Benzoporphyrin analogs, conjugates, and methods of use thereof

Abstract

This disclosure provides a photosensitizer-targeting agent conjugate (e.g., a photosensitizer-antibody conjugate (PAC)) comprising a photosensitizer and a targeting agent (e.g., an antibody or its antigen-binding fragment) that binds to a target molecule, such as an antigen expressed on cancer cells or immune cells. This disclosure also includes photosensitizer compounds, photosensitizer-linker compounds, and modified targeting agents that can be used to prepare photosensitizer-targeting agent conjugates. Metabolites of photosensitizer-targeting agent conjugates are also disclosed. This disclosure relates to methods and compositions useful for treating and / or imaging diseases or conditions expressing target molecules, as well as methods for preparing such compositions. [Formula 1] TIFF2026515775000290.tif5069

Description

[Technical Field]

[0001] Related applications This application claims priority to U.S. Provisional Application No. 63 / 459,338, filed on April 14, 2023. The entire contents of the aforementioned application are expressly incorporated herein by reference.

[0002] Field of Invention This disclosure relates to a photosensitizer-targeting agent conjugate (e.g., a photosensitizer-antibody conjugate (PAC)) comprising a photosensitizer and a targeting agent (e.g., an antibody or its antigen-binding fragment) that binds to a target molecule, such as an antigen expressed on cancer cells or immune cells. This disclosure also relates to methods and compositions useful for treating and / or imaging diseases or conditions that express the target molecule, as well as methods for producing such compositions. [Background technology]

[0003] Photodynamic therapy (PDT) is a treatment method that uses a photosensitizer (PS) in combination with non-ionized light to kill cells and treat disease. The photosensitizer is administered and accumulates in the desired cells or tissues. Photo-induced activation of the photosensitizer in the presence of oxygen is due to singlet oxygen ( 1 It generates reactive oxygen species (ROS) such as O2, or free radicals that are toxic to the irradiated area but not to the rest of the body. One family of PS contains the core structure of benzoporphyrin (BP). For example, benzoporphyrin derivatives (BPD, and verteporfin, marketed as Visudyne®) are FDA-approved photosensitizers for the treatment of macular degeneration.

[0004] Non-targeted photosensitizers have poor selectivity and often accumulate in healthy cells, leading to unwanted extratarget toxicity and photosensitivity. To address this problem, photosensitizer-antibody conjugates (PACs, also known as photoimmunoconjugates or photoimmunotherapy) are molecularly targeted therapies developed to confer cell selectivity, improve pharmacokinetics, and reduce extratarget toxicity. Furthermore, PACs offer two-layer selectivity for treatment, namely, (i) a targeting agent (such as an antibody) targets the desired cells and delivers the photosensitizer, and (ii) photo-induced activation of the photosensitizer kills the desired cells in both spatial and temporal ways.

[0005] The main obstacles in this field lie in the pharmaceutical development of PACs (e.g., synthesis, characterization, purification, and storage). These drawbacks are exacerbated by the undesirable physicochemical properties of photosensitizer BPDs, including (i) BPDs are hydrophobic and highly adsorbent, (ii) BPDs tend to aggregate, and (iii) BPDs form non-covalent interactions such as pi-pi stacking. These physicochemical properties make it difficult to conjugate BPDs to antibodies or other proteins and / or obtain conjugates that behave well. Previously, to overcome some of these drawbacks, large polymers such as 10 kDa polyvinyl alcohol (PVA) or 10 kDa polyethylene glycol were added to PACs to improve their hydrophilicity. While these polymers succeeded in improving the solubility of PACs, their design and synthesis resulted in heterogeneous mixtures, ultimately making the conjugates undevelopable for clinical use.

[0006] Therefore, there is a need for novel analogues of benzoporphyrins that have improved physicochemical properties (e.g., hydrophilicity) for easier conjugation to targeting agents, better properties of the conjugate, and better biological properties for clinical applications. [Overview of the project]

[0007] To overcome challenges in the pharmaceutical development (e.g., synthesis, characterization, purification, and storage) of PACs, including BPD, as photosensitizers, benzoporphyrin analogs of this disclosure with improved physicochemical properties have been developed, enabling easy conjugation to targeting agents (e.g., antibodies or their antigen-binding fragments). Structural modifications have been made to BPD, including (a) the addition of short PEG units and / or the introduction of carboxylate and / or amide groups, and (b) the introduction of bioconjugation handles to enable easy conjugation to targeting agents such as small molecules, peptides, and proteins (see Figures 3, 4, 11, 17B, and 18B for the structures of the benzoporphyrin analogs and their corresponding conjugates). Nonspecific conjugation of two antibodies, namely panitumumab (Vectibix®) and anti-CD2 (clone: ​​RPA-2.10), has been successfully demonstrated. Non-specific methods involved acylation of lysine residues using N-hydroxysuccinimide (NHS) ester chemistry. PACs demonstrated cytotoxicity in EGFR-positive and CD2-positive cancer cell lines (see Figures 7, 8, 10, 17, and 18). The data described herein demonstrate the applicability of the PACs described herein not only to cancer cells but also to other abnormal cells such as immune cells. Furthermore, the structure-activity relationships (SARs) of benzoporphyrin (BP) analogs conjugated to panitumumab were evaluated in cell-based assays and included (a) monoacid derivatives (VertMA, i.e., minimally hydrophilic or maximally hydrophobic PAC designs), (b) diacid derivatives (VertDA, i.e., moderately hydrophilic PAC designs), and (c) triacid derivatives (VertTA, i.e., highly hydrophilic PAC designs). Surprisingly, for both cleavable and non-cleavable linkers (see Figures 17 and 18), the inventors observed that the maximally hydrophilic PAC design (VertTA) resulted in the weakest molecule, which was also the easiest BP analogue to conjugate to the antibody. In other words, the least hydrophilic or maximally hydrophobic constructs (VertMA) yielded the highest observed potency.In the systems presented herein, facile conjugation to an antibody and desired photoactivity can be achieved by selecting benzoporphyrin analogs (BP analogs) having varying degrees of hydrophilicity and hydrophobicity.

[0008] In one aspect, the present disclosure provides a photosensitizer compound that can be used to prepare a photosensitizer-antibody conjugate (PAC) described herein. In some embodiments, the photosensitizer compound of the present disclosure is a benzoporphyrin analog.

[0009] In some embodiments, the photosensitizer compound has the formula (I):

Chemical formula

[0010] In another aspect, this disclosure relates to formula (II): [ka] We provide linker-photosensitizer compounds or pharmaceutically acceptable salts thereof, in the formula, A L B L , X L , and Y L These are -OH and -OC, respectively, independently. 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -Linker-L A -R A And, however, A L B L , X L , and Y L One of them is -ZL P -Linker-L A -R A The condition is that, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl, L P and L A Each of them is an independent spacer. Linker is L P The first reactive group and L bonded to it A This is a connecting portion formed by a second reactive group bonded to it. R A It is a reactive group that can form a covalent bond with the targeting agent.

[0011] In yet another aspect, the present disclosure relates to a conjugate comprising a benzoporphyrin analog covalently bound to a targeting agent, wherein the formula is: [ka] We provide a conjugate represented by or a pharmaceutically acceptable salt thereof, in the formula, T is a targeting agent, L is a spacer that connects the targeting agent and PS. r is an integer between 1 and 20. PS is given by the following formula: [ka] A photosensitizer which is a benzoporphyrin analog represented by or a pharmaceutically acceptable salt thereof, A, B, X, and Y are each independently -OH and -OC. 1~4 Alkyl, -N(R 100 )(R 101 ), or a covalent bond to L, provided that one of A, B, X, and Y is a covalent bond to L, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16.

[0012] In yet another embodiment, the disclosure provides a modified antibody used for covalently binding to a photosensitizer compound described herein (e.g., a compound of formula (I)) or a linker-photosensitizer compound (e.g., a compound of formula (II)). In some embodiments, the modified antibody is of the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, T is a targeting agent, R T This is a reactive group covalently bonded to the targeting agent, L A It is a spacer, Lin is a reactive group, r is an integer between 1 and 20.

[0013] In yet another aspect, this disclosure relates to formula (VI): [ka] We provide compounds of or pharmaceutically acceptable salts thereof, in the formula, A', B', X', and Y' are each independently -OH, -OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZC 1~6 It is alkylene-NH2, where one of A', B', X', and Y' is -ZC 1~6 The condition is that it is alkylene-NH2, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl.

[0014] In another aspect, the Disclosure relates to a method for treating a subject having a disease or condition, a) Administering to a subject an effective amount of the conjugate described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the conjugate or a pharmaceutically acceptable salt thereof, b) A method is provided comprising administering a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a conjugate or a pharmaceutically acceptable salt thereof, and then irradiating a target region of the object with sufficient near-infrared (NIR) light to activate the photosensitizer of the conjugate.

[0015] The disclosure also includes a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a conjugate or a pharmaceutically acceptable salt thereof, for use in a method for treating a subject having a disease or condition. The method includes a) administering to a subject an effective amount of a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a conjugate or a pharmaceutically acceptable salt thereof, and b) irradiating a target area of ​​the subject with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate, after administration of the conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a conjugate or a pharmaceutically acceptable salt thereof. The disclosure also includes the use of a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a conjugate or a pharmaceutically acceptable salt thereof, for the manufacture of a drug for treating a disease or condition. In some embodiments, the disease or condition treated by the present method includes cells or tissues expressing a target molecule that is recognized and / or binds to a conjugate targeting agent described herein (e.g., an antibody or its antigen-binding fragment).

[0016] The Disclosure also provides a method for imaging cells or tissues having a target molecule in a subject, comprising: a) administering to the subject a conjugate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the conjugate or a pharmaceutically acceptable salt thereof; and, after administration of the conjugate or a pharmaceutically acceptable salt thereof, irradiating a target region of the subject with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate, thereby providing an image of the presence of the target molecule associated with the cell or tissue. In some embodiments, the target region includes the cell or tissue to be imaged, or the vicinity of the cell or tissue to be imaged. In some embodiments, the target molecule is recognized and / or bound to a targeting agent of the conjugate described herein (e.g., an antibody or its antigen-binding fragment). [Brief explanation of the drawing]

[0017] [Figure 1A] The normalized ultraviolet-visible spectra of benzoporphyrin analogs in Tris at pH 8 and 50% DMSO are shown. [Figure 1B] The normalized ultraviolet-visible spectra of benzoporphyrin analogs in Tris at pH 8 and 50% DMSO are shown. [Figure 1C] The normalized ultraviolet-visible spectra of benzoporphyrin analogs in Tris at pH 8 and 50% DMSO are shown. [Figure 2A] This shows the reaction oxygen species (ROS) generation of benzoporphyrin analogs at 10 J / cm2 using a singlet oxygen sensor Green (SOSG) assay. The baseline with PBS only is shown by the dotted line. [Figure 2B] This shows the reaction oxygen species (ROS) generation of benzoporphyrin analogs at 50 J / cm2 using a singlet oxygen sensor Green (SOSG) assay. The baseline with PBS only is shown by the dotted line. [Figure 3A]This describes the assembly of a nonspecific photosensitizer-antibody conjugate (PAC) using an uncleavable linker. Specifically, it involves the nonspecific chemical acylation of an amine (N-terminus or lysine) to construct the photosensitizer-antibody conjugate (PAC) through two steps. [Figure 3B] The structure of clickable handles for the conjugation of PACs via strain-enhanced azide-alkyne click chemistry (SPAAC) is shown. The antibody is conjugated via amine acylation using an NHS ester (1) to introduce an azide (indicated as "lin"). Each modified antibody is conjugated to a photosensitizer (PS) with a complementary bicyclononine clickable handle (compounds 2, 3, and 4, indicated as "ker"). The azide and bicyclononine click together to form triazoles (5, 6, and 7) in the final linker structure (indicated as "linker"). For the linker-photosensitizer and photosensitizer, only a single positional isomer is shown. [Figure 4A] This describes the assembly of a nonspecific photosensitizer-antibody conjugate (PAC) using a cleavable linker. Specifically, it involves the nonspecific chemical acylation of an amine (N-terminus or lysine) to construct the photosensitizer-antibody conjugate (PAC) through two steps. [Figure 4B] The structure of the clickable handle for the conjugation of PAC via SPAAC is shown. The antibody is conjugated via amine acylation using an NHS ester to introduce a bicyclononine clickable handle (indicated as "lin"). Each modified antibody is conjugated to a photosensitizer (PS) with a complementary azide (indicated as "ker"). The bicyclononine and azide click together to form a triazole in the final linker structure (indicated as "linker"). For the linker-photosensitizer and photosensitizer, only a single positional isomer is shown. [Figure 5]Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and an uncleavable linker. Figure 5A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) PS-0002 (benzoporphyrin analog), 2) molecular weight standard, 3) panitumumab, 4) panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0002. Figure 5B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) PS-0002 (benzoporphyrin analog), 2) Molecular weight standard, 3) Panitumumab, 4) NHS-PEG6-azide (or NHS-azide) and panitumumab incubated with PS-0002. Figure 5C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 3B for structural details of PAC. [Figure 6]Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using anti-CD2 (clone: ​​RPA-2.10) and a cleavable linker. Figure 6A shows reduced SDS-PAGE of anti-CD2 conjugates (PACs) visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) PS-0025 (benzoporphyrin analog), 2) molecular weight standard, 3) anti-CD2, 4) anti-CD2 incubated with NHS-PEG5-BCN (or NHS-BCN), 5) anti-CD2 incubated with NHS-PEG5-BCN (or NHS-BCN) and PS-0025. Figure 6B shows reduced SDS-PAGE of anti-CD2 conjugates (PACs) visualized by Coomassie staining. Lanes: 1) PS-0025 (benzoporphyrin analog), 2) Molecular weight standard, 3) Anti-CD2, 4) Anti-CD2 incubated with NHS-PEG5-BCN (or NHS-BCN), 5) Anti-CD2 incubated with NHS-PEG5-BCN (or NHS-BCN) and PS-0025. Figure 6C shows the normalized UV-Vis spectrum of the RPA2.10-benzoporphyrin analog conjugate. See Figure 4B for structural details of PAC. [Figure 7A] This study demonstrates the phototoxicity of panitumumab conjugates constructed via nonspecific conjugation. The conjugates were incubated in EGFR-expressing A-431 cells at 50 nM at 37°C for 24 hours. Data are normalized to untreated controls. The given photodose doses were 0, 3, 10, 20, 30, 40, and 50 J / cm². Figures 5A–5C illustrate the characterization of these panitumumab conjugates. [Figure 7B] This study demonstrates the phototoxicity of panitumumab conjugates constructed via nonspecific conjugation. The conjugates were incubated in EGFR-expressing A-431 cells at 25 nM at 37°C for 24 hours. Data are normalized to untreated controls. The given photodose doses were 0, 3, 10, 20, 30, 40, and 50 J / cm². Figures 5A–5C illustrate the characterization of these panitumumab conjugates. [Figure 8A] This study demonstrates the phototoxicity of anti-CD2 conjugates constructed via nonspecific conjugation. The conjugates were incubated in CD2-expressing Jurkat cells at 50 nM at 37°C for 48 hours. Data are normalized to untreated controls. The given photodose doses were 0, 3, 10, 20, 30, 40, and 50 J / cm². Figures 6A–6C illustrate the characterization of these anti-CD2 conjugates. [Figure 8B] This study demonstrates the phototoxicity of anti-CD2 conjugates constructed via nonspecific conjugation. The conjugates were incubated in CD2-expressing Jurkat cells at 25 nM at 37°C for 48 hours. Data are normalized to untreated controls. The given photodose doses were 0, 3, 10, 20, 30, 40, and 50 J / cm². Figures 6A–6C illustrate the characterization of these anti-CD2 conjugates. [Figure 9] This study demonstrates the generation of reactive oxygen species (ROS) of benzoporphyrin analogs at 10 J / cm² and 50 J / cm² using a singlet oxygen sensor Green (SOSG) assay. [Figure 10] This document demonstrates the phototoxicity of anti-CD2 conjugates constructed via nonspecific conjugation. The conjugates were incubated with CD2-expressing HH cells at various concentrations at 37°C for 24 hours, followed by exposure to 100 J / cm2 of NIR light. Figures 6A-C illustrate the characterization of these anti-CD2 conjugates. [Figure 11A] This describes the assembly of a nonspecific photosensitizer-antibody conjugate (PAC) using a cleavable linker. Specifically, it involves the nonspecific chemical acylation of an amine (N-terminus or lysine) to construct the photosensitizer-antibody conjugate (PAC) through two steps. [Figure 11B]The structure of the clickable handle for the conjugation of PAC via SPAAC is shown. The antibody is conjugated via amine acylation using an NHS ester to introduce the azide (clickable handle). Each modified antibody is conjugated to the photosensitizer (PS) with complementary bicyclononine (complementary clickable handle). The bicyclononine and azide click together to form a triazole in the final linker structure. Only a single positional isomer is shown for the linker-photosensitizer and photosensitizer. [Figure 12] Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and a cleavable linker. Figure 12A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0011 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0011 (cleavable VertMA). Figure 12B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0011 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0011 (cleavable VertMA). Figure 12C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 11B for structural details of the PAC. [Figure 13]Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and a cleavable linker. Figure 13A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) PS-0020 (benzoporphyrin analog), 2) molecular weight standard, 3) panitumumab, 4) panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0020 (cleavable VertDA). Figure 13B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) PS-0020 (benzoporphyrin analog), 2) Molecular weight standard, 3) Panitumumab, 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0020 (cleavable VertDA). Figure 13C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 11B for structural details of PAC. [Figure 14]Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and a cleavable linker. Figure 14A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0019 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0019 (cleavable VertTA). Figure 14B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0019 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0019 (cleavable VertTA). Figure 14C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 11B for structural details of PAC. [Figure 15-1]Figures A-D show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and an incleavable linker. Figure 15A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0002 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0003 (incleavable VertDA), 6) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0002 (incleavable VertMA). Figure 15B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0002 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0003 (uncleavable VertDA), 6) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0002 (uncleavable VertMA). Figure 15C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 3B for structural details of the PAC. [Figure 15-2] Figures A-D show the characterization of photosensitizer-antibody conjugates (PACs) using nonspecific conjugation with panitumumab and an uncleavable linker. Figure 15D shows the normalized ultraviolet-visible spectrum of the panitumumab-benzoporphyrin analog conjugate. For details of the PAC structure, see Figure 3B. [Figure 16]Figures A-C show the characterization of photosensitizer-antibody conjugates (PACs) by nonspecific conjugation using panitumumab and an uncleavable linker. Figure 16A shows reduced SDS-PAGE of panitumumab conjugates visualized by fluorescence imaging (excitation 455-485 nm and emission 675-720 nm). Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0004 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0004 (uncleavable VertTA). Figure 16B shows reduced SDS-PAGE of panitumumab conjugates visualized by Coomassie staining. Lanes: 1) Molecular weight standard, 2) Panitumumab, 3) PS-0004 (benzoporphyrin analog), 4) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide), 5) Panitumumab incubated with NHS-PEG6-azide (or NHS-azide) and PS-0004 (uncleavable VertTA). Figure 16C shows the normalized UV-Vis spectrum of the panitumumab-benzoporphyrin analog conjugate. See Figure 3B for structural details of PAC. [Figure 17A] This document shows the structure-activity relationship of cleavable panitumumab conjugates constructed via nonspecific conjugation. The conjugates were incubated with EGFR-expressing A-431 cells at various concentrations at 37°C for 24 hours, followed by exposure to 100 J / cm² of NIR light. Data are normalized to untreated controls. A-431 cells treated with up to 50 nM of PAC without light irradiation are indicated as “No Light”. [Figure 17B] The chemical structures of different PAC constructs are shown. Figures 15A–15C and 16A–16C illustrate the characterization of these panitumumab conjugates. [Figure 18A]This shows the structure-activity relationship of an uncleavable panitumumab conjugate constructed via nonspecific conjugation. The conjugates were incubated with EGFR-expressing A-431 cells at various concentrations at 37°C for 24 hours, followed by exposure to 100 J / cm2 of NIR light. Data are normalized to untreated controls. A-431 cells treated with up to 50 nM of PAC without light irradiation are indicated as “No Light”. [Figure 18B] The chemical structures of different PAC constructs are shown. Figures 12A–12C, 13A–13C, and 14A–14C illustrate the characterization of these panitumumab conjugates. [Modes for carrying out the invention]

[0018] The disclosed compositions and methods may be more readily understood by referring to the following detailed description shown in conjunction with the attached drawings that form part of this disclosure.

[0019] Throughout this text, descriptions refer to compositions and methods of using compositions. Where this disclosure describes or claims features or embodiments relating to compositions, such features or embodiments are equally applicable to methods of using compositions. Similarly, where this disclosure describes or claims features or embodiments relating to methods of using compositions, such features or embodiments are equally applicable to compositions.

[0020] Where a range of values ​​is expressed, it includes their endpoints. Where a value is expressed as an approximation, it will be understood that a particular value forms another embodiment by using the antecedent "approximately". References to a particular number include at least that particular value unless the context otherwise explicitly states. All references cited herein are incorporated by reference for any purpose. In the event of any conflict between the references and this specification, this specification shall prevail.

[0021] Unless otherwise indicated by the context of the explanation, for example, when there are no symbols indicating specific connection points (or multiple connection points), when a structure or structural fragment is drawn, it may be used alone or bound to other components of the PAC, or in any orientation, with an antibody bound at any suitable binding point to a chemical part such as a linker drug. However, if indicated, the components of the PAC are bound in the orientation shown in the given formula.

[0022] For clarity, it should be understood that certain features of the compositions and methods disclosed herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the compositions and methods disclosed in the context of a single embodiment may also be provided separately or in any secondary combination.

[0023] definition The term "Specified Use" refers to the entire application.

[0024] Unless otherwise defined herein, scientific and technical terms used in this application shall have meanings generally understood by those skilled in the art of the field to which this disclosure pertains. Generally, the terms used in relation to the compounds, compositions and methods described herein are well known and commonly used in the art.

[0025] It should be understood that any of the embodiments described herein, including those described under different aspects of this disclosure and different parts thereof (including embodiments described only in the Examples), can be combined with one or more other embodiments of this disclosure unless expressly disclaimed or inappropriate. The combinations of embodiments are not limited to the specific combinations claimed through any of the dependent claims.

[0026] Throughout this specification, where a composition is described as having, including, or comprising (or a variation thereof) specific components, it is intended that the composition is essentially composed of, or may be composed of, the listed components. Similarly, where a method or process is described as having, including, or comprising specific process steps, the process is essentially composed of, or may be composed of, the listed processing steps. Furthermore, it should be understood that the order of steps or the order in which certain operations are performed is not important, as long as the compositions and methods described herein remain operational. Moreover, two or more steps or operations can be performed simultaneously.

[0027] Where used herein, the singular forms “a,” “an,” and “the” include the plural form unless otherwise specified by context. The terms “comprising,” “having,” “including,” and “containing” are to be interpreted as open terms (i.e., “including, but not limited to”) unless otherwise noted. Furthermore, whenever “comprising” or another non-restrictive term is used in an embodiment, it should be understood that the same embodiment can be more narrowly described using the closed terms “essentially consisting of” or “consisting of.”

[0028] When used in the context of numbers and ranges, the terms "about" or "approximately" refer to values ​​or ranges that approximate or are close to the enumerated values ​​or ranges, as will be apparent to those skilled in the art from the teachings contained herein, so that the embodiments may function as intended. In some embodiments, "about" means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of a numerical quantity.

[0029] As used herein, the terms "benzoporphyrin analog" or "BP analog" refer to compounds having a benzoporphyrin core structure: [ka] It refers to.

[0030] The benzoporphyrin core can be substituted or unsubstituted and / or condensed with one or more ring structures.

[0031] As used herein, the terms “alkyl” or “linear or branched alkyl” refer to saturated linear or branched monovalent hydrocarbon radicals. In preferred embodiments, linear or branched alkyls have 30 or fewer carbon atoms (for example, C1-C1 for linear alkyls). 30 , and for branched alkyl groups, C3~C 30 ), more preferably having 20 or fewer carbon atoms. Even more preferably, linear or branched alkyls have 10 or fewer carbon atoms (i.e., for linear alkyls, C1-C 10 , and for branched alkyl groups, C3~C 10)。In other embodiments, the straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (i.e., C1-C6 for a straight-chain alkyl group or C3-C6 for a branched-chain alkyl group). Examples of alkyl include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, -CH2CH(CH3)2), 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl), 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, and the equivalents, but are not limited thereto. Further, as used throughout this specification, the examples, and the claims, the term "alkyl" is intended to include both "unsubstituted alkyl" and "substituted alkyl", the latter referring to an alkyl moiety having a substituent that replaces a hydrogen on one or more carbons of the hydrocarbon backbone. As used herein, (C x ~C xx ) alkyl or C x~xx alkyl means a straight-chain or branched alkyl having from x to xx carbon atoms.

[0032] As used herein, the term "alkylene" refers to a saturated straight-chain or branched divalent hydrocarbon radical. In preferred embodiments, the straight-chain or branched-chain alkylene has 30 or fewer carbon atoms (e.g., C1-C 30 , and C3-C 30 for a branched alkylene), more preferably 20 or fewer carbon atoms. Even more preferably, the straight-chain or branched-chain alkylene has 10 or fewer carbon atoms (i.e., C1-C 10 , and C3-C 10). In other embodiments, the linear or branched alkylene has six or fewer carbon atoms (i.e., C1-C6 for the linear alkylene group, or C3-C6 for the branched alkylene). When used herein, (C x ~C xx ) Alkylene or C x~xx Alkylene refers to a linear or branched alkylene having x to xx carbon atoms.

[0033] The term “compound” is intended to include compounds whose structure or formula or any analogue thereof is disclosed herein, or any structure or formula or any analogue thereof incorporated by reference. The disclosure also includes stereoisomers, regioisomers (or position isomers), tautomers, solvates, metabolites, and salts (e.g., pharmaceutically acceptable salts) of all compounds of the formulas disclosed herein.

[0034] As used herein, the term “conjugate” refers to a compound or analogue described herein that is conjugated to a target conjugate.

[0035] The term "chiral" refers to molecules that possess the property of being non-superimposable with their mirror image partners, while the term "achiral" refers to molecules that can be superimposed on those mirror image partners.

[0036] The term "stereoisomer" refers to a compound that has the same chemical composition and connectivity, but has different orientations of its atoms in space that cannot be interconverted by rotation around a single bond.

[0037] The term "diastereomer" refers to stereoisomers that possess two or more chirality centers, and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as crystallization, electrophoresis, and chromatography.

[0038] The term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other but cannot be superimposed.

[0039] The stereochemical definitions and conventions used herein generally follow SP. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this disclosure contain asymmetric or chiral centers and can therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of this disclosure, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof such as racemic mixtures, are intended to form part of this disclosure. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarization. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute stereochemistry of the molecule around its chiral center(s). The prefixes d and l or (+) and (-) are used to specify the sign of the rotation of plane polarization by the compound, with (-) or 1 indicating that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemic compound, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemic compound” refer to equimolar mixtures of two enantiomer species that lack optical activity.

[0040] The term "tautomer" or "tautomeristic form" refers to structural isomers of different energies that can interconvert across low-energy barriers. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as ketoenols and imine-enamine isomerization. Valence tautomers include interconversions via rearrangement of some of the bonding electrons.

[0041] The term "positional isomer" refers to structural isomers that differ only in the position of their functional groups or substituents. When a compound is described by its structure, it also includes possible positional isomers of the compound unless otherwise specified. For example, for the photosensitizer compound of formula (I), [ka] Groups A, B, X, and Y can be interchanged to form positional isomers. In some embodiments, groups A and B can be interchanged to form positional isomers. In some embodiments, groups X and Y can be interchanged to form positional isomers. In some embodiments, groups A and X, or groups A and Y, can be interchanged to form positional isomers. In some embodiments, groups B and X, or groups B and Y, can be interchanged to form positional isomers. For example, for a compound of formula (IA), it has the following two positional isomers: [ka] Includes.

[0042] In another example, the following formula: [ka] For the compound represented by , it also has the following positional isomers: [ka] Includes.

[0043] In another example, the following formula: [ka] For the compound represented by , it also has the following positional isomers: [ka] Includes.

[0044] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable organic or inorganic salt of the compound or conjugate of the herein disclosure. Examples of salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acidic phosphates, isonicotinates, lactates, salicylates, acidic citrates, tartrates, oleates, tannates, pantothenates, bitartrates, ascorbicates, succinates, maleates, gentisates, fumarates, glucons, glucurons, sugarates, formates, benzoates, glutamates, methanesulfonates ("mesylates"), ethanesulfonates, benzenesulfonates, p-toluenesulfonates, pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. If multiple charged atoms are part of a pharmaceutically acceptable salt, the salt may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0045] If the compound of the Disclosure is a base, a desired pharmaceutically acceptable salt can be prepared by treatment of the free base with any suitable method available in the art, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and equivalents, or an organic acid such as pyranosidylic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, glucuronic acid or galacturonic acid, an α-hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, or equivalents.

[0046] If the compound of the Disclosure is an acid, a desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, or alkaline earth metal hydroxide, or equivalent. Exemplary examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0047] As used herein, the term “solvate” means a compound further comprising stoichiometric or nonstoichiometric amounts of a solvent, such as water, isopropanol, acetone, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine dichloromethane, 2-propanol, or equivalents, bonded by non-covalent intermolecular forces. Solvates or hydrates of compounds are readily prepared by adding at least 1 molar equivalent of a hydroxyl solvent, such as methanol, ethanol, 1-propanol, 2-propanol, or water, to the compound to result in solvation or hydration of the imine moiety.

[0048] The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated with them.

[0049] The term "reactive ester" refers to an ester having an easily substitutable leaving group that can readily react with an amine group to form an amide bond. Examples of reactive esters include, but are not limited to, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, nitrophenyl (e.g., 2 or 4-nitrophenyl) esters, dinitrophenyl (e.g., 2,4-dinitrophenyl) esters, sulfo-tetrafluorophenyl (e.g., 4-sulfo-2,3,5,6-tetrafluorophenyl) esters, or pentafluorophenyl esters.

[0050] The term "reactive group" refers to a group that can react with a moiety located on another molecule, such as a targeting agent or photosensitizer compound, to form a covalent bond. Examples of reactive groups include, but are not limited to, amine reactive groups, thiol reactive groups, azides, and alkynes.

[0051] The term "amine reactive group" refers to a group that can react with an amine group to form a covalent bond. Examples of amine reactive groups include, but are not limited to, reactive ester groups, acyl halides, sulfonyl halides, imide esters, or reactive thioester groups. In certain embodiments, the amine reactive group is a reactive ester group. In one embodiment, the amine reactive group is an N-hydroxysuccinimide ester or an N-hydroxysulfosuccinimide ester.

[0052] The term "thiol reactive group" refers to a group that can react with a thiol (-SH) group to form a covalent bond. Examples of thiol reactive groups include, but are not limited to, maleimide, haloacetyl, alloacetamide, vinylsulfone, vinylsulfonamide, or vinylpyridine. In one embodiment, the thiol reactive group is maleimide.

[0053] As defined herein, the term “spacer” refers to a portion that connects two groups, such as a targeting agent and a photosensitizer compound, or two components of a conjugate described herein. Typically, a spacer is substantially inert under the conditions in which the two groups it connects are bonded. A spacer may contain two reactants, one at each end of the linker portion, such that one reactant is reacted first with the photosensitizer compound to provide a compound having a spacer portion and a second reactant, and then the second reactant can react with the targeting agent. Alternatively, one end of the spacer may be reacted first with the targeting agent to provide a targeting agent having a spacer portion and a second reactant, and then the second reactant can react with the photosensitizer compound. A spacer may be a “cleavable spacer” containing a chemical bond that allows for the release of the photosensitizer at a particular site.Suitable chemical bonds are well known in the art and include enzyme-cleavable bonds, such as disulfide bonds, thioether bonds, pH-unstable bonds, ROS-cleavable bonds, photo-unstable bonds, peptidase-unstable bonds, and esterase-unstable bonds (e.g., Sun et al. Bioconjugate Chem. 2020, 31, 1012-1024, Tong et al. Molecules 2021, 26, 5847, Alfaro et al., Anal. Chem. 2008, 80, 3882-3889, Chari et al., Angew. Chem. Int. Ed. 2014, 53, 3796-3827, Liang et al. Bioengineering & Translational Medicine 2016; 1:239-251, Subramaniyan et al Photochemistry and Photobiology, 2020, 96:668-679, Peterson et al See J.Am.Chem.Soc.2018,140,7343-7346, Vickerman et al. Naure Review Chemistry,2021,5,816-834, Nani et al. Angew.Chem.2015,127,13839-13842, Weinstein et al. Chem.Rev.2020,120,13135-13272, Sun et al. Bioconjugate Chem.2020,31,1012-1024 (all of these references are incorporated herein by reference). Disulfide bonds, thioethers, and peptidase-unstable bonds are preferred. Other spacers that may be used in this disclosure include non-cleavable spacers, such as those described in Chari et al.,Angew.Chem.Int.Ed.2014,53,3796-3827.

[0054] The term "connecting group" refers to the portion formed by the reaction of a first reactant and a second reactant. For example, the first and second reactants may be an amine and a reactive ester, and the connecting group may be an amide formed by the reaction of the amine and reactive ester groups.

[0055] The term "hydrophilic portion" refers to a portion having hydrophilic properties that increases the water solubility of the photosensitizer compound or the linker-photosensitizer compound. Examples of hydrophilic portions include, but are not limited to, polyethylene glycol, polyalkylene glycol, sugars, or oligosaccharides. In some embodiments, the hydrophilic portion is polyethylene glycol (PEG).

[0056] The term "self - cleavable group" refers to a moiety that enables the release of a photosensitizer compound when a remote site is activated. In certain embodiments, this group includes a p - aminobenzyl unit. In some such embodiments, p - aminobenzyl alcohol is linked to an amino acid unit via an amide bond, and a carbamic acid, methylcarbamic acid, or carbonate is created between the benzyl alcohol and the drug (Hamann et al. (2005) Expert Opin. Ther. Patents (2005) 15:1087 - 1103). In some embodiments, this group includes p - aminobenzyloxycarbonyl (PAB). Other examples of self - cleavable groups include, but are not limited to, aromatic moieties electronically similar to PAB groups such as 2 - aminoimidazole - 5 - methanol derivatives (U.S. Patent No. 7,375,078, Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho - or para - aminobenzyl acetals. In some embodiments, substituted and unsubstituted 4 - aminobutyric acid amides (Rodrigues et al (1995) Chemistry Biology 2:223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al (1972) J. Amer. Chem. Soc. 94:5815), and spacers that undergo cyclization upon amide bond hydrolysis such as 2 - aminophenylpropionic acid amide (Amsberry, et al (1990) J. Org. Chem. 55:5867) can be used. The attachment of a photosensitizer compound to the α - carbon of a glycine residue is another example of a self - cleavable group that may be useful in PAC (Kingsbury et al (1984) J. Med. Chem. 27:1447).

[0057] The term "amino acid" refers to a naturally occurring amino acid or a non - naturally occurring amino acid. In some embodiments, the amino acid is represented by NH2 - C(R aa’ R aa ) - C(=O)OH, wherein R aa and R aa’Each is independently a linear, branched, or cyclic alkyl, alkenyl, or alkynyl, aryl, heteroaryl, or heterocyclyl, having H, 1 to 10 carbon atoms, and optionally substituted, or R aa The N-terminal nitrogen atoms can together form a heterocycle (like proline, for example). The term "amino acid residue" is defined as one hydrogen atom being -NH-C(R aa’ R aa This refers to the corresponding residue when an amino acid such as )-C(=O)- is removed from its amine and / or carboxyl terminus.

[0058] The term "peptide" refers to a short chain of amino acid monomers linked by a peptide (amide) bond. In some embodiments, the peptide contains 2 to 20 amino acid residues. In other embodiments, the peptide contains 2 to 10 or 2 to 8 amino acid residues. In yet another embodiment, the peptide contains 2 to 5 amino acid residues. When used herein, if the peptide is part of a cytotoxic agent represented by a specific sequence of amino acids or a linker described herein, the peptide can be linked in both directions to the rest of the cytotoxic agent or linker.

[0059] The term "antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target molecule, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination thereof, through at least one antigen-recognition site within the variable region of the immunoglobulin molecule. Antibodies can be polyclonal or monoclonal, multi-chain or single-chain, or intact immunoglobulins, and may be derived from natural or recombinant sources. Antibodies can be monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, or chimeric antibodies. Antibodies can be any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.

[0060] In some embodiments, the antibody is an antibody that does not exist in nature. In some embodiments, the antibody is purified from a natural component. In some embodiments, the antibody is produced by recombinant DNA. In some embodiments, the antibody is produced by hybridoma.

[0061] The terms "antibody fragment" or "antigen-binding fragment" refer to a portion of an intact antibody, specifically the antigen-determining variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and F v Examples of antibody fragments include, but are not limited to, linear antibodies, single-chain antibodies, and multispecific antibodies (e.g., bispecific, biparatopic) formed from antibody fragments. The term "antigen-binding fragment" of an antibody includes one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by a specific fragment of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include (i) Fab fragments, V L , V H , C L , and C H1 (ii) Monovalent fragments consisting of domains (for example, an antibody digested with papain produces three fragments, namely two antigen-binding Fab fragments and one non-antigen-binding Fc fragment), (ii) single-chain Fab (scFab), V L , V H , C L , and C H1 A fragment consisting of domains, C L and V H (iii) F(ab')2 fragment, a bivalent fragment containing the domain linked via a linker peptide, two Fab fragments linked by disulfide crosslinks at the hinge region (for example, an antibody digested by pepsin produces two fragments, namely a bivalent antigen-binding F(ab')2 fragment and a non-antigen-binding pFc' fragment) and its associated F(ab') monovalent unit, (iv) V H and C H1 F consisting of domains dFragment (i.e., the heavy chain portion contained in Fab), (v) V of a single arm of the antibody L and V H Domains and associated disulfide bonds F v F consisting of v Fragment, (vi)V H (vii) a dAb (domain antibody) or sdAb (single-domain antibody) fragment consisting of domains (Ward et al., Nature 341:544-546, 1989), (viii) an isolated complementarity-determining region (CDR), (viii) a single-strand variable fragment (scFv), linked via a linker peptide. H and V L Examples include (ix) fragments consisting of domains, and (ix) tetravalent antibodies which may include various forms (structures), thereby containing four antigen-binding sites.

[0062] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies within the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific and directed against a single antigen epitope. In contrast, conventional (polyclonal) antibody preparations typically contain a number of antibodies against (or specific to) different epitopes. The modifier “monoclonal” describes the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with this disclosure may be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495 or by the recombinant DNA method (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described, for example, Clackson et al. (1991) Nature 352:624-8 and Marks et al. (1991) J Mol Biol. 222:581-97. This term also includes preparations of antibody molecules in single-molecule compositions. Monoclonal antibody compositions exhibit single-binding specificity and affinity for specific epitopes.

[0063] The monoclonal antibodies described herein may be non-human, human, or humanized. This term specifically includes, insofar as they specifically bind to a target antigen and / or exhibit the desired biological activity, “chimeric” antibodies, as well as fragments of such antibodies, in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody of a particular species or belonging to a particular antibody class or subclass, while the rest of the chain is identical or homologous to a corresponding sequence in an antibody of a different species or belonging to a different antibody class or subclass.

[0064] As used herein, the term “human antibody” refers to an antibody produced by a human, or an antibody having the amino acid sequence of an antibody produced by a human. This term includes antibodies having a variable region in which both the framework and CDR regions are derived from human-derived sequences. Furthermore, if the antibody includes a constant region, the constant region also originates from such a human sequence, e.g., a human germline sequence, or a variant of a human germline sequence, or an antibody-containing consensus framework sequence derived from human framework sequence analysis, as described, for example, in Knappik et al. ((2000) J Mol Biol. 296(1):57-86). The human antibodies of this disclosure may include amino acid residues not encoded by the human sequence (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo, or conserved substitutions to facilitate stability or production). However, as used herein, the term “human antibody” is intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, is transplanted onto a human framework sequence.

[0065] As used herein, the term “recombinant human antibody” refers to human antibodies prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from animals (e.g., mice) or hybridomas prepared therefrom that are transgenic or transchromosomal to human immunoglobulin genes; antibodies isolated from host cells transformed to express human antibodies, for example, antibodies isolated from transfectomas; antibodies isolated from recombinant combinatorial human antibody libraries; and antibodies prepared, expressed, created, or isolated by any other means involving splicing of all or part of a human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have a variable region in which the framework and CDR region are derived from a human germline immunoglobulin sequence. However, in some embodiments, such recombinant human antibodies can undergo in vitro mutagenesis (or in vivo somatic mutagenesis if transgenic animals for the human Ig sequence are used), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibody are derived from and related to human germline VH and VL sequences, while being sequences that may not naturally exist in vivo within the human antibody germline repertoire.

[0066] As used herein, the term “chimeric antibody” refers to an antibody whose immunoglobulin molecule’s amino acid sequence originates from two or more species. In some cases, both the heavy and light chain variable regions correspond to the variable regions of an antibody from one species having the desired specificity, affinity, and activity, while the constant region is homologous to an antibody from another species (e.g., human), minimizing the immune response in the latter species.

[0067] As used herein, the term “humanized antibody” refers to a form of antibody that includes sequences from non-human (e.g., mouse) antibodies as well as human antibodies. Such antibodies are a type of chimeric antibody that includes a minimal sequence derived from non-human immunoglobulins. Generally, a humanized antibody will include at least one, typically two, substantially all of variable domains, where all or substantially all of the hypervariable loop corresponds to that of a non-human immunoglobulin, and all or substantially all of the framework (FR) region is from a human immunoglobulin sequence. A humanized antibody will also optionally include an immunoglobulin constant region (Fc), typically at least a portion of the immunoglobulin constant region of a human immunoglobulin. Humanized antibodies can be further modified by residue substitutions, either within the Fv framework region and / or within the substituted non-human residues, to refine and optimize the antibody's specificity, affinity, and / or activity.

[0068] As used herein, the terms “polypeptide” and “protein” are used synonymously to refer to polymers of amino acid residues. These terms encompass amino acid polymers, which include two or more amino acids linked together by peptide bonds; amino acid polymers, which are artificial chemical mimics of corresponding naturally occurring amino acids, as well as naturally occurring and non-naturally occurring amino acid polymers. These terms include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, and fusion proteins. These terms also include natural peptides, recombinant peptides, synthetic peptides, or combinations thereof. Unless otherwise indicated, a particular polypeptide sequence also implicitly includes its conservedly modified variants.

[0069] The terms “tumor cell” and “cancer cell” are used synonymously herein and may refer to individual cells or entire populations of cells derived from a tumor or cancer, including both non-tumor-generating cells and cancer stem cells.

[0070] The terms “subject” and “patient” are used herein synonymously to refer to any human or non-human animal in need of treatment. Non-human animals include all vertebrates (e.g., mammals and non-mammals), such as any mammal. Non-limiting examples of mammals include humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Non-limiting examples of non-mammals include birds and fish. In some embodiments, the subject is human.

[0071] As used herein, the terms “to treat,” “to treat,” or “treatment” mean to reverse, alleviate, or cessate the symptoms, clinical signs, and underlying pathology of a condition in which the condition is improved or stabilized. As used herein and as is well known in the art, “treatment” is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, alleviation, improvement, or slowing of progression of one or more symptoms or conditions associated with a condition, e.g., cancer, whether detectable or undetectable, a reduction in the severity of the disease, a stabilized (i.e., non-worsening) state of the disease, a delay or slowing of disease progression, improvement or alleviation of the condition, and remission (whether partial or complete). “Treatment” may also mean extending survival compared to the survival expected if no treatment is received.

[0072] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to the amount of the compound or conjugate described herein that elicits a desired biological response in a subject. Such responses include relief of symptoms of the disease or disorder being treated, prevention, inhibition, or delay of recurrence of symptoms of the disease or the disease itself, an increase in the subject’s lifespan compared to the absence of treatment, or prevention, inhibition, or delay of progression of symptoms of the disease or the disease itself. Determining the effective dose is well within the capabilities of those skilled in the art, particularly in light of the detailed disclosures provided herein. The toxicity and therapeutic efficacy of Compound I can be determined by standard pharmaceutical procedures in cell cultures and experimental animals. The effective dose of the compound or conjugate or other therapeutic agent of this disclosure administered to a subject depends on the stage, category, and state of multiple myeloma, as well as the subject’s characteristics such as overall health, age, sex, weight, and drug tolerance. The effective dose of the compound or conjugate or other therapeutic agent of this disclosure administered also depends on the route of administration and dosage form. Dosage and interval can be individually adjusted to provide sufficient plasma levels of the active compound to maintain the desired therapeutic effect.

[0073] The terms "r," "drug load," "drug:antibody ratio," "drug-to-antibody ratio," or "DAR" refer to the number of photosensitizer moieties per targeting agent (e.g., antibody or antigen-binding fragment), or the number of -L-PS moieties per targeting agent (e.g., antibody or antigen-binding fragment) (T) in the conjugate of formula (III). In compositions containing multiple copies of the conjugate of formula (III), "average r" refers to the average number of -L-PS moieties per targeting agent (e.g., antibody or antigen-binding fragment), also referred to as "average drug load."

[0074] Photosensitizer compounds In a first aspect, the disclosure provides a photosensitizer compound which is a benzoporphyrin analog. In a first embodiment of the first aspect, the photosensitizer compound has the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A, B, X, and Y are each independently -OH, -OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -ker, however 、 At least one of A, B, X, and Y is -N(R 100 )(R 101 ), -ZL P -NH2 or -ZL P -conditional on being -ker, and at most one of A, B, X, and Y being -ZL P -NH2 or -ZL P -Assuming it is a ker, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl, L P It is a spacer, Ker is a reactive group.

[0075] In an alternative first embodiment of the first aspect, the photosensitizer compound is of the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A, B, X, and Y are each independently -OH, -OC 1~4 Alkyl, -N(R 100 )(R101 ), or -ZL P -ker, however 、 At least one of A, B, X, and Y is -N(R 100 )(R 101 ) or -ZL P -conditional on being -ker, and at most one of A, B, X, and Y being -ZL P -Assuming it is a ker, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl, L P It is a spacer, Ker is a reactive group.

[0076] In the second embodiment of the first aspect, for the photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, the variables A, B, X, and Y are defined as follows: a) A and B are -OCH3, and one of X and Y is -OCH3, and the other of X and Y is -ZL P -ker, b) A and B are -OCH3, and one of X and Y is -OH, and the other of X and Y is -ZL P -ker, c) One of A and B is -OCH3 and the other is -OH, and one of X and Y is -OH and the other is -ZL P-ker, d) A and B are -OH, and one of X and Y is -OH, and the other of X and Y is -ZL P -ker, e) One of A and B is -OH, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 However, it is either H or Me, and nr is an integer between 2 and 8, or f) Either A or B, -ZL P -ker, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 However, is either H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first embodiment of the first aspect.

[0077] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, A and B are -OCH3, one of X and Y is -OCH3, and the other of X and Y is -ZL P -ker, and the remaining variables are as defined in the first embodiment of the first aspect.

[0078] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, A and B are -OCH3, one of X and Y is -OH, and the other of X and Y is -ZL P -ker, and the remaining variables are as defined in the first embodiment of the first aspect.

[0079] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, one of A and B is -OCH3 and the other is -OH, one of X and Y is -OH and the other is -ZL P -ker, and the remaining variables are as defined in the first embodiment of the first aspect.

[0080] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, A and B are -OH, one of X and Y is -OH, and the other of X and Y is -ZL P -ker, and the remaining variables are as defined in the first embodiment of the first aspect.

[0081] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, one of A and B is -OH, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 is H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first embodiment of the first aspect.

[0082] In some embodiments, for a photosensitizer compound of formula (I) or a pharmaceutically acceptable salt thereof, one of A and B is -ZL P -ker, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 is H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first embodiment of the first aspect.

[0083] In a third embodiment of the first aspect, the photosensitizer compound is of formula (IA): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where one of X and Y is -ZL P One is -ker, the other is -OH, and the remaining variables are as defined in the first embodiment of the first aspect.

[0084] In the fourth embodiment of the first aspect, the photosensitizer compound is of formula (IB): [ka] Represented by or a pharmaceutically acceptable salt thereof, where one of A and B is -OH or -ZL P -ker, and the other is -OH or -OCH3, R 102 is H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first embodiment of the first aspect.

[0085] In the fifth embodiment of the first embodiment, for a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, ker is a reactive group selected from a maleimide group, a thiol group, a cyclooctin group, an azide group, a hydrazide group, a tetrazine group, a cyclooctene group, a ketone group, and an aldehyde group, the remaining variables are as described in the first, second, third, or fourth embodiment of the first embodiment. In some embodiments, ker is [ka] Or -N3, and the remaining variables are as described in the first, second, third, or fourth embodiment of the first aspect, or any embodiment described therein.

[0086] In the sixth embodiment of the first aspect, for a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, Z is -NH-, and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment of the first aspect, or any embodiment described therein.

[0087] In the seventh embodiment of the first aspect, for a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, Z is -O-, and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment of the first aspect, or any embodiment described therein.

[0088] In the eighth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L P L is an inseparable spacer, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiments of the first aspect, or any embodiment described therein. In some embodiments, L P It includes a hydrophilic portion. In some embodiments, L P This includes the PEG portion.

[0089] In the ninth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L P is *-CH2CH2-(OCH2CH2) m- is the expression, where * is the part connected to ker, m is an integer from 0 to 30, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the first aspect, or any embodiment described therein. In some embodiments, m is an integer from 2 to 16. In some embodiments, m is an integer from 2 to 10. In some embodiments, m is an integer from 2 to 8. In some embodiments, m is an integer from 3 to 5. In some embodiments, m is 2, 3, 4, 5, 6, 7, or 8.

[0090] In the tenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L P is *-CH2CH2-(OCH2CH2)4-, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the first aspect, or any embodiment described therein.

[0091] In the eleventh embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L P is a cleavable spacer, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiments of the first embodiment, or any embodiment described therein. In some embodiments, the cleavable space includes an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, or a photo-cleavable group. In some embodiments, the enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase. In some embodiments, the enzyme-unstable group is a group that can be cleaved by cathepsin B.

[0092] In the twelfth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L P The spacer represented by comprises a peptide and a self-degrading group, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the first aspect, or any embodiment described therein.

[0093] In the thirteenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, is provided by spacer L P The formula is as follows: [ka] It is expressed by, in the formula, [ka] This represents the bond to the reactive group represented by ker, [ka] This represents a bond to group Z, L 1 and L 2 Each of them is an independent connecting spacer. P 1 This is a peptide containing 2 to 5 amino acid residues, the remaining variables as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the first aspect, or any embodiment described therein.

[0094] In the fourteenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, P 1is a peptide selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, or Ala-Val, the remaining variables as described in the 13th embodiment of the first aspect or any embodiment described therein.

[0095] In the 15th embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, P 1 teeth, [ka] The remaining variables are as described in the 13th embodiment of the first aspect or any embodiment described therein.

[0096] In the sixteenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L 1 This includes a hydrophilic portion, and the remaining variables are as described in the 13th, 14th, or 15th embodiment, or any embodiment described therein. In some embodiments, L 1 This includes the PEG portion.

[0097] In the seventeenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L 1 is *-CH2-CH2-(OCH2CH2) n -C(=O)-**, where n is an integer from 0 to 30, *- represents a bond to the reactive group represented by ker, and **- represents P 1This represents a coupling to , and the remaining variables are as described in the 13th, 14th, or 15th embodiment, or any embodiment described therein. In some embodiments, n is an integer from 2 to 16. In some embodiments, n is an integer from 2 to 10. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 3 to 5. In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8.

[0098] In the eighteenth embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L 1 *-CH2-CH2-(OCH2CH2)3-C(=O)-**, and the remaining variables are as described in the 13th, 14th, or 15th embodiment, or any embodiment described therein.

[0099] In the 19th embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L 2 is, -NH-C 1~6 Alkyl-**, where ** is a Z-connected portion, and the remaining variables are as described in the 13th, 14th, 15th, 16th, 17th, or 18th embodiment, or any embodiment described therein.

[0100] In the 20th embodiment of the first aspect, a photosensitizer compound of formula (I), (IA), or (IB), or a pharmaceutically acceptable salt thereof, L 2 is -NH-CH2CH2-**, where ** is a part connected to Z, and the remaining variables are as described in the 13th, 14th, 15th, 16th, 17th, or 18th embodiment, or any embodiment described therein.

[0101] In the 21st embodiment of the first aspect, the photosensitizer compound of the present disclosure is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or selected from a pharmaceutically acceptable salt, positional isomer, or pharmaceutically acceptable salt of a positional isomer thereof. Alternatively, as part of a 21st embodiment of the first aspect, the photosensitizer compound of the present disclosure is: [ka] Alternatively, it may be selected from a pharmaceutically acceptable salt, positional isomer, or pharmaceutically acceptable salt of a positional isomer thereof.

[0102] Linker - Photosensitizer compound In a second aspect, the disclosure provides a linker-photosensitizer compound, wherein the photosensitizer compound of the first aspect is modified with a linker having a reactive group capable of forming a covalent bond with a targeting agent (e.g., an antibody or its antigen-binding fragment) as described below. In the first embodiment of the second aspect, the linker-photosensitizer compound is of formula (II): [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A L B L , X L , and Y L These are -OH and -OC, respectively, independently. 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -Linker-L A -R A And, however, A L B L , X L , and Y L One of them is -ZL P -Linker-L A -R A The condition is that, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl, L P and L A Each of them is an independent spacer. Linker is L P The first reactive group and L bonded to it A This is a connecting portion formed by a second reactive group bonded to it. R A It is a reactive group that can form a covalent bond with the targeting agent.

[0103] In the second embodiment of the second aspect, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, R A is a reactive ester, -NH2, or maleimide group, and the remaining variables are as defined in the first embodiment of the second aspect.

[0104] In the third embodiment of the second aspect, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, R A teeth, [ka] Alternatively, it is -NH2, and the remaining variables are as defined in the first embodiment of the second aspect.

[0105] In the fourth embodiment of the second aspect, with respect to the linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, L A L is a spacer including a hydrophilic portion, and the remaining variables are as defined in the first, second, or third embodiments of the second aspect. In some embodiments, L A This is a spacer that includes the PEG portion.

[0106] In the fifth embodiment of the second aspect, with respect to the linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, L A *-CH2CH2(OCH2CH2) p - and in the formula, * is R A The part connected to is p, where p is an integer from 0 to 30, and the remaining variables are as defined in the first, second, or third embodiment of the second aspect, or any embodiment described therein. In some embodiments, p is an integer from 2 to 16. In some embodiments, p is an integer from 2 to 10. In some embodiments, p is an integer from 2 to 8. In some embodiments, p is an integer from 3 to 5. In some embodiments, p is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 6.

[0107] In the sixth embodiment of the second aspect, for the linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, the first and second reactive groups are selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group, respectively, and the remaining variables are as defined in the first, second, third, fourth, or fifth embodiment of the second aspect, or any embodiment described therein.

[0108] In the seventh embodiment of the second aspect, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, the linker in formula (II) is The following formula: [ka] Represented by, During the ceremony, [ka] L P This represents a connection to, [ka] L A This represents a coupling to , and the remaining variables are as defined in the first, second, third, fourth, or fifth embodiment of the second aspect, or any embodiment described therein.

[0109] In the eighth embodiment of the second aspect, with respect to the linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L B L , X L , and Y L It is defined as follows, that is, a) A L and B L However, it is -OCH3, and X L and Y L One of them is -OCH3, and X L and Y L The other of these is -ZL P -Linker-LA -R A Is it, b) A L and B L However, it is -OCH3, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A Is it, c)A L and B L One of them is -OCH3, and A L and B L The other of these is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A Is it, d)A L and B L However, it is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A is, or e) A L and B L One of them is -ZL P -Linker-L A -R A A L and B L The other of these is -OH or -OCH3, X L and Y L Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 However, it is either H or Me, and nr is an integer between 2 and 8. The remaining variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the second aspect, or any embodiment described therein.

[0110] In some embodiments, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L and B L is -OCH3, and X L and Y L One of them is -OCH3, and X L and Y L The other of these is -ZL P -Linker-L A -R A That is the case.

[0111] In some embodiments, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L and B L is -OCH3, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A That is the case.

[0112] In some embodiments, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L and B L One of them is -OCH3, and A L and B L The other of these is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A That is the case.

[0113] In some embodiments, for a linker-photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L and B L is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A That is the case.

[0114] In some embodiments, for a linker photosensitizer compound of formula (II) or a pharmaceutically acceptable salt thereof, A L and B L One of them is -ZL P -Linker-L A -R A A L and B L The other of these is -OH or -OCH3, X L and Y L Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 is either H or Me, and nr is an integer between 2 and 8.

[0115] In the ninth embodiment of the second aspect, the linker-photosensitizer compound of the present disclosure is of formula (IIA): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where X L and Y L One of them is -ZL P -Linker-L A -R A The other is -OH, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiments of the second aspect, or any embodiment described therein.

[0116] In the tenth embodiment of the second aspect, the linker-photosensitizer compound of the present disclosure is of formula (IIB): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where A L and B L One of them is -ZL P -Linker-L A -R A The other is -OH or -OCH3, and R 102 is H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, or seventh embodiment of the second aspect, or any embodiment described therein.

[0117] In the eleventh embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, Z is -NH-, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment of the second aspect, or any embodiment described therein.

[0118] In the twelfth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, Z is -O-, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment of the second aspect, or any embodiment described therein.

[0119] In the thirteenth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L PL is an inseparable spacer, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments of the second aspect, or any embodiment described therein. In some embodiments, L P It includes a hydrophilic portion. In some embodiments, L P This includes the PEG portion.

[0120] In the fourteenth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L P is *-CH2CH2-(OCH2CH2) m - is the formula, where * is a part connected to the linker, m is an integer from 0 to 30, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment of the second aspect, or any embodiment described therein. In some embodiments, m is an integer from 2 to 16. In some embodiments, m is an integer from 2 to 10. In some embodiments, m is an integer from 2 to 8. In some embodiments, m is an integer from 3 to 5. In some embodiments, m is 2, 3, 4, 5, 6, 7, or 8.

[0121] In the 15th embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L P is *-CH2CH2-(OCH2CH2)4-, where * is a part connected to a linker, and the remaining variables are as defined in the 14th embodiment of the second aspect or any embodiment described therein.

[0122] In the sixteenth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L Pis a cleavable spacer, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiments of the second embodiment, or any embodiment described therein. In some embodiments, the cleavable spacer includes an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, or a photo-cleavable group. In some embodiments, the enzyme-unstable group is a group cleavable by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase. In some embodiments, the enzyme-unstable group is a group cleavable by cathepsin B.

[0123] In the seventeenth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L P The spacer represented by comprises a peptide and a self-degrading group, and the remaining variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment of the second aspect, or any embodiment described therein.

[0124] In the eighteenth embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, spacer L P The formula is as follows: [ka] It is expressed by, in the formula, [ka] This represents bonding to the linker group, [ka] This represents a bond to group Z, L1 and L 2 Each of them is an independent connecting spacer. P 1 This is a peptide containing 2 to 5 amino acid residues, the remaining variables as defined in the 17th embodiment of the second aspect or any embodiment described therein.

[0125] In the 19th embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, P 1 is a peptide selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, or Ala-Val, the remaining variables as defined in the 18th embodiment of the second aspect.

[0126] In the 20th embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, P 1 teeth, [ka] The remaining variables are as defined in the 18th embodiment of the second aspect.

[0127] In the 21st embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L 1 This includes a hydrophilic portion, and the remaining variables are as defined in the 18th, 19th, or 20th embodiment of the second aspect. In some embodiments, L 1 This includes the PEG portion.

[0128] In the 22nd embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L 1 is *-CH2-CH2-(OCH2CH2) n-C(=O)-**, where n is an integer from 0 to 30, *- represents bonding to the linker group, and **- represents P 1 This represents a union to , and the remaining variables are as defined in the 18th, 19th, or 20th embodiment of the second aspect. In some embodiments, n is an integer from 2 to 16. In some embodiments, n is an integer from 2 to 10. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 3 to 5. In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8.

[0129] In the 23rd embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L 1 The formula is *-CH2-CH2-(OCH2CH2)3-C(=O)-**, where *- represents bonding to a linker group, and **- represents P 1 This represents a union to , and the remaining variables are as defined in the 18th, 19th, or 20th embodiment of the second aspect.

[0130] In the 24th embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L 2 is, -NH-C 1~6 Alkyl-**, where ** is a Z-connected portion, and the remaining variables are as defined in the 18th, 19th, 20th, 21st, 22nd, or 23rd embodiment of the second aspect, or any embodiment described therein.

[0131] In the 25th embodiment of the second aspect, for a linker-photosensitizer compound of formula (II), (IIA), (IIB), or a pharmaceutically acceptable salt thereof, L 2 is -NH-CH2CH2-**, where ** is a part connected to Z, and the remaining variables are as defined in the 18th, 19th, 20th, 21st, 22nd, or 23rd embodiment of the second aspect, or any embodiment described therein.

[0132] In the 26th embodiment of the second aspect, the linker-photosensitizer compound of the present disclosure is of the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is represented by, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of a positional isomer.

[0133] Modified targeting agents having reactive groups In a third aspect, the disclosure provides a modified targeting agent having a reactive group that can be covalently bonded to a photoenhancing compound as described in the first aspect or a linker-photosensitizing compound as described in the second aspect. In the first embodiment of the third aspect, the modified targeting agent has formula (V): [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, T is a targeting agent, R T This is a reactive group covalently bonded to the targeting agent, L A It is a spacer, Lin is a reactive group, r is an integer between 1 and 20.

[0134] In the second embodiment, for the modified targeting agent of formula (V), R T is -NH-, -C(=O)-, or [ka] Herein, * is the site connected to the targeting agent, and the remaining variables are as described in the first embodiment of the third aspect.

[0135] In the third embodiment, for the modified targeting agent of formula (V), R T is -NH- or -C(=O)-, where * is a site connected to the targeting agent, and the remaining variables are as described in the first embodiment of the third aspect.

[0136] In the fourth embodiment, with respect to the modified targeting agent of formula (V), L A L is a spacer including a hydrophilic portion, and the remaining variables are as described in the first, second, or third embodiments of the third aspect. In some embodiments, L A This is a spacer that includes the PEG portion.

[0137] In the fifth embodiment, with respect to the modified targeting agent of formula (V), L A *-CH2CH2(OCH2CH2) p - and in the formula, * is R T The part connected to is where n is an integer from 1 to 10, p is an integer from 0 to 30, and the remaining variables are as described in the first, second, or third embodiments of the third aspect. In some embodiments, p is an integer from 2 to 8. In some embodiments, p is an integer from 3 to 5. In some embodiments, p is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 6.

[0138] In the fifth embodiment, for the modified targeting agent of formula (V), the lin in formula (V) is, [ka] Or N3, and the remaining variables are as described in the first, second, third, or fourth embodiments of the third aspect.

[0139] In the sixth embodiment, the modified targeting agent is given by the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof.

[0140] Photosensitizer-targeting agent conjugate In a fourth aspect, the disclosure provides a conjugate comprising a targeting agent covalently bound to a photosensitizer, wherein the photosensitizer is a benzoporphyrin analog. In the first embodiment of the fourth aspect, the conjugate of the disclosure is represented by formula (III) or [ka] or a pharmaceutically acceptable salt thereof, in the formula, T is a targeting agent, L is a spacer that connects the targeting agent and PS. r is an integer between 1 and 20. PS is given by the following formula: [ka] A photosensitizer which is a benzoporphyrin analog represented by or a pharmaceutically acceptable salt thereof, A, B, X, and Y are each independently -OH and -OC. 1~4 Alkyl, -N(R 100 )(R 101 ), or a covalent bond to L, provided that one of A, B, X, and Y is a covalent bond to L, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16.

[0141] In the second embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS in formula (III) is given by the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A T、 B T , X T , and Y T These are -OH and -OC, respectively, independently. 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -Linker-L A -R T And, however, A T、 B T , X T , and Y T One of them is -ZLP -Linker-L A -R T Provided that Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl, L P and L A Each of them is an independent spacer. The linker is formed by the first reactive group bonded to L and L A This is a connecting portion formed by a second reactive group bonded to it. R T is a reactive group covalently bonded to the targeting agent, and the remaining variables are as defined in the first embodiment of the fourth aspect.

[0142] In the third embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), and R T is -C(=O)-, -NH-, or [ka] And in the formula, [ka] This indicates binding to the targeting agent, [ka] L A This represents a coupling to , and the remaining variables are as defined in the second embodiment of the fourth aspect.

[0143] In the fourth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), and R T is -C(=O)- or -NH-, and in the formula, [ka] This indicates binding to the targeting agent, [ka] L A This represents a coupling to , and the remaining variables are as defined in the second embodiment of the fourth aspect.

[0144] In the fifth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), and L A L is a spacer including a hydrophilic portion, and the remaining variables are as defined in the second, third, or fourth embodiments of the fourth aspect. In some embodiments, L A This includes the PEG portion.

[0145] In the sixth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), and L A *-CH2CH2(OCH2CH2) p - and in the formula, * is R T The part connected to is p, where p is an integer from 0 to 30, and the remaining variables are as defined in the second, third, or fourth embodiment of the fourth aspect, or any embodiment described therein. In some embodiments, p is an integer from 2 to 10. In some embodiments, p is an integer from 2 to 8. In some embodiments, p is an integer from 3 to 5. In some embodiments, p is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, p is 6.

[0146] In the seventh embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), where the linker in formula (IV) is L P The first reactive group and L bonded to it AThe first and second reactants are formed by a second reactant bonded to the first reactant, and the second reactant is selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group, respectively, with the remaining variables as defined in the second, third, fourth, fifth, or sixth embodiment of the fourth aspect, or any embodiment described therein.

[0147] In the eighth embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), where the linker in formula (IV) is the following: [ka] Represented by, During the ceremony, [ka] L P This represents a connection to, [ka] L A This represents a coupling to , and the remaining variables are as defined in the second, third, fourth, fifth, or sixth embodiment of the fourth aspect, or any embodiment described therein.

[0148] In the ninth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), A T B T , X T , and Y T It is defined as follows, that is, a) A T and B T However, it is -OCH3, and X T and Y T One of them is -OCH3, and X T and Y T The other of these is -ZL P -Linker-L A-R T Is it, b) A T and B T However, it is -OCH3, and X T and Y T One of them is -OH, and X T and Y T The other of these is -ZL P -Linker-L A -R T Is it, c)A T and B T One of them is -OCH3, and A T and B T The other of these is -OH, and X T and Y T One of them is -OH, and X T and Y T The other of these is -ZL P -Linker-L A -R T Is it, d)A T and B T However, it is -OH, and one of X and Y is -OH, X T and Y T The other of these is -ZL P -Linker-L A -R T is, or e) A T and B T One of them is -ZL P -Linker-L A -R T A T and B T The other of these is -OH or -OCH3, and X T and Y T Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102However, is either H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, or eighth embodiment of the fourth aspect, or any embodiment described therein.

[0149] In some embodiments, A T and B T is -OCH3, and X T and Y T One of them is -OCH3, and X T and Y T The other of these is -ZL P -Linker-L A -R T That is the case.

[0150] In some embodiments, A T and B T is -OCH3, and X T and Y T One of them is -OH, and X T and Y T The other of these is -ZL P -Linker-L A -R T That is the case.

[0151] In some embodiments, A T and B T One of them is -OCH3, and A T and B T The other of these is -OH, and X T and Y T One of them is -OH, and X T and Y T The other of these is -ZL P -Linker-L A -R T That is the case.

[0152] In some embodiments, A T and B T is -OH, and one of X and Y is -OH, X T and Y TThe other of these is -ZL P -Linker-L A -R T That is the case.

[0153] In some embodiments, A T and B T One of them is -ZL P -Linker-L A -R T A T and B T The other of these is -OH or -OCH3, X T and Y T Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 is either H or Me, and nr is an integer between 2 and 8.

[0154] In the tenth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is of formula (IVA): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where X T and Y T One of them is -ZL P -Linker-L A -R T The other is -OH, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment of the fourth aspect, or any embodiment described therein.

[0155] In the eleventh embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is of formula (IVB): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where A T and BT One of them is -ZL P -Linker-L A -R T The other is -OH or -OCH3, and R 102 is H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment of the fourth aspect, or any embodiment described therein.

[0156] In the twelfth embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where Z in formula (IV), (IVA), or (IVB) is -NH-, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments of the fourth aspect, or any embodiment described therein.

[0157] In the thirteenth embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where Z in formula (IV), (IVA), or (IVB) is -O-, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments of the fourth aspect, or any embodiment described therein.

[0158] In the fourteenth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) P is an inseparable spacer, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment of the fourth aspect, or any embodiment described therein. In some embodiments, L PIt includes a hydrophilic portion. In some embodiments, L P This includes the PEG portion.

[0159] In the 15th embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) P is *-CH2CH2-(OCH2CH2) m - is the formula, where * is the site bonded to the linker group, m is an integer from 0 to 30, and the remaining variables are as defined in the 14th embodiment. In some embodiments, m is an integer from 2 to 10. In some embodiments, m is an integer from 2 to 8. In some embodiments, m is an integer from 3 to 5. In some embodiments, m is 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 6.

[0160] In the sixteenth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) P This is *-CH2CH2-(OCH2CH2)4-, where * is the site bonded to the linker group, and the remaining variables are as defined in the 14th embodiment.

[0161] In the seventeenth embodiment of the fourth aspect, for a conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) Pis a cleavable group, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment of the fourth aspect, or any embodiment described therein. In some embodiments, the cleavable space includes enzyme-unstable groups, pH-unstable groups, disulfide groups, ROS-cleavable groups, and photo-cleavable groups. In some embodiments, the enzyme-unstable group is a group cleavable by esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase. In some embodiments, the enzyme-unstable group is a group cleavable by cathepsin B.

[0162] In the eighteenth embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) P This comprises a peptide and a self-degrading group, and the remaining variables are as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment of the fourth aspect, or any embodiment described therein.

[0163] In the 19th embodiment of the fourth aspect, with respect to the conjugate of formula (III) or a pharmaceutically acceptable salt thereof, -L-PS is represented by formula (IV), (IVA), or (IVB), where L in formula (IV), (IVA), or (IVB) P The formula is as follows: [ka] It is expressed by, in the formula, [ka] This represents a bond to a group represented by a linker, [ka] This represents a bond to group Z, L 1 and L 2 Each of them is an independent connecting spacer. P 1 This is a peptide comprising 2 to 5 amino acid residues, the remaining variables as defined in the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment of the fourth aspect, or any optional embodiment described therein.

[0164] In the 20th embodiment of the fourth aspect, with respect to the conjugate described in the 18th embodiment or a pharmaceutically acceptable salt thereof, P 1 is a peptide selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, or Ala-Val, the remaining variables as defined in the 19th embodiment of the fourth aspect, or any embodiment described therein.

[0165] In the 21st embodiment of the fourth aspect, with respect to the conjugate described in the 19th embodiment or a pharmaceutically acceptable salt thereof, P 1 teeth, [ka] The remaining variables are as defined in the 18th embodiment of the fourth aspect, or any embodiment described therein.

[0166] In the 22nd embodiment of the fourth aspect, with respect to the conjugate described in the 19th embodiment or a pharmaceutically acceptable salt thereof, L 1 This includes a hydrophilic portion, and the remaining variables are as defined in the 19th, 20th, or 21st embodiment of the fourth aspect. In some embodiments, L 1 This includes the PEG portion.

[0167] In the 23rd embodiment of the fourth aspect, with respect to the conjugate described in the 19th embodiment or a pharmaceutically acceptable salt thereof, L 1 is *-CH2-CH2-(OCH2CH2) n -C(=O)-**, where n is an integer from 0 to 30, *- represents bonding to the linker group, and **- is P 1 This represents a coupling to , and the remaining variables are as defined in the 19th, 20th, or 21st embodiment of the fourth aspect, or any embodiment described therein. In some embodiments, n is an integer from 2 to 16. In some embodiments, n is an integer from 2 to 10. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 3 to 5. In some embodiments, n is 2, 3, 4, 5, 6, 7, or 8.

[0168] In the 24th embodiment of the fourth aspect, with respect to the conjugate described in the 19th embodiment or a pharmaceutically acceptable salt thereof, L 1 The formula is *-CH2-CH2-(OCH2CH2)3-C(=O)-**, where *- represents bonding to a linker group, and **- represents P 1 This represents a coupling to , and the remaining variables are as defined in the 19th, 20th, or 21st embodiment of the fourth aspect, or any embodiment described therein.

[0169] In the 25th embodiment of the fourth aspect, with respect to the conjugate described in the 19th embodiment or a pharmaceutically acceptable salt thereof, L 2 is, -NH-C 1~6 Alkyl-**, where ** is a Z-connected portion, and the remaining variables are as defined in the 19th, 20th, 21st, 22nd, 23rd, or 24th embodiment of the fourth aspect, or any embodiment described therein.

[0170] In the 26th embodiment of the fourth aspect, with respect to the conjugate described in the 18th embodiment or a pharmaceutically acceptable salt thereof, L 2is -NH-CH2CH2-**, where ** is a part connected to Z, and the remaining variables are as defined in the 19th, 20th, 21st, 22nd, 23rd, or 24th embodiments of the fourth aspect, or any embodiment described therein.

[0171] In the 27th embodiment of the fourth aspect, the conjugate of the present disclosure is given by the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is represented by, or a pharmaceutically acceptable salt thereof, in the formula, [ka] This indicates binding to the targeting agent. Alternatively, as part of the 27th embodiment of the fourth aspect, the conjugate of the present disclosure is of the following formula: [ka] It is represented by, or a pharmaceutically acceptable salt thereof, in the formula, [ka] This indicates binding to the targeting agent.

[0172] Targeting agent In some embodiments, the targeting agent may be a small molecule (e.g., folic acid), protein, peptide (e.g., cell-permeable peptide), hormone, hapten, avidin, strepavidin, biotin, carbohydrate, oligosaccharide, polysaccharide, nucleic acid, DNA fragment, RNA fragment, aptamer, or nanocarrier (e.g., liposome, gold nanoparticle, polymer nanoparticle, virus-like particle) that binds to the surface of the target cell.

[0173] In some embodiments, the targeting agent is an antibody or its antigen-binding fragment.

[0174] In some embodiments, the targeting agent is an antibody or its antigen-binding fragment that binds to adipocytes, blood cells, cancer cells, endothelial cells, epithelial cells, immune cells, neurons, skin cells, stem cells, tumor cells, or bone marrow-derived suppressor cells. In some embodiments, the antibody or its antigen-binding fragment binds to cancer-associated fibroblasts, tumor-associated macrophages, T cells, or regulatory T cells.

[0175] In some embodiments, the targeting agents are EGFR / HER1, HER2, HER3, HER4, VEGF, VEGFR, VEGFR2, EpCAM, E-Cad, folate receptor α, fibroblast-activating protein (FAP), CD1c, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a, CD11b, CD11c, CD14, CD16, CD18, CD19, CD20, CD21, and CD2. 3, CD25, CD26, CD27, CD28, CD30, CD31, CD32, CD33, CD44, CD45, CD52, CD56, CD62L, CD64, CD66b, CD69, CD80, CD8 6, CD90, CD103, CD122, CD123, CD127, CD163, CD206, CD235a, CXCR6, MHC-II, CCR4, CCR5, CCR7, CLA, PD-1, PD-L1 CTLA-4, CEA, MUC-1, PSMA, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y antigen, TAG-72, IL-13R, melanoma-associated antigen (MAGE) 1, MAGE 2, MAGE 3, MAGE 4, tumor-associated glycoprotein 72 (TAG-72), gp100, p97 melanoma antigen, human milk fat globules (HMFG), melanoma antigen 1 recognized by T cells (MART1), These are antibodies or antigen-binding fragments that bind to B melanoma antigen (BAGE)1, BAGE2, G antigen (GAGE)1, GAGE2, GAGE3, GAGE4, ​​GAGE5, GAGE6, breast cancer-associated DF3 antigen, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), mesothelin, GITR, OX40, FR4, CXCR4, CCL4, Gr-1, IL-4Ra, IL-1Ra, CXCR2, or LAG-3.

[0176] In some embodiments, the targeting agent is an antibody or its antigen-binding fragment that binds to CD2 or EGFR.

[0177] In some embodiments, the targeting agent described above (e.g., an antibody or its antigen-binding fragment) is R TIt contains a reactive group that can form a covalent bond with R. In some embodiments, the reactive group is selected from an amine group, a thiol group, or an amide group. In some embodiments, the targeting agent described above (e.g., an antibody or its antigen-binding fragment) is R T The compound comprises a lysine, cysteine, or glutamine residue that can form a covalent bond with a group. In some embodiments, the lysine, cysteine, or glutamine residue is connected to a side chain, i.e., the amine group of the lysine residue, the amide group of the glutamine residue, or the thiol group of the cysteine ​​residue through the R group. T It is connected to the base. In some embodiments, the targeting agent (e.g., an antibody or its antigen-binding fragment) is connected to the R through the amine group of the terminal amino acid. T It can form a covalent bond with the base.

[0178] In some embodiments, the targeting agent described above (e.g., an antibody or its antigen-binding fragment) has the following base: [ka] Includes, In the formula, R is the side chain of an amino acid residue. [ka] This represents binding to the remaining targeting agent, [ka] R T This represents a connection to something.

[0179] Method for preparing photosensitizer-targeting agent conjugates The conjugates of this disclosure (for example, the conjugates described in the fourth aspect, the first to twenty-seventh embodiments of the fourth aspect, or any embodiment described therein) can be prepared by any preferred method known in the art.

[0180] In some embodiments, a targeting agent (e.g., an antibody or its antigen-binding fragment) can be conjugated with a linker-photosensitizer compound described herein (e.g., as described in the second embodiment, embodiments 1 to 26 of the second embodiment, or any embodiment described therein) via a reactive group located on the targeting agent. In some embodiments, the reactive group is an amine group of a lysine residue, an amide group of a glutamine residue, a thiol group of a cysteine ​​residue, or an amine group of a terminal amino acid residue. Either chemical conjugation or enzymatic conjugation can be used.

[0181] In some embodiments, the conjugates of the present disclosure can be prepared by reacting a modified targeting agent having a first reactive moiety (e.g., as described in the Third Embodiment, the First to Sixth Embodiments of the Third Embodiment, or any embodiment described therein) with a photosensitizing compound having a second reactive moiety (e.g., as described in the First Embodiment, the First to Twenty-First Embodiments, or any embodiment described therein).

[0182] Other compounds disclosed herein In a fifth aspect, the Disclosure provides a compound that can be used to prepare the photosensitizer compound described in the first aspect. The fifth aspect of the Disclosure also provides a metabolite compound of the conjugate described in the fourth aspect. In the first embodiment of the fifth aspect, the compound is of formula (VI): [ka] It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A', B', X', and Y' are each independently -OH, --OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZC 1~6 It is alkylene-NH2, where one of A', B', X', and Y' is -ZC 1~6 The condition is that it is alkylene-NH2, R 100 is H or C 1~3 It is alkyl, R 101 H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 is H or C 1~3 It is alkyl.

[0183] In the second embodiment of the fifth aspect, with respect to the compound of formula (VI) or a pharmaceutically acceptable salt thereof, A', B', X', and Y' are defined as follows: a) A' and B' are -OCH3, one of X' and Y' is -OCH3, and the other of X' and Y' is -ZC 1~6 Is it alkylene-NH2? b) A' and B' are -OCH3, one of X' and Y' is -OH, and the other of X and Y is -ZC 1~6 Is it alkylene-NH2? c) One of A' and B' is -OCH3, the other of A' and B' is -OH, one of X' and Y' is -OH, and the other of X' and Y' is -ZC 1~6 Is it alkylene-NH2? d) A' and B' are -OH, one of X' and Y' is -OH, and the other of X' and Y' is -ZC 1~6 It is alkylene-NH2, or e) One of A' and B' is -OCH3, and the other of A' and B' is -ZC 1~6 It is alkylene -NH2, and both X' and Y' are -NH(CH2-CH2-O) nr R 102And in the formula, R 102 However, is either H or Me, nr is an integer between 2 and 8, and the remaining variables are as defined in the first embodiment of the fifth aspect.

[0184] In the second embodiment of the fifth aspect, with respect to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, the compound is of formula (VIA): [ka] It is represented by or a pharmaceutically acceptable salt thereof, where one of X' and Y' is -ZC 1~6 The other is alkylene -NH2, the other is -OH, and the remaining variables are as defined in the first embodiment of the fifth aspect.

[0185] In the third embodiment of the fifth aspect, with respect to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, the compound is of formula (VIB): [ka] Represented by or a pharmaceutically acceptable salt thereof, where one of A' and B' is -ZC 1~6 The other is alkylene -NH2, the other is -OH or -OCH3, and the remaining variables are as defined in the first embodiment of the fifth aspect.

[0186] In the fourth embodiment of the fifth aspect, for a compound of formula (VI), (VIA), or (VIB), or a pharmaceutically acceptable salt thereof, Z is -NH-, and the remaining variables are as defined in the first, second, or third embodiment of the fifth aspect.

[0187] In the fifth embodiment of the fifth aspect, for a compound of formula (VI), (VIA), or (VIB), or a pharmaceutically acceptable salt thereof, Z is -O-, and the remaining variables are as defined in the first, second, or third embodiment of the fifth aspect.

[0188] In the sixth embodiment of the fifth aspect, the compound has the following formula: [ka] [ka] It is represented by, or a pharmaceutically acceptable salt, positional isomer, or pharmaceutically acceptable salt of a positional isomer thereof. Alternatively, as part of the sixth embodiment of the fifth aspect, the compound may be of the following formula: [ka] It is represented by, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of a positional isomer.

[0189] Method of use and composition This disclosure also provides compositions (e.g., pharmaceutical compositions) comprising any photosensitizer-targeting agent conjugate described herein, such as those described in the fourth aspect or any embodiment described therein. In some embodiments, the pharmaceutical compositions of this disclosure comprise a photosensitizer-targeting agent conjugate described herein, such as those described in the fourth aspect or any embodiment described therein, and pharmaceutically acceptable excipients (e.g., carriers, diluents, etc.).

[0190] The pharmaceutical compositions described herein can be administered in any number of ways for either topical or systemic treatment. Administration may be topical (e.g., to mucous membranes, including vaginal and rectal delivery) such as transdermal patches, ointments, lotions, creams, gels, infusions, suppositories, sprays, liquids, and powders; pulmonary (e.g., intratracheal, intranasal, epidermal, and transdermal, by inhalation or blowing of powder or aerosol, including nebulizers); oral; parenteral (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion); or intracranial (e.g., intrathecal or intraventricular) administration. In some specific embodiments, administration is intravenous. The pharmaceutical compositions described herein can also be used in vitro or ex vivo.

[0191] Suitable pharmaceutically acceptable carriers, diluents, and excipients are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005, and the books in the series Drugs and the Pharmaceutical Sciences: A Series of Textbooks and Monographs (Dekker, NY)) and can be determined by those skilled in the art depending on the clinical situation. Examples of suitable carriers, diluents, and / or excipients include (1) Dulbecco's phosphate-buffered saline with a pH of approximately 7.4, containing or not containing approximately 1 mg / mL to 25 mg / mL of human serum albumin, (2) 0.9% saline (0.9% w / v NaCl), and (3) 5% (w / v) dextrose, and may also contain antioxidants such as tryptamine and stabilizers such as Tween 20.

[0192] Photosensitizer-targeting agent conjugates or compositions containing conjugates (e.g., pharmaceutical compositions) can be used to treat a variety of diseases or conditions.

[0193] In some embodiments, the Disclosure provides a method for treating a subject having a disease or condition, comprising: a) administering to the subject an effective amount of the conjugate described herein (e.g., as described in the fourth embodiment or any embodiment described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the conjugate or a pharmaceutically acceptable salt thereof; and b) after administration of the agent comprising the conjugate or a pharmaceutically acceptable salt thereof, or the conjugate or a pharmaceutically acceptable salt thereof, irradiating a target region of the subject with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate. In some embodiments, the targeting agent in the conjugate (e.g., an antibody or its antigen-binding fragment) binds to a target molecule of one or more cells located in the targeting region. In some embodiments, the targeting agent in the conjugate (e.g., an antibody or its antigen-binding fragment) binds to a target molecule of one or more cells located in the vicinity of the targeting region.

[0194] In some embodiments, the target region is tumor cells, tumor cell clusters, solid tumors, the vicinity of solid tumors, metastases, metastatic tumor cells, the vicinity of metastases, or precancerous lesions. In some embodiments, the disease or condition that can be treated by the method is cancer. In some embodiments, cancer is selected from the group consisting of colon cancer, colorectal cancer, pancreatic cancer, breast cancer, skin cancer, lung cancer, non-small cell lung cancer, renal cell carcinoma, thyroid cancer, prostate cancer, head and neck cancer, esophageal and gastrointestinal cancer, stomach (gastric) cancer, small intestine cancer, colon cancer, spindle cell neoplasms, liver cancer, bile duct cancer, peripheral nerve cancer, brain cancer, skeletal muscle cancer, smooth muscle cancer, bone cancer, adipose tissue cancer, cervical cancer, uterine cancer, genital cancer, lymphoma, and multiple myeloma.

[0195] As used herein, the term “nearby” refers to the distance at which near-infrared (NIR) light can deliver a dose sufficient to activate the photosensitizer in the conjugate. The distance may depend on the light source and / or the wavelength of the light. In some embodiments, the distance is 30 cm, 25 cm, 20 cm, 15 cm, 10 cm, 8 cm, or 5 cm from the target cell or tissue.

[0196] In some embodiments, the target area is a skin lesion. In some embodiments, the disease or condition that can be treated by this method is psoriasis, atopic dermatitis, lupus, vitiligo, graft-versus-host disease, cutaneous T-cell lymphoma, contact dermatitis, cutaneous hypersensitivity response, lichen planus, keratosis pilaris, rejection of vascularized compound allografts, alopecia areata, scarring alopecia, or sarcoid-related skin lesions.

[0197] In some embodiments, the target region is the kidney in question. In some embodiments, the disease or condition that can be treated by this method is lupus nephritis, autoimmune nephritis, or T cell-mediated kidney or renal pathology / disease associated with kidney graft rejection.

[0198] In some embodiments, the target region is the gastrointestinal tract or intestine of the subject. In some embodiments, the disease or condition that can be treated by this method is gastrointestinal inflammation resulting from an autoimmune and / or inflammatory condition, such as inflammatory bowel disease (Crohn's disease, ulcerative colitis).

[0199] In some embodiments, the target area is the inflamed joint of the subject. In some embodiments, the disease or condition that can be treated by this method is inflammation of the joint from rheumatoid arthritis or spondyloarthritis.

[0200] In some embodiments, the Disclosure provides a method for imaging cells or tissues having a target molecule in a subject, comprising: a) administering to a subject an effective amount of the conjugate described herein (e.g., as described in the fourth embodiment or any embodiment described herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the conjugate or a pharmaceutically acceptable salt; and b) after administration of the agent comprising the conjugate or a pharmaceutically acceptable salt thereof, or the conjugate or a pharmaceutically acceptable salt thereof, irradiating a target region of the subject with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate, thereby providing an image of the presence of the target molecule associated with the cell or tissue. In some embodiments, the targeting agent in the conjugate (e.g., an antibody or its antigen-binding fragment) binds to the target molecule in the cell or tissue being imaged. In some embodiments, the cell or tissue is located within the targeting region. In some embodiments, the cell or tissue is located in the vicinity of the targeting region.

[0201] In some embodiments, the target area is tumor cells, tumor cell clusters, solid tumors, the vicinity of solid tumors, metastases, metastatic tumor cells, the vicinity of metastases, or precancerous lesions. In some embodiments, the target area is a skin lesion. In some embodiments, the target area is the kidney of the subject. In some embodiments, the target area is the gastrointestinal tract or intestine of the subject. In some embodiments, the target area is an inflamed joint of the subject.

[0202] Any suitable NIR light can be used in the manner described above. In some embodiments, the NIR light is in the wavelength range of 600 nm to 850 nm. In some embodiments, the NIR light is in the wavelength range of 660 nm to 740 nm, for example, 660 nm, 670 nm, 680 nm, 690 nm, 700 nm, 710 nm, 720 nm, 730 nm, or 740 nm. The NIR light can be administered by any method known in the art, for example, using a therapeutic laser.

[0203] In some embodiments, the target region can be irradiated with a dose sufficient to activate the conjugate photosensitizer. In some embodiments, the irradiation dose is approximately 1 J / cm². 2 ~About 400J / cm 2 In some embodiments, the irradiation dose is approximately 2 J / cm². 2 ~About 400J / cm 2 In some embodiments, the irradiation dose is approximately 1 J / cm². 2 ~About 300J / cm 2 In some embodiments, the irradiation dose is approximately 10 J / cm². 2 ~About 100J / cm 2 In some embodiments, the irradiation dose is approximately 10 J / cm². 2 ~about 50J / cm 2 That is the case.

[0204] In some embodiments, the irradiation is performed at least 5 minutes after administration of the conjugate in the method described above. In some embodiments, the irradiation is performed 1 to 48 hours after administration of the conjugate. In some embodiments, the irradiation is performed 4 to 30 hours after administration of the conjugate. In some embodiments, the irradiation is performed 1 to 24 hours after administration of the conjugate. In some embodiments, the irradiation is performed 8 to 24 hours after administration of the conjugate. In some embodiments, the irradiation is performed 1, 2, 3, 4, 5, 6, 7, 8, 12, 15, 18, or 24 hours after administration of the conjugate.

[0205] Numbered Embodiments Embodiment 1. The following formula: [ka] A compound represented by or a pharmaceutically acceptable salt thereof, wherein the formula is A, B, X, and Y are each independently -OH, -OC 1~4 Alkyl, -N(R 100 )(R101 ), or -ZL P -ker, however 、 At least one of A, B, X, and Y is -N(R 100 )(R 101 ), -ZL P -NH2 or -ZL P -conditional on being -ker, and at most one of A, B, X, and Y being -ZL P -NH2 or -ZL P -Assuming it is a ker, R 100 However, H or C 1~3 It is alkyl, R 101 However, H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 However, it is either H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 However, H or C 1~3 It is alkyl, L P However, it is a spacer, A compound or a pharmaceutically acceptable salt thereof in which ker is the reactive group.

[0206] Embodiment 2. A, B, X, and Y are each independently -OH, -OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -ker, however 、 At least one of A, B, X, and Y is -N(R 100 )(R 101 ) or -ZL P -conditional on being -ker, and at most one of A, B, X, and Y being -ZL P -Assuming it is a ker, R100 However, H or C 1~3 It is alkyl, R 101 However, H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 However, it is either H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 However, H or C 1~3 It is alkyl, L P However, it is a spacer, A compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein ker is the reactive group.

[0207] Embodiment 3. a) A and B are -OCH3, and one of X and Y is -OCH3, and the other of X and Y is -ZL P -ker, b) A and B are -OCH3, and one of X and Y is -OH, and the other of X and Y is -ZL P -ker, c) One of A and B is -OCH3 and the other is -OH, and one of X and Y is -OH and the other is -ZL P -ker, d) A and B are -OH, and one of X and Y is -OH, and the other of X and Y is -ZL P -ker, e) One of A and B is -OH, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 However, it is either H or Me, and nr is an integer between 2 and 8, or f) Either A or B, -ZL P -ker, the other of A and B is -OH or -OCH3, and both X and Y are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein is H or Me, and nr is an integer from 2 to 8.

[0208] Embodiment 4. The compound is of the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where one of X and Y is -ZL P A compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the other is -ker and the other is -OH.

[0209] Embodiment 5. The compound is of the following formula: [ka] Represented by or a pharmaceutically acceptable salt thereof, where one of A and B is -OH or -ZL P -ker, and the other is -OH or -OCH3, R 102 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1, wherein is H or Me, and nr is an integer from 2 to 8.

[0210] Embodiment 6. A compound according to any one of Embodiments 1 to 5 or a pharmaceutically acceptable salt thereof, wherein ker is a reactive group selected from a maleimide group, a thiol group, a cyclooctin group, an azide group, a hydrazide group, a tetrazine group, a cyclooctene group, a ketone group, and an aldehyde group.

[0211] Embodiment 7.ker is [ka] A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 5, which is -N3.

[0212] Embodiment 8. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 7, wherein Z is -NH-.

[0213] Embodiment 9. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 7, wherein Z is -O-.

[0214] Embodiment 10.L P However, the compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 9 is an inseparable spacer.

[0215] Embodiment 11.L P However, the compound described in Embodiment 10 or a pharmaceutically acceptable salt thereof, which includes a hydrophilic portion.

[0216] Embodiment 12.L P However, the compound described in Embodiment 10 or a pharmaceutically acceptable salt thereof, comprising the PEG portion.

[0217] Embodiment 13.L P However, *-CH2CH2-(OCH2CH2) m - is a compound or a pharmaceutically acceptable salt thereof according to Embodiment 10, wherein * is a site connected to ker and m is an integer from 0 to 30.

[0218] Embodiment 14. The compound or a pharmaceutically acceptable salt thereof described in Embodiment 13, wherein m is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or m is 2, 3, 4, 5, 6, 7, or 8.

[0219] Embodiment 15.L P However, the compound described in Embodiment 10 or a pharmaceutically acceptable salt thereof is *-CH2CH2-(OCH2CH2)4-.

[0220] Embodiment 16.L P However, a severable spacer is a compound or pharmaceutically acceptable salt thereof as described in any one of embodiments 1 to 9.

[0221] Embodiment 17. The compound according to Embodiment 16 or a pharmaceutically acceptable salt thereof, wherein the cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, and a photodegradable group.

[0222] Embodiment 18. The compound according to Embodiment 17 or a pharmaceutically acceptable salt thereof, wherein the enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase.

[0223] Embodiment 19. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein the enzyme-unstable group is a group that can be cleaved by cathepsin B.

[0224] Embodiment 20.L P The spacer represented by comprises a peptide and a self-degrading group, wherein the compound according to Embodiment 16 or a pharmaceutically acceptable salt thereof.

[0225] Embodiment 21. The spacer L P However, the following formula: [ka] It is expressed by, in the formula, [ka] However, this represents the bond to the reactant group represented by ker, [ka] However, this represents a bond to group Z, L 1 and L 2 However, each is an independent connecting spacer. P 1 The compound described in Embodiment 20 or a pharmaceutically acceptable salt thereof, which is a peptide containing 2 to 5 amino acid residues.

[0226] Embodiment 22.P 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 21, wherein the peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val.

[0227] Embodiment 23.P 1 but, [ka] The compound described in Embodiment 22 or a pharmaceutically acceptable salt thereof.

[0228] Embodiment 24.L 1 However, a compound according to any one of embodiments 21 to 23 or a pharmaceutically acceptable salt thereof, which includes a hydrophilic portion.

[0229] Embodiment 25.L 1 However, the compound described in Embodiment 24 or a pharmaceutically acceptable salt thereof, comprising the PEG portion.

[0230] Embodiment 26.L 1 However, *-CH2-CH2-(OCH2CH2) n -C(=O)-**, where n is an integer from 0 to 30, *- represents a bond to the reactant represented by ker, and **- represents P 1 A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 21 to 23, representing binding to.

[0231] Embodiment 27. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 26, wherein n is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or n is 2, 3, 4, 5, 6, 7, or 8.

[0232] Embodiment 28.L 1 However, the compound described in Embodiment 26 or a pharmaceutically acceptable salt thereof is *-CH2-CH2-(OCH2CH2)3-C(=O)-**.

[0233] Embodiment 29.L 2 However, -NH-C 1~6 A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 21 to 28, wherein the compound is alkyl-**, where ** is a Z-linked site.

[0234] Embodiment 30.L 2 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 29, wherein the compound is -NH-CH2CH2-**, where ** is a Z-connected site.

[0235] Embodiment 31. The compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] The compound or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer, as described in Embodiment 1.

[0236] Embodiment 32. The compound is [ka] The compound or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer, as described in Embodiment 1.

[0237] Embodiment 33. Formula (II): [ka] A linker-photosensitizer compound or a pharmaceutically acceptable salt thereof, wherein, A L B L , X L , and Y L However, they are independent of each other: -OH, -OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -Linker-L A -R A And, however, A L B L , X L , and Y L One of them is -ZL P -Linker-L A -R A The condition is that, R 100 However, H or C 1~3 It is alkyl, R 101 However, H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 However, it is either H or Me, nr is an integer between 1 and 16. Z is -O- or -NR 1 -and, R 1 However, H or C 1~3 It is alkyl, L P and L A However, each is an independent spacer. Linker, L P The first reactive group and L bonded to it A This is a connecting portion formed by a second reactive group bonded to it. R A A linker-photosensitizer compound or a pharmaceutically acceptable salt thereof, which is a reactive group capable of forming a covalent bond with a targeting agent.

[0238] Embodiment 34.R A The compound according to claim 33 or a pharmaceutically acceptable salt thereof, wherein the compound is a reactive ester, -NH2, or maleimide group.

[0239] Embodiment 35.R A but, [ka] The compound according to claim 33, or -NH2.

[0240] Embodiment 36.L A However, the spacer includes a hydrophilic portion, and is a compound or pharmaceutically acceptable salt thereof as described in any one of embodiments 33 to 35.

[0241] Embodiment 37.L A However, the compound of Embodiment 36 or a pharmaceutically acceptable salt thereof is a spacer containing a PEG portion.

[0242] Embodiment 38.L A However, *-CH2CH2-(OCH2CH2) p - and in the formula, * is R A A compound or a pharmaceutically acceptable salt thereof according to Embodiment 36, wherein the site is connected to the compound, and p is an integer from 0 to 30.

[0243] Embodiment 39. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 37, wherein p is an integer between 2 and 16, 2 and 10, 2 and 8, or p is 2, 3, 4, 5, 6, 7, or 8.

[0244] Embodiment 40. The compound according to any one of Embodiments 33 to 39, wherein the first reactive group and the second reactive group are each selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group.

[0245] Embodiment 41. The linker is of the following formula: [ka] Represented by, During the ceremony, [ka] However, L P This represents a connection to, [ka] However, L A The compound described in Embodiment 40, which represents binding to.

[0246] Embodiment 42. a) A L and B L However, it is -OCH3, and X L and Y L One of them is -OCH3, and X L and Y L The other of these is -ZL P -Linker-L A -R A Is it, b) A L and B L However, it is -OCH3, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZLP -Linker-L A -R A Is it, c)A L and B L One of them is -OCH3, and A L and B L The other of these is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A Is it, d)A L and B L However, it is -OH, and X L and Y L One of them is -OH, and X L and Y L The other of these is -ZL P -Linker-L A -R A is, or e) A L and B L One of them is -ZL P -Linker-L A -R A A L and B L The other of these is -OH or -OCH3, and X L and Y L Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 33 to 41, wherein is H or Me, and nr is an integer from 2 to 8.

[0247] Embodiment 43. The compound is of the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where X L and Y L One of them is -ZL P -Linker-L A -R A The compound or a pharmaceutically acceptable salt thereof according to Embodiment 42, wherein the other is -OH.

[0248] Embodiment 44. The compound is of the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where A L and B L One of them is -ZL P -Linker-L A -R A The other is -OH or -OCH3, and R 102 A compound or a pharmaceutically acceptable salt thereof according to Embodiment 42, wherein is H or Me, and nr is an integer from 2 to 8.

[0249] Embodiment 45. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 33 to 44, wherein Z is -NH-.

[0250] Embodiment 46. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 33 to 44, wherein Z is -O-.

[0251] Embodiment 47.L P However, the compound or a pharmaceutically acceptable salt thereof described in any one of embodiments 33 to 46 is a non-cuttable spacer.

[0252] Embodiment 48.L P However, the compound described in Embodiment 47 or a pharmaceutically acceptable salt thereof, which includes a hydrophilic portion.

[0253] Embodiment 49.L PHowever, the compound described in Embodiment 48 or a pharmaceutically acceptable salt thereof, comprising the PEG portion.

[0254] Embodiment 50.L P However, *-CH2CH2-(OCH2CH2) m -The compound or a pharmaceutically acceptable salt thereof according to Embodiment 49, wherein * is the portion connected to the linker and m is an integer from 0 to 30.

[0255] Embodiment 51. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 50, wherein m is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or m is 2, 3, 4, 5, 6, 7, or 8.

[0256] Embodiment 52.L P The compound or a pharmaceutically acceptable salt thereof according to Embodiment 50, wherein the compound is *-CH2CH2-(OCH2CH2)4-, where * is the part connected to the linker.

[0257] Embodiment 53.L P However, a severable spacer is a compound or pharmaceutically acceptable salt thereof as described in any one of embodiments 33 to 46.

[0258] Embodiment 54. The compound according to Embodiment 53 or a pharmaceutically acceptable salt thereof, wherein the cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, and a photodegradable group.

[0259] Embodiment 55. The compound according to Embodiment 54 or a pharmaceutically acceptable salt thereof, wherein the enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, regmain, or matrix metalloproteinase.

[0260] Embodiment 56. The compound according to Embodiment 55 or a pharmaceutically acceptable salt thereof, wherein the enzyme-unstable group is a group that can be cleaved by cathepsin B.

[0261] Embodiment 57.L P The spacer represented by comprises a peptide and a self-degrading group, wherein the compound according to Embodiment 53 or a pharmaceutically acceptable salt thereof.

[0262] Embodiment 58. The spacer L P However, the following formula: [ka] It is expressed by, in the formula, [ka] However, this represents bonding to the linker group, [ka] However, this represents a bond to group Z, L 1 and L 2 However, each is an independent connecting spacer. P 1 The compound according to Embodiment 57 or a pharmaceutically acceptable salt thereof, which is a peptide containing 2 to 5 amino acid residues.

[0263] Embodiment 59.P 1 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 58, wherein the peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val.

[0264] Embodiment 60.P 1 but, [ka] The compound described in Embodiment 59 or a pharmaceutically acceptable salt thereof.

[0265] Embodiment 61.L 1 However, a compound according to any one of embodiments 58 to 60 or a pharmaceutically acceptable salt thereof, which includes a hydrophilic portion.

[0266] Embodiment 62.L 1 However, the compound according to Embodiment 61 or a pharmaceutically acceptable salt thereof, comprising the PEG portion.

[0267] Embodiment 63.L 1 However, *-CH2-CH2-(OCH2CH2) n -C(=O)-**, where n is an integer from 0 to 30, *- represents bonding to the linker group, and **- represents P 1 A compound according to Embodiment 62 or a pharmaceutically acceptable salt thereof, representing binding to.

[0268] Embodiment 64. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 63, wherein n is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or n is 2, 3, 4, 5, 6, 7, or 8.

[0269] Embodiment 65.L 1 However, it is *-CH2-CH2-(OCH2CH2)3-C(=O)-**, where *- represents bonding to the linker group, and **- represents P 1 A compound according to Embodiment 63 or a pharmaceutically acceptable salt thereof, representing binding to.

[0270] Embodiment 66.L 2 However, -NH-C 1~6 A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 58 to 68, wherein the compound is alkyl-**, where ** is a Z-linked site in the formula.

[0271] Embodiment 67.L 2 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 66, wherein the compound is -NH-CH2CH2-**, where ** is a Z-connected site.

[0272] Embodiment 68. The compound is of the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is represented by, The compound according to Embodiment 33, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer.

[0273] Embodiment 69. A conjugate comprising a benzoporphyrin analog covalently bound to a targeting agent, wherein the conjugate has the following formula: [ka] A salt of which is represented by, or a pharmaceutically acceptable salt thereof, in the formula, T is a targeting agent, L is a spacer connecting the targeting agent and PS, r is an integer between 1 and 20. PS is given by the following formula: [ka] A photosensitizer which is a benzoporphyrin analog represented by or a pharmaceutically acceptable salt thereof, in the formula, A, B, X, and Y are each independently -OH and -OC. 1~4 Alkyl, -N(R 100 )(R 101 ), or a covalent bond to L, provided that one of A, B, X, and Y is a covalent bond to L, R 100 However, H or C 1~3 It is alkyl, R 101 However, H, C 1~3 Alkyl, or -(CH2-CH2-O) nr R 102 And, R 102 However, it is either H or Me, A conjugate or a pharmaceutically acceptable salt thereof, where nr is an integer between 1 and 16.

[0274] Embodiment 70. -L-PS is given by the following formula: [ka] A salt of which is represented by, or a pharmaceutically acceptable salt thereof, in the formula, A T B T , X T , and Y T However, they are independent of each other: -OH, -OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZL P -Linker-L A-R T And, however, A T B T , X T , and Y T One of them is -ZL P -Linker-L A -R T The condition is that, Z is -O- or -NR 1 -and, R 1 However, H or C 1~3 It is alkyl, L P and L A However, each is an independent spacer. The linker is bonded to the first reactive group and L A This is a connecting portion formed by a second reactive group bonded to it. R T However, the conjugate described in Embodiment 69 or a pharmaceutically acceptable salt thereof is a reactive group covalently bonded to the targeting agent.

[0275] Embodiment 71. The conjugate according to Embodiment 69 or 70 or a pharmaceutically acceptable salt thereof, wherein the targeting agent comprises a polypeptide that binds to the surface of a target cell.

[0276] Embodiment 72. The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 71, wherein the targeting agent is an antibody or an antigen-binding fragment thereof.

[0277] Embodiment 73. The conjugate according to Embodiment 72 or a pharmaceutically acceptable salt thereof, wherein the antibody or its antigen-binding fragment binds to adipocytes, blood cells, cancer cells, endothelial cells, epithelial cells, immune cells, neurons, skin cells, stem cells, tumor cells, or bone marrow-derived suppressor cells.

[0278] Embodiment 74. The conjugate according to Embodiment 72 or a pharmaceutically acceptable salt thereof, wherein the antibody or its antigen-binding fragment binds to cancer-associated fibroblasts, tumor-associated macrophages, T cells, or regulatory T cells.

[0279] Embodiment 75. The antibody or its antigen-binding fragment is EGFR / HER1, HER2, HER3, HER4, VEGF, VEGFR, VEGFR2, EpCAM, E-Cad, folate receptor α, fibroblast-activating protein (FAP), CD1c, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a, CD11b, CD11c, CD14, CD16, CD18, CD19, CD20, CD21, CD 25, CD26, CD27, CD28, CD30, CD31, CD32, CD33, CD44, CD45, CD52, CD56, CD62L, CD64, CD66b, CD69, CD80, CD86, CD90 , CD103, CD122, CD123, CD127, CD163, CD206, CD235a, CXCR6, MHC-II, CCR4, CCR5, CCR7, CLA, PD-1, PD-L1, CTLA-4, CEA, MUC-1, PSMA, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y antigen, TAG-72, IL-13R, melanoma-associated antigen (MAGE) 1, MAGE 2, MAGE 3, MAGE 4, tumor-associated glycoprotein 72 (TAG-72), gp100, p97 melanoma antigen, human milk fat globules (HMFG), melanoma antigen 1 recognized by T cells (MART1), B melanoma antigen (BAGE) 1 Conjugates according to Embodiment 72 or pharmaceutically acceptable salts thereof that bind to BAGE2, G antigen (GAGE)1, GAGE2, GAGE3, GAGE4, ​​GAGE5, GAGE6, breast cancer-associated DF3 antigen, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), mesothelin, GITR, OX40, FR4, CXCR4, CCL4, Gr-1, IL-4Ra, IL-1Ra, CXCR2, or LAG-3.

[0280] Embodiment 76. The conjugate according to Embodiment 75 or a pharmaceutically acceptable salt thereof, wherein the antibody or its antigen-binding fragment is bound to CD2 or EGFR.

[0281] Embodiment 77. The targeting agent is R TA conjugate according to any one of embodiments 70 to 76 or a pharmaceutically acceptable salt thereof, comprising a reactive group capable of forming a covalent bond with a reactive group.

[0282] Embodiment 78. The conjugate according to Embodiment 77 or a pharmaceutically acceptable salt thereof, wherein the targeting agent comprises a reactive group selected from an amine group, a thiol group, or an amide group.

[0283] Embodiment 79. The targeting agent is based on the following: [ka] Includes, In the formula, R is the side chain of an amino acid residue. [ka] However, this represents binding to the remaining targeting agent. [ka] However, R T A conjugate according to Embodiment 77 or a pharmaceutically acceptable salt thereof, representing binding to a compound.

[0284] Embodiment 80.R T However, -C(=O)-, -NH-, or [ka] And in the formula, [ka] However, this represents binding to the targeting agent, [ka] However, L A A conjugate according to any one of embodiments 70 to 79 or a pharmaceutically acceptable salt thereof, representing binding to.

[0285] Embodiment 81.R TThe conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 78, wherein the compound is -C(=O)- or -NH-.

[0286] Embodiment 82.L A A conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 70 to 81, wherein the spacer includes a hydrophilic portion.

[0287] Embodiment 83.L A However, the conjugate of Embodiment 82 or a pharmaceutically acceptable salt thereof is a spacer containing a PEG portion.

[0288] Embodiment 84.L A However, *-CH2CH2-(OCH2CH2) p - and in the formula, * is R T A conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 82, wherein the site is connected to a portion where p is an integer from 0 to 30.

[0289] Embodiment 85. The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 84, wherein p is an integer between 2 and 16, 2 and 10, 2 and 8, or 3 and 5, or p is 2, 3, 4, 5, 6, 7, or 8.

[0290] Embodiment 86. The conjugate according to any one of Embodiments 70 to 85 or a pharmaceutically acceptable salt thereof, wherein the first reactive group and the second reactive group are each selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group.

[0291] Embodiment 87. The linker is of the following formula: [ka] Represented by, During the ceremony, [ka] However, L P This represents a connection to, [Chemical formula] where L is A the conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 86, which represents the bond to L.

[0292] Embodiment 88. a) A T and B T are -OCH3, and one of X T and Y T is -OCH3, and the other of X T and Y T is -Z-L P - linker -L A -R T or b) A T and B T are -OCH3, and one of X T and Y T is -OH, and the other of X T and Y T is -Z-L P - linker -L A -R T or c) One of A T and B T is -OCH3, the other of A T and B T is -OH, and one of X T and Y T is -OH, and the other of X T and Y T is -Z-L P - linker -L A -R T or d) A T and B T are -OH, and one of X and Y is -OH, and the other of X T and Y T is -Z-L P - linker -L A -R T or e) A T and B T One of them is -ZL P -Linker-L A -R T A T and B T The other of these is -OH or -OCH3, and X T and Y T Both are -NH(CH2-CH2-O) nr R 102 And in the formula, R 102 A conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 70 to 87, wherein is H or Me, and nr is an integer from 2 to 8.

[0293] Embodiment 89. -L-PS is given by the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where X T and Y T One of them is -ZL P -Linker-L A -R T The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 88, wherein the other is -OH.

[0294] Embodiment 90. -L-PS is given by the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where A T and B T One of them is -ZL P -Linker-L A -R T The other is -OH or -OCH3, and R 102 The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 88, wherein is H or Me, and nr is an integer between 2 and 8.

[0295] Embodiment 91. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Embodiments 70 to 90, wherein Z is -NH-.

[0296] Embodiment 92. A conjugate or a pharmaceutically acceptable salt thereof according to any one of Embodiments 70 to 90, wherein Z is -O-.

[0297] Embodiment 93.L P However, the conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 70 to 92 is an inseparable spacer.

[0298] Embodiment 94.L P However, the conjugate according to Embodiment 93 or a pharmaceutically acceptable salt thereof, which includes a hydrophilic portion.

[0299] Embodiment 95.L P However, the conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 94, which includes a PEG portion.

[0300] Embodiment 96.L P However, *-CH2CH2-(OCH2CH2) m -The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 95, wherein * is a site connected to the linker group and m is an integer from 0 to 30.

[0301] Embodiment 97. The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein m is an integer between 2 and 16, 2 and 10, 2 and 8, or m is 2, 3, 4, 5, 6, 7, or 8.

[0302] Embodiment 98.L P The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 96, wherein the compound is *-CH2CH2-(OCH2CH2)4-, where * is a site connected to the linker group.

[0303] Embodiment 99.L P However, a severable spacer is the conjugate or a pharmaceutically acceptable salt thereof as described in any one of embodiments 70 to 98.

[0304] Embodiment 100. The conjugate according to Embodiment 99 or a pharmaceutically acceptable salt thereof, wherein the cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, and a photodegradable group.

[0305] Embodiment 101. The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 100, wherein the enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, regmain, or matrix metalloproteinase.

[0306] Embodiment 102. The conjugate according to Embodiment 100 or a pharmaceutically acceptable salt thereof, wherein the enzyme-unstable group is a group that can be cleaved by cathepsin B.

[0307] Embodiment 103.L P The spacer represented by comprises a peptide and a self-degrading group, wherein the conjugate according to Embodiment 99 or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 104. The spacer L P However, the following formula: [ka] It is expressed by, in the formula, [ka] However, it represents a bond to a group represented by a linker, [ka] However, this represents a bond to group Z, L 1 and L 2 However, each is an independent connecting spacer. P 1 The conjugate according to Embodiment 103 or a pharmaceutically acceptable salt thereof, wherein the conjugate is a peptide containing 2 to 5 amino acid residues.

[0309] Embodiment 105.P 1 The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 104, wherein the peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val.

[0310] Embodiment 106.P 1 but, [ka] The conjugate or a pharmaceutically acceptable salt thereof as described in Embodiment 104.

[0311] Embodiment 107.L 1 However, a conjugate according to any one of embodiments 104 to 106 or a pharmaceutically acceptable salt thereof, comprising a hydrophilic portion.

[0312] Embodiment 108.L 1 However, the conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 107, which includes a PEG portion.

[0313] Embodiment 109.L 1 However, *-CH2-CH2-(OCH2CH2) n -C(=O)-**, where n is an integer from 0 to 30, *- represents bonding to the linker group, and **- represents P 1 A conjugate according to Embodiment 107 or a pharmaceutically acceptable salt thereof, representing binding to a compound.

[0314] Embodiment 110. The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 109, wherein n is an integer between 2 and 16, 2 and 10, 2 and 8, or n is 2, 3, 4, 5, 6, 7, or 8.

[0315] Embodiment 111.L 1 However, the conjugate or pharmaceutically acceptable salt thereof according to Embodiment 107 is *-CH2-CH2-(OCH2CH2)3-C(=O)-**.

[0316] Embodiment 112.L 2 However, -NH-C 1~6 A conjugate or a pharmaceutically acceptable salt thereof according to any one of embodiments 104 to 111, wherein the conjugate is alkyl-**, where ** is a Z-linked site.

[0317] Embodiment 113.L 2 The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 112, wherein the compound is -NH-CH2CH2-**, where ** is a site connected to Z.

[0318] Embodiment 114. -L-PS is given by the following formula: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is represented by, or a pharmaceutically acceptable salt thereof, in the formula, [ka] The conjugate or a pharmaceutically acceptable salt thereof as described in Embodiment 69, which exhibits binding to the targeting agent.

[0319] Embodiment 115. -L-PS is given by the following formula: [ka] It is represented by, or a pharmaceutically acceptable salt thereof, in the formula, [ka] The conjugate or a pharmaceutically acceptable salt thereof according to Embodiment 67, which exhibits binding to the targeting agent.

[0320] Embodiment 116. A pharmaceutical composition comprising a conjugate according to any one of Embodiments 69 to 115 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0321] Embodiment 117. A method for treating a subject having a disease or condition, a) Administering to the subject a therapeutically effective amount of the conjugate described in any one of embodiments 69 to 115 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in embodiment 116, b) A method comprising administering the conjugate or a pharmaceutically acceptable salt thereof, or a drug containing the conjugate or a pharmaceutically acceptable salt thereof, and then irradiating the target region of the object with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate.

[0322] Embodiment 118. The method according to Embodiment 117, wherein the NIR light has a wavelength of 600 nm to 850 nm.

[0323] Embodiment 119. The method according to Embodiment 117, wherein the NIR light has a wavelength of 660 nm to 740 nm.

[0324] Embodiment 120. The method according to any one of Embodiments 117 to 119, wherein the irradiation is performed at least 5 minutes after administration of the conjugate.

[0325] Embodiment 121. The method according to Embodiment 116, wherein the irradiation is performed 1 to 48 hours, 4 to 30 hours, or 8 to 24 hours after administration of the conjugate.

[0326] Embodiment 122. The method according to any one of Embodiments 117 to 121, wherein the target region is a tumor cell, a mass of tumor cells, a solid tumor, the vicinity of a solid tumor, a metastasis, a metastatic tumor cell, the vicinity of a metastasis, or a precancerous lesion.

[0327] Embodiment 123. The method according to any one of Embodiments 117 to 122, wherein the disease or condition is cancer.

[0328] Embodiment 124. The method according to Embodiment 123, wherein the cancer is selected from the group consisting of colon cancer, colorectal cancer, pancreatic cancer, breast cancer, skin cancer, lung cancer, non-small cell lung cancer, renal cell carcinoma, thyroid cancer, prostate cancer, head and neck cancer, esophageal and gastrointestinal cancer, stomach (gastric) cancer, small intestine cancer, colon cancer, spindle cell neoplasm, liver cancer, bile duct cancer, peripheral nerve cancer, brain cancer, skeletal muscle cancer, smooth muscle cancer, bone cancer, adipose tissue cancer, cervical cancer, uterine cancer, reproductive organ cancer, lymphoma, and multiple myeloma.

[0329] Embodiment 125. The method according to any one of Embodiments 117 to 121, wherein the disease or condition is an inflammatory or autoimmune condition / disease.

[0330] Embodiment 126. The method according to any one of Embodiments 117 to 121, wherein the target region is a skin lesion.

[0331] Embodiment 127. The method according to Embodiment 126, wherein the skin lesion is psoriasis, atopic dermatitis, lupus, vitiligo, graft-versus-host disease, cutaneous T-cell lymphoma, contact dermatitis, cutaneous hypersensitivity response, lichen planus, keratosis pilaris, rejection of vascularized compound allograft, alopecia areata, scarring alopecia, or a sarcoid-related skin lesion.

[0332] Embodiment 128. The method according to any one of Embodiments 117 to 121, wherein the target region is the kidney of the subject.

[0333] Embodiment 129. The method according to any one of Embodiments 117-121 or 128, wherein the disease or condition is lupus nephritis, autoimmune nephritis, or T cell-mediated kidney or renal pathology / disease associated with kidney graft rejection.

[0334] Embodiment 130. The method according to any one of Embodiments 117 to 121, wherein the target region is the digestive tract or intestine of the subject.

[0335] Embodiment 131. The method according to any one of Embodiments 117-121 or 130, wherein the disease or condition is gastrointestinal inflammation as a result of an autoimmune and / or inflammatory condition, e.g., inflammatory bowel disease (Crohn's disease, ulcerative colitis).

[0336] Embodiment 132. The method according to any one of Embodiments 117 to 121, wherein the target region is the inflamed joint of the subject.

[0337] Embodiment 133. The method according to any one of Embodiments 117-121 or 132, wherein the disease or condition is inflammation of the joints from rheumatoid arthritis or spondyloarthritis.

[0338] Embodiment 134. A method for imaging cells or tissues having a target molecule in a subject, a) Administering to the subject a conjugate described in any one of embodiments 69 to 115 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 116, b) A method comprising administering the conjugate or a pharmaceutically acceptable salt thereof, or a drug containing the conjugate or a pharmaceutically acceptable salt thereof, and then irradiating a target region of the subject with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate, thereby providing an image of the presence of the target molecule associated with the cell or tissue.

[0339] Embodiment 135. The following formula: [ka] A compound represented by or a pharmaceutically acceptable salt thereof, wherein the formula is A', B', X', and Y' are each independently -OH, --OC 1~4 Alkyl, -N(R 100 )(R 101 ), or -ZC 1~6 It is alkylene-NH2, where one of A', B', X', and Y' is -ZC 1~6Provided that it is alkylene-NH2, R 100 is H or C 1~3 alkyl, R 101 is H, C 1~3 alkyl, or -(CH2-CH2-O) nr R 102 and R 102 is H or Me, nr is an integer from 1 to 16, Z is -O- or -NR 1 -, R 1 is H or C 1~3 alkyl, a compound or a pharmaceutically acceptable salt thereof.

[0340] Embodiment 136. a) A' and B' are -OCH3, and one of X' and Y' is -OCH3, and the other of X' and Y' is -Z-C 1~6 alkylene-NH2, or b) A' and B' are -OCH3, and one of X' and Y' is -OH, and the other of X and Y is -Z-C 1~6 alkylene-NH2, or c) One of A' and B' is -OCH3, the other of A' and B' is -OH, and one of X' and Y' is -OH, and the other of X' and Y' is -Z-C 1~6 alkylene-NH2, or d) A' and B' are -OH, and one of X' and Y' is -OH, and the other of X' and Y' is -Z-C 1~6 alkylene-NH2, or e) One of A' and B' is -OCH3, the other of A' and B' is -Z-C 1~6 alkylene-NH2, and both X' and Y' are -NH(CH2-CH2-O) nr R 102 wherein, R102 The compound or a pharmaceutically acceptable salt thereof according to Embodiment 135, wherein is H or Me, and nr is an integer from 2 to 8.

[0341] Embodiment 137. The compound is of the following formula: [ka] Represented by or a pharmaceutically acceptable salt thereof, where one of X' and Y' is -ZC 1~6 A compound according to Embodiment 135 or a pharmaceutically acceptable salt thereof, wherein the other is alkylene-NH2 and the other is -OH.

[0342] Embodiment 138. The compound is of the following formula: [ka] Represented by or a pharmaceutically acceptable salt thereof, where one of A' and B' is -ZC 1~6 A compound according to Embodiment 135 or a pharmaceutically acceptable salt thereof, wherein the other is alkylene-NH2 and the other is -OH or -OCH3.

[0343] Embodiment 139. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 135 to 138, wherein Z is -NH-.

[0344] Embodiment 140. A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1335 to 138, wherein Z is -O-.

[0345] Embodiment 141. The compound is [ka] [ka] The compound or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer, as described in Embodiment 135.

[0346] Embodiment 142. The compound is [ka] Alternatively, the compound or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer, as described in Embodiment 135. [Examples]

[0347] The following embodiments provide illustrative examples of the Disclosure. Those skilled in the art will recognize a number of modifications and variations that can be implemented without altering the spirit or scope of the Disclosure. Such modifications and variations are included within the scope of the Disclosure. The embodiments provided do not limit the Disclosure in any way.

[0348] Example 1. Synthesis of a novel benzoporphyrin analog. Only a single positional isomer is shown for all the structures below. The specific positional isomers shown below are assigned arbitrarily.

[0349] Example 1a [ka] To a solution of verteporfin (230 mg, 0.32 mmol, 1711461, USP) in 10 ml of DMF, HATU (134 mg, 0.35 mmol) and DIPEA (167 µl, 0.96 mmol) were added at room temperature. The reaction mixture was stirred for 30 minutes, and endo-BCN-PEG4-NH2 (132 mg, 0.32 mmol, BroadPharm, BP-24459) was added. The mixture was stirred for 2 hours and diluted with SiO2. The mixture was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by reverse-phase chromatography to obtain the desired compound 1 (PS-0001, 255 mg, 0.23 mmol). 1 H NMR (500 MHz, DMSO-d6): δ 9.88 (d, 1 H, J=5), 9.82 (d, 1 H, J=10), 9.67 (d, 1 H, J=5), 9.31 (d, 1 H, J=5), 8.38 (dd, 1 H, J=15, J=10), 7.77 (m, 3 H), 7.04 (m, 1 H), 6.47 (d, 1 H, J=20), 6.20 (d, 1 H, J=10), 5.25 (s, 1 H), 4.40-4.04 (m, 6 H), 3.91 (s, 3 H), 3.61 (s, 3 H), 3.57 (s, 3 H), 3.48 (s, 3 H), 3.40-3.15 (m, 21 H), 3.07 (m, 2 H), 3.00-2.85 (m, 5 H), 2.66- 2.50 (m, 2 H), 2.20-2.06 (m, 6 H), 1.77 (s, 3 H), 1.45 (m, 2 H), 1.25 (m, 1H), 0.78 (m, 2H), -2.50 (m, 2H); C 62 H 76 N6O 13 The MS calculation value for 1 / 2[M+Na] is 567.8, and the measured value is 568.0. [ka]

[0350] To a solution of compound 1 (36 mg, 0.032 mmol) in 10 mL of THF, LiOH (2N, 2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 2 (PS-0002, 15 mg, 0.014 mmol) and compound 3 (PS-0003, 8 mg, 0.007 mmol). This purification was performed using a Biotage 30 g cartridge KP-C18 with MeCN / H2O as the mobile phase flowing at 25 mL / min with a gradient from 5 to 95%. Compound 3 was eluted first, followed by compound 2. Compound 2: 1 H NMR (500 MHz, DMSO-d6): δ 10.63 (m, 1 H), 10.41 (s, 1 H), 10.36 (s, 1 H), 9.85 (s, 1 H), 9.63 (s, 1 H), 9.25 (d, 1 H, J=10), 8.38 (dd, 1 H, J=15, J=10), 7.76 (s, 1 H), 7.14 (m, 1 H), 6.45 (d, 1 H, J=15), 6.18 (d, 1 H, J=10), 5.22 (s, 1 H), 4.19-3.94 (m, 6 H), 3.90 (s, 3 H), 3.61 (s, 3 H), 3.47-3.21 (m, 24 H), 3.07 (m, 2 H), 3.00-2.85 (m, 5 H), 2.66-2.50 (m, 2 H), 2.20-2.06 (m, 6 H), 1.76 (s, 3 H), 1.42 (m, 2 H), 1.23 (m, 1 H), 0.76 (m, 2 H), -2.25 (m, 2 H); MS calculation value [M+H] for C61H74N6O13 = 1099.5, measured value 1099.4. Compound 3: 1H NMR (500 MHz, DMSO-d6): δ 10.28 (s, 1 H), 10.26 (s, 1 H), 9.77 (s, 1 H), 9.48 (s, 1 H), 9.04 (d, 1 H, J=10), 8.35 (dd, 1 H, J=15, J=10), 7.61 (d, 1 H, J=5), 7.24 (d, 1 H, J=5), 7.12 (m, 1 H), 6.44 (d, 1 H, J=15), 6.17 (d, 1 H, J=10), 5.09 (s, 1 H), 4.22 (m, 2 H), 3.96 (m, 4 H), 3.58 (s, 3 H), 3.43-3.21 (m, 24 H), 3.17 (m, 1 H), 3.08 (m, 2 H), 2.95 (m, 1 H), 2.86 (s, 3 H), 2.63 (m, 2 H), 2.27-2.06 (m, 6 H), 1.67 (s, 3 H), 1.45 (m, 2 H), 1.17 (m, 1 H), 0.76 (m, 2 H), -2.25 (m, 2 H); MS calculation value [M+H] for C60H72N6O13 = 1085.5, measured value 1085.4. [ka]

[0351] To a solution of compound 1 (33 mg, 0.03 mmol) in 10 mL of THF, LiOH (2N, 2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 10 days. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 4 (PS-0004, 18 mg, 0.017 mmol). 1H NMR (500 MHz, DMSO-d6): δ 10.11 (s, 1 H), 10.04 (s, 1 H), 9.68 (s, 1 H), 9.48 (s, 1 H), 8.80 (d, 1 H, J=10), 8.35 (dd, 1 H, J=15, J=10), 7.32 (d, 1 H, J=5), 7.12 (d, 1 H, J=5), 7.12 (m, 1 H), 6.44 (d, 1 H, J=15), 6.15 (d, 1 H, J=10), 5.09 (s, 1 H), 4.15-3.96 (m, 6 H), 3.43-3.21 (m, 24 H), 3.17 (m, 1 H), 3.08 (m, 2 H), 2.95 (m, 1 H), 2.86 (s, 3 H), 2.63 (m, 2 H), 2.27-2.06 (m, 6 H), 1.67 (s, 3 H), 1.45 (m, 2 H), 1.18 (m, 1 H), 0.76 (m, 2 H), -2.20 (m, 2 H); MS calculation value [M+H] for C59H70N6O13 = 1071.5, measured value 1071.4.

[0352] Example 1b [ka] To a solution of verteporfin (compound 6, 270 mg, 0.376 mmol) in 10 ml of DMF, HATU (170 mg, 0.45 mmol) and DIPEA (200 μl, 1.15 mmol) were added at room temperature. The reaction mixture was stirred for 30 minutes, and an amine (compound 5, 72 mg, 0.45 mmol) was added. The mixture was stirred for 2 hours and diluted with SiO2. The mixture was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by reverse-phase chromatography to obtain the desired compound (compound 7, 250 mg, 0.29 mmol). MS calculation for C48H56N6O9, [M+H] = 861.4, experimental value 861.4.

[0353] To a solution of compound 7 (25 mg, 0.03 mmol) in 3 mL of THF, LiOH (2N, 200 μl) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 8 (12 mg, 0.014 mmol). The MS calculation value for C47H54N6O9 was [M+H] = 847.4, and the measured value was 847.3. [ka]

[0354] To a solution of compound 8 (12 mg, 0.014 mmol) in 3 mL of DCM, HCl (4N in dioxane, 1 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to produce compound 9 (PS-0013, 12 mg, 0.014 mmol). The MS calculation value for C42H46N6O7 was [M+H] = 747.3, and the measured value was 747.3. [ka]

[0355] To a solution of compound 9 (25 mg, 0.03 mmol) in 3 mL of THF, LiOH (2N, 400 μl) was added at 0°C. The reaction mixture was stirred overnight at room temperature. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 10 (20 mg, 0.024 mmol). The MS calculation value for C46H52N6O9 was [M+H] = 833.4, and the measured value was 833.3. [ka]

[0356] To a solution of compound 8 (20 mg, 0.024 mmol) in 3 mL of THF, HCl (4N in dioxane, 2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to produce compound 11 (PS-0014, 20 mg, 0.024 mmol). The MS calculation value for C42H46N6O7 was [M+H] = 733.3, and the measured value was 733.3. [ka]

[0357] To a solution of compound 7 (25 mg, 0.03 mmol) in 3 mL of THF, LiOH (1 N, 800 μl) was added at 0°C. The reaction mixture was stirred at room temperature for 10 days. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 12 (10 mg, 0.012 mmol). The MS calculation value for C45H50N6O9 was [M+H] = 819.4, and the measured value was 819.4.

[0358] Compound 12 (10 mg, 0.012 mmol) was mixed with HCl (4N in dioxane, 2 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to produce compound 13 (PS-0015, 10 mg, 0.012 mmol). The MS calculation for C42H46N6O7 was [M+H] = 719.3, and the measured value was 719.4. [ka]

[0359] To a solution of Endo-BCN-PEG3 acid (compound 14, 132 mg, 0.332 mmol) in 5 ml of DMF, HATU (130 mg, 0.34 mmol) and DIPEA (173 µl, 1.0 mmol) were added at room temperature. The reaction mixture was stirred for 10 minutes, and Val-Cit-PAB-OH (compound 15, 126 mg, 0.332 mmol) was added. The mixture was stirred for 2 hours. The mixture was purified by reverse-phase chromatography to obtain compound 16 (170 mg, 0.22 mmol). MS calculation value for C38H58N6O10: [M+H] = 759.4, experimental value: 759.4. [ka]

[0360] Compound 17 (35 mg, 0.11 mmol) and DIPEA (300 µl) were added to a solution of compound 16 (78 mg, 0.10 mmol) in 5 mL of DMF at room temperature. The reaction mixture was stirred overnight. The reaction mixture was slowly added to the HCl salt (compound 9, 90 mg) containing DIPEA (300 µl) in DCM (20 mL). After stirring for 1 hour, the DCM was removed under reduced pressure, the mixture was purified by reverse-phase chromatography, and lyophilized to obtain the final compound 18 (PS-0011, 120 mg, 0.078 mmol). MS calculated value for C81H102N12O18, [1 / 2M+H]=766.4, actual value 766.4. 1H NMR (500 MHz, DMSO-d6): δ 9.97 (s, 2H), 9.88 (s, 1 H), 9.66 (s, 1 H), 9.30 (s, 1 H), 8.38 (dd, 1 H, J=15, J=15), 8.11 (m, 1 H), 7.86 (d, 1 H, J=10), 7.77 (m, 2 H), 7.56 (d, 2 H, J=10), 7.21 (m, 2 H), 7.12 (m, 1 H), 6.48 (m, 1 H), 6.21 (d, 1 H, J=15), 5.96 (m, 1 H), 5.38 (s, 2 H), 5.24 (s, 1 H), 4.85 (d, 1 H, J=10), 4.35 (m, 1 H), 4.21 (m, 3 H), 4.01 (m, 4 H), 3.90 (s, 3 H), 3.61-3.30 (m, 24 H), 3.05-2.80 (m, 15 H), 2.44-2.37 (m, 2 H), 2.19-2.09 (m, 4 H), 1.96-1.90 (m, 1 H), 1.77 (s, 3 H), 1.67 (m, 1 H), 1.60-1.30 (m, 3 H), 1.22 (m, 2 H), 0.98-0.96 (m, 4H), 0.84- 0.80 (m, 8H), -2.51 (m, 2H). [ka]

[0361] To a solution of compound 18 (10 mg, 0.0065 mmol) in 3 mL of THF, LiOH (2N, 1 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 19 (PS-0012) (8 mg, 0.005 mmol). The MS calculation value for C80H100N12O18 was [1 / 2M+H] = 759.4, and the measured value was 759.4.

[0362] Example 1c [ka] To a solution of verteporfin (compound 6, 72 mg, 0.1 mmol) in 5 mL of THF, LiOH (2N, 2.0 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was purified by reverse-phase chromatography to obtain compound 20 (60 mg, 0.085 mmol). The MS calculation value for C40H40N4O8 was [M+H] = 705.3, and the measured value was 705.4.

[0363] To a solution of compound 20 (60 mg, 0.085 mmol) in 8 ml of DMF, HATU (81 mg, 0.21 mmol) and DIPEA (74 µl, 0.42 mmol) were added at room temperature. The reaction mixture was stirred for 30 minutes, and PEG3-amine (compound 21 (32 mg, 0.21 mmol)) was added. The mixture was stirred for 2 hours. The reaction mixture was purified by reverse-phase chromatography to obtain compound 22 (60 mg, 0.06 mmol). The MS calculation value for C52H66N6O12 was [M+H] = 967.5, and the measured value was 967.4.

[0364] To a solution of compound 22 (45 mg, 0.047 mmol) in 2 mL of THF, LiOH (2N, 2.0 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The mixture was purified by reverse-phase chromatography to obtain compound 23 (PS-0016) (28 mg, 0.029 mmol). The MS calculation value for C51H64N6O12 was [M+H] = 953.3, and the measured value was 953.4. [ka]

[0365] To a solution of compound 22 (10 mg, 0.01 mmol) in 2 mL of THF, LiOH (2N, 2.0 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 days. The mixture was purified by reverse-phase chromatography to obtain compound 24 (PS-0017, 8 mg, 0.0084 mmol). The MS calculation value for C50H62N6O12 was [M+H] = 939.4, and the measured value was 939.4. [ka]

[0366] To a solution of compound 23 (21 mg, 0.022 mmol) in 4 ml of DMF, HATU (10 mg, 0.026 mmol) and DIPEA (8 μl, 0.046 mmol) were added at room temperature. The reaction mixture was stirred for 30 minutes, and then amine (compound 5, 4.2 mg, 0.026 mmol) was added. The mixture was stirred for 2 hours. The reaction mixture was purified by reverse-phase chromatography to obtain compound 25 (20 mg, 0.018 mmol). MS calculation for C58H78N8O13, [M+H] = 1095.6, experimental value 1095.6.

[0367] Compound 25 (20 mg, 0.018 mmol) was mixed with HCl (4N in dioxane, 2 ml) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to produce compound 26 (PS-0018, 18 mg, 0.018 mmol). The MS calculation value for C53H70N8O11 was [M+H] = 995.5, and the measured value was 995.4.

[0368] Compound 17 (1.9 mg, 0.006 mmol) and DIPEA (30 µl) were added to a solution of compound 16 (3.2 mg, 0.004 mmol) in 1 mL of DMF at room temperature. The reaction mixture was stirred for 2 days. The reaction mixture was slowly added to HCl salt compound 26 (5 mg) containing DIPEA (30 µl) in 1 mL of DMF. After stirring for 5 hours, the reaction mixture was purified by reverse-phase chromatography and lyophilized to obtain the final compound 27 (PS-0024, 2 mg, 0.001 mmol). The MS calculation value for C92H126N14O22, [1 / 2M+H] = 890.4, and the measured value was 890.6.

[0369] Example 1d [ka] Compound 17 (6.5 mg, 0.021 mmol) and DIPEA (20 µl) were added to a solution of compound 16 (13 mg, 0.017 mmol) in 1.5 mL of DMF at room temperature. The reaction mixture was stirred for 2 days. The reaction mixture was slowly added to HCl salt compound 13 (20 mg) containing DIPEA (200 µl) in 3 mL of DMF. After stirring for 5 hours, the reaction mixture was purified by reverse-phase chromatography and lyophilized to obtain the final compound 28 (PS-0019, 5 mg, 0.0033 mmol). MS calculation value for C79H98N12O18: [1 / 2M+H] = 752.4, experimental value: 752.4.

[0370] Example 1e [ka] To a solution of verteporfin (compound 6, 70 mg, 0.1 mmol) in 20 mL of MeOH, LiOH (2N, 2.5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 2 days. The mixture was concentrated and purified by reverse-phase chromatography to obtain compound 29 (50 mg, 0.072 mmol). The MS calculation value for C39H38N4O8 was [M+H] = 691.3, and the measured value was 691.4.

[0371] To a solution of compound 29 (50 mg, 0.072 mmol) in 10 mL of MeOH, HCl (4N in dioxane, 1 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to produce compound 30 (52 mg, 0.072 mmol). The MS calculation value for C41H42N4O8 was [M+H] = 719.3, and the measured value was 719.3.

[0372] To a solution of compound 30 (48 mg, 0.07 mmol) in 4 ml of DMF, HATU (38 mg, 0.1 mmol) and DIPEA (35 µl, 0.20 mmol) were added at room temperature. The reaction mixture was stirred for 30 minutes, and an amine (compound 31, 12.8 mg, 0.08 mmol) was added. The mixture was stirred for 2 hours. The reaction mixture was purified by reverse-phase chromatography to obtain compound 32 (40 mg, 0.046 mmol). The MS calculation value for C48H56N6O9 was [M+H] = 861.4, and the measured value was 861.4. [ka]

[0373] To a solution of compound 31 (45 mg, 0.052 mmol) in 5 mL of THF, LiOH (2N, 1.5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 3 days. After removing the THF, the residue was purified by reverse-phase chromatography to obtain compound 33 (21 mg, 0.026 mmol). The MS calculation value for C45H50N6O9 was [M+H] = 819.4, and the measured value was 819.4.

[0374] Compound 33 (21 mg, 0.026 mmol) was mixed with HCl (4N in dioxane, 2 ml) at 0°C. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to produce compound 34 (PS-0022, 20 mg, 0.026 mmol). The MS calculation for C40H42N6O7 was [M+H] = 719.3, and the measured value was 719.3. [ka]

[0375] Compound 17 (7.7 mg, 0.025 mmol) and Et3N (20 µl) were added at room temperature to a solution of compound 16 (16 mg, 0.021 mmol) in 1.5 mL of DMF. The reaction mixture was stirred for 24 hours. The reaction mixture was slowly added to HCl salt compound 34 (20 mg) containing Et3N (100 µl) in DMF (3 mL). After stirring for 5 hours, the reaction mixture was purified by reverse-phase chromatography and lyophilized to obtain the final compound 35 (PS-0023, 7 mg, 0.0046 mmol). MS calculation value for C79H98N12O18: [1 / 2M+H] = 752.4, experimental value: 752.4.

[0376] Example 1f [ka] To a solution of compound 31 (15 mg, 0.017 mmol) in 3 mL of THF, HCl (4N in dioxane, 1 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated to produce compound 36 (PS-0021, 15 mg, 0.017 mmol). The MS calculation for C43H48N6O7 was [M+H] = 760.4. [ka]

[0377] Compound 17 (6.5 mg, 0.021 mmol) and Et3N (20 µl) were added at room temperature to a solution of compound 16 (13 mg, 0.017 mmol) in 1 mL of DMF. The reaction mixture was stirred for 24 hours. The reaction mixture was slowly added to HCl salt compound 36 (15 mg) containing Et3N (100 µl) in 2 mL of DMF. After stirring for 5 hours, the reaction mixture was purified by reverse-phase chromatography and lyophilized to obtain compound 37 (10 mg, 0.0065 mmol). MS calculation value for C82H104N12O18: [1 / 2M+H] = 773.4, experimental value: 773.4. [ka]

[0378] To a solution of compound 37 (10 mg, 0.0065 mmol) in 3 mL of THF, LiOH (2N, 200 μl) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase chromatography to obtain compound 38 (PS-0020, 6 mg, 0.005 mmol). The MS calculation value for C80H100N12O18, [1 / 2M+H] = 759.4, and the measured value was 759.4. [ka] Example 1g

[0379] To a solution of compound 39 (49.5 mg, 0.2 mmol) in 4 ml of DMF, HATU (80 mg, 0.21 mmol) and DIPEA (105 µl, 0.6 mmol) were added at room temperature. The reaction mixture was stirred for 10 minutes, and Val-Cit-PAB-OH (76 mg, 0.2 mmol) was added. The mixture was stirred for 2 hours. The mixture was purified by reverse-phase chromatography to obtain compound 40 (70 mg, 0.11 mmol). The MS calculation value for C27H44N8O8 was [M+H] = 609.3, and the measured value was 609.4. [ka]

[0380] Compound 17 (44 mg, 0.14 mmol) was added to a solution of compound 40 (78 mg, 0.13 mmol) in 5 mL of DMF at room temperature. The reaction mixture was stirred overnight. The reaction mixture was slowly added to HCl salt 9 (120 mg) containing DIPEA (300 μl) in DCM (20 mL). After stirring for 1 hour, the DCM was removed under reduced pressure, the mixture was purified by reverse-phase chromatography, and lyophilized to obtain the desired compound 41 (PS-0025, 130 mg, 0.094 mmol). MS calculated value for C70H88N14O16, [M+H]=1381.6, actual value 1381.6. 1H NMR (500 MHz, DMSO-d6): δ 10.44 (d, 1H, J=15), 10.10 (d, 1 H, J=15), 9.86 (m, 1 H), 9.64 (s, 1 H), 9.27 (d, 1 H, J=15), 8.42 (dd, 1 H, J=15, J=10), 8.29 (m, 1 H), 7.89 (m, 1 H), 7.76 (s, 3 H), 7.63 (m, 2 H), 7.31 (m, 2 H), 6.48 (d, 1 H, J=15), 6.20 (m, 1 H), 6.01 (m, 1 H), 5.38 (s, 2 H), 5.23 (s, 1 H), 4.96 (s, 1 H), 4.42-4.36 (m, 2 H), 4.24-4.05 (m, 4 H), 4.03-3.93 (m, 2 H), 3.90 (s, 3 H), 3.61-3.20 (m, 24 H), 3.05-2.85 (m, 7 H), 2.80-2.65 (m, 3 H), 2.45-2.30 (m, 2 H), 2.00-1.90 (m, 1 H), 1.76 (s, 3 H), 1.70-1.65 (m, 1 H), 1.64-1.52 (m, 1 H), 1.45-1.30 (m, 3H), 0.84-0.80 (m, 8H), -2.54 (m, 2H).

[0381] Example 1h [ka] To a solution of compound 7 (12 mg) in 3 mL of DCM, HCl (4N in dioxane, 1 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to produce compound 42 (PS-0030). The MS calculation value for C43H48N6O7 was [M+H] = 761.4, and the measured value was 761.4. [ka]

[0382] Compound 17 (6.5 mg) and DIPEA (5 μl) were added to a solution of compound 16 (11 mg) in 1 mL of DMF at room temperature. The reaction mixture was stirred overnight. The reaction mixture was slowly added to HCl salt 42 (10 mg) containing DIPEA (30 μl) in DCM (2 mL). After stirring for 1 hour, the DCM was removed under reduced pressure, and the mixture was purified twice by reverse-phase chromatography to obtain the final compound 43 (PS-0026, 2 mg). MS calculation value for C82H104N12O18: [1 / 2M+H] = 773.4, experimental value: 773.4.

[0383] Example 1i [ka] To a solution of Fmoc-PEG6-acid 44 (155.0 mg, 0.27 mmol) in 5 ml of DMF, HATU (110 mg, 0.29 mmol) and DIPEA (94 µl, 0.54 mmol) were added at room temperature. The reaction mixture was stirred for 10 minutes, and Val-Cit-PAB-OH 45 (102 mg, 0.27 mmol) was added. The mixture was stirred for 2 hours. The mixture was purified by reverse-phase chromatography to obtain compound 46 (170 mg, 0.18 mmol). MS calculation value for C48H68N6O13: [M+H] = 937.4, experimental value: 937.4. [ka]

[0384] Compound 17 (10 mg, 0.033 mmol) and DIPEA (6.5 µl, 0.037 mmol) were added to a solution of compound 46 (30 mg, 0.032 mmol) in 5 mL of DMF at room temperature. The reaction mixture was stirred overnight. The reaction mixture was slowly added to HCl salt 42 (30 mg) containing DIPEA (30 µl) in DMF (4.0 mL). After stirring for 5 hours, DCM was removed under reduced pressure, the mixture was purified by reverse-phase chromatography, and lyophilized to obtain the desired compound 47 (28 mg, 0.016 mmol). MS calculation value for C92H114N12O21: 1 / 2[M+H] = 862.4, experimental value: 1 / 2[M+H] = 862.4.

[0385] To a solution of compound 47 (28 mg, 0.016 mmol) in 2 mL of DMF, DBU (50 μl) was added at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was purified by reverse-phase chromatography to obtain compound 48 (PS-0028, 10 mg, 0.007 mmol). MS calculation value for C77H104N12O19: 1 / 2[M+H] = 751.4, experimental value: 1 / 2[M+H] = 751.4.

[0386] Example 1j [ka] Compound 17 (10 mg, 0.033 mmol) and DIPEA (6.5 µl, 0.037 mmol) were added to a solution of compound 46 (30 mg, 0.032 mmol) in 5 mL of DMF at room temperature. The reaction mixture was stirred overnight. The reaction mixture was slowly added to HCl salt 9 (30 mg) containing DIPEA (30 µl) in DCM (4.0 mL). After stirring for 5 hours, the DCM was removed under reduced pressure, and the mixture was purified by reverse-phase chromatography to obtain compound 49 (26 mg, 0.015 mmol). MS calculation value for C91H112N12O21: 1 / 2[M+H] = 855.4, experimental value: 1 / 2[M+H] = 855.4.

[0387] To a solution of compound 49 (26 mg, 0.015 mmol) in 2 mL of DMF, DBU (50 μl) was added at room temperature. The reaction mixture was stirred for 1 hour. The reaction mixture was purified by reverse-phase chromatography to obtain compound 50 (PS-0027, 14 mg, 0.01 mmol). The MS calculation value for C76H102N12O19 was 1 / 2[M+H] = 744.4, and the measured value was 1 / 2[M+H] = 744.3.

[0388] Example 1k [ka] To a solution of compound 8 (35.0 mg, 0.041 mmol) in 2.0 ml of DMF, HATU (17 mg, 0.045 mmol) and DIPEA (14 µl, 0.082 mmol) were added at room temperature. The reaction mixture was stirred for 10 minutes, and compound 51 (4 µl, 0.06 mmol) was added. The mixture was stirred for 3 hours. The mixture was purified by reverse-phase chromatography to obtain compound 52 (25 mg, 0.028 mmol). The MS calculation value for C49H59N7O9, [M+H] = 890.4, and the measured value was 890.4.

[0389] To a solution of compound 52 (25 mg, 0.028 mmol) in 3.0 mL of DCM, HCl (4N in dioxane, 0.5 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to produce compound 53 (PS-0029, 20 mg, 0.028 mmol). The MS calculation value for C44H51N7O7 was [M+H] = 790.4, and the measured value was 790.4.

[0390] Example 2. Assembly of a photosensitizer-antibody conjugate (PAC) The concentrations of peptides and proteins were determined using UV absorption at 280 nm and extinction coefficients based on amino acid sequence. All aqueous solutions were prepared using Milli-Q water. All cell culture methods were performed using sterile techniques in a biosafety cabinet.

[0391] Nonspecific conjugation: Amine-reactive acylation reactions for constructing antibody conjugates The reaction mixture contained 100 mM phosphate (pH 7.4), a bioconjugation handle (1.67 mM NHS-PEG6-azide for panitumumab, or 2 mM NHS-PEG4-BCN for anti-CD2), and an antibody (6.7 μM panitumumab or 6.7 μM anti-CD2), and was incubated at 22.5°C for 16–18 hours. The reaction mixture was then quenched with 2 mM Tris (pH 8). To remove excess unreacted reagent, each reaction mixture was desalted in 100 mM Tris (pH 8) using a 50 kDa Amicon MWCO centrifuge filter before the cyclization reaction.

[0392] Strain-accelerated cycloaddition click reaction for introducing a photosensitizer The reaction mixture contained 100 mM Tris (pH 8), a photosensitizer (64 μM PS-0002 for panitumumab, or 42 μM PS-0025 for anti-CD2), an antibody (6.4 μM panitumumab or 4.2 μM anti-CD2, acylated as described above), and 30% dimethylacetamide (DMA), and was incubated at 22.5°C for 16–18 hours. To remove excess unreacted reagent, each reaction mixture was buffer-exchanged to 100 mM Tris (pH 8) and 30% DMA using a size exclusion chromatography resin (Zeba® Spin Desalting Column, ThermoFisher). This mixture was then desalted to 100 mM Tris (pH 8) and 5% DMSO using a 30 kDa Amicon MWCO centrifuge filter prior to analysis.

[0393] Characterization of conjugates using SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was performed using a mini-gel system (Thermo Fisher, A25977). First, the reaction mixture was incubated with 6×SDS sample buffer (Thermo Fisher, J61337AD) at 80°C for 5 minutes. Second, the sample was loaded onto a 12% Tris-glycine precast protein gel (Thermo Fisher, XP00120BOX). A PageRuler® Prestained Protein Ladder (Thermo Fisher, 26617) was used for mass calibration. Electrophoresis was then performed at 200V for 30 minutes. The gel was stained with Coomassie dye (Thermo Fisher, GelCode® Blue Safe Protein Stain, 24594) and then destained using Milli-Q water. The gel was imaged using an iBright FL1000 imaging system (Thermo Fisher Scientific).

[0394] Strain-accelerated cycloaddition click reaction for introducing a photosensitizer Panitumumab PAC for structure-activity relationship (SAR) studies. The reaction mixture contained 100 mM Tris (pH 8), a photosensitizer (34.7 mM of any of PS-0011, PS-0020, PS-0019, PS-0002, PS-0003, or PS-0004), an antibody (3.47 mM panitumumab, acylated as described above), 30% dimethylacetamide (DMA), and 10 mM sodium decanoate (NaDec), and was incubated at 22.5°C for 16–18 hours. For cleavable VertDA PAC conjugates only, the reaction mixture contained 100 mM Tris (pH 8), 66.7 μM PS-0020, 6.7 μM panitumumab (acylated as described above), 30% dimethylacetamide (DMA), and 5 mM sodium decanoate (NaDec), and was incubated at 22.5°C for 16–18 hours. To remove excess unreacted reagent, each reaction mixture was buffer-exchanged to 100 mM Tris (pH 8), 30% DMA, and 10 mM NaDec using a size exclusion chromatography resin (Zeba® Spin Desalting Column, ThermoFisher). This mixture was then desalted to 100 mM Tris (pH 8), 5% DMSO, and 5 mM NaDec using a 30 kDa Amicon MWCO centrifuge filter prior to analysis.

[0395] Example 3. Measurement of Reactive Oxygen Species (ROS) Generation Singlet oxygen sensor green (SOSG, Invitrogen, S36002) was reconstituted according to the manufacturer's instructions and further diluted to 2 μM in fresh PBS. A fresh photosensitizer (PS) was also prepared by diluting it to 2 μM in fresh PBS. 50 μL of SOSG and 50 μL of PS were combined in a 96-well plate with black walls. The samples were then diluted to 0, 10, or 50 J / cm³. 2 The total light dose was measured by irradiating with 690 nm light from an LED light source. Then, the fluorescence (excitation / emission 500 / 540 nm) of SOSG in each sample was measured using a fluorophotometer (SpectraMax iD5). The total amount of singlet oxygen produced was measured by irradiation (10 or 50 J / cm³).2 ) vs. non-irradiated (0 J / cm²) 2 It is calculated as a ratio of the samples and is proportional to the change in SOSG fluorescence magnification ΔF.

[0396] Example 4. Evaluation of cell viability A-431 cells were seeded at 2000 cells per well in 96-well plates and incubated at 37°C for 72 hours. The cell medium was then replaced with medium containing photosensitizer-antibody conjugates (PACs) at various concentrations, incubated at 37°C for 24 hours, and then replaced with fresh medium. The plates were then subjected to various light doses (0, 3, 10, 20, 30, 40, or 50 J / cm²). 2 The cells were then subjected to a solution and immediately irradiated with 690nm light from an LED light source. The cells were incubated for a further 72 hours, and their viability was evaluated using the CellTiterGlo 2.0 viability detection kit (Promega, G9241).

[0397] Jurkat cells were seeded in 96-well plates at a rate of 20,000 cells per well using medium containing PAC at various concentrations, and incubated at 37°C for 48 hours. The plates were then exposed to various light doses (0, 3, 10, 20, 30, 40, or 50 J / cm²). 2 The cells were treated with a 690nm light source from an LED light source. The cells were incubated for a further 72 hours, and their viability was evaluated using the CellTiterGlo 2.0 viability kit.

[0398] HH cells were seeded in 96-well plates at a rate of 20,000 cells per well using medium containing PAC at various concentrations, and incubated at 37°C for 24 hours. The plates were then exposed to 100 J / cm² of LED light. 2 The cells were irradiated with 690nm light. The cells were incubated for a further 24 hours, and their viability was evaluated using the CellTiterGlo 2.0 viability kit.

Claims

1. The following formula: 【Chemistry 1】 A compound represented by or a pharmaceutically acceptable salt thereof, wherein the formula is A, B, X, and Y are each independently —OH, —OC １～４ alkyl, —N(R １００ )(R １０１ ), or —Z—L Ｐ —ker, provided that 、 at least one of A, B, X, and Y is —N(R １００ )(R １０１ ), —Z—L Ｐ —NH ２ , or —Z—L Ｐ —ker, and provided that at most one of A, B, X, and Y is —Z—L Ｐ —NH ２ or —Z—L Ｐ —ker R １００ However, H or C １～３ It is alkyl, R １０１ However, H, C １～３ Alkyl, or -(CH ２ -CH ２ -O) ｎｒ R １０２ And, R １０２ However, it is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR １ - and R １ However, H or C １～３ It is alkyl, L Ｐ However, it is a spacer, A compound or a pharmaceutically acceptable salt thereof in which ker is the reactive group.

2. a) A and B are -OCH ３ And one of X and Y is -OCH ３ And the other of X and Y is -Z-L Ｐ -ker, b) A and B are -OCH ３ And one of X and Y is -OH, and the other of X and Y is -Z-L Ｐ -ker, c) One of A and B is -OCH ３ The other is -OH, and one of X and Y is -OH, and the other of X and Y is -Z-L Ｐ -ker, d) A and B are -OH, and one of X and Y is -OH, and the other of X and Y is -Z-L Ｐ -ker, e) One of A and B is -OH, and the other of A and B is -OH or -OCH ３ And both X and Y are -NH(CH ２ -CH ２ -O) ｎｒ R １０２ And in the formula, R １０２ However, it is either H or Me, and nr is an integer from 2 to 8, or f) One of A and B is -Z-L Ｐ -ker, and the other of A and B is -OH or -OCH ３ And both X and Y are -NH(CH ２ -CH ２ -O) ｎｒ R １０２ And in the formula, R １０２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is H or Me, and nr is an integer from 2 to 8.

3. The aforementioned compound, (i) The following formula: 【Chemistry 2】 It is represented by or a pharmaceutically acceptable salt thereof, where one of X and Y is -Z-L Ｐ -ker, and the other is -OH, or (ii) The following equation: 【Transformation 3】 It is represented by or a pharmaceutically acceptable salt thereof, where one of A and B is -OH or -Z-L Ｐ -ker, and the other is -OH or -OCH ３ And R １０２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is H or Me, and nr is an integer from 2 to 8.

4. (i) ker is a reactive group selected from maleimide group, thiol group, cyclooctin group, azide group, hydrazide group, tetrazine group, cyclooctene group, ketone group, and aldehyde group, or (ii)ker, 【Chemistry 4】 Or -N ３ A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. (i) Z is -NH- or (ii) A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

6. (i) L Ｐ However, it is a spacer that cannot be cut, and is optional. (a) L Ｐ However, does it include a hydrophilic portion? (b) L Ｐ However, does it include the PEG portion? (c) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ｍ - and in the formula, * is the part connected to ker, m is an integer from 0 to 30, and at any choice, m is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or m is 2, 3, 4, 5, 6, 7, or 8, or (d) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ４ - and (ii) L Ｐ However, it is a cuttable spacer, and can be optionally selected. (a) The cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, a photo-cleavable group, and optionally, (1) The enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase, or (2) The enzyme-unstable group is a group that can be cleaved by cathepsin B, (ii) L Ｐ The spacer represented by comprises a peptide and a self-degrading group, or (iii) The aforementioned spacer L Ｐ However, the following formula: 【Transformation 5】 It is expressed by, in the formula, 【Transformation 6】 However, this represents the bond to the reactant group represented by ker, 【Transformation 7】 However, this represents a bond to the group Z, L １ and L ２ However, each is an independent connecting spacer. P １ However, it is a peptide containing 2 to 5 amino acid residues, and can be selected arbitrarily. (a1) P １ The peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val, or P １ but, 【Transformation 8】 and / or (a2)L １ However, does it include a hydrophilic portion? L １ However, does it include the PEG portion? L １ However, -CH ２ -CH ２ - (OCH ２ CH ２ ) ｎ -C(=O)-**, where n is an integer from 0 to 30, *- represents a bond to the reactant represented by ker, and **- represents P １ This represents a combination to a , and optionally n is an integer between 2 and 16, 2 and 10, 2 and 8, or n is 2, 3, 4, 5, 6, 7, or 8, or L １ is *-CH ２ -CH ２ -(OCH ２ CH ２ ) ３ -C(=O)-**, and / or (a3)L ２ However, -NH-C １～６ It is alkyl-**, where ** is a site connected to Z, or L ２ However, -NH-CH ２ CH ２ -**, wherein ** is a site connected to Z, the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound, 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 【Chemistry 9-5】 【Chemistry 9-6】 【Chemistry 9-7】 【Chemistry 9-8】 【Chemistry 9-9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer thereof, or a pharmaceutically acceptable salt thereof.

8. Formula (II): 【Chemistry 10】 A linker-photosensitizer compound or a pharmaceutically acceptable salt thereof, wherein, A Ｌ 、B Ｌ 、X Ｌ 、and Y Ｌ are each independently, -OH, -OC １～４ alkyl, -N(R １００ )(R １０１ ), or -Z-L Ｐ -linker-L Ａ -R Ａ wherein, provided that one of A Ｌ 、B Ｌ 、X Ｌ 、and Y Ｌ is -Z-L Ｐ -linker-L Ａ -R Ａ is a condition, R １００ However, H or C １～３ It is alkyl, R １０１ However, H, C １～３ Alkyl, or -(CH ２ -CH ２ -O) ｎｒ R １０２ And, R １０２ However, it is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR １ - and R １ However, H or C １～３ It is alkyl, L Ｐ and L Ａ However, each is an independent spacer. Linker, L Ｐ The first reactive group and L bonded to it Ａ This is a connecting portion formed by a second reactive group bonded to it. R Ａ A linker-photosensitizer compound or a pharmaceutically acceptable salt thereof, which is a reactive group capable of forming a covalent bond with a targeting agent.

9. R Ａ However, reactive esters, -NH ２ , or a maleimide group, optionally R Ａ but, 【Chemistry 11】 or -NH ２ The compound according to claim 8 or a pharmaceutically acceptable salt thereof.

10. (i) L Ａ However, is it a spacer that includes a hydrophilic portion? (ii) L Ａ However, is it a spacer that includes the PEG portion, or (iii) L Ａ However, *-CH ２ CH ２ (OCH ２ CH ２ ) ｐ - and in the formula, * is R Ａ A compound or a pharmaceutically acceptable salt thereof according to claim 8 or 9, wherein the site is connected to a portion, and p is an integer from 0 to 30, and optionally p is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or p is 2, 3, 4, 5, 6, 7, or 8.

11. (i) The first reactant and the second reactant are each selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group, or (ii) The linker is given by the following formula: 【Chemistry 12】 Represented by, During the ceremony, 【Chemistry 13】 However, L Ｐ This represents a connection to, 【Chemistry 14】 However, L Ａ A compound according to any one of claims 8 to 10, representing a bond to.

12. a) A Ｌ and B Ｌ However, -OCH ３ X Ｌ and Y Ｌ One of them is -OCH ３ X Ｌ and Y Ｌ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ａ Is it, b) A Ｌ and B Ｌ However, -OCH ３ X Ｌ and Y Ｌ One of them is -OH, and X Ｌ and Y Ｌ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ａ Is it, c) A Ｌ and B Ｌ One of them is -OCH ３ A Ｌ and B Ｌ The other of these is -OH, and X Ｌ and Y Ｌ One of them is -OH, and X Ｌ and Y Ｌ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ａ Is it, d) A Ｌ and B Ｌ However, it is -OH, and X Ｌ and Y Ｌ One of them is -OH, and X Ｌ and Y Ｌ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ａ is, or e) A Ｌ and B Ｌ One of them is -Z-L Ｐ -Linker-L Ａ -R Ａ A Ｌ and B Ｌ The other of these is -OH or -OCH ３ X Ｌ and Y Ｌ Both are -NH(CH ２ -CH ２ -O) ｎｒ R １０２ And in the formula, R １０２ The compound according to any one of claims 8 to 11 or a pharmaceutically acceptable salt thereof, wherein is H or Me, and nr is an integer from 2 to 8.

13. (i) The compound is of the following formula: 【Chemistry 15】 It is represented by or a pharmaceutically acceptable salt thereof, where X Ｌ and Y Ｌ One of them is -Z-L Ｐ -Linker-L Ａ -R Ａ And the other is -OH, or (ii) The compound is of the following formula: 【Chemistry 16】 It is represented by or a pharmaceutically acceptable salt thereof, where A Ｌ and B Ｌ One of them is -Z-L Ｐ -Linker-L Ａ -R Ａ And the other is -OH or -OCH ３ And R １０２ The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein is H or Me, and nr is an integer from 2 to 8.

14. (i) Z is -NH- or (ii) The compound according to any one of claims 8 to 13 or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

15. (i) L Ｐ However, it is a spacer that cannot be cut, and is optional. (a) L Ｐ However, does it include a hydrophilic portion? (b) L Ｐ However, does it include the PEG portion? (c) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ｍ - and in the formula, * is the part connected to ker, m is an integer from 0 to 30, and at any choice, m is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or m is 2, 3, 4, 5, 6, 7, or 8, or (d) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ４ - and (ii) L Ｐ However, it is a cuttable spacer, and can be optionally selected. (a) The cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, a photo-cleavable group, and optionally, (1) The enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase, or (2) The enzyme-unstable group is a group that can be cleaved by cathepsin B, (ii) L Ｐ The spacer represented by comprises a peptide and a self-degrading group, (iii) The aforementioned spacer L Ｐ However, the following formula: 【Chemistry 17】 It is expressed by, in the formula, [Chemistry 18] However, this represents the bond to the reactant group represented by ker, 【Chemistry 19】 However, this represents a bond to the group Z, L １ and L ２ However, each is an independent connecting spacer. P １ However, it is a peptide containing 2 to 5 amino acid residues, and can be selected arbitrarily. (a1) P １ The peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val, or P １ but, 【Chemistry 20】 and / or (a2)L １ However, does it include a hydrophilic portion? L １ However, does it include the PEG portion? L １ However, -CH ２ -CH ２ - (OCH ２ CH ２ ) ｎ -C(=O)-**, where n is an integer from 0 to 30, *- represents a bond to the reactant represented by ker, and **- represents P １ This represents a combination to a , and optionally n is an integer between 2 and 16, 2 and 10, 2 and 8, or n is 2, 3, 4, 5, 6, 7, or 8, or L １ However, *-CH ２ -CH ２ - (OCH ２ CH ２ ) ３ -C (=O)-** and / or (a3)L ２ However, -NH-C １～６ It is alkyl-**, where ** is a site connected to Z, or L ２ However, -NH-CH ２ CH ２ -**, wherein ** is a site connected to Z, the compound according to any one of claims 8 to 14 or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound is given by the following formula: 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 【Chemistry 21-4】 【Chemistry 21-5】 【Chemistry 21-6】 【Chemistry 21-7】 【Chemistry 21-8】 【Chemistry 21-9】 【Chemistry 21-10】 【Chemistry 21-11】 It is represented by, The compound according to claim 8, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer.

17. A conjugate comprising a benzoporphyrin analog covalently bound to a targeting agent, wherein the conjugate has the following formula: 【Chemistry 22】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, T is the targeting agent, L is a spacer connecting the targeting agent and PS, r is an integer between 1 and 20. PS is given by the following formula: 【Chemistry 23】 A photosensitizer which is a benzoporphyrin analog represented by or a pharmaceutically acceptable salt thereof, in the formula, A, B, X, and Y are each independently -OH, -OC １～４ Alkyl, -N(R) １００ ) (Caution １０１ ), or a covalent bond to L, provided that one of A, B, X, and Y is a covalent bond to L, R １００ However, H or C １～３ It is alkyl, R １０１ However, H, C １～３ Alkyl, or -(CH ２ -CH ２ -O) ｎｒ R １０２ And, R １０２ However, it is H or Me, A conjugate or a pharmaceutically acceptable salt thereof, wherein nr is an integer between 1 and 16.

18. -L-PS is expressed by the following formula: 【Chemistry 24】 It is represented by or a pharmaceutically acceptable salt thereof, in the formula, A Ｔ , B Ｔ , X Ｔ , and Y Ｔ However, independently of each other, -OH and -OC １～４ Alkyl, -N(R) １００ ) (Caution １０１ ), or -Z-L Ｐ -Linker-L Ａ -R Ｔ And, however, A Ｔ , B Ｔ , X Ｔ , and Y Ｔ One of them is -Z-L Ｐ -Linker-L Ａ -R Ｔ The condition is that, Z is -O- or -NR １ - and R １ However, H or C １～３ It is alkyl, L Ｐ and L Ａ However, each is an independent spacer. The linker is bonded to the first reactive group L and L Ａ This is a connecting portion formed by a second reactive group bonded to it. R Ｔ The conjugate according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the conjugate is a reactive group covalently bonded to the targeting agent.

19. (i) The targeting agent comprises a polypeptide that binds to the surface of a target cell, (ii) The targeting agent is an antibody or an antigen-binding fragment thereof, optionally, (a) The antibody or its antigen-binding fragment binds to adipocytes, blood cells, cancer cells, endothelial cells, epithelial cells, immune cells, neurons, skin cells, stem cells, tumor cells, bone marrow-derived suppressor cells, (b) The antibody or its antigen-binding fragment binds to cancer-associated fibroblasts, tumor-associated macrophages, T cells, or regulatory T cells, (c) The antibody or its antigen-binding fragment is EGFR / HER1, HER2, HER3, HER4, VEGF, VEGFR, VEGFR2, EpCAM, E-Cad, folate receptor α, fibroblast-activating protein (FAP), CD1c, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD11a, CD11b, CD11c, CD14, CD16, CD18, CD19, CD20, CD 21, CD25, CD26, CD27, CD28, CD30, CD31, CD32, CD33, CD44, CD45, CD52, CD56, CD62L, CD64, CD66b, CD69, CD80, CD86, CD90, CD103, CD122, CD123, CD127, CD163, CD206, CD235a, CXCR6, MHC-II, CCR4, CCR5, CCR7, CLA, PD-1, PD-L1, CTLA-4, CEA, MUC-1, PSMA, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y antigen, TAG-72, IL-13R, melanoma-associated antigen (MAGE) 1, MAGE 2, MAGE 3, MAGE 4, tumor-associated glycoprotein 72 (TAG-72), gp100, p97 melanoma antigen, human milk fat globules (HMFG), melanoma antigen 1 recognized by T cells (MART1), B melanoma antigen (BAGE) 1, BAGE 2, G antigen (GAGE) 1, GAGE ​​2, GAGE ​​3, GAGE ​​4, GAGE ​​5, GAGE ​​6, breast cancer-associated DF3 antigen, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), mesothelin, GITR, OX40, FR4, CXCR4, CCL4, Gr-1, IL-4Ra, IL-1Ra, CXCR2, or LAG-3, or (d) The antibody or its antigen-binding fragment binds to CD2 or EGFR, (iii) The targeting agent is R Ｔ It contains a reactive group that can form a covalent bond with, optionally, (a1) The targeting agent contains a reactive group selected from an amine group, a thiol group, or an amide group, or The aforementioned targeting agent has the following base: 【Chemistry 25】 Includes, In the formula, R is the side chain of an amino acid residue. 【Chemistry 26】 However, this represents binding to the remaining targeting agent. 【Chemistry 27】 However, R Ｔ Represents a connection to, and / or (a2)R Ｔ However, -C(=O)-, -NH-, or 【Chemistry 28】 And in the formula, 【Chemistry 29】 However, this represents binding to the targeting agent, 【Transformation 30】 However, L Ａ It represents a connection to, or R Ｔ The conjugate or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein the compound is -C(=O)- or -NH-.

20. (i) L Ａ However, it is a spacer that includes a hydrophilic portion, (ii) L Ａ However, it is a spacer that includes the PEG portion, (iii) L Ａ However, *-CH ２ CH ２ (OCH ２ CH ２ ) ｐ - and in the formula, * is R Ｔ The conjugate or a pharmaceutically acceptable salt thereof according to claim 18 or 19, wherein the site is connected to a portion, and p is an integer from 0 to 30, and optionally p is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or p is 2, 3, 4, 5, 6, 7, or 8.

21. (i) The first reactant and the second reactant are each selected from a maleimide group, a thiol group, a cyclooctin group, and an azide group, or (ii) The linker is given by the following formula: 【Chemistry 31】 Represented by, During the ceremony, 【Chemistry 32】 However, L Ｐ This represents a connection to, 【Transformation 33】 However, L Ａ A conjugate according to any one of claims 18 to 20 or a pharmaceutically acceptable salt thereof, representing a bond to.

22. a) A Ｔ and B Ｔ However, -OCH ３ X Ｔ and Y Ｔ One of them is -OCH ３ X Ｔ and Y Ｔ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ｔ Is it, b) A Ｔ and B Ｔ However, -OCH ３ X Ｔ and Y Ｔ One of them is -OH, and X Ｔ and Y Ｔ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ｔ Is it, c) A Ｔ and B Ｔ One of them is -OCH ３ A Ｔ and B Ｔ The other of these is -OH, and X Ｔ and Y Ｔ One of them is -OH, and X Ｔ and Y Ｔ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ｔ Is it, d) A Ｔ and B Ｔ However, it is -OH, and one of X and Y is -OH, and X Ｔ and Y Ｔ The other of these is -Z-L Ｐ -Linker-L Ａ -R Ｔ is, or e) A Ｔ and B Ｔ One of them is -Z-L Ｐ -Linker-L Ａ -R Ｔ A Ｔ and B Ｔ The other of these is -OH or -OCH ３ X Ｔ and Y Ｔ Both are -NH(CH ２ -CH ２ -O) ｎｒ R １０２ And in the formula, R １０２ The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 18 to 21, wherein is H or Me, and nr is an integer from 2 to 8.

23. (i) - L - PS is given by the following equation: 【Transformation 34】 It is represented by or a pharmaceutically acceptable salt thereof, where X Ｔ and Y Ｔ One of them is -Z-L Ｐ -Linker-L Ａ -R Ｔ And the other is -OH, or (ii) - L - PS is expressed by the following equation: 【Chemistry 35】 It is represented by or a pharmaceutically acceptable salt thereof, where A Ｔ and B Ｔ One of them is -Z-L Ｐ -Linker-L Ａ -R Ｔ And the other is -OH or -OCH ３ And R １０２ The conjugate or a pharmaceutically acceptable salt thereof according to claim 22, wherein is H or Me, and nr is an integer from 2 to 8.

24. (i) Z is -NH- or (ii) The conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 18 to 23, wherein Z is -O-.

25. (i) L Ｐ However, it is a spacer that cannot be cut, and is optional. (a) L Ｐ However, does it include a hydrophilic portion? (b) L Ｐ However, does it include the PEG portion? (c) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ｍ - and in the formula, * is the part connected to ker, m is an integer from 0 to 30, and at any choice, m is an integer from 2 to 16, 2 to 10, 2 to 8, or 3 to 5, or m is 2, 3, 4, 5, 6, 7, or 8, or (d) L Ｐ However, *-CH ２ CH ２ - (OCH ２ CH ２ ) ４ - and (ii) L Ｐ However, it is a cuttable spacer, and can be optionally selected. (a) The cleavable spacer comprises an enzyme-unstable group, a pH-unstable group, a disulfide group, a ROS-cleavable group, a photo-cleavable group, and optionally, (1) The enzyme-unstable group is a group that can be cleaved by an esterase, peptidase, aminopeptidase, β-galactosidase, β-glucuronidase, carboxylesterase, caspase, diaphorase, histone deacetylase, legmine, or matrix metalloproteinase, or (2) The enzyme-unstable group is a group that can be cleaved by cathepsin B, (ii) L Ｐ The spacer represented by comprises a peptide and a self-degrading group, (iii) The aforementioned spacer L Ｐ However, the following formula: 【Transformation 36】 It is expressed by, in the formula, 【Chemistry 37】 However, this represents the bond to the reactant group represented by ker, 【Transformation 38】 However, this represents a bond to the group Z, L １ and L ２ However, each is an independent connecting spacer. P １ However, it is a peptide containing 2 to 5 amino acid residues, and can be selected arbitrarily. (a1) P １ The peptide is selected from Phe-Arg-Arg-Gly, Glu-Val-Cit, Val-Cit, Cit-Val, Gly-Gly-Phe, Val-Ala, and Ala-Val, or P １ but, 【Chemistry 39】 and / or (a2)L １ However, does it include a hydrophilic portion? L １ However, does it include the PEG portion? L １ However, -CH ２ -CH ２ - (OCH ２ CH ２ ) ｎ -C(=O)-**, where n is an integer from 0 to 30, *- represents a bond to the reactant represented by ker, and **- represents P １ This represents a combination to a , and optionally n is an integer between 2 and 16, 2 and 10, 2 and 8, or n is 2, 3, 4, 5, 6, 7, or 8, or L １ However, *-CH ２ -CH ２ - (OCH ２ CH ２ ) ３ -C (=O)-** and / or (a3)L ２ However, -NH-C １～６ It is alkyl-**, where ** is a site connected to Z, or L ２ However, -NH-CH ２ CH ２ -**, wherein ** is a site connected to Z, the compound according to any one of claims 18 to 24 or a pharmaceutically acceptable salt thereof.

26. -L-PS is expressed by the following formula: 【Chemistry 40-1】 【Chemistry 40-2】 【Chemistry 40-3】 【Chemistry 40-4-1】 【Chemistry 40-4-2】 【Chemistry 40-5】 【Chemistry 40-6】 【Chemistry 40-7】 【Chemistry 40-8】 【Chemistry 40-9】 [Transformation 40-10] 【Chemistry 40-11】 【Chemistry 40-12】 It is represented by, or a pharmaceutically acceptable salt thereof, in the formula, 【Chemistry 41】 The conjugate according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the conjugate exhibits binding to the targeting agent.

27. A pharmaceutical composition comprising a conjugate according to any one of claims 17 to 26 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

28. A method for treating a subject having a disease or condition, a) Administering to the subject a therapeutically effective amount of the conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 26, or the pharmaceutical composition according to claim 27, b) After administering the conjugate or a pharmaceutically acceptable salt thereof, or a drug containing the conjugate or a pharmaceutically acceptable salt thereof, irradiating the target region of the object with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate. It includes, and is optional, (ia) The NIR light has a wavelength of 600 nm to 850 nm, or The NIR light is at a wavelength of 660 nm to 740 nm, and / or (ib) The irradiation is performed at least 5 minutes after the administration of the conjugate, or A method wherein the irradiation is performed 1 to 48 hours, 4 to 30 hours, or 8 to 24 hours after administration of the conjugate.

29. (i) Whether the target region is a tumor cell, a mass of tumor cells, a solid tumor, the vicinity of a solid tumor, a metastasis, a metastatic tumor cell, the vicinity of a metastasis, or a precancerous lesion, (ii) Whether the target region is a skin lesion, (iii) Whether the target region is the kidney of the subject, (iv) Whether the target region is the digestive tract or intestine of the subject, (v) The method according to claim 28, wherein the target region is an inflamed joint of the subject.

30. (i) The disease or condition is cancer, and the cancer is optionally selected from the group consisting of colon cancer, colorectal cancer, pancreatic cancer, breast cancer, skin cancer, lung cancer, non-small cell lung cancer, renal cell carcinoma, thyroid cancer, prostate cancer, head and neck cancer, esophageal cancer, gastrointestinal cancer, stomach (gastroc) cancer, small intestine cancer, colon cancer, spindle cell neoplasm, liver cancer, bile duct cancer, peripheral nerve cancer, brain cancer, skeletal muscle cancer, smooth muscle cancer, bone cancer, adipose tissue cancer, cervical cancer, uterine cancer, reproductive organ cancer, lymphoma, and multiple myeloma. (ii) The disease or condition is an inflammatory or autoimmune condition / disease, (iii) The disease or condition is psoriasis, atopic dermatitis, lupus, vitiligo, graft-versus-host disease, cutaneous T-cell lymphoma, contact dermatitis, cutaneous hypersensitivity response, lichen planus, keratosis pilaris, rejection of vascularized compound allograft, alopecia areata, scarring alopecia, or a sarcoid-related skin lesion. (iv) The disease or condition is a T cell-mediated kidney or renal pathology / disease associated with lupus nephritis, autoimmune nephritis, or kidney graft rejection, (v) The disease or condition is gastrointestinal inflammation resulting from an autoimmune and / or inflammatory condition, for example, inflammatory bowel disease (Crohn's disease, ulcerative colitis), (vi) The method according to claim 28 or 29, wherein the disease or condition is inflammation of the joints from rheumatoid arthritis or spondyloarthritis.

31. A method for imaging cells or tissues containing a target molecule in a subject, a) Administering to the subject a conjugate according to any one of claims 17 to 26 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, b) After administering the conjugate or a pharmaceutically acceptable salt thereof, or a drug containing the conjugate or a pharmaceutically acceptable salt thereof, the target region of the object is irradiated with near-infrared (NIR) light sufficient to activate the photosensitizer of the conjugate, thereby providing an image of the presence of the target molecule associated with the cell or tissue. Methods that include...

32. The following formula: 【Chemistry 42】 A compound represented by or a pharmaceutically acceptable salt thereof, wherein the formula is A', B', X', and Y' are each independently -OH, --OC １～４ Alkyl, -N(R) １００ ) (Caution １０１ ), or -Z-C １～６ Alkylene-NH ２ And, however, one of A', B', X', and Y' is -Z-C １～６ Alkylene-NH ２ The condition is that, R １００ However, H or C １～３ It is alkyl, R １０１ However, H, C １～３ Alkyl, or -(CH ２ -CH ２ -O) ｎｒ R １０２ And, R １０２ However, it is H or Me, nr is an integer between 1 and 16. Z is -O- or -NR １ - and R １ However, H or C １～３ A compound that is alkyl, or a pharmaceutically acceptable salt thereof.

33. a) A' and B' are -OCH ３ And one of X' and Y' is -OCH ３ And the other of X' and Y' is -Z-C １～６ Alkylene-NH ２ Is it, b) A' and B' are -OCH ３ And one of X' and Y' is -OH, and the other of X and Y is -Z-C １～６ Alkylene-NH ２ Is it, c) One of A' and B' is -OCH ３ And the other of A' and B' is -OH, and one of X' and Y' is -OH, and the other of X' and Y' is -Z-C １～６ Alkylene-NH ２ Is it, d) A' and B' are -OH, one of X' and Y' is -OH, and the other of X' and Y' is -Z-C １～６ Alkylene-NH ２ is, or e) One of A' and B' is -OCH ３ And the other of A' and B' is -Z-C １～６ Alkylene-NH ２ And both X' and Y' are -NH(CH ２ -CH ２ -O) ｎｒ R １０２ And in the formula, R １０２ The compound according to claim 32 or a pharmaceutically acceptable salt thereof, wherein is H or Me, and nr is an integer from 2 to 8.

34. (i) The compound is of the following formula: 【Chemistry 43】 It is represented by or a pharmaceutically acceptable salt thereof, where one of X' and Y' is -Z-C １～６ Alkylene-NH ２ And the other is -OH, or (ii) The compound is of the following formula: 【Chemistry 44】 It is represented by or a pharmaceutically acceptable salt thereof, where one of A' and B' is -Z-C １～６ Alkylene-NH ２ And the other is -OH or -OCH ３ The compound according to claim 32 or a pharmaceutically acceptable salt thereof.

35. (i) Z is -NH- or (ii) The compound according to any one of claims 32 to 34 or a pharmaceutically acceptable salt thereof, wherein Z is -O-.

36. The aforementioned compound, 【Chemistry 45-1】 【Chemistry 45-2】 【Chemistry 45-3-1】 【Chemistry 45-3-2】 The compound according to claim 32, or a pharmaceutically acceptable salt thereof, a positional isomer, or a pharmaceutically acceptable salt of the positional isomer thereof.

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