Porphyrin derivatives, their preparation methods, and their use for bacteriostasis

Abstract

The present application relates to the compound of formula (I), its preparation method and its use for bacteriostasis, wherein the groups in formula (I) are as defined in the specification. The method for preparing the compound of formula (I) provided by the present application has simple synthesis process and low cost, and good yield can be obtained by using the combination of specific condensation catalyst and condensation agent. Moreover, the compound of formula (I) provided by the present application has good targeting and bacteriostatic ability to gram-negative coccus, bacillus or coccobacillus, and has therapeutic effect on oral diseases such as periodontitis, gingivitis, dental plaque and dental caries.(I).

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to porphyrin derivatives, their preparation methods, and their use for antibacterial purposes, and more specifically to their inhibition of *Porphyromonas gingivalis* in photodynamic therapy. Porphyromonas gingivalis Uses related to Gram-negative bacteria, such as , etc. Background Technology

[0002] Photodynamic therapy (PDT) is a novel therapy that utilizes photosensitizers, light, and oxygen molecules to generate a photodynamic reaction, selectively targeting diseases such as malignant tumors, vascular lesions, and microbial infections. The photosensitizer is the core of PDT. Currently, clinically used photosensitizers include Photofrin from the United States, Photogem from Russia, and Photosan from Germany. However, these photosensitizers have several drawbacks. For example, they are mostly mixed preparations composed of porphyrin derivatives, with unclear active ingredients and no controllable quality standards. Furthermore, because they remain in the skin for several weeks, they can easily cause phototoxic effects such as rashes and blisters. Patients need to avoid direct sunlight for one month or even longer after treatment.

[0003] Periodontitis is a chronic inflammatory disease primarily caused by the destruction of periodontal tissues by bacteria in dental plaque. *Porphyromonas gingivalis* is the main pathogen causing periodontitis and gingivitis; it is a Gram-negative coccobacillus commonly found in the human oral cavity and intestines. Due to antibiotic resistance, periodontitis and oral diseases caused by dental plaque have remained largely untreated.

[0004] Therefore, the development of targeted photosensitizers for Gram-negative bacteria is of great significance. Summary of the Invention

[0005] In view of the current state of the technology, the present invention aims to provide a class of porphyrin derivatives that are simple to synthesize and low in cost. These porphyrin derivatives have high biosafety and can be used as photosensitizers in photodynamic therapy. More specifically, they can be used to inhibit Gram-negative cocci, bacilli, or cocci. They are porphyrin derivatives with potential clinical application value and can be produced on a large scale.

[0006] The first aspect of the present invention relates to providing compounds of formula (I).

[0007] (I),

[0008] in,

[0009] X - It is an acetate ion.

[0010] q is 2, so that X- Balanced with the cation charge,

[0011] R + The following formula (II) is given.

[0012] (II),

[0013] “ "The wavy line indicates the connection point to the rest of the part."

[0014] p is 0 or 1

[0015] K is either (II-a) or (II-b), with (II-a) being the preferred form.

[0016] (II-a) or (II-b),

[0017] R1 is hydrogen, alkyl, cycloalkyl, or heteroarylalkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; preferably hydrogen or heteroarylalkylene.

[0018] R2 is hydrogen or a heteroaryl group, wherein the heteroaryl group contains one or more heteroatoms selected from O and S;

[0019] A + It is either (II-c) or (II-d), with (II-d) being the preferred form.

[0020] (II-c) or (II-d),

[0021] n is an independent integer from 0 to 8;

[0022] m is 0 or 1, so that the N atom carries a positive charge;

[0023] Q is a heterocyclic group or heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N;

[0024] R3 is an alkyl group on its own.

[0025] A second aspect of the present invention relates to a method for preparing a compound of formula (I), the method comprising:

[0026] i) In the presence of a condensation catalyst and a condensation agent, protoporphyrin (PPIX) is condensed with a compound having reactive hydrogen atoms in a polar organic solvent to obtain an intermediate compound.

[0027] iii) To induce alkylation of intermediate compounds;

[0028] in,

[0029] The compound having reactive hydrogen atoms is selected from compounds of general formula (III).

[0030] (III),

[0031] in,

[0032] H represents a reactive hydrogen atom;

[0033] p is as defined above;

[0034] K is as defined above;

[0035] A is either (III-c) or (III-d) below.

[0036] (III-c) or (III-d),

[0037] n is as defined above;

[0038] P is as defined above as Q, and it is electrically neutral;

[0039] R3 is defined as described above.

[0040] A third aspect of the present invention relates to providing a medicament comprising a compound of formula (I).

[0041] A fourth aspect of the present invention relates to providing a method for non-therapeutic purposes of inhibiting Gram-negative cocci, bacilli, or cocci, comprising contacting a compound of formula (I) with Gram-negative cocci, bacilli, or cocci and irradiating them with light of a specific wavelength at which an inhibitory effect is achieved.

[0042] The fifth aspect of the present invention relates to the use of the compound of formula (I) in the preparation of a medicament for treating diseases or conditions caused by Gram-negative cocci, bacilli or cocci.

[0043] The sixth aspect of the present invention relates to the use of a compound of formula (I) in the treatment of diseases or conditions caused by Gram-negative cocci, bacilli or cocci.

[0044] The seventh aspect of the present invention relates to a method for treating a disease or condition caused by Gram-negative cocci, bacilli or cocci, comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need and irradiating a therapeutically effective amount of light at a specific wavelength.

[0045] Technical effects of the present invention:

[0046] This invention provides a class of positively charged porphyrin derivatives that can be used as photosensitizers in photodynamic therapy. The method for preparing compounds of formula (I) according to this invention is simple and inexpensive, and good yields can be obtained by using a specific combination of condensation catalysts and condensing agents. Furthermore, the compounds of formula (I) provided by this invention exhibit good targeting and antibacterial activity against Gram-negative cocci, bacilli, or coccobacilli, and have therapeutic effects on oral diseases such as periodontitis, gingivitis, dental plaque, and dental caries. Attached Figure Description

[0047] Figure 1 Antimicrobial activity of PPIX, 5-ALA and porphyrin derivatives against Porphyromonas gingivalis (Note: **** indicates comparison with PPIX; ^^^^ indicates comparison with P-12-02 (*) P＜ 0.05, **** indicates P＜ 0.0001, ^^^^ represents P ＜ 0.0001));

[0048] Figure 2 : Targeted fluorescence effect of PPIX and porphyrin derivatives on Porphyromonas gingivalis. Detailed Implementation

[0049] The invention will be described in more detail below.

[0050] Unless otherwise stated, “compound of formula (I) of the present invention”, “compound of formula (I)”, “compound of the present invention” and “porphyrin derivative of the present invention” are used synonymously.

[0051] As used herein, the term “comprising” and its synonyms “including” and “containing” mean “including but not limited to”, and are not intended to exclude, for example, other additives, components, integers or steps.

[0052] As used herein, the terms “optional,” “optional,” or “optionally” mean that the event, situation, or substance described below may or may not occur or not exist, and such description includes both the occurrence and absence of the event, situation, or substance.

[0053] Unless otherwise stated, the following definitions apply to groups or substituents used throughout this specification and claims. Within the scope of this invention, the meanings of all repeated groups are independent of each other.

[0054] As used in this article, the term "halogen" refers to, for example, fluorine, chlorine, bromine, or iodine.

[0055] As used herein, the term "alkyl" refers in each case to a saturated straight-chain or branched hydrocarbon group having a specified number of carbon atoms, such as (C1-C8)-alkyl, (C1-C6)-alkyl, and (C1-C4)-alkyl, examples including but not limited to methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 1,1-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, n-octyl, 1-methylheptyl, 2-ethylhexyl, 1,3-dimethylhexyl and 1-ethyl-2-methylpentyl.

[0056] As used herein, the term "alkylene" refers to a hydrocarbon group derived from an alkyl group by removing one hydrogen atom to form a group having two monovalent groups at its center. This group can be a saturated branched alkyl group or a saturated straight-chain alkyl group. Suitable examples include, but are not limited to, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 1,2-propylene, 2,2-propylene, 1,4-butylene, 1,3-butylene, 1,2-butylene, 1,5-pentylene, and 1,6-hexylene.

[0057] As used herein, the term "cycloalkyl" refers to a carbon-ring saturated ring system having a specified number of carbon atoms in each case, examples including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, the cycloalkyl group has 3 to 6 carbon atoms.

[0058] Unless otherwise defined, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic heterocyclic group consisting of a carbon atom and at least one heteroatom selected from oxygen, nitrogen, and sulfur, wherein at least one ring is aromatic. Preferably, the heteroaryl group contains 3, 4, 5, 6, 7, or 8 carbon atoms, which may be partially attached to the parent molecule via any carbon or nitrogen atom contained within the heterocycle. Examples include, but are not limited to, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazoleyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazolyl, pyridinyl, pyrazinyl, pyrid ... Zincyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl, benzofuranyl, benzoisofuranyl, benzothiophenyl, benzoisothiophenyl, indolyl, isoindolyl, indazoleyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, 2,1,3-benzoxadiazole, quinolinyl, isoquinolinyl, terolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, benzotriazinyl, purineyl, pteridyl, imidazopyridyl, thienazinopyrimidyl, thienazinopiperidyl, etc.

[0059] The term "heteroarylalkylene" refers to the combination of the groups "heteroaryl" and "alkylene" as defined according to the present invention, wherein the groups are typically linked to the backbone or the remainder via the alkylene group, wherein the definitions of alkylene and heteroaryl are as described above. Examples include, but are not limited to, pyrrolithylmethylene, pyrrolithylethylene, thienothylmethylene, thienothylethylene, furanylmethylene, furanylethylene, etc.

[0060] Unless otherwise defined, the term "heterocyclic group" refers to a saturated or partially saturated monocyclic ring containing a carbon atom and at least one heteroatom in the ring. Preferably, the heterocyclic group contains 2, 3, 4, 5, or 6 carbon atoms and 1 or 2 heteroatoms selected from oxygen, sulfur, and nitrogen, which can be attached to a portion of the parent molecule via any carbon or nitrogen atom contained in the heterocycle. If the ring contains more than one oxygen atom, they are not directly adjacent. Examples of heterocyclic groups include, but are not limited to, azirropropyl, oxacyclopropyl; azirrobutyl, oxacyclobutyl, thioherrobutyl; tetrahydrofuranyl, 1,3-dioxacyclopentyl, tetrahydrothiophenyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, isoxazolyl, oxazolyl, thiazoalkyl, isothiazolyl; piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, dioxyl, tetrahydro Thianyl, dithiaalkyl, morpholinyl, 1,2-oxazhexaalkyl, oxothiocyclohexaalkyl, thiomorpholinyl; oxazheptanyl, azirheptanyl, 1,4-diazaheptanyl, 1,4-oxazheptanyl; dihydrofuranyl, 1,3-dioxacyclopentenyl, dihydrothiophenyl, pyrrololinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrothiazolyl; pyranyl, thiaranyl, and thiazinyl.

[0061] As used herein, the term "amino protecting group" is a nitrogen-linked protecting group in an intermediate used to prepare a compound of general formula (I). The group may be selected from substituted sulfonyl groups, such as methanesulfonyl, toluenesulfonyl, or benzenesulfonyl; acyl groups, such as benzoyl, acetyl, or tetrahydrofuranone; or carbamate groups, such as tert-butoxycarbonyl (Boc); or may contain silicon, such as 2-(trimethylsilyl)ethoxymethyl (SEM).

[0062] This document does not cover compounds obtained from combinations that contradict the laws of nature and that would therefore be excluded by someone skilled in the art based on his / her expertise. For example, ring structures with three or more adjacent oxygen atoms are excluded.

[0063] According to one aspect of the invention, the invention provides a compound of formula (I).

[0064] (I),

[0065] in,

[0066] X - These are pharmaceutically acceptable balanced ions.

[0067] q is 1 or 2, so that X - Balanced with the cation charge,

[0068] R + The following formula (II) is given.

[0069] (II),

[0070] “ "The wavy line indicates the connection point to the rest of the part."

[0071] p is 0 or 1

[0072] K is either (II-a) or (II-b), with (II-a) being the preferred form.

[0073] (II-a) or (II-b),

[0074] R1 is hydrogen, alkyl, cycloalkyl, or heteroarylalkylene, wherein the heteroarylalkylene contains one or more heteroatoms selected from O and S; preferably hydrogen or heteroarylalkylene.

[0075] R2 is hydrogen or a heteroaryl group, wherein the heteroaryl group contains one or more heteroatoms selected from O and S;

[0076] A + It is either (II-c) or (II-d), with (II-d) being the preferred form.

[0077] (II-c) or (II-d),

[0078] n is an independent integer from 0 to 8;

[0079] m is 0 or 1, so that the N atom carries a positive charge;

[0080] Q is a heterocyclic group or heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N;

[0081] R3 is an alkyl group on its own.

[0082] Among them, X - It is a pharmaceutically acceptable balanced ion, which can be selected from, for example, carbonate ions, sulfate ions, sulfonate ions, citrate ions, trifluoroacetate ions, halide ions (such as iodide ions or chloride ions), and acetate ions, with acetate ions being preferred.

[0083] The inventors unexpectedly discovered that, compared to other anions (such as iodide, chloride, and trifluoroacetate ions), using acetate ions for salt formation is more advantageous for optimizing and balancing the solubility, chemical stability, biocompatibility, ease of preparation, and yield of the compounds. For example, in terms of solubility, the compounds of the present invention formed using acetate ions have higher solubility than the corresponding compounds formed using iodide ions; in terms of chemical stability, the compounds of the present invention formed using acetate ions have higher chemical stability than the corresponding compounds formed using chloride or iodide ions; in terms of ease of preparation and yield, salt formation using acetate ions is easier and yields higher than that using trifluoroacetate ions; and in terms of biocompatibility, acetate ions have better biocompatibility than iodide ions.

[0084] When Q is a heterocyclic group, the linking site between Q and the optional alkylene group can be on any cyclic atom of the heterocyclic group, such as a positively charged N atom, a cyclic carbon atom, or a cyclic heteroatom. When Q is a heteroaryl group, the linking site between Q and the optional alkylene group can be on any cyclic atom other than a positively charged N atom, such as a cyclic carbon atom.

[0085] In a preferred embodiment of the invention, wherein in formula (I),

[0086] R1 is hydrogen, (C1-C8)-alkyl, (C3-C6)-alkyl, or (C4-C6)-alkyl. 10 )-cycloalkyl or (C3-C 10 )-heteroaryl-(C1-C8)-alkylene, wherein the heteroarylalkylene comprises one or more heteroatoms selected from O and S;

[0087] R2 is hydrogen or (C3-C) 10 )-Heteroaryl, wherein the heteroaryl group comprises one or more heteroatoms selected from O and S;

[0088] n is an independent integer from 0 to 8;

[0089] m is 0 or 1, so that the N atom carries a positive charge;

[0090] Q is a (C2-C) group containing one positively charged N atom. 10 )-heterocyclic group or (C3-C 10 )-Heteroaryl, wherein the heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N;

[0091] R3 is independently (C1-C8)-alkyl.

[0092] In a more preferred embodiment of the invention, wherein in formula (I),

[0093] R1 is hydrogen, (C1-C6)-alkyl, (C3-C8)-cycloalkyl, or (C3-C8)-heteroaryl-(C1-C6)-alkylene, wherein the heteroarylalkylene comprises one or more heteroatoms selected from O and S;

[0094] R2 is hydrogen or (C3-C8)-heteroaryl, wherein the heteroaryl group contains one or more heteroatoms selected from O and S;

[0095] n is an independent integer between 0 and 6;

[0096] m is 0 or 1, so that the N atom carries a positive charge;

[0097] Q is a (C2-C7)-heterocyclic group or (C3-C8)-heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N;

[0098] R3 is independently (C1-C6)-alkyl.

[0099] In a more preferred embodiment of the invention, wherein in formula (I),

[0100] R1 is hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl, or (C3-C5)-heteroaryl-(C1-C4)-alkylene, wherein the heteroarylalkylene comprises one or more heteroatoms selected from O and S;

[0101] R2 is hydrogen or (C3-C5)-heteroaryl, wherein the heteroaryl group contains one or more heteroatoms selected from O and S;

[0102] n is an independent integer between 0 and 4;

[0103] m is 0 or 1, so that the N atom carries a positive charge;

[0104] Q is a (C3-C5)-heterocyclic group or (C3-C5)-heteroaryl group containing a positively charged N atom, wherein the heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N;

[0105] R3 is independently (C1-C4)-alkyl.

[0106] In a more preferred embodiment of the invention, wherein in formula (I),

[0107] R1 is hydrogen, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or thienylmethylene, thienyl-1,2-ethylene, thienyl-1,1-ethylene, thienyl-1,3-propylene, thienyl-1,2-propylene, thienyl-2,2-propylene, thienyl- 1,4-Butylene, thienyl-1,3-Butylene, thienyl-1,2-Butylene, furanylmethylene, furanyl-1,2-Ethylene, furanyl-1,1-Ethylene, furanyl-1,3-Propane, furanyl-1,2-Propane, furanyl-2,2-Propane, furanyl-1,4-Butylene, furanyl-1,3-Butylene, or furanyl-1,2-Butylene;

[0108] R2 is hydrogen, thienyl, or furanyl;

[0109] n can be 0, 1, 2 or 3 independently;

[0110] m is 0 or 1, so that the N atom carries a positive charge;

[0111] Q is a morpholino, piperazine, imidazoalkyl, pyrrole, pyrazine, pyrazol, or pyridinyl group containing a positively charged nitrogen atom.

[0112] R3 can be methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, or 1,1-dimethylethyl.

[0113] In a more preferred embodiment of the invention, wherein in formula (I),

[0114] R1 is hydrogen, methyl, cyclopropyl, or thienylmethylene;

[0115] R2 is hydrogen or thiophene group;

[0116] n is an independent integer between 0 and 2;

[0117] m is 0 or 1, so that the N atom carries a positive charge;

[0118] Q is a morpholino, piperazine, imidazoalkyl, or pyridinyl group containing a positively charged nitrogen atom;

[0119] R3 can be methyl or ethyl on its own.

[0120] In a more preferred embodiment of the invention, wherein in formula (I),

[0121] R + Each is independently selected from the following groups:

[0122] , , , , , , , , , , and .

[0123] According to another aspect of the invention, the invention also provides a method for preparing a compound of formula (I), the method comprising:

[0124] i) In the presence of a condensation catalyst and a condensation agent, protoporphyrin (PPIX) is condensed with a compound having reactive hydrogen atoms in a polar organic solvent to obtain an intermediate compound.

[0125] iii) To induce alkylation of intermediate compounds.

[0126] in,

[0127] The compound having reactive hydrogen atoms is selected from compounds of general formula (III).

[0128] (III),

[0129] in,

[0130] H represents a reactive hydrogen atom;

[0131] p is as defined above;

[0132] K is as defined above;

[0133] A is either (III-c) or (III-d) below.

[0134] (III-c) or (III-d),

[0135] n is as defined above;

[0136] P is as defined above as Q, and it is electrically neutral;

[0137] R3 is defined as described above.

[0138] More specifically, P has the same structure as Q as defined above, except that P is electrically neutral and does not carry a positive charge. For example, when Q is a morpholino group containing a positively charged N atom, P is a morpholino group containing a single N atom, where the N atom does not carry a positive charge.

[0139] Depending on the reaction requirements, the compound having reactive hydrogen atoms may optionally contain an amino protecting group known to those skilled in the art and commonly used in amidation reactions, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilylethoxycarbonyl (Teoc), etc. Those skilled in the art can make reasonable selections according to actual needs. Preferably, the amino protecting group is -Boc (tert-butoxycarbonyl).

[0140] In a preferred embodiment of the invention, the compound having reactive hydrogen atoms is selected from 3-aminomethyl-morpholine-4-tert-butyl carbonate, (R)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester, 1-tert-butoxycarbonylpiperazine, imidazoline-1-carboxylic acid tert-butyl ester, 1-(2-thienyl)-3-(dimethylamino)-1-propanol, N1,N1-dimethyl-N2-(thien-2-ylmethyl)ethane-1,2-diamine, 2-morpholine-N-(thien-2-ylmethyl)ethylamine, 4-hydroxymethylpyridine, N-cyclopropylpyridine-4-amine, N-methyl-N-(4-pyridylmethyl)amine, and N,N-diethylethylenediamine.

[0141] The condensation catalyst suitable for the method of the present invention is an organic base catalyst, preferably selected from N,N-diisopropylethylamine (DIPEA), N,N-dimethylcyclohexylamine, N,N-dimethylbenzylamine, N-methylmorpholine, N-ethylmorpholine, N-methylimidazolium, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N,N-dimethylaminopyridine, 2,6-dimethylpyridine or mixtures thereof; more preferably N,N-diisopropylethylamine.

[0142] The condensing agent suitable for the method of the present invention is a urea cation type condensing agent, preferably selected from O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), O-(1, 2-Dihydro-2-oxo-pyridyl)-1,1,3,3-tetramethylurea tetrafluoroborate (TPTU); or a carbodiimide-type condensing agent, preferably selected from 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or 1,3-dicyclohexylcarbodiimide (DCC); or a carbonylimidazolium-type condensing agent, preferably selected from N,N-carbonyldiimidazolium (CDI); or a mixture of the above condensing agents; wherein the condensing agent is preferably selected from HATU, EDCI, CDI or a mixture thereof, more preferably HATU.

[0143] The polar organic solvent suitable for the method of the present invention is selected from N,N-dimethylformamide, N,N-dimethylacetamide, formamide, dimethyl sulfoxide, acetone, pyridine or mixtures thereof, preferably N,N-dimethylformamide.

[0144] In a preferred embodiment of the present invention, the molar ratio of the condensation catalyst to the condensation agent is (0.7-3):1, preferably (0.8-2.5):1, and more preferably (0.9-2):1.

[0145] In a preferred embodiment of the invention, the molar ratio of the condensation catalyst to the compound having reactive hydrogen atoms is (0.7-3):1, preferably (0.65-2.5):1, and more preferably (0.7-2):1.

[0146] In a preferred embodiment of the present invention, the molar content relationship between the protoporphyrin (p), the compound having reactive hydrogen atoms (n), and the condensing agent (q) satisfies the following relationship: 2.5 ≤ q / [np / (n+p)] ≤ 4.5; preferably 2.7 ≤ q / [np / (n+p)] ≤ 4.3; more preferably 2.9 ≤ q / [np / (n+p)] ≤ 4.1.

[0147] In a preferred embodiment of the present invention, the catalyst is DIPEA and the condensing agent is HATU, wherein the molar ratio of the condensing catalyst to the condensing agent is (0.7-3):1, preferably (0.8-2.5):1, and more preferably (0.9-2):1.

[0148] In a preferred embodiment of the present invention, the molar ratio of the compound having reactive hydrogen atoms to the condensation catalyst is 1:(0.6-3), preferably 1:(0.65-2.5), and more preferably 1:(0.7-2).

[0149] In a preferred embodiment of the invention, the weight ratio of the polar organic solvent to the total amount of the protoporphyrin, catalyst, condensing agent and compound having reactive hydrogen atoms is 1:(0.06-0.25), preferably 1:(0.065-0.2), more preferably 1:(0.062-0.18).

[0150] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the condensation catalyst is 1:(1.8-8), preferably 1:(1.8-6), more preferably 1:(1.8-4), and even more preferably 1:(1.9-3).

[0151] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the catalyst is 1:(1.8-8), preferably 1:(1.8-6), more preferably 1:(1.8-4), and even more preferably 1:(1.9-3).

[0152] In a preferred embodiment of the present invention, the molar ratio of the protoporphyrin to the compound having reactive hydrogen atoms is 1:(2-6), preferably 1:(2.5-5), more preferably 1:(2.5-4.5), and even more preferably 1:(2.5-3.5).

[0153] The method for preparing compounds of formula (I) of this invention uses a specific combination of an organic base catalyst and a specific condensing agent in step i), particularly a specific ratio of DIPEA and HATU. This allows for easy post-processing to obtain intermediate compounds with high purity in good yields, thereby further improving the yield of the target product. In step i), both insufficient and excessive amounts of catalyst or condensing agent will adversely affect the intermediate compound. For example, excessive or insufficient amounts of base will lead to difficulties in post-processing, an increased proportion of byproducts, and a low yield of the intermediate compound, thereby further reducing the yield of the target product.

[0154] In the method of the present invention, the reaction time of step i) is 0.5-24 hours, preferably 1-22 hours, and more preferably 1-20 hours.

[0155] In one embodiment of the present invention, the method further includes: step ii) removing the amino protecting group from the intermediate compound if the intermediate compound contains an amino protecting group.

[0156] The removal of the amino protecting group can be carried out by conventional methods known to those skilled in the art, such as using a solution of hydrogen chloride or trifluoroacetic acid in a specific organic solvent (e.g., dioxane, ethyl acetate, methanol, or dichloromethane), preferably a solution of hydrogen chloride in dioxane or a solution of trifluoroacetic acid in dichloromethane.

[0157] In the method of the present invention, the alkylation reaction in step iii) can be carried out in a conventional manner known to those skilled in the art. For example, the intermediate compound can be alkylated with a haloalkane in the presence of a base using methods known to or similar to those known to those skilled in the art. The base can be a carbonate of an alkali metal (e.g., lithium, sodium, or potassium), and the alkylation reaction is preferably carried out at room temperature in a suitable solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, or ethyl acetate.

[0158] In a preferred embodiment of the invention, the intermediate compound is dissolved in... N,NDimethylformamide was added to potassium carbonate, followed by iodomethane or iodoethane, and the mixture was stirred at room temperature until the reaction was complete. The resulting product was then purified and lyophilized to obtain the compound of formula (I).

[0159] In the above-described method for preparing the compounds of the present invention, each step of the method may optionally include other post-processing steps. These post-processing steps may include, for example, conventional purification steps such as pH adjustment, crystallization, extraction, filtration, vacuum concentration, and drying. All of the above steps can be performed in a conventional manner known to those skilled in the art. If present, extraction is typically performed using a mixed solution of dichloromethane and methanol, preferably a dichloromethane / methanol mixture of 10:1 (v / v); drying is typically performed by methods such as freeze-drying or vacuum drying, preferably freeze-drying.

[0160] In a preferred embodiment of the present invention, the method may further include a purification step via a chromatographic column. The purification may be performed using: a normal-phase silica column with silica particle size of 30-100 μm, preferably 40-63 μm, and a charge of 20-120 g, preferably 40 g, eluted with dichloromethane / methanol (elution gradient 100% / 0% to 90% / 10%, gradient elution time 15 min), or dichloromethane / methanol containing 1% triethylamine (elution gradient 100% / 0% to 90% / 10%, gradient elution time 15 min); or a C18 column with packing material particle size of 20-80 μm, preferably 40-63 μm, a charge of 4-120 g, preferably 40 g, and a carbon content between 10-30%, preferably 17%, eluted with water / acetonitrile containing 5% acetic acid (elution gradient 95% / 5% to 5% / 95%, gradient elution time 20-25 min).

[0161] Unless otherwise expressly stated, all operations are performed at room temperature; the reagents or raw materials used are commercially available or prepared by methods known to those skilled in the art.

[0162] The compounds of the present invention can be prepared according to the methods described above. However, it should be understood that those skilled in the art, based on their common sense and available publications, can adjust the methods according to the specific circumstances of the compounds of the present invention to be synthesized.

[0163] According to another aspect of the invention, the invention also provides a medicament comprising a compound of formula (I).

[0164] According to another aspect of the invention, the invention also provides a method for therapeutic or non-therapeutic purposes of inhibiting Gram-negative cocci, bacilli, or cocci, comprising contacting a compound of formula (I) with Gram-negative cocci, bacilli, or cocci and irradiating them with light of a specific wavelength at which an inhibitory effect is achieved. The contact may be performed in vivo or in vitro, for example, in vitro.

[0165] According to another aspect of the invention, the invention also provides the use of the compound of formula (I) in the preparation of a medicament for treating diseases or conditions caused by Gram-negative cocci, bacilli or cocci.

[0166] According to another aspect of the invention, the invention also provides the use of the compound of formula (I) in treating diseases or conditions caused by Gram-negative cocci, bacilli or cocci.

[0167] According to another aspect of the invention, the invention also provides a method for treating a disease or condition caused by Gram-negative cocci, bacilli or cocci, comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need and irradiating a subject with a therapeutically effective amount of light of a specific wavelength; preferably, wherein the subject is a mammal, more preferably a human.

[0168] In one embodiment of the invention, the medicament may further comprise one or more other active compounds. These other active compounds are compounds that are equally effective in treating diseases or conditions caused by Gram-negative cocci, bacilli, or cocci.

[0169] In one embodiment of the invention, the medicament further comprises a pharmaceutically acceptable carrier, excipients, and / or other adjuvants. When a pharmaceutically acceptable carrier, excipients, and / or other adjuvants are included, an effective dose of a compound of formula (I) is typically combined with one or more pharmaceutically acceptable carriers, excipients, and / or other adjuvants to form a suitable administration or dosage form. This process includes mixing, granulating, compressing, or dissolving the components by suitable methods. The carrier may comprise 1 to 98% by weight in the medicament, typically approximately 80% by weight. For convenience, other adjuvants such as local anesthetics, antiseptics, and buffers may be directly dissolved in the carrier.

[0170] In a preferred embodiment of the invention, the drug comprises 0.01 mg-600 mg, preferably 0.05 mg-450 mg, more preferably 0.1 mg-300 mg, more preferably 0.5 mg-200 mg, more preferably 1 mg-120 mg of a compound of formula (I), such as 0.1 mg-600 mg, 0.5 mg-450 mg, 1.0 mg-300 mg, 5 mg-200 mg, 6 mg-120 mg or 10 mg-120 mg, and more specifically, such as 0.01 mg, 0.1 mg, 1 mg, 2 mg, 4 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 120 mg, 200 mg, 400 mg or 600 mg.

[0171] The compounds or drugs of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes of administration, such as oral, pulmonary, nasal, sublingual, tongue, buccal, rectal, vaginal, dermal, transdermal, conjunctival, or ear canal routes, or via subcutaneous, intravenous, intramuscular, intraperitoneal, or intracranial injection or infusion, or as implants or stents.

[0172] For these routes of administration, the compounds of the present invention can be administered in a suitable form.

[0173] The drug of the present invention can be administered in unit dose form. The dosage form can be a liquid, semi-solid, or solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticles, suspensions, etc. Semi-solid dosage forms can be ointments, creams, pastes, gels, etc. Solid dosage forms can be orally disintegrating films, tablets, capsules, pellets, pills, powders, granules, suppositories, lyophilized powder injections, inclusion complexes, implants, patches, etc. The compounds of the present invention can be incorporated into the aforementioned dosage forms. This can be achieved in a known manner by mixing with pharmaceutically suitable excipients.

[0174] In one embodiment, the single-dose dosage of the medicament of the present invention is 0.01-100 mg of active ingredient / kg body weight, preferably 0.02-80 mg of active ingredient / kg body weight, more preferably 0.05-50 mg of active ingredient / kg body weight, even more preferably 0.08-40 mg of active ingredient / kg body weight, particularly preferably 0.1-20 mg of active ingredient / kg body weight, even more preferably 0.2-10 mg of active ingredient / kg body weight, for example 0.2-4 mg of active ingredient / kg body weight, 0.2-2 mg of active ingredient / kg body weight, 0.8-4 mg of active ingredient / kg body weight, 0.4-2 mg of active ingredient / kg body weight. In one embodiment, the medicament of the present invention is administered at least once a month, for example, once, twice or three times a month. Preferably, the medicament of the present invention is administered twice a month. Here, the term "active ingredient" refers to the compound of formula (I) in the present invention.

[0175] In one embodiment of the invention, in the use described herein, the compound of formula (I) is used as a photosensitizer in photodynamic therapy. Photodynamic therapy involves administering a therapeutically effective amount of the compound of formula (I) to a subject in need and irradiating them with a therapeutically effective amount of light at a specific wavelength.

[0176] In one embodiment of the present invention, in the use or method described herein, the specific wavelength range is 300 nm-800 nm, preferably 400 nm-650 nm, for example, it can be 405 nm, 505 nm, 540 nm, 575 nm or 630 nm, more preferably 405 nm.

[0177] In one embodiment of the present invention, in the antibacterial method or treatment method, the irradiation time of the light is 1-1200 s, for example 20s, 30s, 60s, 120s, 180s, 240s, 480s, 600s, 720s, 1000s, 1200s, etc. Preferably 2-800s, more preferably 4-600s, more preferably 8-240s, more preferably 10-120s, and even more preferably 30-120s.

[0178] In one embodiment of the present invention, in the antibacterial method or treatment method, the light dose of the light irradiation is 1-200 J, preferably 10-120 J, more preferably 10-60 J, and even more preferably 20 J and 30 J.

[0179] In the aforementioned antibacterial method or treatment method, the Gram-negative cocci, bacilli, or cocci may be selected from Gram-negative bacilli or cocci, such as Gram-negative anaerobic bacilli or cocci, Gram-negative facultative anaerobic cocci, or Gram-negative aerobic bacilli.

[0180] In a preferred embodiment of the present invention, the Gram-negative cocci, bacilli, or cocci are *Porphyromonas gingivalis* (…). Porphyromonasgingivalis ), Actinobacillus consanguineus ( Actinobacillusactinomycetem comitans ), Fossatanella ( Tannerellaforsythia ), Prevotella intermedia ( Prevotellaintermedia ), Escherichia coli ( Escherichia coli ) or Pseudomonas aeruginosa ( Pseudomonasaeruginosa (More preferably, *Porphyromonas gingivalis*).

[0181] In a preferred embodiment of the present invention, the disease or condition is selected from one or more of the following: periodontitis, gingivitis, dental plaque, and dental caries; preferably, the periodontitis is chronic periodontitis or aggressive periodontitis; more preferably, the disease or condition is selected from one or more of the following: gingival swelling, gingival bleeding, gingival pain, periodontal pocket formation, alveolar bone resorption, and tooth loosening.

[0182] Example

[0183] Detailed synthetic examples of the selected compounds of the present invention are given below. However, these examples are merely illustrative and should not be construed as limiting the scope of the invention in any way.

[0184] The peaks in the synthesis examples are recorded in the form of an NMR peak list. 11H NMR data were obtained on a Bruker 400MHz or 600MHz NMR spectrometer. The structures of the compounds were also characterized by time-of-flight mass spectrometry (ESI source positive ion, TOF MS ES+) and liquid chromatography-mass spectrometry (LC-MS). TOF MS ES+ data were obtained using a Waters instrument (model: XevoG2-XS); LC-MS data were obtained using a Waters instrument (model: SQD2).

[0185] To facilitate understanding of this invention, certain terms used herein are described or defined. Unless otherwise stated or defined, scientific and technical terms used in conjunction with this invention will have the meanings commonly understood by one of ordinary skill in the art.

[0186] The correspondence between compounds with reactive hydrogen atoms, intermediate compounds, and compounds of formula (I) is shown in Table 1 below, where the anion of compound (I) is acetate ion, and the anion of compound (I) is... "The wavy line indicates the connection point to the rest of formula (I); the intermediate compound's " "The wavy line indicates the connection point to the rest of the following equation (IV) "

[0187] (IV).

[0188] Table 1:

[0189]

[0190] Table 1 (continued)

[0191]

[0192] Unless otherwise specified, all reagents and instruments used are commercially available products commonly used in the field. In the embodiments of this invention, unless otherwise stated, all operations are performed at room temperature and normal pressure. Unless otherwise stated, all contents and percentages in the context of this application are based on weight.

[0193]

[0194] A. Synthesis Examples

[0195] Example 1: Synthesis of P-01

[0196] i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 4 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. After stirring for 0.5 hours, 3-aminomethyl-morpholine-4-tert-butyl carbonate (114 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The combined organic phases were dried over anhydrous sodium sulfate and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to obtain intermediate P-01-01 (100 mg, yield 59%) as a black powder.

[0197] ii) 100 mg of intermediate P-01-01 was added to 10 mL of 4 mol / L dioxane hydrochloride solution, stirred for 4 hours, and then freeze-dried to obtain intermediate P-01-02 (75 mg, yield 95%) in the form of a reddish-brown solid.

[0198] iii) Dissolve 75 mg of intermediate P-01-02 in 6 mL of DMF solution, add potassium carbonate (68 mg, 0.49 mmol, 5 equ), stir for 5 minutes, add iodomethane (69 mg, 0.49 mmol, 5 equ), stir for 12 h, and then purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min). The obtained pure product was lyophilized to give product P-01 (61 mg, yield 66%) in the form of a reddish-brown solid.

[0199] LC-MS (m / z): 408.3 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36-10.23 (m,4H), 9.42 (br s, 2H), 8.59-8.48 (m, 2H), 6.48 (dd, J = 17.6, 6.0 Hz, 2H), 6.24(d, J= 11.6 Hz,2H), 4.39-4.35 (m, 4H), 3.76 (s, 3H), 3.75 (s, 3H), 3.66 (s,3H), 3.64 (s, 3H), 3.55-3.51 (m, 4H), 3.21-3.17 (m, 8H), 3.01-2.92 (m, 8H), 2.78-2.74 (m, 12H), 2.70-2.67 (m, 2H), 1.51 (s, 6H), -3.89 (br s, 2H).

[0200] Example 2: Synthesis of P-02

[0201] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, then add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) sequentially, stir for 10 minutes, and then add ( R 3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (230 mg, 1.06 mmol, 3 equ) was stirred for 1 h. The reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the solution was lyophilized to give intermediate P-02-01 (290 mg, 85% yield) as a reddish-brown solid.

[0202] ii) At 0 °C, 290 mg of intermediate P-02-01 was dissolved in 5 mL of 4 mol / L dioxane hydrochloride solution, stirred for 2 h, and then freeze-dried to obtain 218 mg of intermediate P-02-02 in the form of a reddish-brown solid, with a yield of 95%.

[0203] iii) Dissolve 218 mg of intermediate P-02-02 in 10 mL of DMF, add potassium carbonate (118 mg, 0.86 mmol, 3 equ), stir for 5 minutes, add iodomethane (202 mg, 1.435 mmol, 5 equ), stir for 12 hours, then purify by reverse-phase C18 (water / acetonitrile (v / v) 95% / 5% to 5% / 95%, 25 min), and lyophilize to give product P-02 (197 mg, yield 73%) as a reddish-brown solid.

[0204] LC-MS (m / z): 409.6 [M]2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40-10.25 (m,4H), 8.61-8.51 (m, 2H), 6.48 (dd, J = 17.6, 4.8 Hz, 2H), 6.25 (dt, J = 11.6, 2.0Hz,2H), 4.51-4.39 (m, 6H), 4.27-4.23 (m, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.70-3.59 (m, 16H), 3.34-3.17 (m, 8H), 2.96 (s, 6H), 2.91 (s, 6H), 1.55 (s, 6H), -3.83 (br s, 2H).

[0205] Example 3: Synthesis of P-03

[0206] i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. After stirring for 10 minutes, 1-tert-butoxycarbonylpiperazine (99 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to give intermediate P-03-01 (93 mg, yield 58%) as a black powder.

[0207] ii) 93 mg of intermediate P-03-01 was added to a mixed solution of 3 mL trifluoroacetic acid and 12 mL dichloromethane. After stirring for 2 h, the intermediate P-03-02 (68 mg, yield 94%) was obtained by freeze-drying in the form of a reddish-brown solid.

[0208] iii) Dissolve 68 mg of intermediate P-03-02 in 3 mL of DMF solution, add potassium carbonate (67 mg, 0.49 mmol, 5 equ), stir for 5 minutes, add iodomethane (69 mg, 0.49 mmol, 5 equ), stir for 12 h, and then purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min). After lyophilization, the product P-03 (55 mg, yield 65%) was obtained as a reddish-brown solid.

[0209] LC-MS (m / z): 378.7 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40-10.27 (m,4H), 8.61-8.51 (m, 2H), 6.49 (dd, J = 17.6, 3.2 Hz, 2H), 6.25 (d, J = 11.2 Hz,2H), 4.37 - 4.33 (m, 4H), 3.81-3.75 (m, 14H), 3.69(s, 3H), 3.66(s, 3H), 3.13(br s, 6H), 3.04 (br s, 6H), 2.86 (s, 12H), 1.59 (s, 6H), -3.83 (br s, 2H).

[0210] Example 4: Synthesis of P-04

[0211] i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. After stirring for 10 minutes, imidazoline-1-carboxylic acid tert-butyl ester (92 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to give intermediate P-04-01 (120 mg, yield 77%) as a black powder.

[0212] ii) 120 mg of intermediate P-04-01 was added to 10 mL of 4 mol / L dioxane hydrochloride solution and stirred at room temperature for 4 hours. Normal phase thin-layer chromatography was used to confirm that the reaction was complete. The solution was concentrated under reduced pressure below 40 °C to obtain a reddish-brown oily liquid. After freeze-drying, intermediate P-04-02 (90 mg, yield 98%) was obtained in reddish-brown solid form.

[0213] iii) Dissolve 72 mg of intermediate P-04-02 in 3 mL of DMF solution, add potassium carbonate (74 mg, 0.54 mmol, 5 equ), stir for 5 minutes, add iodomethane (76 mg, 0.54 mmol, 5 equ), stir for 12 h, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and freeze-dry to obtain product P-04 (70 mg, yield 77%) in the form of a reddish-brown solid.

[0214] LC-MS (m / z): 364.5 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36-10.27 (m,4H), 8.58-8.49 (m, 2H), 6.48 (dd, J = 18.8, 3.2 Hz, 2H), 6.25 (d, J = 11.6 Hz,2H), 4.99(s, 1H), 4.89(s, 3H), 4.40-4.36 (m, 4H), 3.82-3.66 (m, 20H), 3.33-3.22 (m, 4H), 2,97-2.95 (m, 12H), 1.56 (s, 6H), -3.91 (br s, 2H).

[0215] Example 5: Synthesis of P-05

[0216] i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. After stirring for 10 minutes, imidazoline-1-carboxylic acid tert-butyl ester (92 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min) to give intermediate P-05-01 (120 mg, yield 77%) as a black powder.

[0217] ii) 120 mg of intermediate P-05-01 was added to 10 mL of 4 mol / L dioxane hydrochloride solution, stirred for 4 hours, and then freeze-dried to obtain intermediate P-05-02 (90 mg, yield 98%) in the form of a reddish-brown solid.

[0218] iii) Dissolve 72 mg of intermediate P-05-02 in 3 mL of DMF solution, add potassium carbonate (74 mg, 0.54 mmol, 5 equ), stir for 5 minutes, add iodoethane (84 mg, 0.54 mmol, 5 equ), stir for 12 h, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and freeze-dry to obtain product P-05 (63 mg, yield 65%) in the form of a reddish-brown solid.

[0219] LC-MS (m / z): 392.8 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36-10.24 (m,4H), 8.58-8.49 (m, 2H), 6.50-6.46 (m, 2H), 6.25 (d, J= 11.6 Hz, 2H), 4.88-4.74(m, 4H), 4.47-4.29 (m, 4H), 3.76(s, 3H), 3.75(s, 3H), 3.68-3.63 (m, 10H), 3.57-3.52 (m, 4H), 3.33-3.29 (m, 4H), 3.03-2.87 (m, 8H), 1.59(s, 6H), 0.96-0.94(m, 1H), 0.79-0.68(m, 11H), -3.93 (br s, 2H).

[0220] Example 6: Synthesis of P-06

[0221] i) Protoporphyrin (100 mg, 0.18 mmol, 1 equ) was dissolved in 6 mL of DMF, and HATU (169 mg, 0.45 mmol, 2.5 equ) and DIPEA (69 mg, 0.53 mmol, 3 equ) were added sequentially. After stirring for 10 minutes, 1-(2-thienyl)-3-(dimethylamino)-1-propanol (98 mg, 0.53 mmol, 3 equ) was added. After reacting for 15 hours, the reaction solution was poured into 30 mL of water and extracted with a 10:1 (v / v) mixture of dichloromethane / methanol (30 mL × 3 times). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min) to obtain intermediate P-06-02 (100 mg, 0.18 mmol, 1 equ) in the form of a black powder. mg, yield 63%).

[0222] iii) Dissolve 100 mg of intermediate P-06-02 in 10 mL of DMF, add potassium carbonate (68 mg, 0.49 mmol, 4.3 equ), stir for 5 minutes, add iodomethane (46 mg, 0.33 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and freeze-dry to obtain product P-06 (98 mg, yield 84%) in the form of a reddish-brown solid.

[0223] LC-MS (m / z): 463.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d6) δ 10.37-10.26 (m,4H), 8.59-8.49(m, 2H), 7.25-7.22 (m, 2H), 6.95 (d, J = 3.2 Hz, 2H), 6.76-6.73(m, 2H), 6.87 (dd, J = 19.6, 7.2 Hz, 2H), 6.26 (d, J = 11.6 Hz, 2H), 5.96-5.92(m, 2H), 4.42-4.38 (m, 4H), 3.77 (s, 3H), 3.75 (s, 3H), 3.60 (s, 3H), 3.58(s, 3H), 3.38-3.34 (m, 4H), 2.83-2.76 (m, 4H), 2.45-2.42 (m, 18H), 2.02-1.96(m, 4H), 1.61 (s, 6H), -3.95(br s, 2H).

[0224] Example 7: Synthesis of P-07

[0225] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ), stir for 10 minutes, and then add... N1,N1 -dimethyl- N2 -(thiophene-2-ylmethyl)ethane-1,2-diamine (195 mg, 1.06 mmol, 3 equ) was stirred for 5 h, and the reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the intermediate P-07-02 (289 mg, 91% yield) was lyophilized to obtain a reddish-brown solid.

[0226] iii) Dissolve 289 mg of intermediate P-07-02 in 10 mL of DMF, add potassium carbonate (200 mg, 1.45 mmol, 4.5 equ), stir for 5 minutes, add iodomethane (135 mg, 0.97 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and freeze-dry to obtain product P-07 (272 mg, yield 81%) in the form of a reddish-brown solid.

[0227] LC-MS (m / z): 462.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.31-10.14 (m,4H), 8.51-8.42 (m, 2H), 7.25-7.19 (m, 2H), 6.91-6.64 (m, 4H), 6.39 (dd, J =18.0, 5.2 Hz, 2H), 6.16 (d, J = 11.6 Hz, 2H), 4.64-4.60 (m, 4H), 4.33-4.26 (m,4H), 3.69 (s, 3H), 3.67 (s, 3H), 3.59-3.57 (m, 4H), 3.54 (s, 3H), 3.51 (s,3H), 3.17-3.08 (m, 8H), 2.91-2.87 (m, 14H), 2.63-2.58 (m, 4H), 1.54 (s, 6H), -3.90 (br s, 2H).

[0228] Example 8: Synthesis of P-08

[0229] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ), stir for 10 minutes, then add 2-morpholine- N-(thiophene-2-ylmethyl)ethylamine (240 mg, 1.06 mmol, 3 equ), stirred for 3 h. The reaction mixture was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the solution was lyophilized to give intermediate P-08-02 (299 mg, 85% yield) as a reddish-brown solid.

[0230] iii) Dissolve 299 mg of intermediate P-08-02 in 10 mL of DMF, add potassium carbonate (189 mg, 1.37 mmol, 4.5 equ), stir for 5 minutes, add iodomethane (128 mg, 0.92 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 25 min), and freeze-dry to obtain product P-08 (283 mg, yield 82%) in the form of a reddish-brown solid.

[0231] LC-MS (m / z): 504.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40-10.27 (m,4H), 8.60-8.51 (m, 2H), 7.34-7.27 (m, 2H), 7.01- 6.97 (m, 0.5H), 6.87-6.72(m, 3.5H), 6.49 (dd, J = 17.6, 5.6 Hz, 2H), 6.25 (d, J = 11.2 Hz, 2H), 4.74-4.72(m, 4H), 4.48-4.37 (m, 4H), 3.78 (s, 3H), 3.77 (s, 3H), 3.68-3.66 (m, 8H), 3.64 (s, 3H), 3.61 (s, 3H), 3.44-3.16 (m, 16H), 3.08-3.05 (m, 6H), 2.97 (s,2H), 2.84 (s, 2H), 1.57 (s, 6H), -3.83 (br s, 2H).

[0232] Example 9: Synthesis of P-09

[0233] i) Protoporphyrin (200 mg, 0.36 mmol, 1 equ) was dissolved in 10 mL of DMF, and HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ) were added. After stirring for 10 minutes, 4-hydroxymethylpyridine (115 mg, 1.06 mmol, 3 equ) was added, and the mixture was stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min). After evaporating the solvent, the solution was lyophilized to give intermediate P-09-02 (227 mg, 85% yield) as a reddish-brown solid.

[0234] iii) Dissolve 227 mg of intermediate P-09-02 in 10 mL of DMF, add potassium carbonate (189 mg, 1.37 mmol, 4.5 equ), stir for 5 minutes, add iodomethane (128 mg, 0.92 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile (v / v) 95% / 5% to 5% / 95%, 20 min), lyophilize to obtain product P-09 (225 mg, yield 83%) in reddish-brown solid form.

[0235] LC-MS (m / z): 387.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.40(s, 1H),10.30(s, 2H), 10.19(s, 1H), 8.61-8.51(m, 2H), 8.22 (dd, J = 12.0, 6.4 Hz, 4H), 7.58 (dd, J = 10.0, 6.4 Hz, 4H), 6.52-6.47(m, 2H), 6.28-6.24(m, 2H), 5.31(s,2H), 5.29(s, 2H), 4.47-4.43(m, 4H), 3.78(s, 3H), 3.77(s, 3H), 3.75(s, 3H),3.73(s, 3H), 3.67(s, 3H), 3.65(s, 3H),3.63(br s, 4H), 1.75(s, 6H), -3.97(brs, 2H).

[0236] Example 10: Synthesis of P-10

[0237] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ), stir for 10 minutes, and then add... N -Cyclopropylpyridine-4-amine (142 mg, 1.06 mmol, 3 equ) was stirred for 5 h. The reaction mixture was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the solution was lyophilized to give intermediate P-10-02 (229 mg, 80% yield) as a reddish-brown solid.

[0238] iii) Dissolve 229 mg of intermediate P-10-02 in 10 mL of DMF, add potassium carbonate (176 mg, 1.28 mmol, 4.5 equ), stir for 5 minutes, add iodomethane (119 mg, 0.86 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile containing 5% acetic acid 95% / 5% to 5% / 95%, 20 min), and freeze-dry to obtain product P-10 (199 mg, yield 74%) in the form of a reddish-brown solid.

[0239] LC-MS (m / z): 412.9 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.38-10.30 (m,4H), 8.70-8.69 (m, 4H), 8.59-8.50 (m, 2H), 7.99-7.97 (m, 4H), 6.48 (d, J =18.8, 3.6 Hz, 2H), 6.25 (d, J= 11.6 Hz, 2H), 4.47-4.39 (m, 4H), 4.14 (s, 6H), 3.77 (s, 3H), 3.75 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H), 3.64-3.60 (m, 2H), 3.17-3.10 (m, 4H), 1.61 (s, 6H), 0.99-0.97 (m, 4H), 0.60-0.59 (m, 4H), -3.87 (br s, 2H).

[0240] Example 11: Synthesis of P-11

[0241] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (232 mg, 1.8 mmol, 5 equ), stir for 10 minutes, and then add... N -methyl- N -(4-pyridylmethyl)amine hydrochloride (169 mg, 1.06 mmol, 3 equ), stirred for 5 h. The reaction mixture was poured into 30 mL of water and extracted (30 mL × 3 times) with a mixture of dichloromethane / methanol (10 / 1, v / v). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the solution was lyophilized to give intermediate P-11-02 (233 mg, yield 84%) as a reddish-brown solid.

[0242] iii) Dissolve 233 mg of intermediate P-11-02 in 10 mL of DMF, add potassium carbonate (189 mg, 1.37 mmol, 4.5 equ), stir for 5 minutes, add iodomethane (128 mg, 0.92 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile (v / v) 95% / 5% to 5% / 95%, 20 min), lyophilize to obtain product P-11 (208 mg, yield 75%) in reddish-brown solid form.

[0243] LC-MS (m / z): 400.6 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d6) δ10.33-10.15 (m,4H), 8.75-8.65 (m, 2H), 8.53-8.47 (m, 4H), 7.90-7.64 (m, 4H), 6.47 (d, J =17.6Hz, 2H), 6.25 (d, J = 12.0 Hz, 2H), 4.85-4.81 (m, 2H), 4.73-4.72 (m, 2H), 4.34-4.26 (m, 4H), 4.21-4.15 (m, 2H), 4.04 (d, J = 8.0 Hz, 4H), 3.75-3.71 (m,6H), 3.66-3.63 (m, 6H), 3.58-3.56 (m, 6H), 3.30-3.26 (m, 4H), 1.76 (s, 6H), -4.06 (br s, 2H).

[0244] Example 12: Synthesis of P-12

[0245] i) Dissolve protoporphyrin (200 mg, 0.36 mmol, 1 equ) in 10 mL of DMF, add HATU (338 mg, 0.89 mmol, 2.5 equ) and DIPEA (115 mg, 0.89 mmol, 2.5 equ), stir for 10 minutes, and then add... N,N -Diethylethylenediamine (122 mg, 1.06 mmol, 3 equ), stirred for 4 h. The reaction mixture was poured into 30 mL of water and extracted with a mixture of dichloromethane / methanol (10 / 1, v / v) (30 mL × 3 times). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by normal-phase silica gel column chromatography (dichloromethane / methanol (v / v) containing 1% triethylamine 100% / 0% to 90% / 10%, 15 min). After evaporation of the solvent, the solution was lyophilized to give intermediate P-12-02 (237 mg, yield 87%) as a reddish-brown solid.

[0246] iii) Dissolve 237 mg of intermediate P-12-02 in 10 mL of DMF, add potassium carbonate (193 mg, 1.40 mmol, 4.5 equ), stir for 5 minutes, add iodoethane (147 mg, 0.94 mmol, 3 equ), stir for 12 hours, purify the reaction solution by C18 column (water / acetonitrile (v / v) 95% / 5% to 5% / 95%, 20 min), lyophilize to give product P-12 (245 mg, yield 84%) as a reddish-brown solid.

[0247] LC-MS (m / z): 408.8 [M] 2+ / 2. 1 H NMR (400 MHz, DMSO- d 6) δ 10.17-10.06 (m,4H), 9.35-9.33 (m, 2H), 8.44-8.35 (m, 2H), 6.34 (dd, J = 18.0, 4.8Hz, 2H), 6.12(d, J = 11.6 Hz, 2H), 4.24-4.21 (m, 4H), 3.62 (s, 3H), 3.61 (s, 3H), 3.52 (s, 3H), 3.50 (s, 3H), 3.03-2.98 (m, 8H), 2.36-2.31 (m, 12H), 2.12-2.08 (m, 4H), 1.38 (s, 6H), 0.24-0.20 (m, 18H), -4.23 (br s, 2H).

[0248] Example 13: Synthesis of P-12-02

[0249] As in step i) of Example 12, the synthesis is performed.

[0250] LC-MS (m / z): 759.8 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 10.36-10.25 (m,4H), 8.59-8.49 (m, 2H), 7.86-7.80 (m, 2H), 6.47 (dd, J = 17.6, 6.0 Hz, 2H), 6.24 (d, J = 11.6 Hz, 2H), 4.40-4.27 (m, 4H), 3.77 (s, 3H), 3.76 (s, 3H), 3.65(s, 3H), 3.62 (s, 3H), 3.06-3.02 (m, 4H), 2.97-2.92 (m, 4H), 2.00-1.98 (m,8H), 1.89-1.85 (m, 4H), 0.45 (td, J = 7.2, 3.2 Hz, 12H), -3.85 (br s, 2H).

[0251] Synthetic Comparative Example

[0252] Comparative Example 1: Synthesis of P-02-01

[0253] It is synthesized using a method similar to that of Example 2, except that:

[0254] i) Using 84 mg (0.65 mmol, 1.81 equ) of DIPEA, intermediate P-02-01 (92 mg, yield 27%) was obtained.

[0255] Comparative Example 2: Synthesis of P-02-01

[0256] It is synthesized using a method similar to that of Example 2, except that:

[0257] i) Using 348 mg (2.7 mmol, 7.5 equ) of DIPEA, the intermediate P-02-01 (145 mg, yield 42%) was obtained.

[0258] Comparative Example 3: Synthesis of P-07-02

[0259] It is synthesized using a method similar to that of Example 7, except that:

[0260] i) Using 247 mg (0.65 mmol, 1.8 equ) of HATU, intermediate P-07-02 (149 mg, yield 47%) was obtained.

[0261] Comparative Example 4: Synthesis of P-07-02

[0262] It is synthesized using a method similar to that of Example 7, except that:

[0263] i) Using 479 mg (1.26 mmol, 3.5 equ) of HATU, intermediate P-07-02 (203 mg, yield 64%) was obtained.

[0264] Comparative Example 5: Synthesis of P-09-02

[0265] It is synthesized using a method similar to that of Example 9, except that:

[0266] i) Using 170 mg (0.89 mmol, 2.5 equ) EDCI and 120 mg (0.89 mmol, 2.5 equ) HOBT instead of HATU, intermediate P-09-02 (139 mg, yield 52%) was obtained.

[0267] Comparative Example 6: Synthesis of P-09-02

[0268] It is synthesized using a method similar to that of Example 9, except that:

[0269] i) Using 286 mg (0.89 mmol, 2.5 equ) TBTU instead of HATU, intermediate P-09-02 (179 mg, yield 67%) was obtained.

[0270] Comparative Example 7: Synthesis of P-09-02

[0271] It is synthesized using a method similar to that of Example 9, except that:

[0272] i) Using 463 mg (0.89 mmol, 2.5 equ) of PyBOP instead of HATU, intermediate P-09-02 (104 mg, yield 39%) was obtained.

[0273] Comparative Example 8: Synthesis of P-12-02

[0274] It is synthesized using a method similar to that of Example 12, except that:

[0275] i) Using 298 mg (0.53 mmol, 1 equ) protoporphyrin, 338 mg (0.89 mmol, 1.7 equ) HATU, 115 mg (0.89 mmol, 1.7 equ) DIPEA and 122 mg (1.06 mmol, 2 equ) N,N-diethylethylenediamine, intermediate P-12-02 (123 mg, yield 30%) was obtained.

[0276] Comparative Example 9: Synthesis of P-12-02

[0277] It is synthesized using a method similar to that of Example 12, except that:

[0278] i) Using 111 mg (0.20 mmol, 1 equ) of protoporphyrin, 338 mg (0.89 mmol, 4.5 equ) of HATU, 115 mg (0.89 mmol, 4.5 equ) of DIPEA and 122 mg (1.06 mmol, 5.4 equ) of N,N-diethylethylenediamine, intermediate P-12-02 (72 mg, yield 47%) was obtained.

[0279] Comparative Example 10: Synthesis of P-12-I

[0280] 237 mg of intermediate P-12-02 was dissolved in 10 mL of DMF, and potassium carbonate (193 mg, 1.40 mmol, 4.5 equ) was added. After stirring for 5 minutes, iodoethane (147 mg, 0.94 mmol, 3 equ) was added, and the mixture was stirred for 12 hours. The reaction solution was then slowly added dropwise to 40 mL of methyl tert-butyl ether, and the precipitated reddish-brown crude product was collected. The crude product was washed with 3 × 10 mL of acetone and dried to obtain the reddish-brown solid product P-12-I (212 mg, yield 63%). The cation of product P-12-I and... P-12's Yang Li The same as the child, The anion is an iodide ion.

[0281] The data of the compound examples and comparative examples of the present invention are summarized in Tables 2 and 3 below.

[0282] Table 2: Comparison of condensing agent types between the examples and the comparative examples.

[0283]

[0284] Table 3: Comparison of reagent usage data between the preparation example and the comparative example.

[0285] .

[0286] B. Examples of Antibacterial Effect

[0287] Experiment 1

[0288] 1. Materials and Methods

[0289] 1.1 Information on the drug to be tested

[0290] Antibacterial test drugs: Drugs in Examples 1-12.

[0291] Positive drug 1: Protoporphyrin IX (PPIX).

[0292] Positive drug 2: 5-aminolevulinic acid (ALA).

[0293] 1.2 Information on Main Experimental Reagents

[0294] Table 4: Main Experimental Reagents

[0295]

[0296] 1.3 Information on Major Instruments and Equipment

[0297] Table 5: Information on Major Instruments

[0298]

[0299] 1.4 Test on the killing ability of the compounds of the present invention against Porphyromonas gingivalis

[0300] After resuscitation, *Porphyromonas gingivalis* (purchased from Beijing Beina Chuanglian Biotechnology Research Institute, batch number BNCC353909) was inoculated into BHI medium and cultured under anaerobic conditions of 10% H2, 10% CO2, and 80% N2 until the logarithmic growth phase. 1 mL of the bacterial culture was taken, the OD value was measured, and after centrifugation and discarding the supernatant, a certain amount of BHI medium was added to adjust the bacterial concentration to 10. 10 CFU / mL (1 OD≈9.52*10) 9 (CFU / mL).

[0301] Test drug group: Add 100 μL of bacterial culture, 898 μL of BHI medium, and 2 μL of DMSO solution of the test drug to centrifuge tubes respectively, and shake well (to achieve a final bacterial concentration of 10). 9 (CFU / mL, final concentration of test drug was 10 μg / mL, final concentration of positive drug 1 was 10 μg / mL, and final concentration of positive drug 2 was 80 μg / mL). After incubation in the dark and under anaerobic conditions for 4 h, the supernatant was discarded by centrifugation, and the culture was resuspended in 1 mL of BHI medium. The resuspended culture was added to each well of a 96-well plate, with 100 μL of bacterial culture added to each well, and four replicates were performed each time. Irradiation was performed under a 405 nm laser with a laser output power of 300 mW for 66.67 s and a light dose of 20 J. After the irradiation, the culture was continued under anaerobic conditions for 24 h. Then, the OD value of each group of bacterial cultures at 600 nm was measured, and the inhibition rate was calculated.

[0302] Blank light group: Follow the above method, except that 100 μL of bacterial culture and 900 μL of BHI medium are added to the centrifuge tube.

[0303] The formula for calculating the antibacterial rate is as follows:

[0304]

[0305] Wherein: OD 阴性 This represents the average OD value of the bacterial culture measured in the blank light group; OD 待测 This represents the average OD value of the bacterial culture obtained from the test drug group.

[0306] 1.5 Calculation of statistical differences

[0307] Statistical analysis was performed using GraphPad Prism8 to compare differences in antibacterial rates and evaluate the antibacterial effect. One-way ANOVA was used for multiple group comparisons, with post-hoc multiple comparisons performed. PPIX was the comparison target. A p-value < 0.05 was considered statistically significant. * indicates p < 0.05, ** indicates p < 0.001, and **** indicates p < 0.0001, representing a significant reduction.

[0308] 2. Results and Discussion

[0309] The results are as follows Figure 1 As shown in Figure (a) and Table 6, the 12 porphyrin derivatives and PPIX have good antibacterial effects. Most of the 12 porphyrin derivatives have better antibacterial effects than PPIX, with statistically significant differences (P < 0.0001).

[0310] Table 6: Antibacterial rates of PPIX, 5-ALA, and 12 porphyrin derivatives against Porphyromonas gingivalis

[0311]

[0312] Experiment 2

[0313] 1. Materials and Methods

[0314] The experiment was conducted in a manner similar to Experiment 1, except that the test drug was:

[0315] Antibacterial test drugs: P-12, P-12-02.

[0316] Positive drug 1: Protoporphyrin (PPIX); Positive drug 2: 5-aminolevulinic acid (5-ALA).

[0317] 2. Results and Discussion

[0318] The results are as follows Figure 1 As shown in Figure (b) and Table 7, both P-12 and P-12-02 exhibited significant antibacterial activity compared to PPIX, with statistically significant differences (P < 0.05 was considered statistically significant, **** indicates P < 0.0001 compared to PPIX). Furthermore, P-12 showed stronger antibacterial activity than P-12-02, with a statistically significant difference (P < 0.05 was considered statistically significant, ^^^^ indicates P < 0.0001 compared to P-12-02).

[0319] Table 7: Antibacterial rates of PPIX, 5-ALA, P-12-02, and P-12 against Porphyromonas gingivalis

[0320]

[0321] C. Targeting Effect Examples

[0322] 1. Experimental Materials

[0323] 1.1 Information on the drug to be tested

[0324] Test drugs: P-02, P-06, P-12, P-12-02; Positive control drug: Protoporphyrin (PPIX).

[0325] 1.2 Information on Main Experimental Reagents

[0326] Table 8: Main Experimental Reagents

[0327]

[0328] 1.3 Information on Major Instruments and Equipment

[0329] Table 9: Information on Major Instruments

[0330]

[0331] 2. Experiment

[0332] After resuscitation, *Porphyromonas gingivalis* (purchased from Beijing Beina Chuanglian Biotechnology Research Institute, batch number BNCC353909) was inoculated into BHI medium and cultured to the logarithmic growth phase under anaerobic conditions of 10% H2, 10% CO2, and 80% N2. An appropriate amount of the bacterial suspension was centrifuged at 10000×g for 5 minutes at room temperature, the supernatant was discarded, and the suspension was washed once with physiological saline. The bacterial concentration was adjusted to 10⁻⁶ with physiological saline. 6 bacteria / mL.

[0333] Experimental group: Take 1 mL of bacterial culture and add 1 μL of DMSO solution of the test drug, shake well (to make the final drug concentration 5 μg / mL). After incubating at 37℃ in the dark for 15 minutes, take 10 µL of bacterial culture from each group and drop it onto a glass slide.

[0334] Control group: The procedure was performed as described above, except that no compound was added.

[0335] Bacteria were observed under a fluorescence microscope, and the differences in the fluorescence intensity of compounds among the groups were compared (Ex: 405 nm; Em: 630 nm).

[0336] 3. Results and Discussion

[0337] The results are as follows Figure 2As shown in (a), *Porphyromonas gingivalis* exhibits varying degrees of uptake of PpIX, P-06, P-02, and P-12, with *Porphyromonas gingivalis* showing stronger uptake of P-06, P-02, and P-12 than PpIX. Figure 2 As shown in (b), P-12 uptake by *Porphyromonas gingivalis* was significantly higher than that by P-12-02. P-12 showed stronger targeting of *Porphyromonas gingivalis* than P-12-02.

[0338] D. Examples of Dissolution Effect

[0339] Weigh out P-12 and P-12-I (sample amounts are shown in Table 10) and operate at 25℃. Add water in small amounts several times, shaking vigorously for 30 seconds every 5 minutes. Observe the dissolution within 30 minutes. If no solute particles or droplets are visible to the naked eye, it is considered completely dissolved. Record the total amount of water added as the solvent volume.

[0340] Table 10: Solubility of P-12 and P-12-I

[0341]

[0342] *The approximate solubility of a drug is expressed using the following terms (from the pharmacopoeia):

[0343] Slightly soluble: This means that 1g (ml) of solute can dissolve in 30 to less than 100ml of solvent;

[0344] Very slight solubility: This means that 1g (ml) of solute can dissolve in 1000 to less than 10000ml of solvent.

[0345] The experimental results show that P-12 (the compound of the present invention that forms a salt of acetate ions) has higher solubility than P-12-I (the corresponding compound that forms a salt of iodide ions).

Claims

1. Compounds of formula (I) (I)， in, X - It is an acetate ion. q is 2, so that X - Balanced with the cation charge, R + The following formula (II) is given. (II), " "Wave lines indicate connection points to the rest of the text." p is 0 or 1 K is either (II-a) or (II-b) of the following formula. (II-a)or (II-b) R1 is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or C3-C5 heteroaryl C1-C4 alkylene, wherein the C3-C5 heteroaryl C1-C4 alkylene contains one or more heteroatoms selected from O and S; R2 is hydrogen or a C3-C5 heteroaryl group, wherein the C3-C5 heteroaryl group contains one or more heteroatoms selected from O and S; A + It is either (II-c) or (II-d) below. (II-c) or (II-d), n is an independent integer between 0 and 4; m is 0 or 1, so that the N atom carries a positive charge; Q is a C3-C5 heterocyclic group or a C3-C5 heteroaryl group containing a positively charged N atom, wherein the C3-C5 heterocyclic group optionally further comprises one or more heteroatoms selected from O, S and N; R3 is independently a C1-C4 alkyl group.

2. The compound according to claim 1, wherein, R1 is hydrogen, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or thienylmethylene, thienyl-1,2-ethylene, thienyl-1,1-ethylene, thienyl-1,3-propylene, thienyl-1,2-propylene, thienyl-2,2-propylene, thienyl-1,4-butylene, thienyl-1,3-butylene, thienyl-1,2-butylene, furanylmethylene, furanyl-1,2-ethylene, furanyl-1,1-ethylene, furanyl-1,3-propylene, furanyl-1,2-propylene, furanyl-2,2-propylene, furanyl-1,4-butylene, furanyl-1,3-butylene, or furanyl-1,2-butylene; R2 is hydrogen, thienyl, or furanyl; n can be 0, 1, 2 or 3 independently; m is 0 or 1, so that the N atom carries a positive charge; Q is a morpholino, piperazine, imidazoalkyl, pyrrole, pyrazine, pyrazol, or pyridinyl group containing a positively charged nitrogen atom. R3 can be methyl, ethyl, propyl, or butyl.

3. The compound according to claim 2, wherein, R1 is hydrogen, methyl, cyclopropyl, or thienylmethylene; R2 is hydrogen or thiophene group; n can be 0, 1, or 2 independently; m is 0 or 1, so that the N atom carries a positive charge; Q is a morpholino, piperazine, imidazoalkyl, or pyridinyl group containing a positively charged nitrogen atom; R3 can be methyl or ethyl on its own.

4. The compound according to claim 3, wherein, R + Each is independently selected from the following groups: , , , , , , , , , , and .

5. A method for preparing the compound according to any one of claims 1 to 3, the method comprising: i) In the presence of a condensation catalyst and a condensation agent, protoporphyrin is subjected to a condensation reaction with a compound having reactive hydrogen atoms in a polar organic solvent to obtain an intermediate compound. iii) To induce alkylation of intermediate compounds; in, The compound having reactive hydrogen atoms is selected from compounds of general formula (III). (III), in, H represents a reactive hydrogen atom; p is as defined in any one of claims 1 to 3; K is as defined in any one of claims 1 to 3; A is either (III-c) or (III-d) below. (III-c) or (III-d), n is defined as in any one of claims 1 to 3; P is Q as defined in any one of claims 1 to 3, and is electrically neutral; R3 is defined as in any one of claims 1 to 3.

6. The method according to claim 5, wherein, The method further includes: ii) If the intermediate compound contains an amino protecting group, remove the amino protecting group from the intermediate compound.

7. A method for preparing the compound of claim 4, the method comprising: i) In the presence of a condensation catalyst and a condensation agent, protoporphyrin is subjected to a condensation reaction with a compound having reactive hydrogen atoms in a polar organic solvent to obtain an intermediate compound. ii) If the intermediate compound contains an amino protecting group, remove the amino protecting group from the intermediate compound; iii) To induce alkylation of intermediate compounds; in, The compound having reactive hydrogen atoms is selected from 3-aminomethyl-morpholine-4-tert-butyl carbonate, (R)-3-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester, 1-tert-butoxycarbonylpiperazine, imidazoline-1-carboxylic acid tert-butyl ester, 1-(2-thienyl)-3-(dimethylamino)-1-propanol, N1,N1-dimethyl-N2-(thien-2-ylmethyl)ethane-1,2-diamine, 2-morpholine-N-(thien-2-ylmethyl)ethylamine, 4-hydroxymethylpyridine, N-cyclopropylpyridine-4-amine, N-methyl-N-(4-pyridylmethyl)amine, and N,N-diethylethylenediamine.

8. A medicament comprising the compound of formula (I) according to any one of claims 1 to 4.

9. A method for non-therapeutic purposes of inhibiting Porphyromonas gingivalis, comprising contacting the compound of formula (I) of any one of claims 1 to 4 with Porphyromonas gingivalis and irradiating it with light of a specific wavelength at an effective inhibitory level.

10. Use of the compound of formula (I) according to any one of claims 1 to 4 in the preparation of a medicament for treating conditions caused by Porphyromonas gingivalis.

11. The use according to claim 10, wherein the condition is selected from one or more of the following: periodontitis, gingivitis, dental plaque, and dental caries.

12. The use according to claim 10, wherein the condition is selected from one or more of the following: gingival swelling, gingival bleeding, gingival pain, periodontal pocket formation, alveolar bone resorption, and tooth loosening.

13. Use of the compound of formula (I) according to any one of claims 1 to 4 in the preparation of a medicament for treating diseases caused by Porphyromonas gingivalis.

14. The use according to claim 13, wherein the disease is selected from one or more of the following: periodontitis, gingivitis, dental plaque, and dental caries.

15. The use according to claim 13, wherein the disease is selected from one or more of the following: gingival swelling, gingival bleeding, gingival pain, periodontal pocket formation, alveolar bone resorption, and tooth loosening.

16. The use according to claim 11 or 14, wherein the periodontitis is chronic periodontitis or aggressive periodontitis.

17. The use according to claim 10 or 13, wherein the compound of formula (I) is used as a photosensitizer in photodynamic therapy.

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