitution;

[0333] -R 5’Selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each of which is replaced by -CO2 - Substituted, wherein the phenyl or C5-C6 heteroaryl may be optionally further substituted by one or more 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 -CH3 group substitution;

[0334] -R 8 is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 group;

[0335] -R 8’ is -[NC5H5], which is -CO2 - and optionally further substituted with one or more 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 -CH3 group substitution;

[0336] -R u is hydrogen or C1-C4 alkyl;

[0337] -R v is hydrogen or C1-C4 alkyl;

[0338] n is 1, 2, 3, 4, 5, or 6;

[0339] Y is a counter anion;

[0340] Z is a counter cation; and

[0341] M 2+ It is a metal cation.

[0342] In another particularly preferred embodiment, the first or second aspect of the present invention provides a compound of formula (I") or a complex of formula (II"):

[0343]

[0344] or a pharmaceutically acceptable salt thereof, wherein:

[0345] -U- is -O-, -N(R u )-or-S-;

[0346] -V- is -CH2-, -O-, -N(R v )-or-S-;

[0347] -W-Yes-R α -[N(R 5 )3]Y、-R α -[P(R 5 )3]Y or -R α -[R 8 ]Y;

[0348] -R 10 、-R 11 and -R 12 Each independently selected from -OH or -O-(C1-C4 alkyl);

[0349] -R α -Selected from C1-C 12 Alkylene (preferably C1-C9 alkylene, preferably C2-C6 alkylene), wherein one or more (such as one, two, three or four, preferably one or two) carbon atoms in the main chain of the alkylene may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe (preferably O, NH or NMe, preferably O);

[0350] -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, -O(C1-C4 alkyl) or -O(C1-C4 haloalkyl);

[0351] -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);

[0352] -R u is hydrogen or C1-C4 alkyl;

[0353] -R v is hydrogen or C1-C4 alkyl;

[0354] n is 1, 2, 3, 4, 5, or 6;

[0355] Y is a counter anion; and

[0356] M 2+ It is a metal cation.

[0357] The first aspect of the present invention further provides a compound of formula (III) or a complex of formula (IV):

[0358]

[0359] or a pharmaceutically acceptable salt thereof, wherein:

[0360] -R 1 Selected from -CO2H or -C(O)-R 14 -R 15 ;

[0361] -R 6 Selected from -CO2H or -CO2R 13 ;

[0362] -R 7 Selected from -CO2H or -C(O)-R 14 -R 15 ;

[0363] -R 13 Selected from C1-C3 alkyl;

[0364] -R 14 - is selected from NH, NMe, O or S;

[0365] -R 15 Selected from C1-C 20 alkyl, wherein one or more carbon atoms in the alkyl may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe, and wherein the alkyl may be optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -NH groups; and

[0366] M 2+ It is a metal cation;

[0367] The condition is -R 1 、-R 6 and -R 7 Not at the same time -CO2Me.

[0368] In one embodiment, -R 1 Selected from -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; wherein 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 Selected from -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.

[0369] In one embodiment, -R 7 Selected from -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; wherein 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 Selected from -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.

[0370] In one embodiment, -R 13 It is a methyl or ethyl group.

[0371] In one embodiment, -R 14 - is NH or NMe. Preferably, -R 14 -It's NMe.

[0372] In one embodiment, -R 15 Selected from -(CH2) x -Me, -(CH2) x -OH, -(CH2CH2O) y -Me or -(CH2CH2O) y -H; wherein 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 Selected from -(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.

[0373] In one embodiment, M 2+ is selected from Zn 2+ 、Cu 2+ 、Fe 2+ 、Pd 2+ or Pt 2+ In one embodiment, M 2+ It is Zn 2+ .

[0374] In one embodiment, the compound of formula (III) or the complex of formula (IV) is in the form of a pharmaceutically acceptable salt, such as a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an ammonium salt, an amine salt (such as choline or meglumine), or an amino acid salt (such as arginine). Preferably, the pharmaceutically acceptable salt is a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an ammonium salt, a choline salt, a meglumine salt, or an amino acid salt, or a combination thereof. Preferably, the pharmaceutically acceptable salt is a lithium salt, a sodium salt, a potassium salt, or a meglumine salt, or a combination thereof. Preferably, the pharmaceutically acceptable salt is a sodium salt or a meglumine salt, or a combination thereof.

[0375] 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 monosodium monomeglumine mixed salt.

[0376] Preferably, in the compound or complex according to the first or second aspect of the present invention, the compound or complex is:

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398] or a metal cation complex thereof or a pharmaceutically acceptable salt thereof.

[0399] 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 salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt or an ammonium salt. In one embodiment, the compound or complex is in the form of a sodium salt or a 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).

[0400] The compounds or complexes according to the first or second aspects of the invention have at least two chiral centers. The compounds or complexes of the first or second aspects of the invention are preferably substantially enantiomerically pure, which means that the compounds or complexes contain less than 10%, preferably less than 5%, preferably less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5% (all by weight) of other stereoisomers as measured by XRPD or SFC.

[0401] 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, percent HPLC purity is measured by the area normalization method.

[0402] The third aspect of the present invention provides a composition comprising the compound or complex according to the first or second aspect of the present invention and a pharmaceutically acceptable carrier or diluent.

[0403] In one embodiment, the composition according to the third aspect of the invention further comprises polyvinylpyrrolidone (PVP). In one embodiment, the composition comprises 0.01%-10% w / w PVP as a percentage of the total weight of the composition, preferably 0.1%-5% w / w PVP as a percentage of the total weight of the composition, preferably 0.5%-5% w / w PVP as a percentage of the total weight of the composition. In one embodiment, the PVP is K30.

[0404] In one embodiment, the composition according to the third aspect of the invention further comprises dimethyl sulfoxide (DMSO). In one embodiment, the composition comprises 0.01%-99% w / w DMSO as a percentage of the total weight of the composition, preferably 40%-99% w / w DMSO as a percentage of the total weight of the composition, preferably 65%-99% w / w DMSO as a percentage of the total weight of the composition.

[0405] In one embodiment, the composition according to the third aspect of the present 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, cemiplizumab, atezolizumab, avelumab, durvalumab or ipilimumab.

[0406] Preferably, the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic therapy or cell luminescence therapy.

[0407] Preferably, the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; Diseases characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cavity or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0408] 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 treating diseases characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization.

[0409] Preferably, the compound or complex according to the first or second aspect of the invention and the pharmaceutical composition according to the third aspect of the invention are suitable for the treatment of benign or malignant tumors.

[0410] 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 tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

[0411] Preferably, the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for use in photodynamic diagnosis.

[0412] Preferably, the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for detecting atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; Diseases characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cavity or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0413] 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 by neovascularization.

[0414] Preferably, the compound or complex according to the first or second aspect of the present invention and the pharmaceutical composition according to the third aspect of the present invention are suitable for detecting benign or malignant tumors.

[0415] 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 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 or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

[0416] Preferably, the compound or complex according to the first or second aspect of the invention and the pharmaceutical composition according to the third aspect of the invention are suitable for fluorescent or phosphorescent detection of the diseases listed above, preferably for fluorescent or phosphorescent detection and quantification of said diseases.

[0417] Preferably, the compound or complex according to the first or second aspect of the invention and the pharmaceutical composition according to the third aspect of the invention are suitable for administration simultaneously with or before the administration of radiation or sound, preferably suitable for administration before the administration of radiation.

[0418] If 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 used in photodynamic therapy or cytoluminescence therapy, 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.

[0419] If 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 used in photodynamic diagnosis, they are preferably suitable for administration 3 to 60 hours before irradiation, preferably 8 to 40 hours before irradiation.

[0420] Preferably, the irradiation used in photodynamic therapy, cell luminescence therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength of 500nm to 1000nm, preferably 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. Electromagnetic radiation can be applied for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1-5W, preferably with about 1W. In one embodiment of the invention, two electromagnetic radiation sources (such as lasers and LED lamps) are used, and both sources are suitable for providing irradiation with a wavelength of 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. In another embodiment of the invention, irradiation can be provided by a prostate, anus, vagina, mouth and nose device for insertion into a body cavity. In another embodiment of the invention, irradiation can be provided by interstitial light activation, for example, a fiber laser is inserted into a lung, liver, lymph node or breast using a fine needle. In another embodiment of the invention, illumination can be provided by endoscopic photoactivation, for example, for delivery of light to the lungs, stomach, colon, bladder, or neck.

[0421] The pharmaceutical composition according to the third aspect of the present invention can be 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. The pharmaceutical composition can 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 airway administration, preferably in a form suitable for oral or parenteral administration, preferably in a form suitable for oral administration.

[0422] In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration. Preferably, the pharmaceutical composition is provided in the form of tablets, capsules, hard or soft gelatin capsules, caplets, lozenges or lozenges, provides in powder or granular form, or provides in the form of an aqueous solution, a suspension or a dispersion. More preferably, the pharmaceutical composition is provided in the form of an aqueous solution, a suspension or a dispersion for oral administration, or alternatively provides in the form of a lyophilized powder, which can be mixed with water before use to provide an aqueous solution, a suspension or a dispersion for oral administration. Preferably, the pharmaceutical composition is in the form of a compound according to the first or second aspect of the present invention that is suitable for providing 0.01 to 10mg / kg / days, preferably 0.1 to 2mg / kg / days, preferably about 1mg / kg / days or a complex.

[0423] 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 alternatively provided in the form of a lyophilized powder, which can be mixed with water before administration to provide an aqueous solution for parenteral administration. Preferably, the pharmaceutical composition is an aqueous solution or suspension with a pH of 6 to 8.5. Preferably, the pharmaceutical composition is in the form of a compound or complex according to the first or second aspect of the present invention that is suitable for providing 0.01 to 10 mg / kg / day, preferably 0.1 to 2 mg / kg / day, preferably about 1 mg / kg / day.

[0424] In another preferred embodiment, the pharmaceutical composition is in a form suitable for airway administration. Preferably, the pharmaceutical composition is provided in the form of an aqueous solution, suspension or dispersion for airway administration, or alternatively provided in the form of a lyophilized powder that can be mixed with water before administration to provide an aqueous solution, suspension or dispersion for airway 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 invention.

[0425] The 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 medicament for treating the following diseases: atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis any disease characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization; any benign or malignant tumor; any early stage cancer; any cervical dysplasia; any soft tissue sarcoma; any germ cell tumor; any retinoblastoma; any age-related macular degeneration; any lymphoma; any Hodgkin lymphoma; any cancer of the head and neck; any cancer of the oral cavity or mouth; or any cancer of the blood, prostate, cervix, uterus, vagina, or other female appendages, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, or any hollow organ, esophagus, stomach, bile duct, intestinal tract, colon, colorectum, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0426] The fourth aspect of the present invention also provides the use of the compound or complex according to the first or second aspect of the present invention in the manufacture of a phototherapeutic agent for photodynamic therapy or cell luminescence therapy. Preferably, the phototherapeutic agent is suitable for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin diseases; acne; psoriasis; diseases characterized by excessive proliferation of benign or malignant cells or by the formation of new blood vessels a disease characterized by a uterine septum; a benign or malignant tumor; early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumor; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cavity or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0427] Preferably, the medicament or phototherapeutic agent of the fourth aspect of the invention is suitable for treating a disease characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization.

[0428] Preferably, the medicament or phototherapeutic agent of the fourth aspect of the present invention is suitable for treating benign or malignant tumors.

[0429] Preferably, the medicament or phototherapy agent of the fourth aspect of the invention is suitable for 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 or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

[0430] The fourth aspect of the present invention also provides use of the compound or complex according to the first or second aspect of the present invention in the manufacture of a photodiagnostic agent for photodynamic diagnosis.

[0431] Preferably, the optical diagnostic agent of the fourth aspect of the present invention is suitable for detecting atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; diseases characterized by excessive proliferation or Diseases characterized by areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0432] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for detecting areas affected by excessive proliferation of benign or malignant cells or by neovascularization.

[0433] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for detecting benign or malignant tumors.

[0434] Preferably, the photodiagnostic agent of the fourth aspect of the invention is suitable for detecting 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 or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

[0435] Preferably, the photodiagnostic agent of the fourth aspect of the present invention is suitable for fluorescent or phosphorescent detection of the disease, preferably fluorescent or phosphorescent detection and quantification of the disease.

[0436] Preferably, the pharmaceutical, phototherapeutic or photodiagnostic agent is adapted for administration simultaneously with or prior to the administration of the radiation or sound, preferably prior to the administration of the radiation.

[0437] If the pharmaceutical or phototherapeutic agent is used in photodynamic therapy or cytoluminescence therapy, 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.

[0438] If the photodiagnostic agent is used in photodynamic diagnosis, it is preferably suitable for administration 3 to 60 hours before irradiation, preferably 8 to 40 hours before irradiation.

[0439] Preferably, the irradiation used in photodynamic therapy, cell luminescence therapy or photodynamic diagnosis is electromagnetic radiation with a wavelength of 500nm to 1000nm, preferably 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. Electromagnetic radiation can be applied for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1-5W, preferably with about 1W. In one embodiment of the invention, two electromagnetic radiation sources (such as lasers and LED lamps) are used, and both sources are suitable for providing irradiation with a wavelength of 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. In another embodiment of the invention, irradiation can be provided by a prostate, anus, vagina, mouth and nose device for insertion into a body cavity. In another embodiment of the invention, irradiation can be provided by interstitial light activation, for example, a fiber laser is inserted into a lung, liver, lymph node or breast using a fine needle. In another embodiment of the invention, illumination can be provided by endoscopic photoactivation, for example, for delivery of light to the lungs, stomach, colon, bladder, or neck.

[0440] 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 infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; diseases characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization; benign or malignant tumors; early-stage cancer; A method of treating cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin's lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer; 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.

[0441] The fifth aspect of the present invention also provides a method for photodynamic therapy or cell luminescence 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, chlamydia, bacterial, nanobacterial or parasitic infectious disease; HIV; AIDS; sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disease; acne; psoriasis; benign or malignant cell hyperproliferation or neovascularization Disease characterized by a disease of the following areas: benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral cavity or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

[0442] Preferably, the method of the fifth aspect of the invention is a method of treating an area of benign or malignant cell hyperproliferation or neovascularization.

[0443] Preferably, the method of the fifth aspect of the present invention is a method for treating benign or malignant tumors.

[0444] 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 lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

[0445] The fifth aspect of the present invention also provides a method for photodynamic diagnosis of a human or animal disease, the method comprising administering to a human or animal a diagnostically effective amount of a compound or complex according to the first or second aspect of the present invention. Preferably, the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydia, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; sars virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; benign or malignant cell hyperproliferation or neovascularization Preferably, the human or animal disease is characterized by an area of 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 or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, cancer of the hollow organs, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer. Preferably, the human or animal disease is characterized by an area of benign or malignant cell hyperproliferation or neovascularization. Preferably, the human or animal disease is a benign or malignant tumor. Preferably, the human or animal disease is an 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 or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer. Preferably, the method of photodynamic diagnosis is suitable for fluorescent or phosphorescent detection of the disease, preferably suitable for fluorescent or phosphorescent detection and quantification of the disease.

[0446] In any method of the fifth aspect of the invention, the human or animal is preferably further subjected to irradiation or sound while or after administering the compound or complex according to the first or second aspect of the invention. Preferably, the human or animal is irradiated after administering the compound or complex according to the first or second aspect of the invention.

[0447] If the method is a method of photodynamic therapy or cytoluminescence therapy, 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 after administration, preferably 24 to 48 hours after administration.

[0448] If the method is a method of photodynamic diagnosis, the human or animal is preferably irradiated 3 to 60 hours after administration of the compound or complex according to the first or second aspect of the invention, preferably 8 to 40 hours after administration.

[0449] Preferably, the irradiation is electromagnetic radiation having a wavelength in the range of 500nm to 1000nm, preferably 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. The electromagnetic radiation may be applied at about 0.1-5W, preferably at about 1W, for about 5-60 minutes, preferably for about 15-20 minutes. In one embodiment of the invention, two electromagnetic radiation sources (e.g., a laser and an LED lamp) are used, both sources being adapted to provide irradiation having a wavelength in the range of 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. In another embodiment of the invention, the irradiation may be provided by a prostate, anus, vagina, mouth, and nose device for insertion into a body cavity. In another embodiment of the invention, the irradiation may be provided by interstitial photoactivation, for example, using a fine needle to insert a fiber laser into the lungs, liver, lymph nodes, or breast. In another embodiment of the invention, the irradiation may be provided by endoscopic photoactivation, for example, for delivering light to the lungs, stomach, colon, bladder, or neck.

[0450] In any of the methods of the fifth aspect of the invention, preferably the human or animal is a human.

[0451] A sixth aspect of the present invention provides a pharmaceutical combination or a kit comprising:

[0452] (a) a compound or complex according to the first or second aspect of the invention; and

[0453] (b) Immune checkpoint inhibitors.

[0454] 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.

[0455] Preferably, the combination or kit of the sixth aspect is for use in treating a disease, condition or illness, wherein the disease, condition or illness is responsive to inhibition of PD-1, PD-L1 or CTLA4. 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), renal cancer, bladder cancer, head and neck cancer or Hodgkin's lymphoma.

[0456] The sixth aspect also provides the use of the combination or kit of the sixth aspect of the present invention in the manufacture of a medicament for treating a disease, condition or illness that responds to PD-1, PD-L1 or CTLA4 inhibition. The sixth aspect also provides the use of the combination or kit of the sixth aspect of the present 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), renal cancer, bladder cancer, head and neck cancer, or Hodgkin's lymphoma.

[0457] The sixth aspect of the present invention also provides a method for treating a disease, condition or illness that responds to PD-1, PD-L1 or CTLA4 inhibition, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a person or animal in need. The sixth aspect of the present invention also provides a method for treating cancer, the method comprising administering a therapeutically effective amount of the combination or kit of the sixth aspect of the present invention to a person or animal in need. 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.

[0458] For 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 separately in two pharmaceutical compositions. If provided in two pharmaceutical compositions, these may be administered simultaneously or at different times.

[0459] Preferably, the combination or kit of parts of the sixth aspect is suitable for administration simultaneously with or before the administration of irradiation or sound, preferably suitable for administration before the administration of irradiation. In one embodiment, the combination or kit of parts of the sixth aspect is suitable for administration 5 to 100 hours before irradiation, preferably 6 to 72 hours before irradiation, preferably 24 to 48 hours before irradiation.

[0460] Preferably, the irradiation used in photodynamic therapy or cell luminescence therapy is electromagnetic radiation with a wavelength of 500nm to 1000nm, preferably 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. Electromagnetic radiation can be applied for about 5-60 minutes, preferably for about 15-20 minutes, at about 0.1-5W, preferably with about 1W. In one embodiment of the invention, two electromagnetic radiation sources (such as lasers and LED lamps) are used, and both sources are suitable for providing irradiation with a wavelength of 550nm to 750nm, preferably 600nm to 700nm, preferably 640nm to 670nm. In another embodiment of the invention, irradiation can be provided by a prostate, anus, vagina, mouth and nose device for insertion into a body cavity. In another embodiment of the invention, irradiation can be provided by interstitial light activation, for example, a fiber laser is inserted into a lung, liver, lymph node or breast using a fine needle. In another embodiment of the invention, illumination can be provided by endoscopic photoactivation, for example, for delivery of light to the lungs, stomach, colon, bladder, or neck.

[0461] For the avoidance of doubt, any embodiment of a given aspect of the present invention may be combined with any other embodiment of the same aspect of the present invention within the practical scope. Additionally, it will be understood that any preferred or optional embodiment of any aspect of the present invention is also to be considered as a preferred or optional embodiment of any other aspect of the present invention within the practical scope.

[0462] Synthesis experiment details

[0463] Synthesis Example 1 (Comparative) - Synthesis of Chlorin e6 13-Hydroxymethyltrimethyl Ester (Compound 1)

[0464]

[0465] Step 1:To a 100 mL RBF was added chlorin e6 trimethyl ester (1.00 g, 1.566 mmol, 1 eq), THF (40 mL), osmium tetroxide (4 mg, 0.016 mmol, 0.01 eq), deionized water (3 mL), AcOH (3 mL) and sodium periodate (0.737 g, 3.444 mmol, 2.2 eq). The resulting mixture was stirred under nitrogen in the dark at ambient temperature for 19 hours. Another portion of sodium periodate (0.068 g, 0.313 mmol, 0.2 eq) was added and the solution was stirred for an additional 8 hours. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (60 mL), transferred to a separatory funnel and washed with brine (30 mL), saturated aqueous NaHCO3 (30 mL), water (50 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e6 13-formyltrimethyl ester (1.0 g, quantitative) as a reddish-brown solid.

[0466] 1 H NMR (400MHz, CDCl3) δ11.52(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,1 H),2.30-2.18(m,2H),1.78-1.69(m,7H),-1.31(brs,1H),-1.80(brs,1H).

[0467] Step 2: Chlorin e6 13-formyl trimethyl ester (850 mg, 1.327 mmol, 1 equivalent), MeOH (30 mL), DCM (15 mL) and sodium borohydride (100 mg, 2.653 mmol, 2 equivalents) were added to a 250 mL RBF. The resulting mixture was stirred at ambient temperature for 1 hour under nitrogen. The reaction mixture was diluted with water (60 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2x30 mL) and the combined DCM layers were washed with water (50 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark red solid. The crude product was redissolved in DCM (25 mL) and washed with dilute NaHCO3 aqueous solution (10 mL), then pH=7 phosphate buffer (10 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give compound 1 (0.81 g, 94%) as a dark red solid.

[0468] 1 H NMR(400MHz,CDCl3)δ9.70(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).

[0469] Synthesis Example 2 - Synthesis of Chlorin e6 Trimethyl Ester 13-(6-(Triphenylphosphonium Bromide)hexyl)carbamate (Compound 2)

[0470]

[0471] Step 1: To a 50 mL RBF, (6-((tert-butoxycarbonyl)amino)hexyl)triphenylphosphonium bromide (676 mg, 1.246 mmol, 8 equivalents), DCM (7 mL) and TFA (1.5 mL) were added. The resulting solution was stirred at ambient temperature for 1 hour, then concentrated on a rotary evaporator. The residue was resuspended and concentrated twice from chloroform (2 x 40 mL) to give 6-aminohexyltriphenylphosphonium bromide TFA (0.995 g) as a viscous oil, which was then dissolved in DCM (2 mL) for subsequent coupling reactions.

[0472] Step 2:Chlorin e6 13-hydroxymethyltrimethyl ester (Compound 1) (100 mg, 0.156 mmol, 1 eq), carbonyldiimidazole (76 mg, 0.467 mmol, 3 eq), DCM (5 mL) and 4-dimethylaminopyridine (DMAP) (25 mg, 0.205 mmol, 1.3 eq) were added to a 50 mL RBF. The resulting mixture was stirred under nitrogen for 3 hours and monitored by TLC. TEA (455 mg, 4.496 mmol, 29 eq) was added, followed by 6-aminohexyltriphenylphosphonium bromide (0.995 g, containing approximately 0.444 g TFA in DCM 2 mL) and stirring was continued for 4 days. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with 1 M HCl (2 x 15 mL), 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 residue containing the main dark green spot (R in 5% MeOH / DCM) was combined. f =0.10) fractions to afford compound 2 (53 mg, 31% over 2 steps) as a dark green solid.

[0473] 1 H NMR(400MHz, CDCl3)δ9.65(s,1H),9.61(s,1H),8.74(s,1H),7.60-7.50(m,9H),7.50-7.35(m,7H),6.3 6(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,2 H),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),2.06-1.8 5(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).

[0474] Synthesis Example 3 - Synthesis of Chlorin e6 Trimethyl Ester 13-(N-(3-(3-triphenylphosphoniumpropoxy)propyl)chloride)carbamate (Compound 3)

[0475]

[0476] Step 1:In the 500mL 3 neck RBF that is equipped with 3cm stirring rod, pack into bis(3-chloropropyl) ether (20.00g, 70.15mmol, 1.66 equivalent), triphenylphosphine (18.40g, 70.15mmol, 1 equivalent), sodium iodide (7.01g, 46.77mmol, 0.66 equivalent) and acetonitrile (340mL).RBF is arranged on oil bath and is equipped with air condenser, wherein at N 2, under 90 ℃ external temperature, begin to stir (500rpm).Mixture was stirred 72 hours.After this, reaction flask is cooled to room temperature, and suspension is passed through 2cm The mixture was filtered through a plug and washed thoroughly with acetonitrile (250 mL). The light 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. The combined product was visualized by UV in 6% MeOH / DCM with R f =0.35 fractions and concentrated by rotary evaporation. The resulting residue was further purified by column chromatography (silica gel, 9 x 7 cm). DCM was used as eluent until triphenylphosphine was no longer observed by TLC, and then the eluent was replaced with 10% MeOH in DCM to remove the product from the column. The combined product was visualized by UV in 6% MeOH / DCM with R f = 0.35 fractions and concentrated by rotary evaporation to give (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride (18.74 g, 62%) as a light red solid.

[0477] 1 H NMR (400MHz, CDCl3) δ7.87-7.76(m,9H),7.75-7.63(m,6H),3.93-3.80(m,2H),3.75(td,J=5.7,1.3Hz,2H),3.58(q,J=6.3Hz,4H),2.05-1.88(m,4H).

[0478] Step 2:To 50mL RBF, add (3-(3-chloropropoxy)propyl)triphenylphosphonium chloride (4.0g, 9.23mmol, 1 equivalent), NaN (11.08g, 1.2 equivalents), NaBr (38mg, 0.04 equivalents), tetrapropylammonium bromide (49mg, 0.02 equivalents) and water (10mL). After connecting a water condenser, the flask was heated at 110°C under stirring for 44 hours. The mixture was then cooled and EtOAc (50mL) was added. The mixture was transferred to a separatory funnel and washed with water (3x 30mL) and brine (30mL). The combined aqueous layer was extracted with DCM (3x 20mL). The combined organic layer was then dried (MgSO ), filtered and concentrated to obtain (3-(3-azidopropoxy)propyl)triphenylphosphonium chloride (3.20g, 79%) as a light yellow solid.

[0479] 1 H NMR (400MHz, CDCl3) δ7.86-7.77(m,9H),7.73-7.66(m,6H),3.90-3.80(m,2 H),3.75(t,2H),3.53(t,2H),3.33(t,2H),1.99-1.89(m,2H),1.82(p,2H).

[0480] Step 3: Into 3 neck 100mL RBF, pack into (3-(3-azidopropoxy)propyl)triphenylphosphonium chloride (1.00g, 2.273mmol, 1 equivalent), 10%Pd / C (20mg), methyl alcohol (10mL) and stirring rod.By hydrogen balloon, be connected to the middle joint of flask by short length air condenser, and side arm is connected to 3-way valve.The device is evacuated, then refilled with nitrogen (3 times), evacuated and refilled with hydrogen (2 times).Then gained solution was stirred (550rpm) 2 hours at 35 ℃ under hydrogen atmosphere.Then solution was passed through The mixture was filtered through an elution tube (0.5 x 3 cm), washed with chloroform (2 x 10 mL), and the solvent was removed under reduced pressure to give (3-(3-aminopropoxy)propyl)triphenylphosphonium chloride as a viscous oil which solidified on standing (1.05 g, quantitative).

[0481] 1 H NMR (400MHz, CDCl3) δ7.86-7.76(m,9H),7.73-7.66(m,6H),3.88-3.79(m,2H),3.7 3(t,2H),3.51(t,2H),2.75(t,2H),1.99-1.87(m,2H),1.68(p,2H),1.41(brs,2H).

[0482] Step 4: Chlorin e6 13-hydroxymethyl trimethyl ester (Compound 1) (60 mg, 0.0934 mmol, 1 eq), carbonyldiimidazole (30 mg, 0.1867 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.4 eq) were added to a 25 mL RBF. The resulting mixture was stirred under nitrogen for 3 hours and monitored by TLC. (3-(3-aminopropoxy)propyl)triphenylphosphonium chloride (193 mg, 0.4668 mmol, 5 eq) 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 x 20 mL), pH = 7 phosphate buffer (30 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography (3 x 12 cm) using 3%-5% MeOH / DCM. The fractions containing the major dark green spot (R in 5% MeOH / DCM) were combined. f =0.20) fraction to give compound 3 (33 mg, 33%) as a dark green solid.

[0483] 1 H NMR(400MHz, CDCl3)δ9.68(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),2.62-2.5 2(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).

[0484] Synthesis Example 4 - Synthesis of Chlorin e6 Trimethyl Ester 13-(N-(3-Triphenylphosphoniumpropyl) Bromide) Carbamate (Compound 4)

[0485]

[0486] Chlorin e6 13-hydroxymethyl trimethyl ester (Compound 1) (100 mg, 0.156 mmol, 1 eq), carbonyldiimidazole (50 mg, 0.311 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.25 eq) were added to a 25 mL RBF. The resulting mixture was stirred at 25 ° C under nitrogen for 3 hours. (3-Aminopropyl) triphenylphosphonium bromide (311 mg, 0.778 mmol, 5 eq) 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 1M HCl (2 x 10 mL), pH = 7 phosphate buffer (25 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. The pooled samples contained the main dark green spot (R in 5% MeOH / DCM). f =0.15) fraction to give compound 4 (125 mg, 75%) as a dark green solid.

[0487] 1 H NMR(400MHz, CDCl3)δ9.74(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),4.3 7(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).

[0488] Synthesis Example 5 - Synthesis of Chlorin e6 Trimethyl Ester 13-(N-(2-Triphenylphosphoniumethyl) Bromide) Carbamate (Compound 5)

[0489]

[0490] Chlorin e6 13-hydroxymethyl trimethyl ester (Compound 1) (90 mg, 0.140 mmol, 1 eq), carbonyl diimidazole (45 mg, 0.280 mmol, 2 eq), DCM (4 mL) and DMAP (5 mg, 0.0409 mmol, 0.3 eq) were added to a 25 mL RBF. The resulting mixture was stirred at 22 ° C under nitrogen for 3 hours. (2-aminoethyl) triphenylphosphonium bromide (270 mg, 0.700 mmol, 5 eq) 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 1M HCl (2 x 10 mL), pH = 7 phosphate buffer (25 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3%-6% MeOH / DCM. The pooled samples contained the main dark green spot (R in 5% MeOH / DCM). f =0.10) fraction to give compound 5 (38 mg, 26%) as a dark green solid.

[0491] 1 H NMR(400MHz, CDCl3)δ9.69(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).

[0492] Synthesis Example 6 - Synthesis of Chlorin e6 13-(N-methylamino)methyltrimethyl ester (Compound 6)

[0493]

[0494] Chlorin e6 13-formyl trimethyl ester (50mg, 0.078mmol, 1 equivalent), DCM (1mL), methanol (3mL), TEA (32mg, 0.312mmol, 4 equivalents) and methylamine hydrochloride (11mg, 0.156mmol, 2 equivalents) are added to 25mL RBF. The gained mixture is stirred in the dark for 1 hour under nitrogen, then another part of methylamine hydrochloride (11mg, 0.156mmol, 2 equivalents) and TEA (32mg, 0.312mmol, 4 equivalents) are added, and stirring is continued for another 1 hour. Add NaBH4 (15mg, 0.390mmol, 5 equivalents) and continue stirring for 30 minutes. Reactant is acidified with 2M HCl (1mL) and stirred for 10 minutes. Phosphate buffer pH=7 (15 mL) was added and the mixture was extracted with DCM (2 x 5 mL) before drying (Na2SO4) and concentrating by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3%-7% MeOH / DCM. The residue containing the main dark green spot (R in 10% MeOH / DCM) was combined. f =0.30) fraction to give compound 6 (27 mg, 53%) as a dark green solid.

[0495] 1 H NMR(400MHz, CDCl3)δ9.56(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).

[0496] Synthesis Example 7 - Synthesis of Chlorin e6 13-(N-methyl-5-triphenylphosphonium bromide pentylamide) trimethyl ester (Compound 7)

[0497]

[0498] Chlorin e6 13-(N-methylamino) methyl trimethyl ester (compound 6) (20mg, 0.0305mmol, 1 equivalent), 4-(carboxybutyl) triphenylphosphonium bromide (18mg, 0.0640mmol, 2.1 equivalents), DCM (1mL) and DMTMM (18mg, 0.0640mmol, 2.1 equivalents) are added to 25mL RBF. The gained mixture is stirred in the dark for 2 hours at ambient temperature under nitrogen. The reaction mixture is transferred to a separating funnel, diluted with DCM (15mL) and washed with 0.5M HCl (10mL). Re-extracted aqueous layer is obtained with DCM (2x 5mL), and the organic matter merged is washed with pH 7 phosphate buffers (10mL), then washed with 1M NaHCO the aqueous solution (10mL). By organic phase drying (Na sO ) and concentrated by rotary evaporation, a blue-black film is obtained. The residue was purified by column chromatography using 3%-7% MeOH / DCM. The fractions containing the main dark green spot (R in 10% MeOH / DCM) were combined. f =0.30) fraction to give compound 7 (10 mg, 30%) as a dark green solid.

[0499] 1 H NMR (400MHz, CDCl3) δ9.73(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),2.6 2-2.52(m,1H),2.23-2.12(m,4H),1.90-1.65(m,18H),-1.44(brs,1H),-1.56(brs,1H).

[0500] Synthesis Example 8 - Synthesis of Chlorin e6 Trimethyl Ester 13-(N-methyl-(3-triphenylphosphoniumpropoxy)chloride)carbamate (Compound 8)

[0501]

[0502] Chlorin e6 13-(N-methylamino)methyl trimethyl ester (Compound 6) (100 mg, 0.152 mmol, 1 eq), carbonyldiimidazole (49 mg, 0.304 mmol, 1.5 eq) and DCM (4 mL) were added to a 25 mL RBF. The resulting mixture was stirred under nitrogen for 1 hour. (3-Hydroxypropyl)triphenylphosphonium chloride (108 mg, 0.304 mmol, 1.5 eq) in DCM (2 mL) was added and stirring was continued overnight in the dark at 23 ° C. The reaction mixture was diluted with DCM (15 mL), transferred to a separatory funnel and washed with water (15 mL), extracted with DCM (2 x 5 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 3%-8% MeOH / DCM. The product containing the main dark green spot (R in 7% MeOH / DCM) was merged. f =0.25) fraction to give compound 8 (56 mg, 35%) as a dark green solid.

[0503] 1 H NMR(400MHz, CDCl3)δ9.73(s,1H),9.55(s,1H),8.72(s,1H),7.75-7.60(m,5H),7.55-7.45(m,2 H),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).

[0504] Synthesis Example 9 - Synthesis of Chlorin e6 (2-methoxyethyl) methylamine dimethyl ester 13-(N-(3-triphenylphosphoniumpropyl) bromide) carbamate (Compound 9)

[0505]

[0506] Step 1:Chlorin e6 (0.5 g, 1 eq), di-tert-butyl dicarbonate ((Boc)2O) (188 mg, 1.03 eq) and DCM (60 ml) were loaded into a 1-neck 250 mL RBF. DMAP (8 mg, 0.08 eq) was added and the resulting solution was stirred at 40 ° C under a nitrogen atmosphere for 2 hours. 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 x 10 ml) and dried to give chlorin e6 anhydride (475 mg, 98%) as a black solid. It was used in the next step without further purification.

[0507] 1 H NMR(400MHz, CDCl3)δ9.52(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).

[0508] Step 2: Chlorin e6 anhydride (470mg, 1 equivalent), (2-methoxyethyl) methylamine (108mg, 1.5 equivalents) and DCM (30ml) were loaded into a 1-neck 250mL RBF. The resulting solution was stirred overnight at 35°C under a nitrogen atmosphere. The gained black solution was concentrated under reduced pressure and precipitated with ether. The precipitate was filtered and washed with ether (2x 10ml). The remaining black solid was purified by column chromatography using 10%-50% MeOH / DCM, and the fractions containing the first dark band of elution were merged to obtain chlorin e6 (2-methoxyethyl) methylamine (320mg, 59% yield, 95.33% according to HPLC purity) as a bluish-green solid.

[0509] 1H NMR(400MHz,DMSO-d6)δ9.80(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),4.3 0-4.10(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).

[0510] Step 3: Chlorin e6 (2-methoxyethyl) methylamine (310g, 1 equivalent), potassium carbonate (192mg, 3 equivalents), DMF (10mL) and stirring bar are added to 1 neck 250mL RBF. The flask is placed under nitrogen and stirred at 300rpm, and an air condenser is connected. Then iodomethane (0.072mL, 3 equivalents) is added. The solution is stirred at 25°C over the weekend. The solvent is removed under reduced pressure at 60°C to obtain a dark green solid. The crude material is dissolved in DCM (30mL), washed with water (2x 10mL), dried (Na2SO4) and concentrated under reduced pressure to obtain a crude product (350mg) as a dark blue / green solid. Now HPLC analysis shows that the purity is about 96%. The residual blue / 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)methanamine dimethyl ester (310 mg, 98% yield, 98.69% purity by HPLC) as a blue-green solid.

[0511] 1 H NMR(400MHz, CDCl3)δ9.70(s,1H),9.55(m,1H),8.72(m,1H),8.10-8.00(m,2H),6.4 4(d,1H),6.14(d,1H),5.50-5.20(m,2H),4.50(m,2H),4.30-4.10(m,2H),3.90-3.6 5(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).

[0512] Step 4:Chlorin e6 (2-methoxyethyl) methylamine dimethyl ester (310 mg, 1 equivalent), THF (10 mL), osmium tetroxide (about 1 mg, 0.01 equivalent), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 equivalents) are added to 250 mL RBF. The gained mixture is stirred overnight at ambient temperature in the dark under nitrogen. The reaction mixture is concentrated using a rotary evaporator to remove THF, and then dissolved in DCM (20 mL), transferred to a separating funnel and washed with salt solution (10 mL), saturated NaHCO (10 mL), water (10 mL), dried (Na SO ) and concentrated by rotary evaporation to obtain a reddish-brown powdery solid. The residual 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)methanamine dimethyl ester (210 mg, 68% yield, 93.43% purity by HPLC) as a reddish-brown powdery solid.

[0513] 1 H NMR (400MHz, CDCl3) δ11.55(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,14H),3.55(m,7H),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).

[0514] Step 5:Chlorin e6 13- formyl (2-methoxyethyl) methylamine dimethyl ester (210mg, 1 equivalent), MeOH (5mL), DCM (2mL) and sodium borohydride (22mg, 2 equivalents) are added to 100mL RBF. The gained mixture is stirred at ambient temperature for 1 hour under nitrogen. Use rotary evaporator to concentrate the reaction mixture. Then the mixture is diluted with DCM (20mL) and washed with water (20mL). Collect the DCM layer and further extract the aqueous layer with DCM (10mL). The DCM layer merged is washed with salt water (20mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid (about 200mg). Column chromatography is carried out on residue. The crude product is dissolved in DCM and the gradient elution using 1% MeOH / DCM (300mL), then 2% MeOH / DCM (200mL), then 3% MeOH / DCM (200mL). When the first color starts to elute, collect fractions of approximately 20 mL in size. Combine fractions containing product (main dark green spot, R in 5% MeOH / DCM) and f = about 0.7) to afford chlorin e6 13-hydroxymethyl(2-methoxyethyl)methanamine dimethyl ester (Compound 9A) (110 mg, 52% yield, 97.34% purity by HPLC) as a blue / green solid.

[0515] 1 H NMR(400MHz, CDCl3)δ9.70(s,1H),9.60(m,1H),8.78(m,1H),5.90(s,2H),5.5 0-5.30(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).

[0516] Step 6:Chlorin e6 13-hydroxymethyl (2-methoxyethyl) methylamine dimethyl ester (Compound 9A) (70 mg, 1 equivalent), carbonyl diimidazole (32 mg, 2 equivalents), DCM (3 mL) and DMAP (2 mg) were added to 25 mL RBF. The resulting mixture was stirred under nitrogen for 3 hours. (3-aminopropyl) triphenylphosphonium bromide (200 mg, 5 equivalents) was added and continued to stir overnight at ambient temperature. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (15 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue (about 100 mg). The residue was purified by column chromatography (3 x 12 cm) using 0%-6% MeOH / DCM (as the solution load in the eluent). The main dark green band (R in 5% MeOH / DCM) was purified by column chromatography (3 x 12 cm). f =0.15) and concentrated to give compound 9 (65 mg, 58% yield, 97.25% purity according to HPLC) as a dark green solid.

[0517] 1 H NMR(400MHz, CDCl3)δ9.78(m,1H),9.65(m,1H),8.75(m,1H),7.48(t,1H),7.25( m,9H),7.00(m,9H),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),2.7 0-2.40(m,1H),2.30-2.00(m,2H),1.80-1.60(m,8H)-1.40(m,1H),-1.60(m,1H).

[0518] Synthesis Example 10 - Synthesis of Chlorin e6 N-Methylbutylamine Dimethyl Ester 13-(N-(3-Triphenylphosphoniumpropyl) Bromide) Carbamate (Compound 10)

[0519]

[0520] Step 1:Chlorin e6 anhydride (500 mg, 1 equivalent), N-methylbutylamine (108 mg, 1.5 equivalents) and DCM (30 ml) were loaded into a 1-neck 250 mL RBF. 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 ether. The precipitate was filtered, washed with ether (2 x 10 ml) and dried on a rotary evaporator to give chlorin e6 N-methylbutylamine (670 mg, quantitative yield, 85.80% purity according to HPLC) as a bluish-green solid. The crude product was used in the next step without further purification.

[0521] 1 H NMR(400MHz,DMSO-d6)δ9.75(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).

[0522] Step 2: Chlorin e6 N-methylbutylamine (650g, 1 equivalent), potassium carbonate (404mg, 3 equivalents), DMF (10mL) and a stirring bar were added to a 1-neck 250mL RBF. The flask was placed under nitrogen. Iodomethane (0.150mL, 2.5 equivalents) was then added. The solution was stirred overnight at 25°C. The solvent was removed under reduced pressure at 60°C to give a dark green solid. The crude material was dissolved in DCM (30mL), washed with water (2x 10mL), dried (Na2SO4) and concentrated under reduced pressure to give chlorin e6 N-methylbutylamine dimethyl ester (700mg, quantitative yield, 86.64% according to HPLC purity) as a dark blue / green solid. The crude product was used in the next step without further purification.

[0523] 1H NMR(400MHz, CDCl3)δ9.70(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).

[0524] Step 3: Chlorin e6 N-methylbutylamine dimethyl ester (700 mg, 1 eq), THF (10 mL), osmium tetroxide (approximately 2 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (561 mg, 2.6 eq) were added to a 250 mL RBF. The resulting mixture was stirred (420 rpm) at ambient temperature under nitrogen. The reaction mixture was concentrated using a rotary evaporator to remove THF and then redissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated NaHCO3 aqueous solution (10 mL), water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e6 13-formyl N-methylbutylamine dimethyl ester (670 mg, quantitative yield, 85.31% purity according to HPLC) as a reddish-brown powdery solid. The crude product was used in the next step without further purification.

[0525] 1 H NMR (400MHz, CDCl3) δ11.55(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,17H),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).

[0526] Step 4: Chlorin e6 13-formyl N-methylbutylamine dimethyl ester (650mg, 1 equivalent), MeOH (15mL), DCM (4mL) and sodium borohydride (70mg, 2 equivalents) are added to 100mL RBF. The gained mixture is stirred at ambient temperature for 2 hours under nitrogen. The reaction mixture is concentrated using a rotary evaporator. The mixture is then diluted with DCM (20mL) and washed with water (20mL). The DCM layer is collected and further extracted with DCM (10mL). The DCM layer merged is washed with salt water (20mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid (about 300mg). Column chromatography is carried out on residue. The crude product is dissolved in DCM and the gradient elution using 1% MeOH / DCM (300mL), then 2% MeOH / DCM (300mL), then 3% MeOH / DCM (300mL). When the first color starts to elute, collect fractions of approximately 20 mL in size. Combine fractions containing product (main dark green spot, R in 5% MeOH / DCM) and f = about 0.7) of fractions 6, 7, and 8 to afford chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (Compound 10A) as a blue / green solid (230 mg, 36% yield, 98.49% purity by HPLC).

[0527] 1 H NMR(400MHz, CDCl3)δ9.70(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,3H),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).

[0528] Step 5:Chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (Compound 10A) (140 mg, 1 equivalent), carbonyl diimidazole (64 mg, 2 equivalents), DCM (6 mL) and DMAP (2 mg) were added to a 100 mL RBF. The resulting mixture was stirred under nitrogen for 3 hours. (3-aminopropyl) triphenylphosphonium bromide (400 mg, 5 equivalents) was added and continued to stir overnight at ambient temperature. After spending the night, additional carbonyl diimidazole (32 mg) was added and the reactants were then heated at 30 ° C (heating block) for another 3 hours. At this stage, the reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (2 x 10 mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green residue. Carbonyl diimidazole (64 mg), DCM (6 mL) and DMAP (2 mg) were added to the residue. The gained mixture was stirred 3 hours under nitrogen at 30 ℃ (outside).Add (3-aminopropyl) triphenylphosphonium bromide (400mg, 5 equivalents) again and continue stirring overnight at 30 ℃.Then the reaction mixture was diluted with DCM (20mL), transferred to a separating funnel and washed with water (20mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain dark green residue (about 150mg). Residue is purified by column chromatography using 0%-6% MeOH / DCM (as the solution load in the eluent). The main dark green band (R in 5% MeOH / DCM) was purified by column chromatography. f =0.15) and concentrated to afford compound 10 (62 mg, 28% yield, 98.08% purity by HPLC) as a dark green solid.

[0529] 1 H NMR (400MHz, CDCl3) δ9.70(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,5 H),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,2 H),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).

[0530] Synthesis Example 11 - Synthesis of Chlorin e6 13-Hydroxymethyl N-(methylaminopropyl)triphenylphosphonium dimethyl bromide (Compound 11)

[0531]

[0532] Step 1: A 1-neck 100 mL RBF was charged with chlorin e6 anhydride (500 mg, 1 equivalent), (3-(methylamino)propyl)triphenylphosphonium bromide hydrobromide (641 mg, 1.5 equivalents) and DCM (30 ml). The resulting solution was stirred at 35 ° C under a nitrogen atmosphere overnight. The resulting black solution was concentrated under reduced pressure and precipitated with diethyl ether. The precipitate was filtered, washed with diethyl ether (2x10 ml) and dried on a rotary evaporator to give chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide (1.20 gm, quantitative yield, 72.47% purity according to HPLC) as a blue / green solid. The crude product was used in the next step without further purification.

[0533] 1 H NMR(400MHz,DMSO-d6)δ9.75(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),4.6 0(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).

[0534] Step 2: Chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide (1.0 gm, 1 equivalent), potassium carbonate (415 mg, 3 equivalents), DMF (10 mL) and a stirring rod were added to a 1-neck 250 mL RBF. The flask was placed under nitrogen and stirred at 300 rpm, with an air condenser connected. Iodomethane (0.150 mL, 2.5 equivalents) was then added. The solution was stirred overnight at 30 ° C. The solvent was removed under reduced pressure at 60 ° C to obtain a dark green solid. The crude material was dissolved in DCM (30 mL), washed with water (2 x 10 mL), dried (Na SO ) and concentrated under reduced pressure to obtain a crude product (700 mg) as a dark blue / green solid. HPLC analysis showed that the purity was approximately 75%. The residual blue / green solid was purified by column chromatography using 2%-3% MeOH / DCM, and fractions containing the first dark band to elute were combined to give chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide (440 mg, quantitative yield, 99.69% purity by HPLC) as a blue / green solid.

[0535] 1 H NMR(400MHz, CDCl3)δ9.60(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).

[0536] Step 3: Chlorin e6 N-(methylaminopropyl)triphenylphosphonium bromide dimethyl ester (200 mg, 1 eq), THF (10 mL), osmium tetroxide (approximately 1 mg, 0.01 eq), deionized water (0.8 mL), AcOH (0.8 mL) and sodium periodate (247 mg, 2.6 eq) were added to a 250 mL RBF. The resulting mixture was stirred (420 rpm) at ambient temperature overnight in the dark under nitrogen. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (20 mL), transferred to a separatory funnel and washed with brine (10 mL), saturated aqueous NaHCO 3 solution (10 mL), water (10 mL), dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give chlorin e6 13-formyl N-(methylaminopropyl)triphenylphosphonium dimethyl bromide (220 mg, quantitative yield, 72.47% purity according to HPLC) as a reddish-brown powdery solid. The crude product was used in the next step without further purification.

[0537] 1H NMR (400MHz, CDCl3) δ11.50(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),3.7 0(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).

[0538] Step 4: Chlorin e6 13-formyl N-(methylaminopropyl) triphenylphosphonium bromide dimethyl ester (210mg, 1 equivalent), MeOH (15mL), DCM (4mL) and sodium borohydride (15mg, 2 equivalents) are added to 100mL RBF. The gained mixture is stirred at ambient temperature for 2 hours under nitrogen. Use rotary evaporator to concentrate the reaction mixture. Then the mixture is diluted with DCM (20mL) and washed with water (20mL). Collect the DCM layer and further extract the aqueous layer with DCM (10mL). The DCM layer merged is washed with salt water (20mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid (about 200mg). Column chromatography is carried out on residue. The crude product is dissolved in DCM and the gradient elution with 1% MeOH / DCM (300mL), then 2% MeOH / DCM (300mL), then 3% MeOH / DCM (300mL) is used. When the first color starts to elute, collect fractions of approximately 20 mL in size. Combine fractions containing product (main dark green spot, R in 5% MeOH / DCM) and f = about 0.7) of fractions 6, 7 and 8 to give compound 11 (45 mg, 21% yield, 90.77% purity according to HPLC) as a green solid.

[0539] 1H NMR(400MHz, CDCl3)δ9.60(s,1H),9.40(m,1H),8.65(s,1H),7.80-7.50(m,12H),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).

[0540] Synthesis Example 12 - Synthesis of Chlorin e6β-D-1-thioglucose-N-methylpropylamide Conjugate Tetraacetate 13-Hydroxymethyldimethyl Ester (Compound 12)

[0541]

[0542] 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 (420 rpm) at ambient temperature for 1 hour and then concentrated on a rotary evaporator. The residue was resuspended and concentrated twice from chloroform (2 x 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.

[0543] Step 2:Into a 1-neck 250 mL RBF was charged chlorin e6 anhydride (2.0 g, 1 eq), (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 eq), sodium bicarbonate (435 mg, 1.5 eq) and DCM (30 ml). The resulting solution was stirred at 30 ° C under a nitrogen atmosphere overnight. The resulting black solution was concentrated under reduced pressure and precipitated with ether. The precipitate was filtered, washed with ether (2 x 10 ml) and dried over a rotary evaporator. The residual 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 dihydrochlorin e6β-D-1-thioglucosinolate-N-methylpropylamide conjugate tetraacetate diacid (1.2 g, 34% yield, 96.19% purity by HPLC) as a blue-green solid.

[0544] 1 H NMR(400MHz,DMSO-d6)δ9.75(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,1 H),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).

[0545] Step 3:Chlorin e6β-D-1-thioglucosinolate-N-methylpropylamide conjugate tetraacetate diacid (1.0gm, 1 equivalent), potassium carbonate (490mg, 3 equivalents), DMF (10mL) and stirring bar are added to a 1-neck 250mL RBF. The flask is placed under nitrogen and stirred at 300rpm, with an air condenser connected. Iodomethane (0.218mL, 2.5 equivalents) is then added. The solution is stirred overnight at 30°C. The solvent is removed under reduced pressure at 60°C to obtain a dark green solid. The crude material is dissolved in DCM (30mL), washed with water (2x 10mL), dried (Na2SO4) and concentrated under reduced pressure to obtain a crude product (about 1.2g) as a dark blue / green solid. HPLC analysis now shows that the purity is about 65%. The residual 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 e6β-D-1-thioglucosinolate-N-methylpropylamide conjugate tetraacetate dimethyl ester (700 mg, 69% yield, 85.89% purity by HPLC) as a blue / green solid.

[0546] 1 H NMR(400MHz, CDCl3)δ9.70(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).

[0547] Step 4:Chlorin e6β-D-1-thioglucosinolate-N-methylpropylamide conjugate tetraacetate dimethyl ester (700 mg, 1 eq), THF (25 mL), osmium tetroxide (approximately 2 mg, 0.01 eq), deionized water (2.5 mL), AcOH (2.5 mL) and sodium periodate (373 mg, 2.6 eq) were added to a 250 mL RBF. The resulting mixture was stirred (420 rpm) at ambient temperature overnight and at 30° C. for one hour in the dark under nitrogen. The reaction mixture was concentrated using a rotary evaporator to remove THF, then redissolved in DCM (20 mL), transferred to a separatory funnel and washed with water (10 mL), dried (Na2SO4) and concentrated by rotary evaporation to give chlorin e6β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-formyldimethyl ester (700 mg, 47.93% purity according to HPLC) as a reddish-brown powdery solid. The crude product was used in the next step without further purification.

[0548] 1 H NMR (400MHz, CDCl3) δ11.55(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,24H),3.32(s,3H),2.70-2.60(m,2H),2.30-2.10(m,6H),2.00(m,16H),1.70(m,8H),-1.75(brs,1H).

[0549] Step 5:Chlorin e6β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-formyl dimethyl ester (700mg, 1 equivalent), MeOH (20mL), DCM (8mL) and sodium borohydride (19mg, 0.72 equivalent) are added to 100mL RBF. The gained mixture is stirred at ambient temperature for 1 hour under nitrogen. Use rotary evaporator to concentrate the reaction mixture, obtain dark green solid (about 800mg), which is redissolved among MeOH (10mL), and use rotary evaporator to concentrate (3 circulations) under about 65 ℃ and 700 millibar. Finally, solvent MeOH is evaporated completely, and crude product (about 700mg) is obtained. Column chromatography is carried out to residue. The crude product is dissolved among the DCM, and the gradient elution of 1%MeOH / DCM (300mL), then 2%MeOH / DCM (200mL), then 3%MeOH / DCM (200mL) is used. When the first color starts to elute, collect fractions of approximately 20 mL in size. Combine fractions containing product (main dark green spot, R in 5% MeOH / DCM) and f = about 0.7) of fractions 6, 7, and 8 and concentrated to afford compound 12 (410 mg, 59% yield, 39.06% purity by HPLC) as a blue / green solid.

[0550] 1 H NMR(400MHz, CDCl3)δ9.65(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).

[0551] Synthesis Example 13 - Synthesis of Chlorin e6β-D-1-thioglucose-N-methylpropylamide Conjugate 13-Hydroxymethyldimethyl Ester (Compound 13)

[0552]

[0553] To a solution of chlorin e6β-D-1-thioglucosinolate-N-methylpropylamide conjugate tetraacetate 13-hydroxymethyldimethyl ester (Compound 12) (120 mg, 0.095 mmol, 1 eq) in MeOH (3 mL) and DCM (3 mL) was added NaOMe (4.6 M in MeOH, 0.020 mL, 0.095 mmol, 1 eq) and the mixture was stirred under nitrogen (420 rpm) for 1 hour. After 45 minutes, HPLC analysis 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 eluted with a gradient of 5%-7% MeOH / DCM (to elute high R f The mixture was eluted with a gradient of 7% to 12% MeOH / DCM. Fractions were collected when the first dark band began to elute. Fractions 6-14 were combined and concentrated to afford compound 13 (52 mg, 62% yield, 98.34% purity by HPLC) as a dark green solid.

[0554] 1 H NMR(400MHz,DMSO-d6)δ9.75(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,3 H),2.70-2.45(m,2H),1.60-1.40(m,6H),-1.60(m,1H),-1.80(m,1H).

[0555] Synthesis Example 14 - Synthesis of Chlorin e6β-D-1-thioglucose-N-methylpropylamide Conjugate Tetraacetate 13-(3-(Triphenylphosphoniumpropyl)bromide)carbamate dimethyl ester (Compound 14)

[0556]

[0557] Chlorin e6β-D-1-thioglucose-N-methylpropylamide conjugate tetraacetate 13-hydroxymethyl dimethyl ester (compound 12) (300mg, 1 equivalent), carbonyl diimidazole (92mg, 2 equivalents), DCM (6mL) and DMAP (5mg) are added to 50mL RBF. The resulting mixture is stirred for 3 hours under nitrogen. (3-aminopropyl) triphenylphosphonium bromide (573mg, 5 equivalents) is added and continues to stir overnight at ambient temperature. The reaction mixture is concentrated and redissolved in 5mL of 3% MeOH in DCM solution and directly loaded onto the post. The residue is purified by column chromatography using 0%-6% MeOH / DCM (as 3% MeOH in DCM solution loading). The main dark green band (R in 5% MeOH / DCM) is purified. f =0.15) fractions were concentrated to give compound 14 (80 mg, 19% yield, 77.81% purity according to HPLC) as a dark green solid.

[0558] 1 H NMR(400MHz, CDCl3)δ9.60(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,15H),1.60-1.40(m,12H),0.80(m,6H)-1.40 -1.80(m,2H).

[0559] Synthesis Example 15 - Synthesis of Chlorin e6 N-Methylbutylamine 13-N-Methylaminodimethyl Ester (Compound 15)

[0560]

[0561] To a 50 mL RBF was added chlorin e6 13-formyl N-methylbutylamine dimethyl ester (327 mg, 0.470 mmol, 1 equivalent), DCM (5 mL), methanol (20 mL), triethylamine (119 mg, 1.18 mmol, 2.5 equivalents) and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 equivalents). The resulting mixture was stirred in the dark under nitrogen for 2.5 hours. Triethylamine (119 mg, 1.18 mmol, 2.5 equivalents) and methylamine hydrochloride (79 mg, 1.19 mmol, 2.5 equivalents) were then added, and the reactants were stirred for another 1.5 hours. NaBH4 (178 mg, 4.70 mmol, 10 equivalents) was added and stirring continued for 16 hours. The reactants were acidified with 2M HCl (approximately 4 mL) and stirred for 10 minutes. Phosphate buffer pH=7 (20 mL) was added and the mixture was extracted with DCM (3 x 20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using 4%-6% MeOH / DCM (as the solution load in the eluent). The main fraction (R in 10% MeOH / DCM) was concentrated by rotary evaporation. f =0.30) to give compound 15 (304 mg, 91%) as a dark blue solid.

[0562] 1 H NMR (400 MHz, chloroform-d) δ9.56 (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=7.3Hz,1H),0.95(t,J=7.3Hz,2H),-1.38–-1.75(m,2H).

[0563] Synthesis Example 16 - Synthesis of Chlorin e6 N-Methylbutylamine 13-(N-methyl-5-triphenylphosphonium bromide pentylamide) dimethyl ester (Compound 16)

[0564]

[0565] Chlorin e6 N-methylbutylamine 13-N-methylaminodimethyl ester (compound 15) (100mg, 0.141mmol, 1 equivalent), 4-(carboxybutyl) triphenylphosphonium bromide (125mg, 0.282mmol, 2.2 equivalents), DCM (6mL) and 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM) (83mg, 0.282mmol, 2.2 equivalents) were added to 25mL RBF. The resulting mixture was stirred in the dark under nitrogen at ambient temperature for 16 hours. The reaction progress was monitored by HPLC. The reaction mixture was transferred to a separatory funnel, diluted with DCM (30mL) and washed with 0.5M HCl (20mL). 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 3 (20 mL). The organic phase was dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark green film. The dark green film was subjected to column chromatography by dissolving in 4% MeOH / DCM and using a gradient elution of 4%-10% MeOH / DCM. When the first color began to elute, 25 mL sized fractions were collected. Fractions containing product (mainly dark green spots, R in 10% MeOH / DCM) were combined. f =0.3) fraction to give compound 16 (76 mg, 48%) as a dark green solid (purity 97.98% according to HPLC).

[0566] 1H NMR (400MHz, chloroform-d) δ9.77(s,1H),9.66(s,1H),8.73(d,J=8.9Hz,1H),7.63(dq,J=13.2,7.6Hz,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=6.4Hz,3H),3.85-3.71(m,4H),3.67(s,2H),3.56(d,J=7.3Hz,4H),3.46(d,J=3.3Hz,3H),3.41(d,J=2.8Hz ,3H),3.20(d,J=2.8Hz,3H),3.16(s,3H),3.09(s,1H),2.76(t,J=6.7Hz ,2H),2.69-2.45(m,1H),2.33-2.08(m,5H),1.88(d,J=7.8Hz,1H),1.82 -1.50(m,17H),1.40(q,J=7.5Hz,1H),1.33(s,1H),1.22(d,J=6.6Hz,1H),1.09(t,J=7.3Hz,1H),0.96(t,J=7.3Hz,2H), -1.53(d,J=31.5Hz,1H).

[0567] Synthesis Example 17 - Synthesis of Chlorin e6 13-Hydroxymethyl Triethyl Ester (Compound 17)

[0568]

[0569] Step 1: To a 1-neck 500 mL RBF was added chlorin e6 (10.0 g, 0.016 mol, 1 eq), potassium carbonate (8.33 g, 0.060 mol, 3.6 eq), DMF (120 mL) and a stirring bar. The flask was placed under nitrogen and stirred at 300 rpm with an air condenser attached. Ethyl iodide (6.73 mL, 0.083 mmol, 5 eq) was then added. The solution was heated at 40 ° C over the weekend. The solution was diluted with DCM (100 mL), stirred for 15 minutes, and filtered through The mixture was stirred for 2 hours at 4 ℃ for 10 minutes.Then, 1 hour at 4 ℃ for 10 minutes, 3 hours at 4 ℃ for 20 minutes, 4 hours at 8 ℃ for 30 minutes, 5 minutes at 8 ℃ for 5 minutes, 8 minutes at 1 ℃ for 10 minutes, 1 hour at 8 ℃ for 20 minutes, 2 hours at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 5 minutes, 8 minutes at 8 ℃ for 3 ...30 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 40 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 50 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 2 hours at 8 ℃ for 30 minutes, 1 hour at 8 ℃ for 30 minutes, 1 hour f = 0.50) fractions and concentrated to give chlorin e6 triethyl ester (9.37 g, 82%).

[0570] 1 H NMR(400MHz, CDCl3)δ9.70(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),2.3 0-2.12(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).

[0571] Step 2:Chlorin e6 triethyl ester (2.01 g, 2.95 mmol, 1 equivalent), THF (75 mL), osmium tetroxide (7.5 mg, 0.0295 mmol, 0.01 equivalent), deionized water (6 mL), AcOH (6 mL) and sodium periodate (1.64 g, 7.67 mmol, 2.6 equivalents) were added to a 250 mL RBF. The resulting mixture was stirred (420 rpm) for 3 days at ambient temperature in the dark under nitrogen. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove THF, then dissolved in DCM (90 mL), transferred to a separatory funnel and washed with brine (60 mL), saturated NaHCO (60 mL) and water (75 mL), then dried (Na SO ) and concentrated by rotary evaporation to give a crude product (2.09 g) as a dark blue solid. The crude product was purified by column chromatography using 2% MeOH in DCM as eluent. The red spots (5% MeOH in DCM) were pooled. f = 0.85) fractions and concentrated by rotary evaporation to afford chlorin e6 13-formyltriethyl ester (1.05 g, 52%) as a dark blue solid.

[0572] 1 H NMR (400MHz, CDCl3) δ11.55(s,1H),10.27(s,1H),9.68(s,1H),8.96(s,1H),5.42(d,J=18.8Hz,1H),5.27(d,J=18.8Hz ,1H),4.87(dq,J=10.7,7.1Hz,1H),4.74(dq,J=10.8,7.1Hz,1H),4.54-4.43(m,2H),4.25(dtt,J=18.1,11.0,7.2Hz,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=7.3Hz,3H), 1.72(t,J=7.6Hz,3H), 1.66(t,J=7.2Hz,3H), 1.20(q,J=7.0Hz,7H), -1.32(s,1H), -1.82(s,1H).

[0573] Step 3:Chlorin e6 13-formyl triethyl ester (850 mg, 1.24 mmol, 1 eq), MeOH (20 mL), DCM (10 mL) and sodium borohydride (94 mg, 2.48 mmol, 2 eq) were added to a 250 mL RBF. The resulting mixture was stirred (600 rpm) for 10 minutes at ambient temperature under nitrogen. The reaction mixture was diluted with water (15 mL) and stirred for 10 minutes. The mixture was then extracted with DCM (2 x 30 mL) and the combined DCM layers were washed with water (50 mL), then dried (Na2SO4) and concentrated by rotary evaporation to give a crude product as a dark green solid. The crude product was purified by silica chromatography (4 × 20 cm) eluting with 2% MeOH / DCM. The product containing spots (R in 5% MeOH / DCM) were combined. f = 0.7) fractions and concentrated by rotary evaporation to give compound 17 (628 mg, 74%) as a dark green solid.

[0574] 1 H NMR(400MHz, CDCl3)δ9.69(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,1 H),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).

[0575] Synthesis Example 18 - Synthesis of Chlorin e6 13-(Oxopentyl)triphenylphosphonium triethyl bromide (Compound 18)

[0576]

[0577] Chlorin e6 13-hydroxymethyl triethyl ester (Compound 17) (200 mg, 0.292 mmol, 1 eq), 4-(carboxybutyl) triphenylphosphonium bromide (259 mg, 0.584 mmol, 2 eq), EDC.HCl (112 mg, 0.584 mmol, 2 eq), DMAP (71 mg, 0.584 mmol, 2 eq) and DCM (15 mL) were added to a 50 mL RBF. The resulting mixture was stirred (600 rpm) in the dark at ambient temperature under nitrogen. The reaction progress was monitored by TLC. After 1 hour, the solvent was removed by rotary evaporation, leaving a green oil. The green oil was subjected to column chromatography by dissolving in 3% MeOH / DCM and using a gradient elution of 3%-5% MeOH / DCM. The product (main dark green spot, R in 5% MeOH / DCM) was combined. f =0.15) fraction to afford compound 18 (290 mg, 90%) as a dark green solid.

[0578] 1 H NMR (400MHz, CDCl3) δ9.67(s,1H),9.57(s,1H),8.78(s,1H),7.31-7.26(m ,3H),7.24(dd,J=7.1,1.5Hz,3H),7.20-7.13(m,3H),7.05(td,J=7.8,3.4H z,7H),6.35(s,2H),5.40(d,J=18.8Hz,1H),5.26(d,J=18.7Hz,1H),4.85(d q,J=10.9,7.1Hz,1H),4.74(dq,J=10.9,7.2Hz,1H),4.53-4.42(m,2H),4.3 4-4.18(m,2H),4.16-4.03(m,2H),3.76(q,J=7.6Hz,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=7.3Hz,4H),1.67(dt,J=10.0,7.4Hz,8H),1.44-1.28(m,3H) ,1.24(t,J=7.1Hz,3H),1.19(t,J=7.1Hz,3H),-1.60(s,1H),-1.78(s,1H).

[0579] Synthesis Example 19 - Synthesis of Chlorin e6 Triethyl Ester 13-(N-(3-Triphenylphosphoniumpropyl) Bromide) Carbamate (Compound 19)

[0580]

[0581] Carbonyldiimidazole (38 mg, 0.2336 mmol, 2 eq) was added to a 25 mL RBF containing chlorin e6 13-hydroxymethyltriethyl ester (Compound 17) (80 mg, 0.1168 mmol, 1 eq), DCM (4 mL) and DMAP (5 mg). The resulting mixture was stirred at 30 ° C for 1 hour under nitrogen. (3-Aminopropyl)triphenylphosphonium bromide (234 mg, 0.5841 mmol, 5 eq) was added and stirring was continued at 30 ° C for 3 hours, then stirred at 25 ° C overnight. The reaction mixture was diluted with water (5 mL), transferred to a separatory funnel and extracted with DCM (3x 5 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 4%-6% MeOH / DCM. The main dark green spot (R in 5% MeOH / DCM) was combined. f =0.15) fraction to afford compound 19 (96 mg, 74%) as a dark green solid.

[0582] 1 H NMR(400MHz, CDCl3)δ9.75(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,1 H),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).

[0583] Synthesis Example 20 - Synthesis of Chlorin e6 13-Hydroxymethyl N-methylbutylamine Diethyl Ester (Compound 20)

[0584]

[0585] Step 1:Chlorin e6 N-methylbutylamine (761 mg, 1.14 mmol, 1 equivalent), potassium carbonate (788 mg, 5.70 mmol, 5 equivalents), DMF (15 mL) and a stirring rod were added to a 100 mL RBF. The flask was placed under nitrogen and stirred at 400 rpm, with an air condenser connected. Iodoethane (445 mg, 2.85 mmol, 2.5 equivalents) 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 material was dissolved in DCM (50 mL), washed with water (2 x 20 mL), dried (Na2SO4) and concentrated under reduced pressure to give a crude product as a dark blue solid. The crude product was purified by silica gel column chromatography using 1% MeOH in DCM as eluent. Combined in 1% MeOH / DCM f = 0.5 fractions and concentrated by rotary evaporation to give chlorin e6 N-methylbutylamine diethyl ester (400 mg, 49%) as a dark blue solid.

[0586] 1 H NMR (400MHz, CDCl3) δ9.67(d,J=1.4Hz,1H),9.56(d,J=6.2Hz,1H),8.73(d,J=5. 5Hz,1H),8.07(ddd,J=17.9,11.5,3.6Hz,1H),6.34(dd,J=17.8,1.6Hz,1H),6.12 (dd,J=11.5,1.5Hz,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=2.0Hz,3H), 3.47(d,J=2.3Hz,3H),3.44(s,2H),3.30(d,J=2.2Hz,3H),3.08(s,1H),2.64-2.4 2(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=7.2,2.8Hz,2H),1.39(q,J=7.4Hz,1H),1.22(t,J=7.1Hz,2H),1.14(t, J=7.2Hz,1H),1.06(t,J=7.3Hz,1H),0.96(t,J=7.3Hz,2H),-1.18–-1.63(m,2H).

[0587] Step 2:Chlorin e6 N-methylbutylamine diethyl ester (390 mg, 0.540 mmol, 1 eq), THF (6 mL), osmium tetroxide (1.4 mg, 0.0054 mmol, 0.01 eq), deionized water (0.5 mL), AcOH (0.5 mL) and sodium periodate (299 mg, 1.40 mmol, 2.6 eq) were added to a 25 mL RBF. The resulting mixture was stirred (420 rpm) at ambient temperature under nitrogen for 18 hours. The reaction mixture was concentrated using a rotary evaporator to remove THF and then dissolved in DCM (30 mL), transferred to a separatory funnel and washed with brine (20 mL), saturated NaHCO (20 mL) and water (20 mL), then dried (Na SO) 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. Combined with 2% MeOH in DCM R f = 0.4 spot and concentrated by rotary evaporation to afford chlorin e6 13-formyl N-methylbutylamine diethyl ester (310 mg, 79%) as a dark blue solid.

[0588] 1 H NMR (400MHz, CDCl3) δ11.55(d,J=2.2Hz,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. 4Hz, 1H), 1.24 (t, J = 7.1Hz, 2H), 1.13 (dt, J = 21.3, 7.3Hz, 2H), 0.96 (t, J = 7.3Hz, 4H), -1.08–-1.55 (m, 1H), -1.75 (d, J = 16.9Hz, 1H).

[0589] Step 3:Chlorin e6 13-formyl N-methylbutylamine diethyl ester (240 mg, 0.332 mmol, 1 equivalent), MeOH (9 mL), DCM (3 mL) and sodium borohydride (25 mg, 0.664 mmol, 2 equivalents) were added to a 50 mL RBF. The resulting mixture was stirred (400 rpm) at 25 ° C for 2 hours under nitrogen. 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 layer was washed with brine (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid (346 mg). The dark green solid was subjected to column chromatography by being dissolved in DCM and eluted with 2% MeOH / DCM. The product containing the main dark green spots (R in 5% MeOH / DCM) was merged. f = about 0.6) to give compound 20 (119 mg, 49%) as a dark blue solid.

[0590] 1 H NMR (400MHz, CDCl3) δ9.62(d,J=7.4Hz,1H),9.47(d,J=3.4Hz,1H),8.73(d,J=6.5Hz,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=0.9Hz,3H),3.25(d,J=1.7Hz,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=7.2Hz,3H),1.71-1.63(m,3H),1.60(td,J=7.2,3.2Hz,3H ),1.45-1.32(m,1H),1.22(t,J=7.1Hz,2H),1.14(t,J=7.1Hz,1H),1.07(t,J=7.3Hz,1H),0.95(t,J=7.3Hz,2H),-1.69(d,J=39.4Hz,2H).

[0591] Synthesis Example 21 - Synthesis of Chlorin e6 N-Methylbutylamine Diethyl Ester 13-(N-(3-Triphenylphosphoniumpropyl) Bromide) Carbamate (Compound 21)

[0592]

[0593] Chlorin e6 13-hydroxymethyl N-methylbutylamine diethyl ester (compound 20) (55mg, 0.0757mmol, 1 equivalent), carbonyl diimidazole (24mg, 0.151mmol, 2 equivalents), DCM (4mL) and DMAP (2mg) are added to 25mL RBF. The resulting mixture is stirred (400rpm) for 3 hours under nitrogen. The reaction progress is monitored by TLC. (3-aminopropyl) triphenylphosphonium bromide (152mg, 0.379mmol, 5 equivalents) is added and continued to stir for 27 hours at 30°C. The reaction progress is monitored by HPLC. The reaction mixture is diluted with DCM (20mL), transferred to a separating funnel and washed with water (20mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green residue (103mg). The residue is purified by column chromatography using 5%-8% MeOH / DCM (as the solution load in the eluent). The pooled samples contained the main dark green band (R in 10% MeOH / DCM) f = 0.4) and concentrated by rotary evaporation to give compound 21 (31 mg, 36%) as a dark green solid.

[0594] 1 H NMR (400MHz, CDCl3) δ9.77(d,J=7.8Hz,1H),9.65(s,1H),8.74(d,J=7.5Hz,1H ),7.59(d,J=57.2Hz,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=2.9Hz,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=7.4Hz,2H),3.56(s,3 H),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=7.1Hz,1H),1.09(t ,J=7.3Hz,1H),0.94(t,J=7.3Hz,2H),0.90-0.78(m,1H),-1.33–-1.90(m,2H).

[0595] Synthesis Example 22 - Synthesis of Chlorin e6 N-Methylbutylamine Diethyl Ester 13-(Oxopentyl)triphenylphosphonium Bromide (Compound 22)

[0596]

[0597] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl N-methylbutylamine diethyl ester (Compound 20) (55 mg, 0.0757 mmol, 1 eq), 4-(carboxybutyl)triphenylphosphonium bromide (67 mg, 0.151 mmol, 2 eq), EDC.HCl (29 mg, 0.151 mmol, 2 eq), DMAP (18 mg, 0.145 mmol, 2 eq) and DCM (5 mL). The resulting mixture was stirred at 25 ° C under nitrogen (600 rpm). The progress of the reaction was monitored by TLC. After 2 hours, the solvent was removed by rotary evaporation, leaving a dark green residue. The residue was subjected to column chromatography by dissolving in 5% MeOH / DCM and eluting with a gradient of 5%-7% MeOH / DCM. The product (main dark green spot, R in 5% MeOH / DCM) was combined. f =0.3) fraction to give compound 22 (65 mg, 75%) as a dark green solid.

[0598] 1 H NMR (400MHz, CDCl3) δ9.71-9.47(m,2H),8.78(d,J=7.0Hz,1H),7.18-6.99(m,10H),6.97-6.80(m,6H),6.35(d,J=2.6Hz,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=8.3Hz,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=7.9Hz,1H),1.77(d,J=7.1Hz,3H),1.72-1.64(m,6H),1. 61(td,J=7.1,2.6Hz,3H),1.39(q,J=7.4Hz,1H),1.25(d,J=7.1Hz,5H),1.18-1.09(m,2H),0.95(t,J=7.3Hz,2H),-1.76(d,J=29.4Hz,1H).

[0599] Synthesis Example 23 - Synthesis of Chlorin e6 N-Methylbutylamine Dimethyl Ester 13-(Oxopentyl)triphenylphosphonium Bromide (Compound 23)

[0600]

[0601] Chlorin e6 13-hydroxymethyl N-methylbutylamine dimethyl ester (60 mg, 0.0859 mmol, 1 eq), 4-(carboxybutyl)triphenylphosphonium bromide (76 mg, 0.172 mmol, 2 eq), EDC.HCl (33 mg, 0.172 mmol, 2 eq), DMAP (21 mg, 0.172 mmol, 2 eq) and DCM (5 mL) were added to a 25 mL RBF. The resulting mixture was stirred at 25 ° C (400 rpm) under nitrogen. The reaction progress was monitored by TLC. After 2 hours, the solvent was removed by rotary evaporation, leaving a dark green residue. The residue was subjected to column chromatography by dissolving in 5% MeOH / DCM and using a gradient elution of 5%-10% MeOH / DCM. The product (main dark green spot, R in 5% MeOH / DCM) was combined. f = 0.2) and concentrated by rotary evaporation to give compound 23 (80 mg, 83%) as a dark green solid.

[0602] 1 H NMR (400MHz, CDCl3) δ9.64(s,1H),9.56(d,J=6.7Hz,1H),8.76(d,J=7.1Hz,1H),7.17-7.00(m,9H),6.97-6.86(m,6H),6.34(d,J=3 .0Hz,2H),5.54-5.32(m,2H),4.49-4.31(m,2H),4.20(d,J=6.3Hz,3H),3.76(q,J=8.2Hz,2H),3.68(s,2H),3.58(s,1H),3.56(d,J =2.3Hz,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=7.9Hz,1H ),1.81-1.74(m,3H),1.74-1.52(m,8H),1.40(h,J=7.4Hz,1H),1.12(t,J=7.3Hz,1H),0.96(t,J=7.3Hz,2H),-1.51--1.84(m,1H).

[0603] Synthesis Example 24 - Synthesis of Chlorin e6 13-Hydroxymethyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (Compound 24)

[0604]

[0605] Step 1: Chlorin e6 anhydride (6.90g, 11.9mmol, 1 equivalent), N-methyl-3,6,9,12-tetraoxatridecan-1-amine (3.96g, 17.9mmol, 1.5 equivalents) and DCM (400mL) were loaded into a 1-neck 1L RBF. The resulting solution was stirred (400rpm) for 18 hours at 35°C under a nitrogen atmosphere. The gained dark green solution was concentrated under reduced pressure until approximately 10mL of DCM remained, then ether (100mL) was added and the mixture was manually vortexed in a RBF. The solvent was decanted, and a viscous dark green paste remained. The paste was further washed with ether (2x 100mL) until a viscous dark blue solid remained. The residual solvent was removed from the solid by rotary evaporation to afford chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine amide (7.34 g, 77%) as a dark blue solid.

[0606] 1 H NMR (400MHz, DMSO-d6) δ9.77-9.67(m,2H),9.10(d,J=1.7Hz,1H),8.33(dd,J=17.8,11.7Hz,1H),6.44(dd,J=17.7,1.6Hz,1H),6.1 6(dd,J=11.6,1.4Hz,1H),5.90-5.70(m,1H),5.56-5.34(m,1H),4.58(q,J=7.4Hz,1H),4.36(d,J=10.5Hz,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=4.5Hz,1H),2.25-2.12(m,1H),1.72-1.57(m,6H),-1.75–-2.03(m,1H),-2.28(s,1H).

[0607] Step 2:Chlorin e6 15-N- methyl -3,6,9,12- tetraoxa tridecane -1- amine amide (5.50g, 6.88mmol, 1 equivalent), potassium carbonate (4.75g, 34.4mmol, 5 equivalents), DMF (180mL) and stirring bar were added to a 1-neck 500mL RBF. The flask was placed under nitrogen and stirred at 400rpm, with an air condenser connected. Iodomethane (2.44g, 17.2mmol, 2.5 equivalents) was then added. The solution was stirred at 25°C for 18 hours. The reaction progress was monitored by HPLC. The solvent was removed at 70°C under reduced pressure to obtain a crude product as a dark green solid. The crude product was dissolved in DCM (300mL), washed with water (2x150mL), dried (Na2SO4) and concentrated under reduced pressure to give a dark blue solid (5.82g). The blue solid was purified by column chromatography using 2%-4% MeOH / DCM as eluent. f = 0.4 of the major band and concentrated by rotary evaporation to afford chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (3.10 g, 53%) as a dark blue solid.

[0608] 1 H NMR (400MHz, CDCl3) δ9.67(d,J=3.0Hz,1H),9.54(d,J=6.9Hz,1H),8.72(d,J=6.9Hz,1H),8.11-8.02(m,1H),6.34(dd,J=17.8,1.5Hz, 1H),6.12(dd,J=11.5,1.5Hz,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. 2,4.8,2.7Hz,5H),3.73-3.65(m,7H),3.64(s,3H),3.59-3.52(m,8H),3.46(d,J=2.4Hz,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=7.2,3.4Hz,3H),1.74-1.68(m,3H),-1.28(d,J=25.8Hz,1H),-1.44(d,J=25.4Hz,1H).

[0609] Step 3:Chlorin e6 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (3.00 g, 3.62 mmol, 1 equivalent), THF (120 mL), osmium tetroxide (about 9.2 mg, 0.0362 mmol, 0.01 equivalent), deionized water (12 mL), AcOH (12 mL) and sodium periodate (2.01 g, 9.41 mmol, 2.6 equivalents) were added to a 500 mL RBF. The resulting mixture was stirred (420 rpm) at 25 ° C. in the dark under nitrogen for 16 hours. 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 and 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 (3.53 g) as a dark blue solid. The crude product was purified by column chromatography using 2%-2.5% MeOH / DCM and the first dark band containing the elution (R in 5% MeOH / DCM) was combined. f = 0.5) fractions and concentrated by rotary evaporation to afford chlorin e6 13-formyl 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (2.01 g, 67%) as a dark blue solid.

[0610] 1 H NMR (400MHz, CDCl3) δ11.53(d,J=2.0Hz,1H),10.23(d,J=4.4Hz,1H),9.64(s,1H),8.92(d,J=4.7Hz,1H),5.54-5.3 1(m,2H),4.44(q,J=6.8,6.4Hz,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=7.1Hz,4H),3.59(s,2H),3.56(d,J=2.4Hz,6H),3.38(s,3H),3.32(d,J=1.2Hz, 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 = 17.5Hz, 1H).

[0611] Step 4:Chlorin e6 13-formyl 15-N-methyl-3,6,9,12-tetraoxa tridecane-1-amine dimethyl ester amide (1.00 g, 1.20 mmol, 1 equivalent), MeOH (30 mL), DCM (15 mL) and sodium borohydride (91 mg, 2.40 mmol, 2 equivalents) were added to 100 mL RBF. The resulting mixture was stirred (600 rpm) for 2 hours at ambient temperature under nitrogen. The reaction progress 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 layer was washed with brine (80 mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid. The dark green solid was subjected to column chromatography by being dissolved in 2% MeOH in DCM and using a gradient elution of 2%-5% MeOH in DCM. The main dark green spot (R in 5% MeOH / DCM) was combined f = about 0.4) and concentrated by rotary evaporation to give compound 24 (802 mg, 80%) as a dark green solid.

[0612] 1 H NMR (400MHz, CDCl3) δ9.66(d,J=2.6Hz,1H),9.43(d,J=4.0Hz,1H),8.70(d,J=6.2Hz,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 =1.9Hz,3H),3.58-3.52(m,8H),3.38(d,J=1.1Hz,3H),3.35(s,3H),3.25(d,J=1.5Hz,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=7.2,3.6Hz,3H),1.69(t,J=7.6Hz,3H),-1.30–-1.73(m,2H).

[0613] Synthesis Example 25 - Synthesis of Chlorin e6 13-(N-(3-triphenylphosphoniumpropyl)bromide)carbamate 15-N-methyl-3,6,9,12-tetraoxatridecan-1-amine dimethyl ester amide (Compound 25)

[0614]

[0615] 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 equivalent), carbonyldiimidazole (39 mg, 0.240 mmol, 2 equivalents), DCM (4 mL) and DMAP (3 mg) were added to a 25 mL RBF. The resulting mixture was stirred (600 rpm) at 30 ° C for 3 hours under nitrogen. The reaction progress was monitored by TLC. (3-aminopropyl) triphenylphosphonium bromide (240 mg, 0.600 mmol, 5 equivalents) was added and continued stirring at 30 ° C for 18 hours. The reaction was monitored by HPLC. The reaction mixture was diluted with DCM (30 mL), transferred to a separatory funnel and 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 solution in eluent). The samples with the main dark green spot (R in 10% MeOH / DCM) were combined. f =0.60) fractions and concentrated to give compound 25 (89 mg, 59%) as a dark green solid.

[0616] 1 H NMR (400MHz, CDCl3) δ9.72(d,J=6.0Hz,1H),9.62(d,J=3.5Hz,1H),8.71(d,J=8.0Hz,1H),7.41(t,J=6.3Hz,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=2.5Hz,3H),3.46-3.38(m,1H),3.36(d,J=9.6Hz,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=7.4,2.2Hz,2H),1.69-1.61(m,2H),-1.37--1.92(m,1H).

[0617] Synthesis Example 26 - Synthesis of Chlorin e6 13-Hydroxymethyl 15-N-methyl-1-dodecylamine dimethyl ester amide (Compound 26)

[0618]

[0619] Step 1: Chlorin e6 anhydride (7.00 g, 12.1 mmol, 1 equivalent), N-methyl-1-dodecylamine (4.03 g, 18.2 mmol, 1.5 equivalents) and DCM (400 mL) were loaded into a 1-neck 1L RBF. The resulting solution was stirred (400 rpm) for 16 hours at 35 ° C under a nitrogen atmosphere. 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 vortexed in the RBF. The solvent was decanted, and a viscous dark green paste was left. The paste was further washed with hexane (2x100 mL) until a dark green solid remained. The residual solvent was removed from the solid by rotary evaporation to obtain chlorin e6 15-N-methyl-1-dodecylamine amide (9.16 g, 97%) as a dark green solid.

[0620] 1 H NMR (400MHz, methanol-d4) δ9.66(s,1H),9.42(d,J=5.2Hz,1H),8.98(d,J=4.7Hz,1H),7.86(ddd,J=17.8,11.6,3.3Hz,1H),6.16-6.04(m,1H),5.94(dd,J= 19.7,13.5Hz,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=10.7Hz,5H),3.08(s,3H),3.02(s,1H),2.7 4(ddd,J=22.8,11.1,6.4Hz,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=7.1Hz,6H),0.76( p,J=7.2Hz,2H),0.52-0.34(m,4H),0.29-0.15(m,2H),0.08--0.09(m,4H).

[0621] Step 2:Chlorin e6 15-N-methyl-1-dodecanamine amide (7.00 g, 9.00 mmol, 1 equivalent), potassium carbonate (6.21 g, 45.0 mmol, 5 equivalents), DMF (220 mL) and a stirring rod were added to a 1-neck 500 mL RBF. The flask was placed under nitrogen and stirred at 400 rpm, with an air condenser connected. Iodomethane (3.19 g, 22.5 mmol, 2.5 equivalents) was then added. The solution was stirred at 25 ° C for 18 hours. The reaction process was monitored by HPLC. The solvent was removed at 70 ° C under reduced pressure to obtain a crude product as a dark green solid. The crude product was dissolved in DCM (300 mL), washed with water (2 x 150 mL), dried (Na2SO4) and concentrated under reduced pressure to obtain 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. Collect the R f =0.4 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 eluent. The fraction containing R in 5% MeOH / DCM was re-purified by column chromatography. f The first pure fraction of the major band with a pH = 0.4 was combined with the first fraction from the first column and concentrated by rotary evaporation to give chlorin e615-N-methyl-1-dodecylamine dimethyl ester amide (3.45 g, 48%) as a dark green solid.

[0622] 1H NMR (400MHz, CDCl3) δ9.67(d,J=1.7Hz,1H),9.55(d,J=6.9Hz,1H),8.73(d,J=5.7Hz,1H),8.06(ddd,J=17.9,11.5,4.1Hz,1H),6 .34(dd,J=17.8,1.6Hz,1H),6.12(dd,J=11.5,1.5Hz,1H),5.47-5.18(m,2H),4.48-4.27(m,2H),4.20(d,J=4.0Hz,3H),3.79(q, J=7.7,2.2Hz,2H),3.67(s,3H),3.59-3.54(m,4H),3.46(d,J=2.7Hz,5H),3.30(d,J=2.6Hz,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=27.7Hz,1H),-1.43(d,J=28.5Hz,1H).

[0623] Step 3: Chlorin e6 15-N-methyl-1-dodecylamine dimethyl ester amide (3.40 g, 4.22 mmol, 1 equivalent), THF (140 mL), osmium tetroxide (about 10.7 mg, 0.0422 mmol, 0.01 equivalent), deionized water (14 mL), AcOH (14 mL) and sodium periodate (2.35 g, 11.0 mmol, 2.6 equivalents) were added to a 500 mL RBF. The resulting mixture was stirred (420 rpm) at 25 ° C for 16 hours in the dark under nitrogen. The reaction progress was monitored by HPLC. The reaction mixture was concentrated using a rotary evaporator to remove THF, then dissolved in DCM (250 mL), transferred to a separatory funnel and washed with saline (120 mL), saturated NaHCO (120 mL) and water (120 mL), then dried (Na SO ) and concentrated by rotary evaporation to obtain a crude product as a dark blue solid. The crude product was purified by column chromatography using 2% MeOH / DCM and the first dark band containing R in 5% MeOH / DCM was combined. f =0.5) to afford chlorin e6 13-formyl-15-N-methyl-1-dodecylamine dimethyl esteramide (1.88 g, 55%) as a dark blue solid.

[0624] 1H NMR (400MHz, CDCl3) δ11.53(d,J=2.8Hz,1H),10.22(d,J=2.2Hz,1H),9.63(d,J=2.9Hz,1H),8.91(d,J=2.7Hz,1H),5 .56-5.18(m,2H),4.52-4.28(m,2H),4.19(d,J=3.6Hz,3H),3.81-3.72(m,5H),3.68(s,2H),3.56(d,J=4.0Hz,4H),3 .47(s,2H),3.45-3.36(m,1H),3.31(d,J=1.3Hz,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=16.7Hz,1H),-1.76(d,J=18.5Hz,1H).

[0625] Step 4: Chlorin e6 13-formyl 15-N-methyl-1-dodecylamine dimethyl ester amide (920mg, 1.14mmol, 1 equivalent), MeOH (30mL), DCM (15mL) and sodium borohydride (86mg, 2.28mmol, 2 equivalents) are added to 100mL RBF. The resulting mixture is stirred (600rpm) for 2 hours at ambient temperature under nitrogen. The reaction process is monitored by TLC. The reaction mixture is then concentrated by rotary evaporation. The mixture is diluted with DCM (80mL) and washed with water (80mL). The DCM layer is collected and the aqueous layer is further extracted with DCM (40mL). The combined DCM layer is washed with brine (80mL), dried (Na2SO4) and concentrated by rotary evaporation to obtain a dark green solid. The dark green solid is subjected to column chromatography by being dissolved in 2% MeOH in DCM and using a gradient elution of 2% MeOH in DCM. The main dark green spot (R in 5% MeOH / DCM) was combined f = about 0.4) fraction to give compound 26 (688 mg, 72%) as a dark blue solid.

[0626] 1H NMR (400MHz, CDCl3) δ9.67(d,J=1.2Hz,1H),9.41(d,J=3.1Hz,1H),8.69(d,J=5.0Hz,1H),5.67(d,J=2.9Hz,2H),5 .51-5.22(m,2H),4.48-4.30(m,2H),4.19(d,J=4.2Hz,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=2.1Hz,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=7.2,3.3Hz,3H),1.70(q,J=6.9,6.2Hz,4H),1.44-1.20(m,18H),0.94-0.83(m,3H),-1.26–-1.77(m,2H).

[0627] Synthesis Example 27 - Synthesis of Chlorin e6 13-(N-(3-triphenylphosphoniumpropyl)bromide)carbamate 15-N-methyl-1-dodecylamine dimethyl ester amide (Compound 27)

[0628]

[0629] To a 25 mL RBF was added chlorin e6 13-hydroxymethyl 15-N-methyl-1-dodecylamine dimethyl ester amide (compound 26) (100 mg, 0.1234 mmol, 1 eq), carbonyldiimidazole (40 mg, 0.2469 mmol, 2 eq), DCM (4 mL) and DMAP (3 mg). The resulting mixture was stirred at 30 ° C for 3 hours under nitrogen. (3-Aminopropyl)triphenylphosphonium bromide (247 mg, 0.6172 mmol, 5 eq) was added and stirring was continued at 30 ° C for 18 hours. The reaction mixture was diluted with DCM (20 mL), transferred to a separatory funnel and washed with water (20 mL), dried (Na2SO4) and concentrated by rotary evaporation to give a dark green residue. The residue was purified by column chromatography using a gradient of 3%-7% MeOH / DCM. The residue containing the main dark green spot (R in 7% MeOH / DCM) was combined. f =0.40) fraction to give compound 27 (123 mg, 80%) as a dark green solid.

[0630] 1H NMR(400MHz, CDCl3)δ9.75(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).

[0631] Synthesis Example 28 - Synthesis of Chlorin e6 13-Hydroxymethyl(2-methoxyethyl)methylamine (Compound 28)

[0632]

[0633] Chlorin e6 13-hydroxymethyl (2-methoxyethyl) methylamine dimethyl ester (159 mg, 0.227 mmol, 1 equivalent), lithium hydroxide monohydrate (29 mg, 0.681 mmol, 3 equivalents), THF (9 mL) and water (3 mL) were added to 50 mL RBF. The mixture was stirred at 25 ° C for 2 hours. The reaction process was monitored by HPLC. The reaction mixture was diluted in EtOAc (50 mL) and transferred to a separatory funnel, and 1M HCl solution (25 mL) was then added. After the separatory funnel was vibrated for about 1 minute, pH 7 buffer solution (40 mL) was added, and the funnel was vibrated for about 1 minute. The organic layer was then separated, dried over MgSO4, and concentrated by rotary evaporation to give compound 28 (140 mg, 92% yield, 98.12% according to HPLC purity) as a dark blue solid.

[0634] 1H NMR (400MHz, CDCl3) δ9.66(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=2.3Hz,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).

[0635] Synthesis Example 29 - Synthesis of Chlorin e6 13-Hydroxymethyl(2-methoxyethyl)methylamine Bis(N-methyl-D-reduced Glucosamine) Salt (Compound 29)

[0636]

[0637] Chlorin e6 13-hydroxymethyl (2-methoxyethyl) methylamine (compound 28) (60 mg, 0.0893 mmol, 1 equivalent) was weighed into a 25 mL RBF, followed by addition of distilled deionized water (5 mL) under a stirring bar. Meglumine (35 mg, 0.179 mmol, 2 equivalents) was added, and the mixture was stirred while heating at 40 ° C for 1 hour. The solution was cooled to ambient temperature, diluted with water (20 mL), and then filtered through a 3 porosity filter (3 cm diameter) into a 250 mL RBF with a side arm adapter. The reaction flask was rinsed with deionized water (approximately 10 mL) and then passed through a filter to complete the transfer. The filtrate was then freeze-dried for 17 hours to obtain compound 29 (86 mg, 91% yield, 97.76% purity according to HPLC) as a dark brown fluffy solid.

[0638] 1H NMR (400MHz, DMSO-d6) δ9.73(dd,J=7.0,2.8Hz,2H),8.99(d,J=4.5Hz,1H),5.77(s,2H),5.47-5.26(m,2H),4.53(q,J=7.2 Hz,1H),4.31(dd,J=20.9,10.1Hz,1H),4.14(s,1H),3.80(q,J=8.0,6.0Hz,2H),3.72(q,J=5.2Hz,3H),3.64(d,J=5.3Hz,2 H),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=7.2Hz,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=14.9Hz,1H),-1.83(d,J=13.0Hz,1H).

[0639] Synthesis Example 30 - Synthesis of Chlorin e6 13-Hydroxymethyl (2-methoxyethyl) Methamine Disodium Salt (Compound 30)

[0640]

[0641] Chlorin e6 13-hydroxymethyl(2-methoxyethyl)methanamine (Compound 28) (60 mg, 0.0893 mmol, 1 eq) was weighed into a 100 mL RBF, followed by addition of distilled deionized water (5 mL) under a stirring bar. 0.1 M sodium hydroxide solution (1.70 mL, 0.170 mmol, 1.9 eq) was added, and the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was then freeze-dried overnight (16 hours) to give Compound 30 (64 mg, quantitative yield, 94.43% purity according to HPLC) as a dark green fluffy solid.

[0642] 1H NMR (400MHz, DMSO-d6) δ9.77-9.66(m,2H),9.00(d,J=7.2Hz,1H),5.86(d,J=16.0Hz,1H),5.76(d,J=4.9Hz,2H),5.65(d,J=18.4Hz,1 H),5.51-5.34(m,1H),4.50(q,J=6.9Hz,1H),4.30(dd,J=24.4,10.5Hz,1H),4.20(s,2H),4.15(s,1H),4.03(t,J=5.2Hz,1H),3.92-3 .74(m,3H),3.52(d,J=2.4Hz,6H),3.44(d,J=2.3Hz,3H),3.33(s,2H),3.29(d,J=3.7Hz,3H),2.97(s,1H),2.43-2.22(m,1H),2.15-1 .92(m,1H),1.68(td,J=7.6,1.7Hz,3H),1.60(d,J=6.5Hz,4H),1.47-1.19(m,1H),-1.65(d,J=26.0Hz,1H),-1.85(d,J=25.8Hz,1H).

[0643] Biological experiment details

[0644] Example 1 - Determination of the Solubility of Chlorin e6 Analogs

[0645] 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%.

[0646] Where necessary, polyvinyl pyrrolidone (K30) was added to a final concentration of 1% w / v. Absorbance was measured using a Cytation 3 multi-mode plate reader (Biotek) in spectral scanning mode, capturing spectra at 2 nm increments between 500 and 800 nm. An equivalent blank solution was also measured and subtracted accordingly. Each spectrum was normalized to a minimum signal of 0 and a maximum signal of 100% in pure DMSO solution (the most soluble state).

[0647] Example 2 - Cytotoxicity, Phototoxicity and Therapeutic Index

[0648] Preparation of photosensitizer stock solution

[0649] Photosensitizers such as chlorin e6 analogs, chlorin e4 disodium (supplied 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 in the dark.

[0650] Preparation of photosensitizers for in vitro studies

[0651] For in vitro experiments, the photosensitizer (stock solution 5.5 mM in 100% DMSO) was diluted 1:100 in a concentrated vehicle solution (final 55 μM photosensitizer in 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). Serial dilutions were prepared at a constant 1:55 dilution 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 vehicle solution.

[0652] Cell culture

[0653] 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% CO2. Once the cells reached approximately 80% confluence, the spent medium was replaced with medium containing the desired concentration of photosensitizer, and the cells were incubated for the desired period of time to allow for photosensitizer uptake.

[0654] Statistical analysis

[0655] All data were analyzed using GraphPad PRISM v8.3.1 (549) (GraphPad Software, CA). Spectral absorbance and activity measurements were normalized within the range of 0%-100%, with a minimum of 0 and a maximum determined by the data set. Dose responses were determined using a sigmoidal four-point nonlinear regression with a variable slope, and the IC10 or IC90 for each compound was calculated. All data are shown as mean ± SD (where appropriate).

[0656] Cytotoxicity

[0657] SKOV3 cells were seeded in 96-well black-walled plates (Greiner #655090) at a cell density of 5,000 cells per well in 100 μl of culture medium. Upon reaching approximately 60% confluence, the culture medium was aspirated and replaced with fresh culture medium containing 0-100 μM of the relevant chlorin e6 analog in DMSO. The cells were incubated for an additional 24 hours to allow for uptake of the chlorin e6 analog.

[0658] To test the intrinsic cytotoxicity (i.e., "dark toxicity") of the chlorin e6 analog, the culture medium was replaced after 24 hours with fresh culture medium containing 10% (v / v) AlamarBlue cell viability reagent (ThermoFisher), and the cells were incubated at 37°C for 6 hours. Untreated cells served as a control. Fluorescence (Ex 555 nm / Em 596 nm) was measured using a Cytation 3 Cell Imaging Multimode Reader (Biotek), and cytotoxicity was assessed based on the percentage of remaining viable cells. All measurements were performed in quadruplicate.

[0659] Phototoxicity

[0660] SKOV3 cells were seeded in 96-well black-walled plates (Greiner #655090) at a cell density of 5,000 cells per well in 100 μl of culture medium. Upon reaching approximately 60% confluence, the culture medium was aspirated and replaced with fresh culture medium containing 0-100 μM of the relevant chlorin e6 analog in DMSO. The cells were incubated for an additional 24 hours to allow for uptake of the chlorin e6 analog.

[0661] To test phototoxicity, cells incubated with chlorin e6 analogs (0–10 μM in DMSO) were exposed to a light power density of 50 mW / cm2 after 24 h with a culture medium replacement (as described above). 2 660 nm laser (Invion) or light emitting diode (LED) panel (Invion) for 5 min (total 15 J / cm 2 Laser and LED exposure induced equivalent responses with respect to phototoxicity. After activation, cells were cultured for an additional 24 hours. The medium was then replaced with fresh medium containing AlamarBlue, and the remaining % viable cells were assessed as described above. Controls included cells treated with the chlorin e6 analog but not activated by laser; cells not treated with the chlorin e6 analog but treated with laser light; and an untreated control. All measurements were performed in quadruplicate.

[0662] Toxicity characteristics of chlorin e6 analogs

[0663] The phototoxicity and intrinsic cytotoxicity (i.e., "dark toxicity") of the chlorin e6 analogs were evaluated using SKOV3 ovarian cancer cells as previously described. For comparative purposes, the chlorin e6 analogs were compared with chlorin e4 disodium and talaporfin sodium, a clinically approved photosensitizer for photodynamic therapy of lung cancer. Phototoxicity IC90 values and dark toxicity IC10 values were calculated using a log[inhibitor]-versus-normalized response dose curve with a variable slope using the formula Y = 100 / (1 + (IC90 / X)^Hill slope (phototoxicity IC90)) or Y = 100 / (1 + (IC10 / X)^Hill slope (dark toxicity IC10)).

[0664] The phototoxicity and dark toxicity values are provided in Table 1. Most of the chlorin e6 analogs had phototoxicity IC90 values below 10 nM (Table 1). These were significantly better than chlorin e4 disodium (IC90 21.32 μM) or talaporfin sodium (IC90 22.83 μM); in fact, the best performing compound (Compound 3) achieved a phototoxicity that was four orders of magnitude higher than talaporfin sodium. Thus, compared to the clinically approved photosensitizer talaporfin sodium, the chlorin e6 analogs achieved an increase in phototoxicity of up to approximately 10,000-fold.

[0665] Significant changes in dark toxicity were observed for the chlorin e6 analogs of the invention (Table 1). However, the greater phototoxicity provided by the chlorin e6 analogs of the invention is expected to offset any dark toxicity issues through reduced dosage requirements in use.

[0666] Therapeutic index of chlorin e6 analogs

[0667] To evaluate the therapeutic potential of chlorin e6 analogs, the therapeutic index (TI) was calculated. By comparing the drug concentration required for a desired effect with the concentration that causes undesirable off-target toxicity, the TI provides a quantitative measure describing relative drug safety. The TI was calculated using the phototoxicity IC90 versus the dark toxicity IC10.

[0668] TI values are provided 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 although its relative cytotoxicity is low, its potential therapeutic window of use is small. The chlorin e6 analog of the present invention has a relatively significantly improved TI and significantly greater phototoxicity (Table 1).

[0669] Therefore, the chlorin e6 analogs of the present invention have a better ideal therapeutic index than clinically used photosensitizers. Furthermore, the greater phototoxicity of the chlorin e6 analogs suggests their potential for use at significantly reduced doses in vivo. Therefore, the chlorin e6 analogs have an acceptable therapeutic profile for clinical use.

[0670] In addition, the chlorin e6 analogs of the present invention carrying an ammonium, phosphonium, pyridinium or sugar group (e.g., -R as defined in the specification and claims) 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 saccharide groups) are particularly preferred because they have better phototoxicity than similar compounds without this group. This can be observed when comparing, for example:

[0671] Compare compound 1 with compounds 2-5

[0672] Compare compound 6 with compounds 7-8

[0673] Compare compound 15 with compound 16

[0674] Compare compound 17 with compounds 18-19

[0675] Compare compound 20 with compounds 21-22

[0676] Compare compound 24 with compound 25

[0677] Of course, compounds not containing such groups can be used as intermediates in the preparation of compounds having such groups.

[0678] Table 1. Toxicity profiles and therapeutic indices of chlorin e6 analogs: * indicates phototoxicity measured by LED

[0679]

[0680]

[0681] Example 3 - Study on the Stability of Chlorin e6 Analog Salts in Aqueous Solutions

[0682] program

[0683] The reaction solution was prepared by dissolving 2-3 mg of the corresponding 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. Sample HPLC analysis was performed at 0.5, 4, or 66 hours (unless otherwise stated). The purpose was to look for degradation over time. The test results are summarized in Table 2 below.

[0684]

[0685] Table 2: HPLC purity of chlorin e6 analog salts in aqueous solution after 0.5, 4 and 66 hours (unless otherwise stated).

[0686] The structure of Photolon and Photodithiazine is as follows:

[0687]

[0688] HPLC method

[0689] Column and instrument details

[0690] Instrument: Waters Alliance HPLC equipped with a Waters e2695 separation module and a Waters 2998 PDA detector

[0691] Column: YMC-Pack Pro C18 / S-3μm / 12nm. 150 x 4.6mm. DS / N: 112YB00270

[0692] Guard cartridge: Phenomenex Security Guard Cartridge C18 4 x 3.0 mm ID PRD-281272

[0693] HPLC method

[0694] time Flow rate (ml / min) ％A ％B 1 0.01 1.00 85.0 15.0 2 25.00 1.00 2.0 98.0 3 29.00 1.00 2.0 98.0 4 30.00 1.00 85.0 15.0 5 31.00 1.50 85.0 15.0 6 35.00 1.50 85.0 15.0 7 36.00 0 85.0 15.0

[0695] Mobile phase: A = 0.05% w / v phosphoric acid in distilled water; B = acetonitrile

[0696] Injection volume: 5 μL

[0697] HPLC run time: 35 minutes

[0698] Detection wavelength: 406nm

[0699] Column temperature: 40°C

[0700] in conclusion

[0701] As can be seen from the experimental results, in -R 7 An ester or amide group (such as -CO2R as defined in the specification and claims) is present at 13 or -C(O)-R 14 -R 15 The compound containing the α-amino group is more stable in aqueous solution than the compound without the α-amino group.

[0702] It should be understood that the present invention has been described above by way of example only. The embodiments are not intended to limit the scope of the present invention. Various modifications and embodiments may be made without departing from the scope and spirit of the present invention, which is limited only by the appended claims.

Claims

1. A compound of formula (I) or a complex of formula (II): or a pharmaceutically acceptable salt thereof, wherein: -R 1 Selected from -CH2OR 2 、-CH2SR 2 、-CH2S(O)R 2 、-CH2S(O)2R 2 、-CH2N(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; -R 2 Each independently selected from -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’ ; -R 3 and -R 4 Each independently selected from -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’ )]、-R α -[P(R 5 )2(R 5’ )] or -R α -[R 8’ ]; -R α - each independently selected from C1-C 42 Alkylene, wherein the alkylene may be optionally substituted with one or more C1-C4 alkyl, C1-C4 haloalkyl, or halo, and wherein one or more carbon atoms in the backbone of the alkylene may be optionally replaced with heteroatoms or groups independently selected from O, S, NH, or NMe; -R β each independently a saturated or unsaturated hydrocarbon group, wherein the hydrocarbon group may be linear or branched, or may be or include a cyclic group, wherein the hydrocarbon group may be optionally substituted, and wherein the hydrocarbon group may optionally include one or more heteroatoms N, O, S, P or Se in its carbon skeleton; -R 5 Each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, wherein the phenyl or C5-C6 heteroaryl may be optionally replaced by one or more 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 -CH3 group substitution; -R 5’ Selected from C1-C4 alkyl, C1-C4 haloalkyl, -(CH2CH2O) n -H, -(CH2CH2O) n -CH3, phenyl or C5-C6 heteroaryl, each of which is replaced by -CO2 - Substituted, wherein the phenyl or C5-C6 heteroaryl may be optionally further substituted by one or more 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 -CH3 group substitution; -R 6 selected from -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; -R 7 selected from -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; -R 8 is optionally substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), halo, -CO2H, -CO2Z, -CO2NH2, -O-(CH2CH2O) n -H or -O-(CH2CH2O) n -[NC5H5] substituted with -CH3 group; -R 8’ is -[NC5H5], which is -CO2 - and optionally further substituted with one or more 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 -CH3 group substitution; -R 9 Select from -OR 2 、-N(R 2 )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 halogen group; Y is a counter anion; Z is a counter cation; and M 2+ It is a metal cation; The conditions are: (i)-R 1 、-R 7 and -R 9 At least one of them contains -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 a sugar group; or (ii)-R 9 Selected from -N(R 2 )2、-SR 2 、-S(O)R 2 、-S(O)2R 2 or -X.

2. The compound or complex according to claim 1, wherein each -R α - independently selected from C1-C6 alkylene.

3. A compound or complex according to any preceding claim, wherein -R 2 、-R 3 and -R 4 At least one selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β It's a sugar group.

4. The compound or complex according to claim 3, wherein -R β is a saccharide selected from the group consisting of:

5. The compound or complex according to claim 4, wherein the sugar group is:

6. The compound or complex according to claim 3, wherein -R β is a saccharide selected from the group consisting of: Where -R 11 Selected from C1-C4 alkyl.

7. The compound or complex according to claim 6, wherein -R 11 It's methyl.

8. A compound or complex according to any preceding claim, wherein -R 1 YES-C(O)-OR 3 , R 3 Yes-R β , and -R β It is a C1-C4 alkyl group.

9. The compound or complex according to any one of claims 1 to 7, wherein -R 1 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ is H or C1-C4 alkyl.

10. A compound or complex according to any preceding claim, wherein -R 6 YES-C(O)-OR 3 , and -R 3 It is a C1-C4 alkyl group.

11. The compound or complex according to any one of claims 1 to 9, wherein -R 6 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ is H or C1-C4 alkyl.

12. A compound or complex according to any preceding claim, wherein -R 7 YES-C(O)-OR 3 , and -R 3 It is a C1-C4 alkyl group.

13. The compound or complex according to any one of claims 1 to 11, wherein -R 7 Selected from -C(O)-OR 3 、-C(O)-SR 3 or -C(O)-N(R 3 )(R 3’ ), where -R 3 Selected from -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 sugar group, and -R 3’ is H or C1-C4 alkyl.

14. A compound or complex according to any preceding claim, wherein -R 9 Select from -OR 2 or -SR 2 , and -R 2 Selected from -R α -OR β 、-R α -SR β 、-R α -S(O)R β or -R α -S(O)2R β , and -R β It's a sugar group.

15. A compound of formula (III) or a complex of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: -R 1 Selected from -CO2H or -C(O)-R 14 -R 15 ; -R 6 Selected from -CO2H or -CO2R 13 ; -R 7 Selected from -CO2H or -C(O)-R 14 -R 15 ; -R 13 Selected from C1-C3 alkyl; -R 14 - is selected from NH, NMe, O or S; -R 15 Selected from C1-C 20 alkyl, wherein one or more carbon atoms in the alkyl may be optionally replaced by heteroatoms or groups independently selected from O, S, NH or NMe, and wherein the alkyl may be optionally substituted with one or more (such as one, two, three, four, five, six, seven or eight) -OH or -NH groups; and M 2+ It is a metal cation; The condition is -R 1 、-R 6 and -R 7 Not at the same time -CO2Me.

16. The compound or complex according to any preceding claim, wherein the compound or complex is: or a metal cation complex thereof or a pharmaceutically acceptable salt thereof.

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

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

19. A compound or complex according to any preceding claim for use in the treatment of atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; benign or malignant Diseases characterized by excessive cell proliferation or areas of new blood vessel formation; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female appendages, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

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

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

22. A compound or complex according to any preceding claim for use in the treatment of early stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ cancer, esophagus, stomach, bile duct, intestinal cancer, colon cancer, colorectal cancer, rectum cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

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

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

25. The compound or complex of claim 24, wherein the radiation 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. The pharmaceutical composition according to claim 26, further comprising polyvinylpyrrolidone.

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

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

30. The pharmaceutical composition according to any one of claims 26 to 29, which is used in photodynamic therapy or cell luminescence therapy.

31. The pharmaceutical composition according to any one of claims 26 to 30, wherein the pharmaceutical composition is used to treat atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; benign or malignant Diseases characterized by excessive sex cell proliferation or areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female appendages, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

32. The pharmaceutical composition according to any one of claims 26 to 31, for use in treating a disease characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization.

33. The pharmaceutical composition according to any one of claims 26 to 32, which is used to treat benign or malignant tumors.

34. A pharmaceutical composition according to any one of claims 26 to 33, wherein the pharmaceutical composition is used to treat early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

35. The pharmaceutical composition according to claim 26 or 27, which is used in photodynamic diagnosis.

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

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

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

40. Use of a compound or complex according to any one of claims 1 to 25 in the manufacture of a medicament for treating the following diseases: atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; Diseases characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

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

42. The use according to claim 41, wherein the phototherapeutic agent is used to treat atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; diseases characterized by excessive growth of benign or malignant cells Diseases characterized by proliferation or areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, 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 medicament or the phototherapeutic agent is used to treat a disease characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization.

44. The use according to any one of claims 40 to 43, wherein the medicament or the phototherapeutic agent is for treating a benign or malignant tumor.

45. The use of any one of claims 40-44, wherein the medicament or the phototherapeutic agent is used to treat early-stage cancer; cervical dysplasia; soft tissue sarcoma; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

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

47. The use of any one of claims 40-46, wherein the pharmaceutical agent, the phototherapeutic agent or the photodiagnostic agent is adapted for administration prior to administration of radiation.

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

49. A method for treating atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; diseases characterized by benign or malignant cell hyperproliferation or by areas of neovascularization; benign or malignant tumors; early cancer; cervical dysplasia a method of treating a person or animal in need thereof; wherein the method comprises 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. A method for photodynamic therapy or cell luminescence 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 any one of claims 1-25.

51. The method of claim 50, wherein the human or animal disease is atherosclerosis; multiple sclerosis; diabetes; diabetic retinopathy; arthritis; rheumatoid arthritis; fungal, viral, chlamydial, bacterial, nanobacterial or parasitic infectious diseases; HIV; AIDS; SARS virus (preferably severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)), Asian (chicken) influenza virus, dengue virus, herpes simplex or herpes zoster infection; hepatitis; viral hepatitis; cardiovascular disease; coronary artery stenosis; carotid artery stenosis; intermittent claudication; skin disorders; acne; psoriasis; excessive growth of benign or malignant cells; Diseases characterized by proliferation or areas of neovascularization; benign or malignant tumors; early-stage cancers; cervical dysplasia; soft tissue sarcomas; germ cell tumors; retinoblastoma; age-related macular degeneration; lymphoma; Hodgkin lymphoma; head and neck cancer; oral or mouth cancer; or cancer of the blood, prostate, cervix, uterus, vagina, or other female adnexa, breast, nasopharynx, trachea, larynx, bronchus, bronchioles, lung, hollow organ, esophagus, stomach, bile duct, intestinal cancer, colon, colorectal cancer, rectum, bladder, ureter, kidney, liver, gallbladder, spleen, brain, lymphatic system, bone, skin, or pancreas.

52. The method of any one of claims 49-51, wherein the human or animal disease is characterized by excessive proliferation of benign or malignant cells or by areas of neovascularization.

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

54. The method of any one of claims 49-53, 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 lymphoma; head and neck cancer; oral or mouth cancer; or blood cancer, prostate cancer, cervical cancer, uterine cancer, vaginal cancer or other female adnexa cancer, breast cancer, nasopharyngeal cancer, tracheal cancer, laryngeal cancer, bronchial cancer, bronchiolar cancer, lung cancer, hollow organ cancer, esophageal cancer, stomach cancer, bile duct cancer, intestinal cancer, colon cancer, colorectal cancer, rectal cancer, bladder cancer, ureter cancer, kidney cancer, liver cancer, gallbladder cancer, spleen cancer, brain cancer, lymphatic system cancer, bone cancer, skin cancer or pancreatic cancer.

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

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

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 pharmaceutical combination or kit comprising: (a) a compound or complex according to any one of claims 1 to 25; and (b) As a combination agent with immune checkpoint inhibitors.

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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