Phthalocyanine dye compounds, conjugates, and methods of use thereof

Abstract

Phthalocyanine dyes and conjugates thereof are provided that are useful as photosensitizers in light-based therapies, including photoimmunotherapy (PIT), as fluorescent reporters in bioassays, optical imaging, and as therapeutic conjugates. For example, the phthalocyanine compound (2-3) can be prepared according to the following scheme 2. JPEG2022191210000179.jpg47152

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 008,476 and U.S. Provisional Patent Application No. 63 / 008,502, both filed on April 10, 2020, both of which are incorporated herein by reference in their entirety.

[0002] Field of Invention Phthalocyanine dye compounds and conjugates containing phthalocyanine dye compounds are provided herein for therapeutic and diagnostic applications, such as use as photosensitizers in bioassays, as reporters for optical imaging, and as photosensitizers in light-based therapies including photoimmunotherapy. Methods for preparing phthalocyanine dye compounds, as well as compositions and kits containing the phthalocyanine dye compounds provided herein, are also provided herein. Methods for preparing phthalocyanine dye conjugates and methods for treatment using phthalocyanine dye conjugates are also provided herein.

[0003] Background of the Invention Phthalocyanine (Pc) dye compounds are currently used as fluorescent reporter groups in bioassays, as fluorescent markers in optical imaging, and as photosensitizers in light-based therapies, such as photodynamic therapy (PDT), photothermal therapy (PTT), and photoimmunotherapy (PIT). Pc is particularly attractive in light-based therapies given the near-infrared radiation stability and high extinction coefficient of certain phthalocyanine dyes. Improvements to phthalocyanine dyes are needed to enhance the efficacy, cost, and availability of biological assays, optical imaging, and therapies that rely on these dyes. Compounds, compositions, and methods that satisfy such needs are provided herein.

[0004] Summary of the Invention In one aspect, phthalocyanine dye compounds are provided herein that can be used as unconjugated fluorescent dyes, or, when conjugated to molecules, can be used in biological assays, diagnostics, and photo-based therapies. In another aspect, phthalocyanine dye compounds and their conjugates for use in biological assays, diagnostics, and photo-based therapies are provided herein. In one embodiment, a phthalocyanine dye compound of formula (0) is provided herein, comprising an unsubstituted phthalocyanine scaffold containing a core metal or metalloid atom coordinated to two axial ligands, wherein the first ligand comprises at least one water-soluble group and the second ligand comprises at least one reactive group. The phthalocyanine dye compounds provided herein do not exist as positional isomers. Since the core phthalocyanine structure is unsubstituted, the synthesis of the compounds herein does not produce positional isomers, and therefore the production of the compounds is efficient, cost-effective, and improves the effectiveness of isolation and / or separation procedures.

[0005] In one aspect, a conjugate comprising a phthalocyanine dye covalently linked to a targeting molecule is provided herein, wherein the phthalocyanine dye for use in the conjugate, pharmaceutical composition and method herein comprises formula (0), and the formula (0) compound comprises a metal or metalloid atom, such as a silicon atom, coordinated by (a) an unsubstituted phthalocyanine, (b) a first axial silicon-containing ligand having a conjugable group, and (c) a second axial silicon-containing ligand having a water-soluble group that is not a conjugable group. In some embodiments of formula (0), the axial silicon-containing ligand having a conjugable group further comprises a water-soluble group. In some embodiments, the chemical structures of the first and second axial ligands are different from each other.

[0006] On one side, equation (X): [ka] [wherein, M is a metal or a metalloid, X is [Chemical formula] and Y is [Chemical formula] and R , , m , m , m , m , 3 , 4 , 5 , 5 , , 3 , 4 , 4 , 4 , 3 , 4 , 5 , 4 and R 2 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, R 3 , R 4 or R 5 is selected from substituent (a) or substituent (b), (a) R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z, R 4 is -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z, R 5 is -L 5 -H or -L 5 -A, (b) R 3 is -L 3 -H or -L3 -A, R 4 is, -L 4 -H, -(NH) m -L 4 -A or -(O) m -L 4 -A and R 3 and R 4 These are connected by a join, -L 4 -Forms a heterocycline substituted with A, R 5 is, -L 5 -H or -L 5 -A, However, R 3 , R 4 and R 5 At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the second part, or a protected form thereof or a reacted form thereof. R 6 and R 7 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H or -L 8 -Z is, R 9 is, -L 9 -H, -(NH) n -L 9 -Z or -(O) n -L 9 -Z is, R10 is, -L 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z is, However, R 8 , R 9 and R 10 At least one of these is a group containing Z, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 1 and L 2 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkyl, or optionally substituted heterocycline. L 3 , L 4 , L 5 , L 8 , L 9 and L 10 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. a is either 0 or 1. b is either 0 or 1. c is either 0 or 1. d is either 0 or 1. m is either 0 or 1. n is either 0 or 1. However, if b is 1, then a is 0, If d is 1, then c is 0, If m is 1, then b is 1, If n is 1, then c is 1. Phthalocyanine dye compounds having the same, or salts, stereoisomers, or tautomers thereof, are provided herein.

[0007] In another aspect, compounds of formula (0) containing a silicon atom are provided herein, coordinated by (a) an unsubstituted phthalocyanine, (b) an axial silicon-containing ligand having a conjugateable group, and (c) an axial silicon-containing ligand having a water-soluble group that is not a conjugateable group.

[0008] The conjugates provided herein comprise one or more targeting molecules, such that the targeting molecule is a polypeptide or other molecule bound to the surface of a cell. In some embodiments, one or more targeting molecules of the conjugate are antibodies or antigen-binding antibody fragments. In some embodiments, one or more targeting molecules are antigen-binding antibody fragments, such as Fab, a single VH domain, multiple VH domains, a single-strand variable fragment (scFv), a polyvalent scFv, a bispecific scFv and / or an scFv-CH3 dimer. In some embodiments, one or more targeting molecules are antibodies or antigen-binding antibody fragments bound to at least one of CD25, CEA, CTLA-4, EGFR / HER1, FAP, HER2, MUC-1, PD-1, PD-L1 and / or PSMA. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to CD25, for example, an antibody or antigen-binding fragment that binds to CD25 but does not block interleukin-2 (IL-2) signaling at the IL-2 receptor. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to CEA. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to CTLA-4. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to EGFR / HER1. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to HER2. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to MUC-1. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to PD-1. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to PD-L1. In some embodiments, the targeting molecule is an antibody or antigen-binding antibody fragment that binds to PSMA.

[0009] In some embodiments, the conjugates provided herein include 3F8, 8H9, AB122, ab75705, avagovomab, abcikimab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, ADG116, ADU-1604, aducanumab, afasevikumab, aferimomab, aftuzumab, AGEN1181, AGEN1884, AGX-115, AK104, AK105, and alacizumab pegol. pegol), alemtuzumab, alirocumab, altumomab pentetate, amatsuximab, AMG 404, AMP-224, AMP-514, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, anti-CD133, apolizumab, aprutumab ixadotin ixadotin), alcitumomab, alcitumomab Fab fragment, ascrinvacumab, aselizumab, atezolizumab, atidortoxumab, atinumab, atlizumab (tocilizumab), ATOR-1015, atorolimumab, avelumab, azintuxizumab vedotin Vedotin), B72.3, Bapineuzumab, Basiliximab, Bavituximab, BCD-100, BCD-135, BCD-145, BCD-217, Vectumomab, Begelomab, Belantamab mahodotinmafodotin), belimumab, bemarituzumab, benralizumab, berlimatoxumab, bermekimab, bersanlimab, bertilimumab, becilesomab, bevacizumab, bezlotoxumab, BGB-A333, BI 754091, biciromab, bimaglumab, bimekizumab, birtamimab, vibatuzumab, bibatuzumab meltansine Mertansine), BL-8040, Bleserumab, Blinatumomab, Blontuvetmab, Blosozumab, BMS-936559, BMS-986218, Vococizumab, Brazikumab, Brentuximab Vedotin, Briakinumab, Brodalumab, Brolucizumab, Brontictuzumab, Blosumab, Cabiralizumab, Camidanlumab tesirine, Camrelizumab, Canakinumab, Cantuzumab mertansine, Cantuzumab mertansine ravtansine), caplacizumab, capromab, capromab pendetide, carlumab, carotuximab, catumakisomab, cBR96-doxorubicin immune complex, CBT-502, CC-90002, CDC-022, cedelizumab, semiprimab, cergutuzumab amunaleukin, certolizumab pegol, cetrelimab, cetuximab, cibisatamab, cirmtuzumab, citatuzumab vogatoxbogatox), cizutumumab, crazakizumab, clenoliximab, cribatuzumab tetraxetan, CMAB302, codrituzumab, cofetuzumab pelidotin, coltuximab ravtansine), conatumumab, concizumab, cosfroviximab, cosibelimab, CP-870, 893, CR6261, crenezumab, crizanlizumab, clotedumab, CS1001, CS1003, cusatuzumab, CX-188, dasetuzumab, dacrizumab, darotuzumab, dapirolizumab pegol, daratumumab, dectrekumab, demicizumab, denintuzumab mahodotin mafodotin), denosumab, depatuxizumab mafodotin, derlotuximab biotin, detumomab, dezamizumab, diridavumab, domagrozumab, domagrozumab, dorlimomab aritox), Dostarlimab, Drodizumab, DS-8201, Duligotumab, Duligotuzumab, Dupilumab, Durvalumab, Dusigitumab, Duvortuxizumab, Eclomeximab, Eculizumab, Edobacomab, Edrecolomab, Efalizumab, Eftilagimod alfaalpha), Efungumab, Eldelumab, Elezanumab, Elgemtumab, Elotuzumab, Elsilimomab, Emactuzumab, Emapalumab, Emibetuzumab, Emicizumab, Enapotamab vedotin, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol pegol), enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomabcituxetan), epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etalacizumab, etigilimab, etrolizumab, evinacumab, evolocumab, exbivirumab, F3, F520, fanolesoma b) Faralimomab, Faricimab, Faretuzumab, Facinumab, FAZ053, FBTA05, Felvizumab, Fezakinumab, Fibatuzumab, Ficlatuzumab, Figitumumab, Firivumab, Flambotumab tumab), fletikumab, flotezumab, fortrizumab, foralumab, foravirumab, fremanezumab, fresolimumab, phrovocimab, frunevetmab, fluranumab, futuximab, galcanezumab, galiximab, gankota Gancotamab, Ganitumab, Gantenerumab, Gatipotuzumab, Gavilimomab, GB221, Gedivumab, Gemtuzumab ozogamicin, Genolimzumab, Gevokizumab, Gilvetmab, Gymcirumab, Gilentuximab, Glembatumumab vedotinVedotin, GLS-010, Gomiliximab, Gosuranemab, Guselkumab, HD201, Hervycta, HLX02, HLX10, HLX20, HLX22, HX008, HX009, Ianalumab, Ibalizumab, IBI308, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Ieramilimab, Ifabotuzumab, Igovomab, Iladatuzumab vedotin Indusatumab vedotin, IMAB362, Imalumab, Imaprelimab, Imciromab, Imgatuzumab, INBRX-105, Inclacumab, Indatuximab ravtansine, Indusatumab vedotin Vedotin, Innebilizumab, Infliximab, Inorimomab, Inotuzumab Ozogamicin, Intetumumab, Iomab-B, IPH2101, Ipilimumab, Iratumumab, Isatuximab, Iscarimab, Istiratumab, Itorizumab, Ixekizumab, JTX-4014, Keriximab, KN035, KN046, Labetuzumab, Lacnotuzumab, Ladiratuzumab Vedotin Vedotin, lambrolizumab (pembrolizumab), lampalizumab, lanadermab, landogrozumab, laprituximab emtansineemtansine), Larcabiximab, LDP, Lebrikizumab, Lemalesomab, Lendalizumab, Lenvervimab, Lenzilumab, Lerdelimumab, Leronlimab, Lesofavumab, Letolizumab, Lexatumumab, Livivirumab, Lifastuzumab vedotin, Ligelizumab, Lilotomab (satetraxetan) satetraxetan), lintuzumab, lirulumab, lodelcizumab, lokivetmab, loncustuximab tesirin (Lo ncastuximab tesirine), lorvotuzumab mertansine, losatuxizumab vedotin, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, lupartumab, lupartumab amadotin amadotin), Lutikizumab, LY3300054, LY3415244, LZM009, mAb114, Mapatumumab, Margetuximab, Marstacimab, Maslimomab, Matsuzumab, Mavrilimumab, MCLA-145, MED16469, MEDI6383, Mepolizumab, Metelimumab, MGA012, MGD013, MGD019, Miratuzumab, Minretumomab, Mirikizumab, Milbetuximab sorabtansine soravtansine), mitumomab, MK-1308, MK-4166, MNRP1685A, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motabizumab, moxetumomab pasudotox, MOXR0916, MSB2311, muromonab-CD3, nacolomab tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansineemtansine), narnatumab, natalizumab, navicixizumab, navivumab, naxitamab, nevacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesvacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, NM-01, nofetumomab merpentan Merpentan), Obiltoxaximab, Obinutuzumab, OC125 monoclonal antibody, Ocaratuzumab, Ocrelizumab, Odulimomab, Ofatumumab, Olaratumab, Oleclumab, Olendalizumab, Olokizumab, Omalizumab, Omburtamab, OMS721, Onartuzumab, Ontuxizumab, Onvatilimab, Opicinumab, Oportuzumab monatox Monatox), olegobomab, orticumab, otelixizumab, otilimab, otreltuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pankomab, panobacumab mab), Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Patrizumab, PDR001, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Paxerizumab, PF-05280014, PF-06801591, Pidilizumab, Pinatuzumab Vedotinvedotin), pintumomab, placulumab, prozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabicimab, prasinezumab, prezalizumab, prezalumab, priliximab, pritoxaximab, pritumumab, PRO 140, Quilizumab, Racotumomab, Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranevetmab, Ranibizumab, Ravagalimab, Rabrizumab, Laxibakumab, Refanezumab nezumab), Regavirumab, REGN2810, REGN3504, REGN4659, REGN-EB3, Relatlimab, Remtolumab, Reslizumab, rHIgM12B7, Rilotumumab, Rinucumab, Risankizumab, Rituximab, Rituximab, Rivabazumab pegol pegol), Rmab, RO7121661, lobatumumab, loredumab, romilkimab, romosozumab, rontalizumab, rosmantuzumab, rovalpituzumab tesirine, robelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab, sacituzumab govitecan, samalizumab, samalizumab vedotinVedotin, sarilumab, satralizumab, satumomab pendetide, SB3, SCT-I10A, SEA-CD40, secukinumab, selicrelumab, seribantumab, setoxaximab, setrusumab, sevilumab, SG001, SGN-CD19A, SHP647, SHR-1316, SIBP-01, sibrotuzumab, sifalimumab, siltuzumab, simtuzumab, sintilimab, cilprizumab, siltratumab vedotin Vedotin, silukumab, sofituzumab, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, STI-3031, sulesomab, suptavumab, stimulimab, subizumab, suuvratoxumab, Sym021, tabarmab, tacatuzumab tetraxetan tetraxetan), tadocizumab, talacotuzumab, talizumab, tamtuvetmab, tanezumab, taplitumomab paptox, tarextumab, tavolimab, tefibazumab, telimomab aritox, telisotuzumab, telisotuzumab vedotinVedotin, Tenatumomab, Teneriximab, Teprizumab, Tepoditamab, Teprotumumab, Tesidolumab, Tetulomab, Tezeperumab, TG-1501, TGN1412, Tibrizumab, Ticilimumab, Tigatuzumab, Childurakizumab, Timigutuzumab, Timolumab, Tiragolumab, Tiragotumab, Tislelizumab, Tisotumab Vedotin Vedotin, TNX-650, Tocilizumab, Tocilizumab, Tomzotuximab, Tralizumab, Tripalimab, Tosatoxumab, Toshitumomab, Toshitumomab, Tovetumab, Tralokinumab, Trastuzumab, Trastuzumab deruxtecan, Trastuzumab-anns, Trastuzumab-dkst Trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, TRX385, TRX518, TSR-042, tucotsuzumab selmoloukin, tubirumab, TX05, ublituximab, urocuprumab, urerumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talirine, vanalimaiba, vanadortuzumab vedotinVedotin, Vantictumab, Vanucizumab, Vapaliximab, Varisacumab, Varlilumab, Baterizumab, Vedolizumab, Beltuzumab, Vepalimomab, Vesencumab, Vizilizumab, Vobarilizumab, Boroxiximab, Bonrelorizumab, Vopratelimab, Borsetuzumab mahodotin This includes antibodies or antigen-binding antibody fragments of mafodotin, botumumab, bunakizumab, xentuzumab, XmAb20717, XmAb22841, XMAB-5574, zaltumumab, zanolimumab, zatuximab, xenocutuzumab, ziralimumab, ZKAB001, zolbetuximab, and zolimomab aritox, or targeting molecules that are antigen-binding fragments thereof.

[0010] In some embodiments, the conjugates provided herein include targeting molecules that are aracizumab pegol, cetuximab, depatuxizumab mahodotin, futuximab, iclucumab, imugatuzumab, laprituximab emtansine, matsuzumab, modotuximab, nesitumumab, nimotuzumab, panitumumab, ramucirumab, tomzotuximab, zaltumumab, or antigen-binding fragments thereof.

[0011] In some embodiments, the conjugates provided herein include targeting molecules that are anti-CD25 antibodies, such as basiliximab (Symlect), camidanrumab tesirin, daclizumab (Zinbryta, Xenapax), inorimomab, RA8, STI-003, Xenopax, or antigen-binding fragments thereof.

[0012] In some embodiments, the conjugates provided herein are anti-PD-L1 antibodies, such as atezolizumab (MPDL3280A, Tecentriq), avelumab (Bavencio), durvalumab (MEDI4736, Imfinzi), LDP, NM-01, STI-3031, KN035, LY3300054, M7824 (MSB0011359C), BMS-936559, This includes MSB2311, BCD-135, BGB-A333, CBT-502, Kosiberimab (CK-301), CS1001, FAZ053, MDX-1105, SHR-1316, TG-1501, ZKAB001, INBRX-105, MCLA-145, KN046, LY3415244, REGN3504, HLX20, and targeting molecules that are antigen-binding fragments of any of these.

[0013] In some embodiments, the conjugates provided herein include pembrolizumab (MK-3475, Keytruda), nivolumab (Opdivo), semiprimab (Libtayo), tripalimab (JS001), HX008, SG001, GLS-010, dostallimab (TSR-042), tislerizumab (BGB-A317), and cetrelimab (JNJ-6372328). 3) Pidilizumab (CT-011), Genolimuzumab (APL-501, GB226), BCD-100, Semiprimab (REGN2810), F520, Syntilimab (IBI308), GLS-010, CS1003, LZM009, Camrelizumab (SHR-1210), SCT-I10A, MGA012, AK105, PF-06801591, AMP-224, AB122, AMG This includes anti-PD-1 antibodies selected from the group consisting of 404, BI 754091, HLX10, JTX-4014, MEDI0680, Sym021, MGD019, MGD013, AK104, XmAb20717, RO7121661, CX-188, and spartalizumab, as well as targeting molecules that are antigen-binding fragments of any of these antibodies.

[0014] In some embodiments, the conjugates provided herein include targeting molecules that are ipilimumab (Yervoy®), tremelimumab (tisilimunab), AGEN1181, AGEN1884, ADU-1064, BCD-145, BCD-217, or any of these antigen-binding fragments.

[0015] In some embodiments, the conjugates provided herein include targeting molecules such as CDC-022 (HERtiCAD), CMAB302 (Cipterbin), DS-8201, Gancotamab, GB221, HD201, Helvicta, HLX02, HLX22, Margetuximab, Pertuzumab (Perjeta), PF-05280014 (Trazimera), SB3, SIBP-01, Thimigutuzumab, Trastuzumab (Herseptin), Trastuzumab Deruxtecan (ENHERTU), Trastuzumab Emtansine (Kadcyla), Trastuzumab-anns (Kanjinti), Trastuzumab-dkst (Ogivri), TX05, or antigen-binding fragments thereof.

[0016] In some embodiments, the conjugates provided herein include targeting molecules that contain antibodies or antigen-binding antibody fragments of cetuximab, basiliximab, daclizumab, F3, trastuzumab, or panitumumab, or the antigen-binding antibody fragment thereof. In some embodiments, the conjugates provided herein include targeting molecules that are peptides or small molecules that bind to EGFR, HER2, CD25, PD-1, PD-L1, MUC1, PSMA, FAP, or CTLA-4. In some embodiments, the conjugates provided herein include targeting molecules that bind to viral particles or viral capsid proteins or a portion thereof.

[0017] In some aspects, the conjugate of the targeting molecule and the phthalocyanine dye of formula (X), formula (0), formula (I), or formula (II) has a dye-to-targeting molecule ratio of about 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the conjugate has a dye-to-targeting molecule ratio between about 1:1 to 5:1, 1.5:1 to 4:1, 1.5:1 to 3.5:1, 1.5:1 to 3:1, or about 2:1 to 3:1.

[0018] In some respects, the conjugate phthalocyanine dyes, such as compounds of formula (X), formula (0), formula (I), or formula (II), have maximum absorption at wavelengths between approximately 600 nm and 800 nm, approximately 620 nm and 720 nm, approximately 640 nm and 700 nm, or approximately 640 nm and 680 nm.

[0019] Among the conjugates provided herein are conjugates of a targeting molecule (also synonymously called a targeting moiety) and a phthalocyanine dye selected from compounds 1, 5, 12, 13, 14, 16, 17, 18, or 19 of Table A.

[0020] Among the conjugates provided herein are conjugates of a targeting molecule (also synonymously called a targeting moiety) and a phthalocyanine dye selected from Table A.

[0021] Pharmaceutical compositions of conjugates and pharmaceutically acceptable excipients are also provided herein. The conjugates and pharmaceutical compositions provided herein are found to be used in methods of treatment. In some embodiments, the method involves administering the conjugate or pharmaceutical composition of a conjugate described herein to a subject, followed by injecting 10 J / cm² at a wavelength of 600 nm or about 600 nm to 850 nm or about 850 nm. 2 Alternatively, approximately 10 J / cm² 2 The dose is ~200 J / cm². 2 Alternatively, approximately 200 J / cm² 2The method includes treating an object having a disease or condition, comprising the steps of: irradiating a target area of ​​the object with a dose of 10 J or about 10 J per 1 cm of fiber length to 100 J or about 100 J per 1 cm of fiber length, thereby treating the disease or condition in the object. In some embodiments of the method, the wavelength is at least about 600 nm, 610 nm, 620 nm, 630 nm, 640 nm, 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, or 700 nm. In some embodiments of the method, the wavelength is between 660 nm and 680 nm. In some embodiments of the method, the wavelength is 670 ± 50 nm or about 670 ± 50 nm, or 670 ± 40 nm or about 670 ± 40 nm, or 670 ± 20 nm or about 670 ± 20 nm, or 670 ± 10 nm or about 670 ± 10 nm. In some embodiments of the method, the wavelength is less than 690 nm or less than 680 nm.

[0022] In certain respects, the methods of treatment described herein include treatments in which the target area is tumor cells, tumor cell aggregates, solid tumors, the vicinity of solid tumors, metastases, metastatic tumor cells, the vicinity of metastases, or precancerous lesions.

[0023] In some embodiments of the method, irradiation is performed at least 5 minutes after administration of the conjugate. In some embodiments of the method, irradiation is performed approximately 1 hour, 5 hours, 10 hours, 15 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 72 hours, or 96 hours after administration of the conjugate. In some embodiments of the method, irradiation is performed 24 + / - 4 hours after administration of the conjugate.

[0024] The methods provided herein include those in which the disease or condition for treatment is cancer. In some aspects, 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, gastrointestinal cancer, stomach cancer, small intestine cancer, spindle cell neoplasm, hepatoma, 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. In some aspects of the treatment methods provided herein, the steps of administering the conjugate and irradiating are repeated.

[0025] Furthermore, this specification provides a method for imaging cells or tissues having a target molecule, comprising the steps of administering a conjugate or a pharmaceutical composition of a conjugate described herein to a subject, and, after the step of administering the conjugate, irradiating a target region of the subject with a wavelength of 600 nm or approximately 600 nm to 850 nm or approximately 850 nm, thereby providing an image of the presence of the target molecule on the cell or tissue.

[0026] Furthermore, this specification provides a system for treating subjects having a disease or condition, comprising a conjugate or pharmaceutical composition of a conjugate as described herein, a laser capable of emitting light with a wavelength between 600 nm and about 800 nm, for example, 670 ± 20 nm, an optical fiber optionally connected to the laser for transmitting light to a target area of ​​the subject, and an optical diffusion device including a non-circular core fiber. In some embodiments, the non-circular core fiber has a "top-hat" core irradiance distribution. In some embodiments, the optical diffusion device is a cylindrical diffuser or a front diffuser.

[0027] In a further particular embodiment, a kit comprising a compound of formula (X), formula (0), formula (I), or formula (II) and instructions for use is provided herein. In a further particular embodiment, the kit further comprises additional reagents. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows the UV-Vis spectrum of chemical synthesis example 1. [Figure 2] Figure 2 shows the UV-Vis spectrum of chemical synthesis example 12. [Figure 3] Figure 3 shows the dose-dependent cytotoxicity of free dye compounds 12 and 13 after irradiation. [Figure 4] Figure 4 shows the dose-dependent cytotoxicity of CTX-C12 and CTX-C13 conjugates after photoimmunotherapy (PIT). [Figure 5A] Figure 5A shows the dose-response curve of the percentage of cell death after PIT with antibody conjugates. [Figure 5B] Figure 5B shows the dose-response curve of the percentage of cell death after PIT for Fab conjugates. [Figure 5C] Figure 5C shows the dose-response curve of the percentage of cell death after PIT with VHH / nanobody conjugates. [Figure 6] Figure 6 shows the time course of tumor treatment with CTX-C13 and CTX-C13 when irradiation (CTX-C13 + PIT) is used as described in Example 8. [Figure 7] Figure 7 shows the time course of tumor treatment with anti-EphA2-C13 conjugates and anti-EphA2-C13 conjugates when irradiation is used as described in Example 9.

[0029] Detailed description of the invention A. Phthalocyanine pigment compounds Phthalocyanines are a group of photosensitive compounds having a phthalocyanine ring structure. Phthalocyanines are azaporphyrins (i.e., C) containing four benzoindole groups connected by nitrogen bridges to a 16-membered ring of alternating carbon and nitrogen atoms. 32 H 18These compounds are N8 and form stable chelates with metal or metalloid cations. In these compounds, the ring center is occupied by a metal ion (either diamagnetic or paramagnetic) that can hold zero, one, or two ligands, depending on the ion. Furthermore, the periring of the ring may be unsubstituted or substituted.

[0030] In some embodiments, phthalocyanines strongly absorb red or near-IR radiation, with absorption peaks between approximately 600 nm and 810 nm, allowing for deep tissue penetration by light in some cases. Phthalocyanines are generally photostable. This photostability is usually advantageous in pigments and dyes, and in many other applications of phthalocyanines.

[0031] In some embodiments, the phthalocyanine dye is water-soluble and contains a luminescent fluorophore moiety having at least one water-soluble moiety. In some embodiments, the aqueous-soluble moiety contains silicon. In some embodiments, the phthalocyanine dye has a core atom, for example, Si, Ge, Sn, Al, or Zn. In some embodiments, the phthalocyanine dye contains a linker having a reactive group that can form a bond between the linker and another molecule, i.e., can form a conjugate. In some embodiments, the phthalocyanine dye can be tuned to fluoresce at a specific wavelength.

[0032] In some embodiments, the phthalocyanine dye contains a linker, i.e., a linker-phthalocyanine dye moiety (LD). In some embodiments, the linker contains a reactive group. In one aspect, formula (X): [ka] [In the formula, M is a metal or metalloid. X is [ka] And, Y is [Chemical formula] being R 1 and R 2 are each independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, R 3 , R 4 or R 5 is selected from substituent (a) or substituent (b), (a) R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z, R 4 is -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z, R 5 is -L 5 -H or -L 5 -A, (b) R 3 is -L 3 -H or -L 3 -A, R 4 is -L 4 -H, -(NH) m -L 4 -A or -(O) m -L 4 z -A, and R 3 and R 4 are connected by a bond to -L4 -Forms a heterocycline substituted with A, R 5 is, -L 5 -H or -L 5 -A, However, R 3 , R 4 and R 5 At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the second part, or a protected form thereof or a reacted form thereof. R 6 and R 7 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H or -L 8 -Z is, R 9 is, -L 9 -H, -(NH) n -L 9 -Z or -(O) n -L 9 -Z is, R 10 is, -L 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z is, However, R 8 , R 9 and R 10 At least one of these is a group containing Z, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 1 and L 2 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkyl, or optionally substituted heterocycline. L 3 , L 4 , L 5 , L 8 , L 9 and L 10 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. a is either 0 or 1. b is either 0 or 1. c is either 0 or 1. d is either 0 or 1. m is either 0 or 1. n is either 0 or 1. However, if b is 1, then a is 0, If d is 1, then c is 0, If m is 1, then b is 1, If n is 1, then c is 1. Phthalocyanine dye compounds having the same, or salts, stereoisomers, or tautomers thereof, are provided herein.

[0033] In some embodiments, the phthalocyanine dye contains a linker, i.e., a linker-phthalocyanine dye moiety (LD). In some embodiments, the linker contains a reactive group. In some embodiments, the phthalocyanine dye is of formula (I): [ka] [In the formula, M is a metal or metalloid. X is [ka] And, Y is [ka] And, R 1 and R 2 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 3 , R 4 or R 5 This is selected from substituent (a) or substituent (b), (a)R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z is, R 4 is, -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z is, R 5 is, -L 5 -H or -L 5 -A, (b)R 3 is, -L 3 -H or -L 3 -A, R 4 is, -L 4 -H, -(NH) m -L 4 -A or -(O) m -L 4 -A and R 3 and R 4 These are connected by a join, -L 4 -Forms a heterocycline substituted with A, R5 is, -L 5 -H or -L 5 -A, However, R 3 , R 4 and R 5 At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the second part, or a protected form thereof or a reacted form thereof. R 6 and R 7 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H or -L 8 -Z is, R 9 is, -L 9 -H, -(NH) n -L 9 -Z or -(O) n -L 9 -Z is, R 10 is, -L 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z is, However, R 8 , R 9 and R10 At least one of these is a group containing Z, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 1 and L 2 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkyl, or optionally substituted heterocycline. L 3 , L 4 , L 5 , L 8 , L 9 and L 10 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. a is either 0 or 1. b is either 0 or 1. c is either 0 or 1. d is either 0 or 1. m is either 0 or 1. n is either 0 or 1. However, if b is 1, then a is 0, If d is 1, then c is 0, If m is 1, then b is 1, If n is 1, then c is 1, However, R 6 and R 7 Both are methyl, L 2 If is propylene, c is 1, and d is 0, then L 8 , L 9 and L 10 [Each of these is not propylene] or its salts, stereoisomers, or tautomers.

[0034] In a particular manner, R 6 and R 7 Both are methyl, L 2 When is propylene, c is 1, and d is 0, L 8 , L 9 and L 10 Compounds of formula (I), wherein each of the elements is not propylene, are provided herein.

[0035] In a particular manner, R 6 and R 7 Both are methyl, L 2 Compounds of formula (I) are provided herein, wherein c is 0 and d is 1, when is propylene.

[0036] In a particular manner, R 6 and R 7 Both are methyl, L 2 is propylene, c is 1, d is 0, L 8 , L 9 and L10 When each of them is propylene, Z is -SO3 - Compounds of formula (I), which are not provided herein, are provided.

[0037] In a particular manner, R 1 , R 2 , R 6 and R 7 The alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl may be optionally substituted with halo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, amino, or cyano.

[0038] In a particular manner, L 1 and L 2 The carbon atoms of the alkylene, heteroalkylene, alkenylene, or heteroalkenylene may be independently and optionally substituted with halo, oxo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, amino, or cyano.

[0039] In a particular embodiment, the compound of formula (I): [ka] [In the formula, M is a metal or metalloid. X is [ka] And, Y is [ka] And, R 1 and R 2Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 3 , R 4 or R 5 (a) or (b) is selected, (a)R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z is, R 4 is, -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z is, R 5 is, -L 5 -H or -L 5 -A, (b)R 3 and R 4 These are connected by a join, -L 4 -Forms a heterocycline substituted with A, R 5 is, -L 5 -H or -L 5 -A, However, R 3 , R 4 and R 5 At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the second part, or its protected form, or its reacted form. R 6 and R 7 Each of them is methyl, R 8 is, -L 8 -Z is, R 9 is, -L 9 -Z is, R 10 is, -L 10 -Z is, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 1 is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene. L 2 It is propylene, L 3 , L 4 , L 5 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene, wherein the carbon atoms of the alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, or arylene may be further optionally substituted with Z, and each nitrogen atom of the heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene. L 8 , L 9 and L 10Each of the following is propylene, where a is 0 or 1, b is 0 or 1, c is 0 or 1, d is 0 or 1, m is 0 or 1, and n is 0 or 1. However, if b is 1, then a is 0, If d is 1, then c is 0, If m is 1, then b is 1, If n is 1, then c is 1. This is provided herein.

[0040] In a particular manner, L 3 , L 4 , L 5 , L 8 , L 9 and L 10 The carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, or arylene may be optionally substituted with halo, oxo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, amino, cyano, or Z, and the nitrogen atoms of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z, where L' is independently alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, or heteroarylene, and the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, or heteroarylene may be optionally substituted with halo, oxo, haloalkyl, hydroxyl, alkoxy, haloalkoxy, amino, or cyano.

[0041] In a particular manner, L 3 , L 4 , L 5 , L 8 , L 9 and L 10Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene, where each nitrogen atom of the heteroalkylene or heteroalkenylene may be further optionally substituted with one or two L'-Z atoms, and L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene.

[0042] In a particular manner, L 1 and L 2 Each of these can be substituted independently and arbitrarily. 1~10 Alkylene, optionally substituted hetero-C 1~10 Alkylene, C may be optionally substituted. 2~10 Alkenylene or hetero-C 2~10 It is an alkenylene. Furthermore, in certain aspects, L 1 and L 2 Each is independent of C 2~4 Alkylene, HeteroC 2~4 Alkylene, C may be optionally substituted. 2~4 Alkenylene or optionally substituted hetero-C 2~4 It is an alkenylene. Furthermore, in certain aspects, L 1 and L 2 Each of these can be replaced as desired. 2~4 It is alkylene.

[0043] In a particular embodiment, each reactive group A is independently -C(O)OR 11 , -NR 12 R 13 ,-NHC(O)R 14 , -C(O)R 15 , -OR 16 , -SR 16 -OS(O)2R 17 , -OP(OR 18 )(NR 19 R 20), -N=C=O, -N=C=S, -SC≡N, -SO2-F, -SO2-Cl, -SO2-Br, -S-SR 21 or a 5-membered or 6-membered dioxosubstituted heterocyclyl, Each R 11 These are independently hydrogen, alkyl, haloalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl, and each of the heterocyclyl, aryl, or heteroaryl is independently halo, -SO3 - And may be optionally replaced with one to five groups selected from -SO2F. Each R 12 These are independently hydrogen, alkyl, or haloalkyl, Each R 13 These are independently aryl or heteroaryl, and each aryl or heteroaryl is independently halo, -SO3 - And may be optionally substituted with one to five groups selected from -SO2F, or optionally, R 12 and R 13 It may also form a cyclic imide together with the bonded nitrogen. Each R 14 They are independently haloalkyl, Each R 15 These are independently, and each is independently halo, heterocyclyl, and -SO3. - Or an aryl which may be optionally substituted with one to five groups that are -SO2F, Each R 16 Each is an aryl that may be independently substituted with 1 to 5 groups that are independently halo or heterosilyl. Each R 17 Each is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each heterocyclyl, aryl, or heteroaryl is independently a halo, -SO3 - -SO2F and -C(O)ORc It may be arbitrarily replaced by one to five elements selected from, Each R c These are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl, R 18 , R 19 and R 20 Each of these is independently an optionally substituted alkyl or optionally substituted haloalkyl, R 21 It is a heteroaryl compound.

[0044] In a particular embodiment, reactive group A is [ka] ,-NHC(O)R 14 , -COOH and -OSO2R 17 Selected from the group consisting of each R x and R y R is independently hydrogen or halo, z is hydrogen or -SO3 - And, R 14 is an optionally substituted haloalkyl or optionally substituted aralkyl, R 17 Each R is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 17 Therefore, heterocyclyl, aryl, or heteroaryl are each independently halo, -SO3 - -SO2F and -C(O)OR c It may be arbitrarily replaced by one to five elements selected from, Each R cThese are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl.

[0045] Furthermore, in certain embodiments, the reactive group A or the conjugateable group A' is [ka] ,-NHC(O)R 14 and -OSO2R 17 Selected from the group consisting of each R x and R y R is independently hydrogen or halo, z is hydrogen or -SO3 - And, Each R 14 These are independently haloalkyl or alkyl-substituted aralkyl compounds. Each R 17 Each is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each heterocyclyl, aryl, or heteroaryl is independently a halo, -SO3 - -SO2F and -C(O)OR c It may be arbitrarily replaced by one to five elements selected from, Each R c These are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl.

[0046] Furthermore, in certain embodiments, reactive group A is [ka] or COOH, and each Rx and R y R is independently hydrogen or halo, z is hydrogen or -SO3 - That is the case.

[0047] In certain embodiments, the reactive groups are each independently -C(O)OR 11 or -NR 12 R 13 And R 11 Each of these is independently hydrogen, alkyl, haloalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl, and the heterocyclyl, aryl, or heteroaryl may be optionally substituted. R 12 Each is independently either hydrogen or alkyl, and R 13 These are, independently, Halo, -SO3 - And, an aryl or heteroaryl which may be optionally substituted with one to five (give) groups selected from -SO2F, or R 12 and R 13 It combines with the bonded nitrogen to form a heterosilyl.

[0048] In a particular embodiment, the water-soluble group Z is -C(O)OH, -(CH2) q (OCH2CH2) v (CH2) q C(O)OH, -(CH2CH2O) v (CH2) p C(O)OH, -(CH2) q (OCH2CH2) v Ure 22 , -(CH2CH2O) v (CH2) p Ure 22 , -(CH2) q (OCH2CH2) v SR 22 , -(CH2CH2O) v (CH2)p SR 22 、 -O(CH2) v N[(CH2CH2O) n CH2CH2OR 22 ] t 、 -(CH2) q (OCH2CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t 、 -(CH2CH2O) m (CH2) p N[(CH2CH2O) w CH2CH2OR 22 ] t 、 -NH2、 -(CH2) q N[(CH2CH2O) v CH2CH2OR 22 ] t 、 -(CH2) q NR b [(CH2CH2O) w CH2CH2OR 22 ] u 、 -(CH2) q N[(CH2) p (OCH2CH2) v OR 22 ] t 、 -(CH2) q N[(CH2) p SO3H] t 、 -(CH2) q NR b [(CH2) p SO3H] u 、 -(CH2) q NR b (CH2) p CH(SO3H)2、 -(CH2) q N[(CH2) p S(O) u OH] t 、 -(CH2) q N[(CH2) p OSO3H] t , -(CH2) q (OCH2CH2) v (CH2) q SO3H, -(CH2) q (OCH2CH2) v (CH2) q S(O) u OH, -(CH2) q (OCH2CH2) v (CH2) q OSO3H, -SO3H, -CH(SO3H)2, -OSO3H, -S(O) u OH, -PO3H, -CH(PO3H)2, -(CH2) q N[(CH2) p PO3 - ] t , -(CH2) q (OCH2CH2) v (CH2) q PO3H, -(CH2) q N[(CH2) p OPO3H] t , -OPO3H, -(CH2) q (OCH2CH2) v (CH2) q P(O)(OH)2, -(CH2) q N[(CH2) p P(O)(OH)2] t , -P(O)(OH)2, Glutamic acid, aspartic acid, histidine, 1,3-beta-glucan, or 1,4-beta-glucan, Each R 22These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, an alkyl which may be optionally substituted with -CO2H, a heteroalkylene which may be optionally substituted with -CO2H, a haloalkyl or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0049] In a particular embodiment, the water-soluble group Z is -(CH2) q (OCH2CH2) v Ure 22 , -(CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q N[(CH2) p (OCH2CH2) v Ure 22 ] t , -(CH2) q N[(CH2) p SO3H] t , -(CH2) q NR b [(CH2) p SO3H] u , -(CH2) q NR b [(CH2) p CH(SO3H)2] u , -SO3H, -CH(SO3H)2, -PO3H, -(CH2) q N[(CH2) p PO3H] t , -(CH2)q NR b [(CH2) p PO3H] u , or -(CH2) q NR b (CH2) p Selected from CH(PO3H)2, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, alkyl, haloalkyl, or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0050] In a particular embodiment, the water-soluble group Z is -(CH2) q (OCH2CH2) v Ure 22 , -(CH2CH2O) v (CH2) p Ure 22 , -(CH2) q (OCH2CH2) v SR 22 , -(CH2CH2O) v (CH2) p SR 22 , -(CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q (OCH2CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2CH2O) m (CH2) pN[(CH2CH2O) w CH2CH2OR 22 ] t 、 -NH2ぁ -(CH2) q N[(CH2CH2O) v CH2CH2OR 22 ] t 、 -(CH2) q NR b [(CH2CH2O) w CH2CH2OR 22 ] u 、 -(CH2) q N[(CH2) p (OCH2CH2) v OR 22 ] t 、 -(CH2) q N[(CH2) p SO3 - ] t 、 -(CH2) q NR b [(CH2) p SO3 - ] u 、 -(CH2) q NR b [(CH2) p CH(SO3 - )2] u 、 -(CH2) q N[(CH2) p S(O) u OH] t 、 -(CH2) q N[(CH2) p OSO3 2- ] t 、 -(CH2) q (OCH2CH2) v (CH2) q SO3 - 、 -(CH2) q (OCH2CH2) v (CH2) q S(O)u OH, -(CH2) q (OCH2CH2) v (CH2) q OSO3 2- , -CH(SO3 - )2, -SO3 - , -OSO3 2- , -S(O) u OH, -PO3 2- , -CH(PO3 2- )2, -(CH2) q N[(CH2) p PO3 - ] t , -(CH2) q (OCH2CH2) v (CH2) q PO3 - , -(CH2) q N[(CH2) p OPO3 - ] t , -OPO3 - , -(CH2) q (OCH2CH2) v (CH2) q P(O)(OH)2, -(CH2) q N[(CH2) p P(O)(OH)2] t , -P(O)(OH)2, Glutamic acid, aspartic acid, histidine, 1,3-beta-glucan, or 1,4-beta-glucan, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, alkyl, haloalkyl, or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0051] Furthermore, in certain embodiments, the water-soluble group Z is -(CH2) q (OCH2CH2) v Ure 22 , -(CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q N[(CH2) p (OCH2CH2) v Ure 22 ] t , -(CH2) q N[(CH2) p SO3 - ] t , -(CH2) q NR b [(CH2) p SO3 - ] u , -(CH2) q NR b [(CH2) p CH(SO3 - )2] u , -SO3 - , -CH(SO3 - )2, -PO3 2- , -(CH2) q N[(CH2) p PO3 - ] t , -(CH2) q NR b [(CH2) p PO3 - ]u or -(CH2) q NR b (CH2) p CH(PO3 - )2, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, alkyl, haloalkyl, or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0052] Furthermore, in certain embodiments, the water-soluble group Z is -(CH2) q (OCH2CH2) v Ure 22 , -(CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q N[(CH2) p SO3 - ] t , -(CH2) q NR b [(CH2) p SO3 - ] u , -(CH2) q NR b [(CH2) p CH(SO3 - )2] u , -(CH2) q CH[(CH2)] p N[(CH2)(SO3 - )2] t , -SO3 - , -PO3 2- or -(CH2) q N[(CH2) p PO3 - ] t And, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, alkyl, haloalkyl, or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0053] In a particular embodiment, a and c are 0, and b and d are 1. In another particular embodiment, a and c are 1, and b and d are 0. In yet another particular embodiment, c is 0 and d is 1.

[0054] In certain circumstances, X is [ka] [In the formula, R 1 , R 2 , R 3 , L 1 , L 3 , L 4 , L 5 Z and A are as described in equation (I).

[0055] In a particular manner, L 4 is an optionally substituted alkylene or optionally substituted alkenylene. In a particular embodiment, L 4 is an alkylene which may be optionally substituted.

[0056] In a particular manner, Y is [ka] That is the case.

[0057] In certain embodiments, M is Si, Ge, Sn, or Al. In even more specific embodiments, M is Si or Ge.

[0058] In certain manner, [ka] [ka] [ka] [ka] Compounds of formula (X) or formula (I), selected from the group consisting of the above, are provided herein.

[0059] Furthermore, in certain embodiments, the compound of formula (X) or formula (I) is [ka] It is selected from the group consisting of the following.

[0060] In certain embodiments, the reactive group can form a covalent bond.

[0061] In certain embodiments, compounds selected from Table 1 are provided herein. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20]

[0062] Furthermore, in certain embodiments, compounds selected from Table 2A are provided herein. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0063] One embodiment is given by equation (II): [ka] [In the formula, M is a metal or metalloid. X is [ka] And, Y is [ka] And, R 1 and R 2 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 3 , R 4 or R 5 This is selected from substituent (a) or substituent (b), (a)R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z is, R 4 is, -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z is, R 5 is, -L 5 -H or -L 5 -A, (b)R 3 and R 4 These are connected by a join, -L 4 -Forms a heterocycline substituted with A, R 5 is, -L 5 -H or -L 5 -A, However, R 3 , R 4 and R 5At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the second part, or its protected form, or its reacted form. R 6 and R 7 Each of them is methyl, R 8 is, -L 8 -Z is, R 9 is, -L 9 -Z is, R 10 is, -L 10 -Z is, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 1 This is selected from optionally substituted alkylenes, optionally substituted heteroalkylenes, optionally substituted alkenylenes, or optionally substituted heteroalkenylenes. L 2 It is propylene, L 3 , L 4 and L 5 Each is independently selected from optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. L 8 , L 9 and L 10 Each of these is propylene, a is either 0 or 1. b is either 0 or 1. c is either 0 or 1. d is either 0 or 1. m is either 0 or 1. n is either 0 or 1. However, if b is 1, then a is 0; if d is 1, then c is 0; if m is 1, then b is 1; and if n is 1, then c is 1. The present invention provides compounds having the structure of the same, or salts thereof, stereoisomers, or tautomers.

[0064] Another aspect is, [ka] The present invention provides a compound of formula (II) selected from the group consisting of the following, or a salt thereof, stereoisomer, or tautomer.

[0065] One aspect is structure: [ka] [In the formula, M is selected from Si, Ge, Sn, Al, or Zn, and is a metal or metalloid optionally further bonded to the metal or metalloid. R 1 and R 2Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 3 , R 4 or R 5 This is selected from substituent (a) or substituent (b), (a)R 3 is hydrogen, -L 3 -H, -L 3 -A or -L 3 -Z is, R 4 is, -L 4 -H, -(NH) m -L 4 -A, -(NH) m -L 4 -Z, -(O) m -L 4 -A or -(O) m -L 4 -Z is, R 5 is, -L 5 -H or -L 5 -A, (b)R 3 is, -L 3 -H or -L 3 -A, R 4 is, -L 4 -H, -(NH) m -L 4 -A or -(O) m -L 4 -A and R 3 and R 4 These are connected by a join, -L 4 -Forms a heterocycline substituted with A, R 5 is, -L 5 -H or -L 5 -A, However, R3 , R 4 and R 5 At least one of them is a group containing A, A is a reactive group capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the second part, or a protected form thereof or a reacted form thereof. L 1 is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene. Z is a water-soluble group which may be optionally substituted with A or L'-A. L 3 , L 4 and L 5 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. a is either 0 or 1. b is either 0 or 1. m is either 0 or 1. However, if b is 1, then a is 0, If m is 1, then b is 1. The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer having the above characteristics.

[0066] Another aspect is L 3 , L 4 , L 5 The present invention provides a compound of formula (III) or a salt, stereoisomer, or tautomer thereof, wherein each of is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene, and each nitrogen atom of the heteroalkylene or heteroalkenylene may be further optionally substituted with one or two L'-Z atoms, and L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene.

[0067] Another aspect is L 1 and L 2 Each of these can be substituted independently and arbitrarily. 1~10 Alkylene, optionally substituted hetero-C 1~10 Alkylene, C may be optionally substituted. 2-10 Alkenylene or hetero-C 2~10 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkenylene.

[0068] Another aspect is L 1 and L 2 Each of them operates independently, C 2~4 Alkylene, HeteroC 2~4 Alkylene, C may be optionally substituted. 2~4 Alkenylene or optionally substituted hetero-C2-4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkenylene.

[0069] Another aspect is L 1 and L 2 Each of these may be replaced as desired. 2~4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkylene.

[0070] In another embodiment, each reactive group A is independent of the others. -C(O)OR 11 , -NR 12 R 13 , -NHC(O)R 14 , -C(O)R 15 , -OR 16 , -SR 16 , -OS(O)2R 17 , -OP(OR 18 )(NR 19 R 20 ), -N=C=O; -N=C=S, -SC≡N, -SO2-F, -SO2-Cl, -SO2-Br, -S-SR 21 ; or Selected from 5-membered or 6-membered dioxosubstituted heterocyclines, Each R 11 Each R is independently hydrogen, alkyl, haloalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl, and each R 11 They became independent, and each became independent, Haro, -SO3 - And may be optionally replaced with one to five groups selected from -SO2F. Each R 12 These are independently hydrogen, alkyl, or haloalkyl, Each R13 However, each R is aryl or heteroaryl, 13 They became independent, and each became independent, Haro, -SO3 - And may be optionally substituted with one to five groups selected from -SO2F, or optionally, R 12 and R 13 However, it may also form a cyclic imide together with the bonded nitrogen. Each R 14 These are independently optionally substituted haloalkyl or optionally substituted aralkyl, Each R 15 These independently form halos, heterocyclines, and -SO3 groups. - Or an aryl which may be optionally substituted with one to five groups that are -SO2F, Each R 16 Each of these is an aryl group that may be independently substituted with one to five groups that are either halo or heterosilyl groups. Each R 17 Each of these is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of the heterocyclyl, aryl, or heteroaryl is independently a halo, -SO3 - -SO2F and -C(O)OR c It may be arbitrarily replaced by one to five elements selected from, Each R c These are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl, R 18 , R 19 and R 20 Each of these is independently an optionally substituted alkyl or optionally substituted haloalkyl, R 21The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein is a heteroaryl compound.

[0071] In another embodiment, reactive group A is [ka] ,-NHC(O)R 14 , -COOH and -OSO2R 17 Selected from the group consisting of, Each R x and R y R is independently hydrogen or halo, z However, hydrogen or -SO3 - And, R 14 However, it is a haloalkyl or aralkyl which may be optionally substituted, R 17 Each of these is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of the heterocyclyl, aryl, or heteroaryl is independently a halo, -SO3 - -SO2F and -C(O)OR c It may be arbitrarily replaced by one to five elements selected from, Each R c The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein each is independently an optionally substituted alkyl, an optionally substituted haloalkyl, an optionally substituted cycloalkyl, or an optionally substituted aryl.

[0072] Another embodiment is in which the reactive groups are each independently -C(O)OR 11 or -NR 12 R 13 The present invention provides a compound of formula (III), or a salt thereof, stereoisomer, or tautomer.

[0073] Another aspect is that the water-soluble group Z is -C(O)OH, -(CH2) q (OCH2CH2) v (CH2) q C(O)OH, -(CH2CH2O) v (CH2) p C(O)OH, -(CH2) q (OCH2CH2) v OR 22 、 -(CH2CH2O) v (CH2) p OR 22 、 -(CH2) q (OCH2CH2) v SR 22 、 -(CH2CH2O) v (CH2) p SR 22 、 -O(CH2) v N[(CH2CH2O) n CH2CH2OR 22 t 、 -(CH2) q (OCH2CH2) v N[(CH2CH2O) w CH2CH2OR 22 t 、 -(CH2CH2O) m (CH2) p N[(CH2CH2O) w CH2CH2OR 22 t 、 -NH2, -(CH2) q N[(CH2CH2O) v CH2CH2OR 22 t 、 -(CH2) q NR b [(CH2CH2O) w CH2CH2OR​​​​22 ] u 、 -(CH2) q N[(CH2) p (OCH2CH2) v OR 22 ] t 、 -(CH2) q N[(CH2) p SO3 - ] t 、 -(CH2) q NR b [(CH2) p SO3 - ] u 、 -(CH2) q NR b (CH2) p CH(SO3 - 2. -(CH2) q N[(CH2) p S(O) u OH] t 、 -(CH2) q N[(CH2) p OSO3 2- ] t 、 -(CH2) q (OCH2CH2) v (CH2) q SO3 - 、 -(CH2) q (OCH2CH2) v (CH2) q S(O) u OH、 -(CH2) q (OCH2CH2) v (CH2) q OSO3 2- 、 -SO3 - 、 -CH(SO3 - 2. -OSO3 2- 、 -S(O) u OH、 -PO3 2-, -CH(PO3 2- )2, -(CH2) q N[(CH2) p PO3 - t , -(CH2) q (OCH2CH2) v (CH2) q PO3 - , -(CH2) q N[(CH2) p OPO3 - t , -OPO3 - , -(CH2) q (OCH2CH2) v (CH2) q P(O)(OH)2, -(CH2) q N[(CH2) p P(O)(OH)2] t , -P(O)(OH)2, Glutamic acid, Aspartic acid, Histidine, 1,3-beta-glucan, or 1,4-beta-glucan, and each R 22 is independently alkyl, haloalkyl, cycloalkyl or aryl, each R b is independently hydrogen, alkyl optionally substituted with -CO2H, heteroalkylene optionally substituted with -CO2H, haloalkyl or cycloalkyl, each v, w and p is independently an integer from 1 to 10, each q is independently an integer from 0 to 10, t is 2 or 3, u is 1 or 2, a compound of formula (III) or a salt, stereoisomer or tautomer thereof is provided.

[0074] Another aspect is that the water-soluble group Z is,​​ -(CH2) q (OCH2CH2) v Ure 22 , -(CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q N[(CH2) p (OCH2CH2) v Ure 22 ] t , -(CH2) q N[(CH2) p SO3 - ] t , -(CH2) q NR b [(CH2) p SO3 - ] u , -(CH2) q NR b [(CH2) p CH(SO3 - )2] u , -SO3 - , -CH(SO3 - )2, -PO3 2- , -(CH2) q N[(CH2) p PO3 - ] t , -(CH2) q NR b [(CH2) p PO3 - ] u or -(CH2) q NR b (CH2) p CH(PO3 - )2, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl, Each R b These are independently hydrogen, an alkyl which may be optionally substituted with -CO2H, a heteroalkylene which may be optionally substituted with -CO2H, a haloalkyl or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein u is 1 or 2.

[0075] Another embodiment provides a compound of formula (III) or a salt thereof, a stereoisomer, or a tautomer, where a is 0 and b is 1.

[0076] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where a is 1 and b is 0.

[0077] Another aspect is that the compound of formula (III) has the structure: [ka] The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer having the above characteristics.

[0078] Another aspect is L 1 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer selected from -(CH2)2-, -(CH2)3-, or -(CH2)4-.

[0079] Another aspect is L 1 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)3-.

[0080] Another aspect is L 4The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer selected from -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, or -(CH2)5-. Another embodiment is L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)- or -(CH2)2-. Another embodiment is L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)3-. Another embodiment is L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)4-. Another embodiment is L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)5-.

[0081] Another aspect is L 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, selected from -(CH2)3-, -(CH2)4-, or -(CH2)5-. Another embodiment is L 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)3-. Another embodiment is L 5 The present invention provides a compound of formula (III) having -(CH2)4-, or a salt thereof, stereoisomer, or tautomer. Another embodiment is L 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -(CH2)5-.

[0082] Another aspect is R 3 , R 4 or R 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer selected from substituent (a).

[0083] Another aspect is R 3 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein R is hydrogen. 3The present invention provides a compound of formula (III) or a salt thereof, a stereoisomer, or a tautomer, wherein a is hydrogen, a is 0, and b is 1.

[0084] Another aspect is R 3 ga-L 3 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -Z.

[0085] Another aspect is R 4 However, -(NH) m -L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -Z. Another embodiment provides R 4 However, -(O) m -L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -Z.

[0086] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where m is 0.

[0087] Another aspect is L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein is an alkylene, and the carbon atoms of the alkylene are further substituted with a second Z. Another embodiment is L 4 Alkilen is C 2~5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkylene. In another embodiment, the second Z is -(CH2) q N[(CH2) p SO3 - ] t The present invention provides a compound of formula (III), or a salt thereof, stereoisomer, or tautomer.

[0088] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where t is 3, q ​​is 2 to 6, and p is 2 to 4.

[0089] Another aspect is R 5ga-L 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -A.

[0090] Another aspect is R 3 , R 4 or R 5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer selected from substituent (b).

[0091] Another aspect is L 4 C 2~5 It is an alkylene, and Z is -(CH2). q N[(CH2) p SO3 - ] t The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where q is 0.

[0092] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 2 to 5. Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 3. Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 4.

[0093] Another aspect is L 4 C 2~5 It is an alkylene, and Z is -(CH2) q N[(CH2) p PO3 - ] t The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 2 to 5 and t is 3. Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 3. Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 4.

[0094] Another aspect is L4 C 2~5 It is an alkylene, and Z is -(CH2) q NR b (CH2) p CH(SO3 - The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where q is 2 and q is 0.

[0095] Another aspect is R b The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkyl or heteroalkylene optionally substituted with -CO2H.

[0096] Another aspect is R b The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein the compound is hydrogen.

[0097] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 2 to 5.

[0098] Another aspect is L 4 C 2~5 It is an alkylene, and Z is -(CH2). q NR b [(CH2) p PO3 - The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where q is 2 and q is 0.

[0099] Another aspect is R b The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkyl or heteroalkylene optionally substituted with -CO2H.

[0100] Another aspect is R b The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, wherein the compound is hydrogen.

[0101] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where p is 2 to 5.

[0102] Another aspect is L 4 However, C 1~5 It is an alkylene or heteroalkylene, and Z is -C(O)OH or -(CH2). q (OCH2CH2) v Ure 22 The present invention provides a compound of formula (III), or a salt thereof, stereoisomer, or tautomer.

[0103] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where q is 1 to 3 and v is 1 to 3.

[0104] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where m is 1.

[0105] Another aspect is L 4 C 1~5 It is an alkylene, and Z is -SO3 - or -CH(SO3 - The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is 2.

[0106] Another aspect is L 4 C 2~5 It is an alkylene, and Z is -(CH2). q N[(CH2CH2O) v CH2CH2OR 22 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where q is 0 and v is 1 to 3.

[0107] Another aspect is R 4 ga-(NH) m -L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -A.

[0108] Another aspect is R4 ga-(O) m -L 4 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is -A.

[0109] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where m is 0.

[0110] Another aspect is L 4 However, C 1~5 The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, which is an alkylene or heteroalkylene.

[0111] Another aspect is that A, [ka] The present invention provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer selected from the group consisting of the above.

[0112] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, where M is Si or Ge.

[0113] Another embodiment provides a compound of formula (III) or a salt thereof, stereoisomer, or tautomer, selected from the group consisting of: [ka] [ka]

[0114] In certain embodiments, compounds of formula (0) are provided herein, comprising (a) an unsubstituted phthalocyanine, (b) an axial silicon-containing ligand having a conjugateable group A', and (c) a silicon atom coordinated by an axial silicon-containing ligand having a water-soluble group Z that is not a conjugateable group.

[0115] One embodiment provides a compound or a salt, stereoisomer or tautomer thereof comprising (a) an unsubstituted phthalocyanine, (b) a first axial silicon-containing ligand containing a conjugateable group, and (c) a silicon atom coordinated by a second axial silicon-containing ligand containing a water-soluble group but not containing a conjugateable group, wherein the chemical structures of the first and second axial ligands are different. Another embodiment provides a compound or a salt, stereoisomer or tautomer thereof wherein the axial silicon-containing ligand having a conjugateable group further comprises a water-soluble group. Another embodiment provides a compound or a salt, stereoisomer or tautomer thereof wherein the water-soluble group is a group containing one or more polar and / or ionic substituents. Another embodiment provides compounds or salts thereof, stereoisomers or tautomers thereof, in which one or more polar and / or ionic substituents on a water-soluble group are selected from carboxylate (-CO2), poly(ethylene glycol), sulfonate (-SO3H) group, sulfonyl (-SO2H) group, sulfate (-SO4) group, hydroxyl (-OH) group, phosphate (-OPO3H) group, phosphonate (-PO3H) group, amine (-NH2) group, and optionally substituted quaternary nitrogen. Another embodiment provides compounds or salts thereof, stereoisomers or tautomers thereof, in which one or more polar and / or ionic substituents on a water-soluble group are selected from trivalent or tetravalent nitrogen-containing groups, tris-sulfoalkyl quaternary ammonium, tris-sulfonate quaternary ammonium, bis-sulfoalkylamine, bis-sulfonateamine, or bis-alkoxypolyethylene glycolamine. Another embodiment involves an axial silicon-containing ligand having a water-soluble group, [ka] [R 6 and R 7Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H or -L 8 -Z is, R 9 is, -L 9 -H, -(NH) n -L 9 -Z or -(O) n -L 9 -Z is, R 10 is, -L 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z, where R 8 , R 9 and R 10 At least one of these is a group containing Z, Z is a water-soluble group, L 2 is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene. L 8 , L 9 and L 10Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylenearalkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. c is either 0 or 1. d is either 0 or 1. n is either 0 or 1. If d is 1, then c is 0, If n is 1, then c is 1, However, R 6 and R 7 Both are methyl, L 2 If is propylene, c is 1, and d is 0, then L 8 , L 9 and L 10 [Each of these is not propylene] The present invention provides a compound or a salt thereof, a stereoisomer, or a tautomer having the structure shown.

[0116] Another embodiment involves an axial silicon-containing ligand having a water-soluble group, [ka] [R 6 and R 7 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H or -L 8 -Z is, R 9 is, -L 9 -H, -(NH) n -L 9 -Z or -(O) n -L 9 -Z R 10 is, -L 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z, where R 8 , R 9 and R 10 At least one of these is a group containing Z, Z is a water-soluble group, L 2is an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, or optionally substituted heteroalkenylene. L 8 , L 9 and L 10 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylenearalkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. c is either 0 or 1. d is either 0 or 1. n is either 0 or 1. If d is 1, then c is 0, If n is 1, then c is 1. The present invention provides a compound or a salt thereof, a stereoisomer, or a tautomer having the structure shown.

[0117] Another aspect is formula (XX): [ka] [M is a metal or metalloid, Each Y is selected independently, and Y is, [ka] And, L is a member selected from the group consisting of direct bonds or covalent bonds, the covalent bonds having 1 to 60 atoms selected from the group consisting of C, N, P, O, and S, being linear or branched, cyclic or heterocyclic, saturated or unsaturated, and L may have additional hydrogen atoms to satisfy the valence, and the bonds contain any combination of ether, thioether, amine, ester, carbamate, urea, thiourea, oxy or amide bonds, or single, double, triple or aromatic carbon-carbon bonds, or phosphorus-oxygen, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen or nitrogen-platinum bonds, or aromatic or heteroaromatic bonds. Q is a reactive or activatable group. R 6 and R 7 Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R 8 , R 9 or R 10 This is selected from substituent (a) or substituent (b), (a)R 8 is hydrogen, -L 8 -H, -L 8 -A or -L 8-Z is, R 9 is, -L 9 -H, -L 9 -A, -(NH) n -L 9 -Z or -(O) n -L 9 -Z is, R 10 is, -L 10 -AL 10 -Z is, (b)R 8 and R 9 These are connected by a join, -L 9 -Z is substituted, forming a heterocycline, R 10 is, -L 10 -H or -L 10 -Z is, However, R 8 , R 9 and R 10 At least one of these is a group containing Z, Z is a water-soluble group which may be optionally substituted with A or L'-A. L 8 , L 9 and L 10 Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z. Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene. A is a reactive group capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the second part, or a protected form thereof or a reacted form thereof. c is either 0 or 1. d is either 0 or 1. n is either 0 or 1. However, if d is 1, then c is 0, and if n is 1, then c is 0. The present invention provides phthalocyanine dyes or salts thereof, stereoisomers, or tautomers having the same properties.

[0118] In some embodiments, M is Si or Ge.

[0119] In some embodiments, each group Z is -C(O)OH, -(CH2) q (OCH2CH2) v (CH2) q C(O)OH, -(CH2CH2O) v (CH2) p C(O)OH, -(CH2) q (OCH2CH2) v Ure 22 , -(CH2CH2O) v (CH2) p Ure 22 , -(CH2) q (OCH2CH2) v SR 22 , -(CH2CH2O)v (CH2) p SR 22 、 -O(CH2) v N[(CH2CH2O) n CH2CH2OR 22 ] t 、 -(CH2) q (OCH2CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t 、 -(CH2CH2O) m (CH2) p N[(CH2CH2O) w CH2CH2OR 22 ] t 、 -NH2、 -(CH2) q N[(CH2CH2O) v CH2CH2OR 22 ] t 、 -(CH2) q NR b [(CH2CH2O) w CH2CH2OR 22 ] u 、 -(CH2) q N[(CH2) p (OCH2CH2) v OR 22 ] t 、 -(CH2) q N[(CH2) p SO3H] t 、 -(CH2) q NR b [(CH2) p SO3H] u 、 -(CH2) q NR b (CH2) p CH(SO3H)2、 -(CH2) q N[(CH2) p S(O) u OH] t, -(CH2) q N[(CH2) p OSO3H] t , -(CH2) q (OCH2CH2) v (CH2) q SO3H, -(CH2) q (OCH2CH2) v (CH2) q S(O) u OH, -(CH2) q (OCH2CH2) v (CH2) q OSO3H, -SO3H, -CH(SO3H)2, -OSO3H, -S(O) u OH, -PO3H, -CH(PO3H)2, -(CH2) q N[(CH2) p PO3 - ] t , -(CH2) q (OCH2CH2) v (CH2) q PO3H, -(CH2) q N[(CH2) p OPO3H] t , -OPO3H, -(CH2) q (OCH2CH2) v (CH2) q P(O)(OH)2, -(CH2) q N[(CH2) p P(O)(OH)2] t , -P(O)(OH)2, Glutamic acid, aspartic acid, histidine, 1,3-beta-glucan and 1,4-beta-glucan were independently selected. Each R 22These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, an alkyl which may be optionally substituted with -CO2H, a heteroalkylene which may be optionally substituted with -CO2H, a haloalkyl or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0120] In some embodiments, each group Z is independent, (CH2) q (OCH2CH2) v Ure 22 , (CH2) q O(CH2) v N[(CH2CH2O) w CH2CH2OR 22 ] t , -(CH2) q N[(CH2) p (OCH2CH2) v Ure 22 ] t , -(CH2) q N[(CH2) p SO3H] t , -(CH2) q NR b [(CH2) p SO3H] u , -(CH2) q NR b [(CH2) p CH(SO3H)2] u , -SO3H, -CH(SO3H)2, -PO3H, -(CH2) q N[(CH2) p PO3H] t , -(CH2)q NR b [(CH2) p PO3H] u , or -(CH2) q NR b (CH2) p Selected from CH(PO3H)2, Each R 22 These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R b These are independently hydrogen, alkyl, haloalkyl, or cycloalkyl. Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

[0121] In some embodiments, each base A is independent, -C(O)OR 11 , -NR 12 R 13 , -NHC(O)R 14 , -C(O)R 15 , -OR 16 , -SR 16 , -OS(O)2R 17 , -OP(OR 18 )(NR 19 R 20 ), -N=C=O; -N=C=S, -SC≡N, -SO2-F, -SO2-Cl, -SO2-Br, -S-SR 21 , or Selected from 5-membered or 6-membered dioxosubstituted heterocyclines, Each R 11R is independently hydrogen, alkyl, haloalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl, and each R 11 Each of these may be independently replaced by one to five groups selected from halo, -SO3H, and -SO2F. Each R 12 These are independently hydrogen, alkyl, or haloalkyl, Each R 13 is an aryl or heteroaryl, and each R 13 Each of these may be independently and optionally replaced by one to five groups selected from halo, -SO3H, and -SO2F, or optionally, R 12 and R 13 It may also form a cyclic imide together with the bonded nitrogen. Each R 14 These are independently optionally substituted haloalkyl or optionally substituted aralkyl, Each R 15 Each is an aryl that may be independently substituted with one to five groups that are a halo, heterocyclyl, -SO3H, or -SO2F. Each R 16 Each is an aryl that may be independently substituted with 1 to 5 groups, each independently being a halo or heterocyclyl. Each R 17 Each is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each heterocyclyl, aryl, or heteroaryl is independently a halo, -SO3H, -SO2F, and -C(O)OR c It may be arbitrarily replaced by one to five elements selected from, Each R cThese are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl, R 18 , R 19 and R 20 Each of these is independently an optionally substituted alkyl or optionally substituted haloalkyl, R 21 It is a heteroaryl compound.

[0122] In some embodiments, each base Y is independent, [ka] Selected from.

[0123] One embodiment is given by formula (XXa): [ka] The present invention provides a phthalocyanine dye having the positional chemistry shown.

[0124] One embodiment is given by formula (XXb): [ka] This provides a phthalocyanine dye having the properties of [the specified material].

[0125] Another embodiment is that the MY group operates independently. [ka] [ka] We provide a compound of formula (XX) selected from the group consisting of the following.

[0126] In some embodiments, the compound of formula (XX) is selected from the compounds in Table 2B. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12]

[0127] The compounds of this disclosure contain one or more chiral centers and may therefore occur as racemic compounds and racemic mixtures, enantiomerically concentrated mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers. The compounds of this disclosure may exist in the form of isomers (e.g., enantiomers, diastereomers) due to the properties of the chiral centers or due to restricted rotation.

[0128] It will be understood that if a compound of the present disclosure contains two or more chiral centers, there are often several diastereomers and enantiomers of the exemplified structures. Pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof are intended to be within the scope of the present disclosure. If a compound contains stereochemistry, it is referred to as "(racemic)" or "rac" if the stereoisomers are not separated, and as "(R)" or "(S)" if the stereoisomers are separated.

[0129] All isomers of the compounds of this disclosure, whether separated, pure, partially pure, or in a racemic mixture, are included within the scope of this disclosure. The purification of such isomers and the separation of such isomer mixtures can be achieved by various methods. For example, a mixture of diastereomers can be separated into individual isomers by chromatographic processes or crystallization, and a racemic compound can be separated into its respective enantiomers by chromatographic processes in the chiral phase or by resolution.

[0130] The compounds of this disclosure encompass all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and mixtures thereof. The compounds of this disclosure may also be represented in multiple tautomers, in which case this disclosure explicitly encompasses all tautomers of the compounds described herein, even if only a single tautomer may be represented. Furthermore, if the terms used in this disclosure encompass a group that can be tautomerized, all tautomers are explicitly encompassed thereunder. For example, hydroxy-substituted heteroaryls include 2-hydroxypyridine and 2-pyridone, 1-hydroxyisoquinoline and 1-oxo-1,2-dihydroisoquinoline, etc. All such isomeric forms of such compounds are explicitly encompassed in this disclosure.

[0131] The compounds of this disclosure include the compounds themselves and, where applicable, their salts, solvates, solvates of salts, and prodrugs. Salts for the purposes of this disclosure are preferably pharmaceutically acceptable salts of the compounds according to this disclosure. Salts that are not suitable for pharmaceutically use on their own but can be used, for example, for the isolation or purification of the compounds according to this disclosure are also included. Salts may be formed, for example, between an anion and a positively charged substituent (e.g., amino) on the compounds described herein. Suitable anions include chlorides, bromides, iodides, sulfates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, and acetates. Similarly, salts may also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on the compounds described herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations, such as tetramethylammonium.

[0132] This disclosure also encompasses suitable isotopic variants of compounds conforming to this disclosure, whether radioactive or not. An isotopic variant of a compound conforming to this disclosure is understood to mean a compound in which at least one atom in the compound conforming to this disclosure is replaced by another atom having the same atomic number but a different atomic mass than that which occurs naturally or primarily. Examples of isotopes that may be incorporated into compounds conforming to this disclosure include those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I. Certain isotopic variants of compounds relating to this disclosure, particularly those incorporating one or more radioactive isotopes, may be useful, for example, for studying the mechanism of action or the distribution of active compounds in the body. 3 H, 14 C and / or 18 Compounds labeled with 1F isotopes are suitable for this purpose. Furthermore, the incorporation of isotopes, such as deuterium, can lead to certain therapeutic benefits as a result of greater metabolic stability of the compound, e.g., an extension of the half-life in the body or a reduction in the required active dose. In some embodiments, hydrogen atoms of the compounds described herein can be replaced with deuterium atoms. In certain embodiments, “deuterated,” as applied to a chemical group, refers to a chemical group that isotopeally enriched with substantially greater amounts of deuterium than its natural abundance, unless otherwise specified. Isotope variants of compounds according to this disclosure can be prepared by various methods, including, for example, those described below and in the examples, using specific reagents and / or corresponding isotope modifications of the starting compounds.

[0133] In certain embodiments, the phthalocyanine dye compound of formula (I) is used, unconjugated or not, as a free dye for biomedical imaging, including magnetic resonance imaging (MRI), fluorescence imaging, positron emission tomography (PET), and photoacoustic imaging. In certain embodiments, a kit comprising the phthalocyanine dye compound of formula (I) and instructions for its use is provided herein. In certain embodiments, a kit comprising the phthalocyanine dye compound of formula (I) and additional reagents, such as additional detection reagents, references or standards, luminescence standards, enzymes, antibodies, enzyme inhibitors, or solvents, is provided herein.

[0134] The phthalocyanine dye compounds provided herein are generally photoactivatable dyes that absorb at wavelengths between 600 nm and 810 nm. In some embodiments, the wavelengths at which the phthalocyanine dye compounds are absorbed and excited are between approximately 600 nm and 810 nm, between approximately 640 nm and 750 nm, or between approximately 660 nm and 710 nm. In some embodiments, the wavelengths at which the phthalocyanine dye compounds are absorbed and excited are approximately 650 nm, 660 nm, 670 nm, 680 nm, 690 nm, or 700 nm. In some embodiments, the maximum wavelength for absorption is approximately 690 nm, approximately 680 nm, approximately 675 nm, or approximately 670 nm or less.

[0135] B. Phthalocyanine pigment compound conjugate Compositions and combinations are provided that contain a phthalocyanine dye compound as described herein, conjugated to a target molecule, for example, a target molecule on the surface of a cell or pathogen. In some embodiments, the conjugate contains a phthalocyanine dye compound as described herein, conjugated to a biomolecule, for example, an antibody, antibody fragment, antibody-like molecule, DNA probe, avidin, streptavidin, lipid, biochemical analog, polymer, peptide, or drug. In some embodiments, the conjugates and combinations provided are to be used in the methods and uses described herein.

[0136] In some embodiments, conjugates of phthalocyanine dye compounds described herein, for example, compounds of formula (X), formula (0), formula (I), or formula (II) conjugated to a targeting molecule, are used, for example, in methods of treatment to inhibit and / or kill the growth of cells, such as cancer tumor cells. In some embodiments, conjugates of phthalocyanine dye compounds described herein, for example, compounds of formula (X), formula (0), formula (I), or formula (II) conjugated to a targeting molecule, are used in imaging methods. Thereafter, the conjugate binds to a target, such as on cells (e.g., certain types of tumor cells) or pathogens, as a result of the targeting molecule, and when the compound of formula (X), formula (0), formula (I), or formula (II) in the conjugate is exposed to light of an appropriate wavelength, imaging of the targeted cell type is possible. Such imaging can be used in conjunction with or separately from treatments using the conjugate.

[0137] In some embodiments, the conjugate's targeting molecule binds to target molecules expressed on the surface of cells or pathogens, such as proliferating cells, cancer cells, hyperplastic cells, tumor cells, cells in the tumor microenvironment (TME), immune system cells, neurons, or pathogens. In some embodiments, the cells are stem cells, proliferating cells, hyperplastic cells, or cells infected with a pathogen. In some embodiments, the pathogens are selected from viruses, bacteria, fungi, biofilms, and other prokaryotic cell lines. In some examples, the targeting molecule in the provided composition binds to target molecules on the surface of certain cancer or tumor cells or cells in the TME. In some embodiments, the immune system cells are leukocytes, such as neutrophils, eosinophils, basophils, lymphocytes, or monocytes. In some embodiments, the targeting molecule binds to target molecules expressed on the surface of one or more immune cells, such as lymphocytes (T cells, B cells, and NK cells), neutrophils and / or monocytes, or macrophages. In some embodiments, the targeting molecule in the provided composition binds to a target molecule expressed on the surface of immunosuppressive cells, such as TAMs, tDCs, MDSCs, TANs, CAFs, and / or regulatory T cells (Tregs). In some embodiments of the provided composition, the targeting molecule binds to an immune checkpoint inhibitor on the surface of immunosuppressive cells. In some embodiments, the targeting molecule binds to a target molecule on the surface of a neuron, such as a peripheral nervous system neuron or a central nervous system neuron. In some embodiments, the neuron is a nociceptor, such as a thermal nociceptor, a mechanonociceptor, a cheminonociceptor, or a polymorphic nociceptor. In some embodiments, the targeting molecule binds to a pathogen, such as a virus, bacteria, fungi, biofilm, or other prokaryotic cell lineage. In some embodiments, the pathogen is a Gram-negative or Gram-positive bacterium.

[0138] In some embodiments, the target molecule to which the stable conjugate targeting molecule binds includes antigens, polypeptides, peptides, lipids, or carbohydrates, or combinations thereof. In some embodiments, the target molecule is a cell surface molecule.

[0139] In some embodiments, one or more target molecules include cell membrane phospholipids, prokaryotic peptidoglycans, bacterial cell envelope proteins, viral capsid proteins, 1-40-β-amyloid, 1AR, 2AR, 4-1BB (CD137), 5AC, 5'-nucleotidase, 5T4, ACTHR, activating factor IX, activin receptor-like kinase 1, ACVR2B, adenocarcinoma antigen, ALK, alpha-4-integrin, alpha-5-be Alpha-3 integrin, alpha-5-beta-5 integrin, alpha-fetoprotein (AFP), aminopeptidase N, amyloid, Ang-2, angiopoietin 2, angiopoietin 3, ANPA, ANPB, anthrax protective antigen, anthrax toxin, anti-alpha-1 fetoprotein, AOC3, AOC3 (VAP-1), APA, APN, APP, AT1, AXL, B1, B2, B7-DC, B7-H3, Bacillus anthrax Anthrax) Bacillus anthrax, bacterial cell envelope protein, BAFF, BAFF-R, BAGE1, BAGE2, B cell receptor BB1, BB2, BB4, BCMA, BCR complex, Bcr-Abl, beta-amyloid, B1, B lymphoma cell, bombesin receptor, BRAF, BRAF(V600E), BRCA, BTK, C1s, C242 antigen, C5, CAIX, calcitonin gene-related peptide (CGRP), calcitonin gene-related peptide alpha, calcitonin receptor, cancer antigen 125 (CA125), canine (Canis lupus) (familiaris) IL31, Caprin-1, Carbonic anhydrase 9 (CA-IX), Cardiac myosin, CCK1, CCK2, CCL11 (Eotaxin-1), CCR2, CCR4, CCR5, CD2, CD3, CD3 epsilon, CD3 T cell coreceptor, CD4, CD5, CD6, CD7, CD10, CD11, CD11a, CD13, CD14, CD15, CD18, CD19, CD20, CD22, CD23 (IgE receptor), CD25, CD27, CD28, CD30 (TNFRSF8), CD33, CD34, CD37, CD38, CD40, CD41 (Integrin alpha-IIb), CD44, CD44 v6, CD45, CD47, CD51, CD52, CD68, CD70, CD74, CD79B, CD80, CD90, CD97B, CD123, CD125, CD133,CD134 / OX40 / TNFRSF4, CD147 (Basidine), CD154 (CD40L), CD200, CD206, CD271, CD276, CD276 / B7-H3, CD278 (also known as ICOS), CD319, CDK4 / 6, CDS, CEA (carcinoembryonic antigen), CEACAM1, CEACAM3, CEACAM5, CEACAM6, CEA-related antigen, cell membrane phospholipid, cell surface plectin-1, cell surface annexin-1, CFD, chemokine receptor, c-KIT, claudin 18 isoform 2, CLDN18.2, Clostridium difficile Difficile), Agglutination Factor A, c-Met, Blood Coagulation Factor III, Complement C5a, Cripto-1, CRLR, CSF1, CSF1R, CSF2, CTGF, CTLA-4, CXCR2, CXCR4 (CD184), CXCR4 Antagonist, Cytomegalovirus, Cytomegalovirus Glycoprotein B, Dabigatran, DCC, Dendritic Cell-Associated Lectin 2, DLL3, DLL4, DPP4, DR5, Escherichia coli Shiga Toxin 1, Escherichia coli Shiga Toxin 2, E2 Glycoprotein, Ebola Virus Glycoprotein, EGFL7, EGFR / ERBB1 / HER1, EGFR Extracellular Domain III, EGFRvIII, EML4-ALK, EMR1, Endoglin, Endosialin, Endothelial Cell Anxa-1, Endotoxin, EP2, EP4, EpCAM, EphA2, Ephrinrigan Ephrin receptor, Ephrin receptor A3, Escherichia coli, ET receptor, F protein of respiratory syncytial virus, factor X, FAP, FAS-ligand, FCGRT, FGF23, FGFR, FGFR2, fibrin II, beta chain, fibronectin, fibronectin ED-B, fibronectin extradomain-B, folate hydrolase, folate receptor 1, folate receptor alpha, folate-binding protein, Frizzled receptor, G protein-coupled receptor of family B (secretin receptor-like), GAGE1, GAGE2, GAGE3, GAGE4, ​​GAGE6, ganglioside (GD2, GD3, GM1 and GM2, etc.), GARP / inactive TGF-β complex, GCGR, GD2 ganglioside, GD3 ganglioside, GDF-8, gelatinase B, GITR (glucocorticoid-induced tumor necrosis factor receptor),GLP-1 receptor, glypican-3, GMCSF receptor α chain, GP120, gp72, gpA33, GP100, GPNMB, Family A G protein-coupled receptor (rhodopsin-like), Family C G protein-coupled receptor (metabotropic glutamate receptor-like), growth and differentiation factor 8, GUCY2C, hemagglutinin (HA), heparin sulfate, hepatitis B surface antigen, hepatitis B virus, HER1 / EGFR, H ER2 / ERBB2 / neu, HER2 / neu, HER3 / ERBB3, HER4, HGF receptor, histone complex, HIV-1, HLA-DR10β, HLA-DR antigen, HMFG, HNGF, HPV16 / 18 and E6 / E7 antigen, Hsp90, hTERT, human scattering coefficient receptor kinase, human TNF, human beta-amyloid, ICAM-1, ICAM-1(CD54), ICOSL, IgE, IgE Fc region, IGF-1 receptor (CD221), IGHE, ILGF2, ILT3, influenza A virus hemagglutinin, integrin α4β7, integrin α5β1, integrin αVβ3, integrin α4, integrin α4β7, integrin α5β1, integrin αIIbβ3, integrin αvβ3, integrin β7, interferon receptor, interferon α / β receptor, interferon gamma-inducible protein, interleukin-1 (IL-1), interleukin-1 alpha, interleukin-1β, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5 (IL-5), Interleukin-6 (IL-6), Interleukin-7 (IL-7), Interleukin-8 (IL-8), Interleukin-9 (IL-9), Interleukin-10 (IL-10), Interleukin-11 (IL-11), Interleukin-12 (IL-12), Interleukin-13 (IL-13), Interleukin-15 (IL-15), Interleukin-17 (IL-17), Interleukin-17A (IL-17A), Interleukin-17F (IL-17F), Interleukin-19 (IL-19), Interleukin-20, Interleukin-22, Interleukin-23, Interleukin-23 (IL-23), Interleukin-23A,Interleukin receptors (e.g., IL-2R, IL-3R, IL-4Rα, IL-6R, IL-11R, IL-13R, IL-31RA), ITGA2 (CD49b), ITGAM, ITGB2 (CD18), JAK1, JAK2, kallikrien-9, kallikrien, KIR, KIR2D, KIT, LAG-3, Lewis Y antigen, LFA-1 (CD11a), LH receptor (LHR), luteinizing-releasing hormone receptor, LINGO-1, lipoteichoic acid, LIV-1, LOXL2, LPA1 LRRC15, L-selectin (CD62L), LTA, LYPD3, MAC-1, MAGE1, MAGE2, MAGE3, MAGE4, ​​MART1, MASP-2, MCAM, MC1R, MCP-1, MCSF, MEK1, MEK2, Member 1 (SLITRK1), Member 2 (SLITRK2), Member 3 (SLITRK3), Member 4 (SLITRK4), Member 5 (SLITRK5), Member 6 (SLITRK6), Mesothelin, MET, Metalloproteinase, MIF, MS4A1, M SLN, MST1R (also known as RON), mTOR, MUC1 (episialin), MUC16, mucin CanAg, mucin, mucosal adrenergic cell adhesion molecule 1 (MAdCAM-1), mutant p53, mutant Ras, myelin-related glycoprotein, myostatin, NACP, NCA-90 (granule cell antigen), nectin-4, neprilysin, Neu (cell surface nucleolin), neuronal apoptosis-regulating proteinase 1, neuropilin-1 (NRP1), neuropilin-2, NG2, NGNA ganglioside, NK1, NK2, NK3, NKG2A, NMB-R, NOGO-A, Notch receptor, Notch-1, NRP1, NTR2, NTR3, nuC242, NY-ESO-1, OT-R, OX40, oxLDL, Pseudomonas aeruginosa type III secretory system, p32 (p32 / gC1qR / HABP1), p75, p97 melanoma antigen, PAC1, PAR1, Patched (PTCH), PCDC1, PCSK9, PD-1, PDFG receptor, PDGF receptor, PDGF-R α, PD-L1, PDT, PEM antigen, phosphatidylserine, platelet-derived growth factor receptor beta, plexin, PMSA, inhibitorProkaryotic peptidoglycan, prostate cancer cells, protease-cleaved collagen IV, protein tyrosine kinase 7, proteinase 3, PSA, Pseudomonas aeruginosa, PSMA, PTK7, purine P2X family (e.g., P2Xl-5), rabies virus G glycoprotein, rabies virus glycoprotein, RAMP1, RAMP2, RAMP3 patched, RANKL, RBB3, respiratory syncytial virus, RET, RET receptor, RGMA, RHD, rhesus monkey factor, operculum (root plate) specific spongein 3, ROR1, ROS, ROS1, RSVFR, RTN4, Staphylococcus aureus (S. aureus) alpha toxin, Staphylococcus aureus (S. aureus) two-component leucocsis, sclerostin, SDC1, selectin P, serum amyloid A protein, serum amyloid P component, SK1 antigen, SLAMF7, SMO, Smoothund, SOST, sphingosine-1-phosphate, SRC, sst1, sst2A, sst2B, sst3, sst4, sst5, Staphylococcus aureus (Staphylococcus aureus), Staphylococcus aureus (Staphylococcus aureus) alpha toxin, STEAP1, TAG-72, tau protein, T cell receptor (TCR), TEM1, TEM, tenascin C, tenascin glycoprotein, TFPI, TGFBR2, TGFBR1, TGF-β, Tie-1, Tie-2, TIGIT, TIM-3, TNF, TNFR superfamily member 4, TNF-α, TR1, TRAIL-R1, TRAIL-R2, TRAP, Trk-A, Trk-B, Trk-C, TROP-2, TRPA, TRPC, TRPM, TRPML, TRPP (for example, TRPV1-6, TRPA1, TRPC1-7, TRPM1-8, TRPP1-5, TRPML1-3), TRPV, TSC1, TSC2, TSH receptor, TSLP, tumor antigen CTAA16.88, tumor necrosis factor alpha (TNF-α), tumor-specific glycosylation of MUC1, tumor-associated glycoprotein 72 (TAG72), TWEAK receptor, TYRP1 (glycoprotein 75), VEGF receptor (VEGFR1 or Flt-1, VEGFR2 or FLK-1 / KDR and VEGF-3 or FLT-4), VEGFA, vimentin,The following are selected from viral capsid proteins, voltage-gated ion channels, VPAC1, VPAC2, VSIR, VWF, Wilms tumor 1, Y1 receptor, Y2 receptor, Y4 receptor, Y5 receptor, and Zaire Ebola virus glycoprotein.

[0140] In some embodiments, one or more target molecules, for example, cell surface target molecules, include HER1 / EGFR, HER2 / ERBB2, CD20, CD25 (IL-2Ra receptor), CD33, CD52, CD133, CD206, CEA, CEACAM1, CEACAM3, CEACAM5, CEACAM6, cancer antigen 125 (CA125), alpha-fetoprotein (AFP), Lewis Y, TAG72, caprin-1, mesothelin, PDGF receptor, PD-1, PD-L1, CTLA-4, IL-2 receptor, vascular endothelial growth factor ( VEGF, CD30, EpCAM, EphA2, Glypican-3, gpA33, Mucin, CAIX, PSMA, Folate-binding protein, Gangliosides (GD2, GD3, GM1 and GM2, etc.), VEGF receptor (VEGFR), VEGFR2, VEGF-A, Integrin αVβ3, Integrin α5β1, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, RANKL, FAP, Tenascin, AFP, BCR complex, CD3, CD18, CD44, CTLA-4, gp72, HLA-DR The following are selected from 10β, HLA-DR antigen, IgE, MUC-1, nuC242, PEM antigen, metalloproteinase, ephrin receptor, ephrin ligand, HGF receptor, CXCR4, CXCR4, bombesin receptor, SK1 antigen, Bcr-Abl, RET, MET, TRKB, TIE2, ALK, ROS, EML4-ALK, ROS1, BRAFV600E, SRC, c-KIT, PDGFR, mTOR, TSC1, TSC2, BTK, KIT, BRCA, CDK4 / 6, JAK1, JAK2, BRAF, FLT-3, MEK1, MEK2, and SMO. In some embodiments, one or more cell surface target molecules are HER1 / EGFR, HER2, PD-L1, CD25, EpCAM, EphA2, FAP, CD206, CD20, CD44, CD133, mesothelin, MUC1, PSMA, glypican-3, and carcinoembryonic antigen (CEA). In some embodiments, the cell surface target molecules are one or more of CD25, CEA, FAP, HER1 / EGFR, HER2, MUC1, PD-L1, or PSMA.

[0141] When used herein, “dye-containing conjugate” or “conjugate” means having a targeting molecule linked to a phthalocyanine dye compound provided herein, for example, a phthalocyanine dye compound of formula (X), formula (0), formula (I), or formula (II). In some embodiments, at least a portion of the targeting molecule is a protein, glycoprotein, antibody, antibody fragment, aphibody, antigen, antigen-binding fragment, peptide, polypeptide, tissue-homing peptide, small molecule, polymer synthesis molecule, polymer nanoparticle, liposome, enzyme substrate, hormone, neurotransmitter, cellular metabolite, viral particle, viral capsid, viral nanoparticle, bacterial particle, marker, cell, hapten, avidin, streptavidin, monomeric streptavidin, biotin, carbohydrate, oligosaccharide, polysaccharide, nucleic acid, deoxyribonucleotide, DNA fragment, RNA fragment, aptamer, nucleotide triphosphate, acycloterminator triphosphate, PNA, or a combination thereof. In some cases, the targeting molecule may include an antigen-binding molecule, such as an antibody or antibody fragment (e.g., an antigen-binding fragment), or a target molecule, such as another protein, peptide, or small molecule that binds to a target molecule on the surface of a cell. In some aspects, the exemplary conjugate contains a targeting molecule that is an antibody or antibody fragment. In some aspects, the exemplary conjugate contains a targeting molecule that is an antigen-binding fragment derived from an antibody, its functional equivalent, or an antibody fragment. In some examples, the targeting molecules in the provided conjugate include bispecific antibodies, scFv, single-domain antibodies (sdAb) or nanobodies, VHH, isolated single variable domains, affibody or z-domain structures, DARPin, monobodies, anticalin, affilin, affimer type 1 molecule, affimer type 2 molecule, affitin, alphabody, anticalin, avimer, fynomer, Knitz domain peptide, or nanoclamp.

[0142] In some embodiments, the targeting molecule binds directly or indirectly to a target molecule, such as an antigen or protein. For example, in some embodiments, the targeting molecule is a second binding molecule that binds to a first binding molecule capable of binding to the target molecule, such as an antigen or protein. For example, the targeting molecule may be a secondary antibody that binds to a primary antibody capable of binding to the first binding molecule, such as a protein or antigen, such as a cell surface protein or cell surface receptor. Thus, in some embodiments, the phthalocyanine dye is conjugated to the secondary antibody.

[0143] In some embodiments, the targeting molecule is an activatable cell-permeable peptide (ACPP) comprising an RGD polypeptide, iRGD polypeptide, Lyp-1 polypeptide, cripto-1 binding polypeptide, somatostatin receptor binding polypeptide, inhibitor-binding polypeptide, NGR polypeptide, iNGR polypeptide, or a polycation cell-permeable peptide (CPP) linked to a neutralizing polyanion via a cleavable linker.

[0144] In some embodiments, the targeting molecule is a viral particle, such as a virus-like particle, virus-like nanoparticle, or virus capsid. In some embodiments, the targeting molecule is a virus-like nanoparticle. In some embodiments, the virus-like nanoparticle is assembled from an L1 capsid protein. In some embodiments, the virus-like nanoparticle is assembled from a combination of L1 and L2 capsid proteins. In some embodiments, the targeting molecule binds to and infects cells. In some embodiments, the targeting molecule is, for example, one described in WO2015042325.

[0145] In some embodiments, virus-like particles (VLPs) refer to roughly spherical or cylindrical morphologies that include a structured capsid-like structure, such as a regular arrangement of self-organizing L1 or L1 and L2 capsomeres, but do not contain a viral genome. In some embodiments, virus-like particles are morphologically and antigenically similar to true virions, but lack viral genetic material, such as viral nucleic acids, and are therefore non-infectious. VLPs may be used to deliver drugs, such as prophylactic, therapeutic, or diagnostic agents, or encapsulated circular or linear DNA or RNA molecules to recipient cells.

[0146] In some embodiments, VLPs may have modified immunogenicity and / or antigenicity compared to wild-type VLPs. VLPs can be assembled, for example, from capsomeres having variant capsid proteins having modified immunogenicity and / or antigenicity. In some embodiments, variant capsid proteins having modified immunogenicity and / or antigenicity are naturally or synthetically modified by amino acids to reduce or hinder the recognition of the capsid protein by existing, for example, endogenous viral serotype-specific antibodies, such as being mutated, substituted, deleted, pegylated, or inserted. Variant capsid proteins may be human papillomavirus (HPV) L1 variants, non-human papillomavirus L1 variants, or papillomavirus L1 variants based on combinations of amino acids derived from different HPV serotypes.

[0147] In some embodiments, VLPs are papillomavirus VLPs. VLPs may be human papillomavirus VLPs, such as those derived from viruses capable of infecting humans, while in other embodiments, VLPs may be non-human papillomavirus VLPs. Examples of non-human VLPs include, but are not limited to, those derived from bovine papillomavirus, mouse papillomavirus, cotton rabbit papillomavirus, and macaque or rhesus monkey papillomavirus particles. In some embodiments, VLPs are assembled from bovine papillomavirus-like nanoparticles, such as type 1 virus-like nanoparticles, such as BPV L1 capsid protein or a combination of BPV L1 and BPV L2 capsid proteins. In some embodiments, capsid protein refers to protein monomers, some of which form capsomere oligomers. In some embodiments, capsomere refers to the basic oligomeric structural unit of the viral capsid, which is the protein outer covering that protects the viral genetic material. In some embodiments, the capsid protein may include the papillomavirus L1 major capsid protein and the papillomavirus L2 trace capsid protein. In some embodiments, the VLP contains only the L1 capsid protein, while in other embodiments, the VLP contains a mixture or combination of the L1 and L2 capsid proteins.

[0148] In some embodiments, the percentage of L1 capsid protein in virus-like particles is greater than the percentage of L2 capsid protein in virus-like particles. For example, in some embodiments, the percentage of L1 capsid protein in virus-like particles is 80% to 100% of the total number of capsid proteins in virus-like particles. In some embodiments, the percentage of L1 capsid protein in virus-like particles is at least or about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the percentage of L2 capsid protein in virus-like particles is 1% to 25% of the total number of capsid proteins in virus-like particles. For example, in some embodiments, the percentage of L2 capsid protein in the virus-like particle is at least or about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0149] In some embodiments, the virus-like particles contain 12–72 L2 proteins. In some embodiments, the virus-like particles contain 360 L1 proteins and 12–72 L2 proteins. In some embodiments, the capsid protein is assembled into virus-like nanoparticles having a diameter of 20–60 nm. For example, the capsid protein may be assembled into virus-like nanoparticles having a diameter of at least or about 20, 25, 30, 35, 40, 45, 50, 55, or 60 nm.

[0150] In some embodiments, the targeting molecule is DARPin (designed ankyrin repeat protein). Typically, DARPin is derived from natural ankyrin repeat proteins and binds to proteins including, for example, human receptors, cytokines, kinases, human proteases, viruses, and membrane proteins (Molecular Partners AG Zurich Switzerland; Chapter 5, "Designed Ankyrin Repeat Proteins (DARPins): From Research to Therapy," Methods in Enzymology, Vol. 503: IOC134 (2012); and "Efficient Selection of DARPins with Sub-nanomolar Affinities using SRP Phage Display," J. Mol. Biol. (2008)). See Volume 382, ​​pages 1211–1227, the full disclosures thereof are incorporated herein by reference. In some embodiments, DARPin is an antibody-mimetic protein having high specificity and high binding affinity to a target protein, which is prepared by genetic engineering. In some embodiments, DARPin has a structure containing at least two ankyrin repeat motifs, for example, at least three, four, or five ankyrin repeat motifs. DARPin may have any suitable molecular weight depending on the number of repeat motifs. For example, DARPin containing three, four, or five ankyrin repeat motifs may have molecular weights of about 10 kDa, about 14 kDa, or about 18 kDa, respectively.

[0151] In some embodiments, DARPin comprises a core portion that provides structure and a target-binding portion located outside the core that binds to a target. In some embodiments, the structural core comprises a conserved amino acid sequence, and the target-binding portion comprises a different amino acid sequence depending on the target.

[0152] In some embodiments, the targeting molecule is an affibody molecule. An "affibody" refers to a protein engineered to bind to a target protein or peptide with high affinity. In some examples, affibody mimics an antibody. Typically, an affibody molecule contains an alpha-helix, e.g., three alpha-helices, which contribute to binding to the target molecule. In some examples, the affibody protein scaffold is based on the B or Z domain of Staphylococcus protein A or a protein scaffold with amino acid substitutions thereof. Affibodies can be engineered and synthesized, and molecules with desired binding properties can be identified and selected, for example, using phage display. Affibody molecules are outlined by reference in Lofblom et al. (2010), FEBS Letters 584(12): pp. 2670–2680.

[0153] In some embodiments, the targeting molecules include adrenocorticotropic hormone (ACTH), angiotensin II, atrial sodium excretion increasing factor (ANF), bombesin, bradykinin, brain-derived neurotrophic factor (BDNF), bone morphogenetic protein 2 (BMP-2), bone morphogenetic protein 6 (BMP-6), bone morphogenetic protein 7 (BMP-7), bone morphogenetic protein 2 (BMP-2), calcitonin, cardiotrophin 1 (CT-1), CD22, CD40, cholecystokinin (CCK), ciliary neurotrophic factor (CNTF), CCL1-CCL28, CXCL1- CXCL17, XCL1, XCL2, CX3CL1, Crypt-1 binding peptide, Vascular endothelial growth factor (VEGF), Epidermal growth factor (EGF), Endothelin 1, Endothelin 1 / 3, FAS-ligand, Fibroblast growth factor 1 (FGF-1), Fibroblast growth factor 2 (FGF-2), Fibroblast growth factor 4 (FGF-4), Fibroblast growth factor 5 (FGF-5), Fibroblast growth factor 6 (FGF-6), Fibroblast growth factor 1 (FGF-7), Fibroblast growth factor 1 (FGF-10), Flt-3, Gastrin, Gastrin-releasing peptide (GR P), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage-stimulating factor (GM-CSF), glucagon-like peptide (GLP-1), hepatocyte growth factor (HGF), interferon alpha (IFN-a), interferon beta (IFN-b), interferon gamma (IFN-γ), insulin-like growth factor I (IGF-1), insulin-like growth factor II (IGF-2), interleukin I (IL-1), interleukin II (IL-2), interleukin III (IL-3), interleukin IV (IL-4), interleukin V (IL-5) L-5), interleukin 6 (IL-6), interleukin 7 (IL-7), interleukin 8 (IL-8), interleukin 9 (IL-9), interleukin 10 (IL-10), interleukin 11 (IL-11), interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 15 (IL-15), interleukin 17 (IL-17), interleukin 19 (IL-19), luteinizing hormone (LH), luteinizing-releasing hormone (LHRH), macrophage colony-stimulating factor (M-CSF),Monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 3a (MIP-3a), macrophage inflammatory protein 3b (MIP-3b), nerve growth factor (NGF), neuromedin B, neurotrophin 3 (NT-3), neurotrophin 4 (NT-4), neurotensin, neuropeptide Y, oxytocin, pituitary adenylate cyclase activating peptide (PACAP), platelet-derived growth factor AA (PDGF-AA), platelet-derived growth factor AB (PDGF-AB), platelet-derived growth factor BB (PDGF-BB), platelet-derived growth factor Growth factor CC (PDGF-CC), platelet-derived growth factor DD (PDGF-DD), netrin-1 (NTN1), netrin-2 (NTN2), netrin-4 (NTN4), netrin-G1 (NTNG1) and netrin-G2 (NTNG2), ephrin Al (EFNA1), ephrin A2 (EFNA2), ephrin A3 (EFNA3), ephrin A4 (EFNA4), ephrin A5 (EFNA5), semaphorin 3A (SEMA3A), semaphorin 3B (SEMA3B), semaphorin 3C (SEMA3C), semaphorin 3D (SEMA3D), semaphorin 3F (SEMA3F), Semaphorin 3G (SEMA3G), Semaphorin 4A (SEMA4A), Semaphorin 4B (SEMA4B), Semaphorin 4C (SEMA4C), Semaphorin 4D (SEMA4D), Semaphorin 4F (SEMA4F), Semaphorin 4G (SEMA4G), Semaphorin 5A (SEMA5A), Semaphorin 5B (SEMA5B), Semaphorin 6A (SEMA6A), Semaphorin 6B (SEMA6B), Semaphorin 6D (SEMA6D), Semaphorin 7A (SEMA7A), SLIT1, SLIT2, SLIT3, SLIT and NTRK-like family, member 1 (SLITRK1), SLIT and NTRK-like family, member 2 (SLITRK2), SLIT and NTRK-like family, member 3 (SLITRK3), SLIT and NTRK-like family, member 4 (SLITRK4), SLIT and NTRK-like family, member 5 (SLITRK5), SLIT and NTRK-like family, member 6 (SLITRK6), prostaglandin E2 (PGE2), RANTES, somatostatin-14, somatostatin-28, stem cell factor (SCF),The following are selected from stromal cell-derived factor 1 (SDF-1), substance P, thyroid-stimulating hormone (TSH), transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), thrombin, vasoactive intestinal peptide (VIP), Wnt1, Wnt2, Wnt2b / 13, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt7c, Wnt8, Wnt8a, Wnt8b, Wnt8c, Wntl0a, Wntl0b, Wnt11, Wntl4, Wntl5 or Wntl6, Sonic Hedgehog, Desert Hedgehog, and Indian Hedgehog.

[0154] In some embodiments, the targeting molecule is an antibody, antibody fragment, or functional equivalent (e.g., an affibody) of an antibody or antibody fragment that specifically binds to an antigen, such as a cell surface molecule on tumor cells or immune cells (one or more). Such antibodies include antibodies, affibo, or antigen-binding antibody fragments that are capable of binding to cell surface molecules, such as cell surface proteins, such as cell surface receptors, as described herein. In some cases, the antibody may bind to an antigen of a protein expressed on cells in a tumor, including a tumor-specific protein. In some cases, the antibody may bind to an antigen of a protein expressed on immune cells, such as lymphocytes (T cells, B cells, and NK cells), neutrophils, and / or monocytes or macrophages.

[0155] An antibody is a polypeptide ligand containing at least a light chain or heavy chain immunoglobulin variable region that specifically recognizes and binds to an antigen, such as an epitope of a tumor-specific protein. Generally, an antibody contains a heavy chain and a light chain, each of which has variable regions called the heavy chain variable (VH) region and the light chain variable (VL) region. Together, the VH and VL regions are involved in binding to the antigen recognized by the antibody.

[0156] Antibodies encompass intact immunoglobulins and antigen-binding antibody fragments, e.g., Fab fragments, Fab' fragments, F(ab)'2 fragments, single-chain Fv proteins ("scFv"), and disulfide-stabilized Fv proteins ("dsFv"). scFv proteins are fusion proteins in which the light chain variable region and heavy chain variable region of immunoglobulin are linked by a linker, while dsFv proteins are fusion proteins in which the chain is mutated to introduce a disulfide bond to stabilize chain association. The term also encompasses genetically modified forms, e.g., chimeric antibodies, e.g., humanized mouse antibodies, and heteroconjugate antibodies, e.g., bispecific antibodies. See also Pierce Catalog and Handbook, 1994–1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J. Immunology, 3rd edition, WH Freeman & Co., New York, 1997.

[0157] Typically, naturally occurring immunoglobulins have heavy (H) and light (L) chains interconnected by disulfide bonds. There are two types of light chains: lambda (λ) and kappa (κ). There are five main heavy chain classes or isotypes that determine the functional activity of antibody molecules: IgM, IgD, IgG, IgA, and IgE.

[0158] Each heavy and light chain contains a constant region and a variable region, also known as a “domain.” In combination, the heavy and light chain variable regions generally bind specifically to the antigen. The light and heavy chain variable regions may contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs.” The precise amino acid sequence boundaries of a given CDR or framework region (FR, the non-CDR portion of the variable region of the heavy and light chains) can be found in: Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., (1997), JMB Vol. 273, pp. 927-948 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol. Vol. 262: pp. 732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. Vol. 262, pp. 732-745 ("Contact" numbering scheme); Lefranc MP et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, 2003, Vol. 27 (No. 1): pp. 55-77 ("IMGT" numbering scheme); Honegger A and Pluckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001, Vol. 309 (No. 3): pp. 657-70 ("Aho" numbering scheme); and Martin et al., "Modeling antibody hypervariable loops: a combined algorithm The CDR can be determined using one of several known schemes, including the one described by the algorithm ("AbM" numbering scheme) in PNAS, 1989, Vol. 86 (No. 23): pp. 9268-9272. The sequences of various light or heavy chain framework regions are relatively conserved within species such as humans. The antibody framework region, a combined framework region of light and heavy chain components, works to position and align the CDR in three-dimensional space.

[0159] CDRs are typically involved in the binding of antigens to their epitopes. The CDRs on each chain are usually called CDR1, CDR2, and CDR3, sequentially numbered starting from the N-terminus, and are generally identified by the chain on which a particular CDR is located. Thus, VH CDR3 is located in the heavy chain variable domain of the antibody in which it is found, while VL CDR1 is a CDR1 derived from the light chain variable domain of the antibody in which it is found. Antibodies with different specificities, for example, different combination sites of different antigens, will have different CDRs. While CDRs vary from antibody to antibody, only a limited number of amino acid positions within a CDR are directly involved in antigen binding. These positions within a CDR are called specificity-determining residues (SDRs).

[0160] References to "VH" or "VH" refer to the variable region of the immunoglobulin heavy chain, encompassing those of Fv, scFv, dsFv, or Fab. References to "VL" or "VL" refer to the variable region of the immunoglobulin light chain, encompassing those of Fv, scFv, dsFv, or Fab.

[0161] Among the provided antibodies are antibody fragments. An "antibody fragment" refers to a molecule other than the intact antibody, containing a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments, but not limited to them, include Fv, Fab, Fab', Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments. Other antibody fragments or multispecific antibodies formed from antibody fragments include polyvalent scFv, bispecific scFv, or scFv-CH3 dimers. Antibody fragments can be produced by various techniques, but not limited to them, including proteolytic digestion of intact antibodies and production by recombinant host cells.

[0162] A "monoclonal antibody" is an antibody produced by a single clone of a B lymphocyte or by cells transfected with the light and heavy chain genes of a single antibody. Monoclonal antibodies are produced by methods known to those skilled in the art, for example, by creating hybrid antibody-forming cells from the fusion of myeloma cells with immunosplenic cells. Monoclonal antibodies include humanized monoclonal antibodies.

[0163] A "chimeric antibody" generally has a CDR that confers antigen-binding ability, derived from one species, e.g., a framework residue from human antibodies, and another species, e.g., a mouse antibody that specifically binds to mesothelin.

[0164] "Humanized" immunoglobulins are immunoglobulins that contain a human framework region and one or more CDRs derived from non-human (e.g., mouse, rat, or synthetic) immunoglobulins. The non-human immunoglobulin providing the CDRs is called the "donor," and the human immunoglobulin providing the framework is called the "acceptor." In some embodiments, the CDRs are derived from the donor immunoglobulin in the humanized immunoglobulin. Constant regions are not required to be present, but if they are present, they may be substantially identical to the human immunoglobulin constant region, e.g., at least about 85–90%, e.g., about 95% or higher. Thus, some humanized immunoglobulins are substantially identical to the corresponding portion of the natural human immunoglobulin sequence, except perhaps for the CDRs. "Humanized antibodies" are antibodies containing humanized light chain and humanized heavy chain immunoglobulins. Humanized antibodies bind to the same antigen as the donor antibody providing the CDRs. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of amino acid substitutions made from the donor framework. Humanized or other monoclonal antibodies may have further conserved amino acid substitutions that have substantially no effect on antigen-binding or other immunoglobulin functions. Humanized immunoglobulins can be constructed by genetic engineering (see, for example, U.S. Patent No. 5,585,089).

[0165] A “human” antibody (also called a “fully human” antibody) is an antibody that contains a human framework region and CDR derived from human immunoglobulin. In some embodiments, the framework and CDR are derived from the same human heavy and / or light chain amino acid sequence. However, a framework derived from one human antibody can be manipulated to contain a CDR derived from a different human antibody. A portion of human immunoglobulin may be substantially identical to a corresponding portion of the natural human immunoglobulin sequence.

[0166] "Specifically binding" refers to the ability of a molecule, such as an antibody or antigen-binding fragment, to specifically bind to an antigen, such as a tumor-specific antigen, compared to binding to an unrelated protein, such as a non-tumor protein, such as β-actin. In some embodiments, a molecule, such as an antibody or fragment, that is bound to a phthalocyanine dye molecule specifically binds to a target, such as a cell surface protein.

[0167] In some embodiments, a phthalocyanine dye molecule, for example, a phthalocyanine dye of formula (X), formula (0), formula (I), or formula (II), is conjugated to an antibody or an antigen-binding antibody fragment. For example, in some aspects, the conjugate is a phthalocyanine dye of formula (X) and an antibody or antigen-binding antibody fragment. In some aspects, the conjugate is a phthalocyanine dye of formula (0) and an antibody or antigen-binding antibody fragment. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and an antibody or antigen-binding antibody fragment. In some aspects, the conjugate is a phthalocyanine dye of formula (II) and an antibody or antigen-binding antibody fragment. Exemplary antibodies that can be conjugated to one or more dyes of formula (X), formula (0), formula (I), and / or formula (II) provided herein include 3F8, 8H9, AB122, ab75705, avagovomab, absicimab, abituzumab, abrazekimab, abrilumab, actoxumab, adalimumab, adecatumumab, ADG116, ADU-1604, aducanumab, afasebicumab, aferimomab, aftuzumab, AGEN1181, AGEN1884, AGX-115, AK104, AK105, aracizumab pegol, alemtuzumab, alirocumab, pentetate artumomab, amatsuximab, and AMG. 404, AMP-224, AMP-514, anatumomab mafenatox, anddecaliximab, anetumablavtansine, aniflorumab, anlukinzumab, anti-CD133, apolizumab, apultumab ixadotin, alsitumomab, alsitumomab Fab fragment, ascrinbakumab, aselizumab, atezolizumab, atidolotoxumab, atinumab, atorizumab (tocilizumab), ATOR-1015, atrolimumab, Avelumab, Adintuxizumab Vedotin, B72.3, Bapineuzumab, Basiliximab, Bavituximab, BCD-100, BCD-135, BCD-145, BCD-217, Vectumomab, Begeromab, Verantamab Mahodotin, Belimumab, Bemarituzumab, Benralizumab, Perlimatoxumab, Bermekimab, Versanlimab, Vertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, BGB-A333, BI 754091, Bisilomab, Bimaglumab, Bimekizumab, Viltamimab,Vibatuzumab, vibatuzumab meltansine, BL-8040, preserumab, blinatumomab, bronzvetomab, brosozumab, BMS-936559, BMS-986218, vococizumab, brazicumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, bronticutuzumab, brosumab, kabilizumab, camidanrumab tesirin, camrelizumab, canakinumab Cantuzumab meltansine, cantuzumab lavtansine, caplacizumab, capromab, capromab pendetide, carrumab, carotuximab, catumakisomab, cBR96-doxorubicin immune complex, CBT-502, CC-90002, CDC-022, sedelizumab, semiprimab, cergutuzumab amnaleukin, certolizumab pegol, cetrerimab, cetuximab, sibisatamab, silimutuzumab, sitatuzumab vogatox, sizutum Mab, crazakizumab, clenoliximab, cribatuzumab tetraxetan, CMAB302, codlituzumab, cofetuzumab peridotin, coltuximab labutancin, konatumumab, concizumab, cosflobiximab, cosiberimab, CP-870, 893, CR6261, crenezumab, chryzanlizumab, clotedumab, CS1001, CS1003, kusatuzumab, CX-188, dasetuzumab, dacrizumab, darotuzumab, dapylori Zumab pegol, daratumumab, dectrecumab, demicizumab, denintuzumab mahodotin, denosumab, depatuxizumab mahodotin, delrotuximab biotin, detumomab, dezamizumab, dinutuximab, ziridabumab, domaglozumab, dorulimomab aritox, dostalurimab, dorodizumab, DS-8201, durigotuzumab, durigotuzumab, dupilumab, durvalumab, ducidizumab, duvortuxizumab, eclomexima Eculizumab, edovacomab, edrecolomab, eftalizumab, eftilagimodalfa, efungumab, erderumab, erezanumab, elgemzumab, elotuzumab, elcilimomab, emuctuzumab, emapalmab, emibetuzumab, emicizumab, enapotamab vedotin, enabatuzumab, enfortumab vedotin, enrimomab pegol, enobrituzumab, enokizumab, enochicumab, encituximab, epitumomab citucetan,Epratuzumab, eptinezumab, erenumab, erlizumab, erzmakisomab, etalacizumab, etigirimab, etrolizumab, evinacumab, evolocumab, exevivirumab, F3, F520, fanolesomab, falarimomab, falisimab, faretuzumab, facinumab, FAZ053, FBTA05, felbizumab, fezakinumab, fibatuzumab, ficratuzumab, figitumumab, firivumab, framotumab, freticumab, florotuzumab Tetuzumab, fontrizumab, foralmab, folavirmab, fremanezumab, fresolimumab, flubokimab, flunebetomab, fluranumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gabirimomab, GB221, gezibumab, gemtuzumab ozogamicin, genolimuzumab, gebokizumab, gilvetomab, gymcirumab, girentuximab, grembatumumab vedotin, GLS-010 Golimumab, Gomiliximab, Goslanemab, Guselkumab, HD201, Helvicta, HLX02, HLX10, HLX20, HLX22, HX008, HX009, Ianalumab, Ibalizumab, IBI308, Ibritumomab tiuxetan, Icurcumab, Idarucizumab, Yeramirimab, Ifadotuzumab, Igobomab, Iradatuzumab vedotin, IMAB362, Imarumab, Imaprelimab, Imsilomab, Imugatuzumab, INBRX-105, I Cunclacumab, indatuximab tansine, indusatumab vedotin, inebilizumab, infliximab, inorimomab, inotuzumab ozogamisin, intetumumab, iomab-B, IPH2101, ipilimumab, iratumumab, isatuximab, iscarimab, istilatumab, itorizumab, ixekizumab, JTX-4014, keriximab, KN035, KN046, rabetsuzumab, lacunotuzumab, radilatuzumab vedotin, lambrolizumab (Pembrolizumab), lampalizumab, lanadelmab, landgrozumab, laprituximab emtansine, larcabiximab, LDP, lebrikizumab, remaresomab, lendarizumab, lembervimab, redinilumab, reldelimumab, leronlimab, resofabumab, letrizumab, lexatumumab, rivivirumab, rifastuzumab vedotin,Rigerizumab, Rirotomab Satetraxetan, Lintuzumab, Rilurumab, Rodelcizumab, Lokivetomab, Roncastuximab Tecilin, Rorbotuzumab Meltansine, Rosatuxizumab Vedotin, Lucatumumab, Rulizumab Pegol, Lumiliximab, Lumuletuzumab, Rupalzumab, Rupalzumab Amadotin, Lutikizumab, LY3300054, LY3415244, LZM009, mAb114, Mapatumumab, Margetuximab, Marstacimab, Masurimomab, Matuzumab, Maprilimumab, MCLA-145, MED16469, MEDI6 383, Mepolizumab, Meterimumab, MGA012, MGD013, MGD019, Miratuzumab, Minretumomab, Mirikizumab, Milbetuximab sorabtansine, Mitsumomab, MK-1308, MK-4166, MNRP1685A, Modotuximab, Mogamulizumab, Monalizumab, Morolimmab, Mosnetuzumab, Motabizumab, Moxetumomab Pasdotox, MOXR0916, MSB2311, Muromonab-CD3, Nacolomabutafenatox, Namilumab, Naptumomab estafenatox, Naratuximab emtansine, Narunatumamab, Natalizumab, Navixixizumab, Navibumab, Naxitamab, Nevacumab, Necitumumab, Nemolizumab, NEOD001, Nerelimomab, Nesbacumab, Netakimab, Nimotuzumab, Nilsevimab, Nivolumab, NM-01, Nofetumomab merpentan, Oviltoxaximab, Obinutuzumab, OC125 monoclonal antibody, Okalatuzumab, Ocrelizumab, Odurimomab, Ofatumumab, Oralatuzumab, Olekurmab, Orendalizumab, Orokizumab, Omalizumab, Ombrutamab, OMS721, Onartuzumab, Ontuxizumab Bu, Onbachirimab, Opicinumab, Oportuzumab Monatox, Olegobomab, Ortikumab, Oterixizumab, Ochirimab, Otreltuzumab, Oxerumab, Ozanezumab, Ozoralizumab, Pagibaximab, Palivizumab, Pamrebulumab, Panitumumab, Pancomab, Panobacumab, Pulsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab, Patrizumab, PDR001, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab, Paxerizumab, PF-05280014, PF-06801591, Pidilizumab,Pinatuzumab vedotin, pintumomab, pracumab, prozarizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, pracinezumab, prezarizumab, prezalumab, priliximab, pritoxaximab, pritumumab, PRO140, kirizumab, lacosumomab, radrezumab, rafibirumab, larpancizumab, ramucirumab, lanebetomab, ranibizumab, labagalimab, ravulizumab, laxibakumab, refanezumab, regavirumab, REGN2810, REGN3504, REGN4659, REGN-E B3, relatrimab, remtolumab, reslizumab, rHIgM12B7, rilotumumab, linucumab, risankizumab, rituximab, rituximab, ribabazumab pegol, Rmab, RO7121661, lobatumumab, loredumab, romilukimab, romosozumab, lontalizumab, rosmantuzumab, lovalpituzumab tesirin, loberizumab, rozanolixizumab, luprizumab, SA237, sacituzumab, sacituzumab, govitecan, samalizumab, samlotamab vedotin, sarilumab, satralizumab, satumomab pendetide, SB3, SCT-I10A, SEA-CD40, secukinumab, sericrelumab, cerivantuzumab, cetoxaximab, setorusumab, sevilumab, SG001, SGN-CD19A, SHP647, SHR-1316, SIBP-01, cibrotuzumab, cifarimumab, siltuximab, simtuzumab, cintilimab, ciprizumab, siltratumab vedotin, silutuzumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamlumab, STI-3031, thresomab, subtabumab, stimulama Subizumab, subratoxumab, Sym021, tavarumab, tacutuzumab tetraxetan, tadocizumab, tarakotsuzumab, talizumab, tamtuvetomab, tanezumab, tapritumomab paptox, tarexuzumab, tavolimab, tefivazumab, terimomab aritox, terisotuzumab, terisotuzumab vedotin, tenatumomab, teneriximab, teprizumab, tepositamab, teprotumumab, tesidorumab, tetulomab, tezeperumab, TG-1501, TGN1412, tibrizumab, tisilimmab, tigatuzumab, tildrakizumab,Timigutuzumab, thymolumab, tilagorumab, tilagotumab, tislerizumab, tisotumab vedotin, TNX-650, tocilizumab, tocilizumab, tomzotuximab, tralizumab, tripalimab, tosatoxumab, tositumomab, tositumomab, tobetumab, tralokinumab, to, Trastuzumab, Trastuzumab Deruxtecan, Trastuzumab-ANNS, Trastuzumab-DKST, Trastuzumab Emtansine, TRBS07, Tregalizumab, Tremelimumab, Trevoglumab, TRX385, TRX518, TSR-042, Tucotsuzumab Selmoloukin, Tubirumab, TX05, Ublituximab, Urocuprumab, Urelumab, Urtoxazumab, Ustekinumab, Utomirumab, Vadasutuximab, Banarimab, Bundutuzumab Vedotin, Bunchikutuzumab, Vanucizumab This includes bapariximab, valisakumab, valrirumab, baterizumab, vedolizumab, beltuzumab, bepalimomab, besenkumab, vizilizumab, bovalilizumab, borosiximab, bonrelorizumab, voplaterimab, borsetuzumab mahodotin, botumumab, bunakizumab, xentuzumab, XmAb20717, XmAb22841, XMAB-5574, zaltumumab, zanolimumab, zatuximab, xenoctuzumab, diralimumab, ZKAB001, zolbetuximab, and zolimomab aritox.

[0168] In some embodiments, the antibodies include cetuximab (Erbitux), panitumumab, zaltumumab, nimotuzumab, trastuzumab, Ado-trastuzumab emtansine, tocitumomab (Bexal®), rituximab (Rituxan, Mabcera), ibritumomab tiuxetan (Zevalin), basiliximab, daclizumab (Xenapax), gemtuzumab (Mylotarg), alemtuzumab, CEA-Scan Fab fragment, OC125 monoclonal antibody, ab75705, B72.3, bevacizumab (Avastin®), afatinib, and Axylamine. Citinib, Bosutinib, Cabozantinib, Ceritinib, Crizotinib, Dabrafenib, Dasatinib, Erlotinib, Everolimus, Ibrutinib, Imatinib, Lapatinib, Lenvatinib, Nilotinib, Olaparib, Palbociclib, Pazopanib, Pertuzumab, Ramucirumab, Regorafenib, Ruxolitinib, Sorafenib, Sunitinib, Temsirolimus, Vandetanib, Vemurafenib, Bismodegib, Basiliximab, Ipilimumab, Nivolumab, Pembrolizumab, Lambrolizumab, MPDL3280A, Pidilizumab (CT-011), MS This is BOO 1078C, BMS-935559, MEDI4736, AMP-224, or an antigen-binding fragment thereof.

[0169] In some embodiments, the antibodies include AB122, ADG116, ADU-1604, AGEN1181, AGEN1884, AK105, AMG404, AMP-224, AMP-514 (MEDI0680), atezolizumab (Tecentriq, MPDL3280A, RG7446), avelumab (Bavencio; MSB0010718C; M7824), basiliximab (Symlect), BCD-100, BCD-135, BCD-145, BGB-A333, BI 754091, BMS-936559 (MDX-1105), BMS-986218, camidanrumab tesirin, and camrelizumab. (SHR1210), Cantuzumab tancin, CBT-502 (TQB-2450), Semiprimab (LIBTAYO; REGN2810), Cetrelimab (hPAM4-Cide), Cetuximab (Erbitux), Cribatuzumab tetraxetan, Kosiberimab (CK-301), CS1001 (WPB3155), CS1003, CX-188, Daclizumab (Zimbrita, Zenapak) S), Depatuxizumab mahodotin, Dostallumab, Durvalumab (IMFINZI), F520, FAZ053, Futuximab, Gatipotuzumab, Genolimuzumab (APL-501; GB226; CBT-501), GLS-010, HLX10, HLX20, HX008, IBI308, Imugatuzumab, Inorimomab, Ipilimumab (Yervoy), JTX-4014, KN035, Lapri Tuximab emtansine, LDP, LY3300054, LZM009, matuzumab, MGA012 (INCMGA0012), MK-1308, modotuximab, MSB2311, necitumumab (PORTRAZZA), nimotuzumab (THERACIM, THERALOC), nivolumab (Opdivo), NM-01, panitumumab (Vectibix; ABX-EGF), PDR001, pemm Brolizumab (Keytruda; Lambrolizumab; MK-3475), Pemtumomab (THERAGYN), PF-06801591, RA8, REGN2810, REGN3504, REGN4659, SCT-I10A, SG001, SHR-1316, Sibrotuzumab, Syntilimab (TYVYT), Spartalizumab (PDR001), STI-003, STI-3031 (IMC-001;These include STI-A1015), Sym021, TG-1501, tislerizumab, tomzotuximab, tripalimab, tremelimumab (tisilimmab), TSR-042, Xenopax, zaltumumab (HuMax-EGFR), ZKAB001 (STI-A1014), or their binding fragments.

[0170] In some embodiments, the targeting molecule of the conjugate binds to EGFR. For example, in some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and an antibody or antigen-binding fragment that binds to EGFR. In some aspects, antibodies of a conjugate that target or bind to EGFR include, but are not limited to, aracizumab pegol, cetuximab, depatuxizumab mahodotin, futuximab, iclucumab, imugatuzumab, laprituximab emtansine, matsuzumab, modotuximab, nesitumumab, nimotuzumab, panitumumab, ramucirumab, tomzotuximab, zaltumumab, or their EGFR-binding fragments. In some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and cetuximab or an antigen-binding fragment of cetuximab. In some aspects, the conjugate is a polypeptide or small peptide that binds to a phthalocyanine dye of formula (X) or formula (0) and EGFR. In some aspects, the conjugate is an antibody or antigen-binding fragment that binds to a phthalocyanine dye of formula (I) and EGFR. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and cetuximab or an antigen-binding fragment of cetuximab. In some aspects, the conjugate is a polypeptide or small peptide that binds to a phthalocyanine dye of formula (I) and EGFR.

[0171] In some aspects, the targeting molecule of the conjugate binds to CD25. For example, in some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and an antibody or antigen-binding fragment that binds to CD25. In some aspects, antibodies of a conjugate that target or bind to CD25 include, but are not limited to, basiliximab, camidanrumab tecillin, daclizumab, inorimomab, RA8, STI-003, xenopax, or their CD25-binding fragments. In some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and basiliximab or an antigen-binding fragment of basiliximab. In some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and daclizumab or an antigen-binding fragment of daclizumab. In some aspects, the conjugate is a phthalocyanine dye of formula (X) or formula (0) and an IL-2 non-blocking CD25 antibody, e.g., the antibody disclosed in WO2018167104 and WO2019008386. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and an antibody or antigen-binding fragment that binds to CD25. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and basiliximab or an antigen-binding fragment of basiliximab. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and daclizumab or an antigen-binding fragment of daclizumab. In some aspects, the conjugate is a phthalocyanine dye of formula (I) and an IL-2 non-blocking CD25 antibody, e.g., the antibody disclosed in WO2018167104 and WO2019008386.

[0172] In some embodiments, the targeting molecule of the conjugate is an antibody or antigen-binding fragment thereof that targets or binds to PD-L1, for example, an anti-PD-L1 antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibody of the conjugate that targets or binds to PD-L1 is not limited to, atezolizumab (MPDL3280A, Tecentriq), avelumab (Bavencio), durvalumab (MEDI4736, IMFINZI), LDP, NM-01, STI-3031, KN035, LY3300054, M7824 This includes (MSB0011359C), BMS-936559, MSB2311, BCD-135, BGB-A333, CBT-502, Kosiberimab (CK-301), CS1001, FAZ053, MDX-1105, SHR-1316, TG-1501, ZKAB001, INBRX-105, MCLA-145, KN046, LY3415244, REGN3504, and HLX20. Exemplary anti-PD-L1 antibodies include MEDI4736 (Medimmune), MPDL3280A (Genentech), BMS-935559 (Bristol-Myers Squibb), and MSB0010718C and any of the aforementioned antigen-binding fragments.

[0173] In some embodiments, the targeting molecule of the conjugate is an antibody or antigen-binding fragment thereof that targets or binds to PD1, for example, an anti-PD1 antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibody of the conjugate that targets or binds to PD1 is not limited to, but includes pembrolizumab (MK-3475, Keytruda), nivolumab (Opdivo), semiprimab (ribtayo), tripalimab (JS001), HX008, SG001, GLS-010, dostallimab (TSR-042), tislerizumab (BGB-A317), cetrelimab (JNJ- 63723283), Pidilizumab (CT-011), Genolimuzumab (APL-501, GB226), BCD-100, Semiprimab (REGN2810), F520, Syntilimab (IBI308), GLS-010, CS1003, LZM009, Camrelizumab (SHR-1210), SCT-I10A, MGA012, AK105, PF-06801591, AMP-224, AB122, AMG This includes 404, BI 754091, HLX10, JTX-4014, MEDI0680, Sym021, MGD019, MGD013, AK104, XmAb20717, RO7121661, CX-188, and spartalizumab.

[0174] In some embodiments, the conjugate targeting molecule is an antibody or antigen-binding fragment thereof that targets or binds to CTLA-4, for example, an anti-CTLA-4 antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibodies of the conjugate that target or bind to CTLA-4 include, but are not limited to, ipilimumab (Yervoy®), tremelimumab (tisilimunab), AGEN1181, AGEN1884, ADU-1064, BCD-145, and BCD-217.

[0175] In some embodiments, the targeting molecule of the conjugate is an antibody or antigen-binding fragment thereof that targets or binds to HER2, for example, an anti-HER2 antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some respects, antibodies that target or bind to HER2, or have a conjugate to it, include, but are not limited to, CDC-022 (HERtiCAD), CMAB302 (Cipterbin), DS-8201, Gancotamab, GB221, HD201, Helvicta, HLX02, HLX22, Margetuximab, Pertuzumab (Perjeta), PF-05280014 (Trazimera), SB3, SIBP-01, Timigutuzumab, Trastuzumab (Herseptin), Trastuzumab Deruxtecan (ENHERTU), Trastuzumab Emtansine (Kadcyla), Trastuzumab-anns (Canzinch), Trastuzumab-dkst (Ogibri), and TX05.

[0176] In some embodiments, the conjugate targeting molecule is an antibody or antigen-binding fragment thereof that targets or binds to MUC1, for example, an anti-MUC1 antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the conjugate antibody that targets or binds to MUC1 includes, but is not limited to, cantuzumab tansine, cribatuzumab tetraxetan, gatipotuzumab, and pemtumomab.

[0177] In some embodiments, the targeting molecule of the conjugate is an antibody or antigen-binding fragment thereof that targets or binds to PSMA, for example, an anti-PSMA antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibody of the conjugate that targets or binds to PSMA includes, but is not limited to, capromab pendetide.

[0178] In some embodiments, the targeting molecule of the conjugate is an antibody or its antigen-binding fragment that targets or binds to CEA, for example, an anti-CEA antibody or its antigen-binding fragment, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibody of the conjugate that targets or binds to CEA includes, but is not limited to, pentetate artumomab, artumomab, artumomab Fab fragment, becylesomab, cibisatamab, F3, and rabetuzumab. In some embodiments, the targeting molecule of the conjugate is an antibody or antibody fragment, for example, an antibody fragment disclosed in EP1505076 or a full-length antibody having the antigen-binding domain of the antibody fragment disclosed in EP1505076.

[0179] In some embodiments, the targeting molecule of the conjugate is an antibody or antigen-binding fragment thereof that targets or binds to FAP, for example, an anti-FAP antibody or antigen-binding fragment thereof, and the phthalocyanine dye has formula (X), formula (0), formula (I), or formula (II). In some aspects, the antibody of the conjugate that targets or binds to FAP includes, but is not limited to, cibrotuzumab.

[0180] In some embodiments, the conjugate targeting molecule is a biosimilar, compatible, or biobetter of any of the targeting molecules described herein.

[0181] In some embodiments, the conjugate contains 1 or about 1 to about 1000 pigment residues per targeting molecule, for example, 1 or about 1 to about 100, 1 or about 1 to about 50, 1 or about 1 to about 25, 1 or about 1 to about 10, or 1 or about 1 to about 5. In some embodiments, the ratio of dye molecules to targeting molecules is 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 25:1, 50:1, 75:1, 100:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1, or approximately 1: 1, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 25:1, 50:1, 75:1, 100:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1, or between any two of these values ​​or approximately between them. In some embodiments, the targeting molecule may contain up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 dye molecules.

[0182] In some embodiments, when the targeting molecule is a polypeptide, such as an antibody or antigen-binding fragment, the number of dye molecules per targeting molecule may be 1 to 5 or about 1 to 5, for example, 1 to 4 or about 1 to 4, for example, 1 or about 1, 2 or about 2, or 3 or about 3. In some embodiments, the ratio of dye residues per targeting molecule is about 3:1. In some embodiments, the ratio of dye residues per targeting molecule is about 4:1. In some embodiments, the ratio of dye residues per targeting molecule is about 2:1. In some embodiments, the ratio of dye residues per targeting molecule is about 1:1. In some embodiments, the ratio of dye residues per targeting molecule is between about 2:1 and about 3:1. In some embodiments, the ratio of dye residues per targeting molecule is between about 1:1 and about 2:1. In some embodiments, the ratio of dye residues per targeting molecule is between about 1.5:1 and about 2:1. In some embodiments, the number of pigment residues per targeting molecule is between approximately 3:1 and approximately 4:1.

[0183] C. Formulation and Administration Furthermore, compositions containing any of the conjugates provided herein, such as pharmaceutical compositions, are also provided herein. In some aspects, the compositions contain phthalocyanine dye conjugates, such as targeting molecules and phthalocyanine dyes of formula (X), formula (0), formula (I), or formula (II) and pharmaceutically acceptable carriers. In some embodiments, the compositions containing the conjugates are for use in treatment or therapy according to any of the embodiments provided, for example, for administration to subjects having a disease or condition, or for the treatment of a disease or condition. The dose of phthalocyanine dye conjugate to be administered to a subject is not subject to absolute limitations but varies depending on the properties of the composition, its active ingredients and its unwanted side effects, such as the immune response to the drug, the type of subject and condition being treated and the method of administration. Generally, the dose will be a therapeutically effective amount, for example, a sufficient amount to achieve the desired biological effect, such as reducing the size of a tumor, such as volume and / or weight, or attenuating further tumor growth, or reducing unwanted symptoms of the tumor.

[0184] In some embodiments, compositions used for the administration of phthalocyanine dye conjugates contain an effective amount of the drug together with conventional pharmaceutical carriers and excipients appropriate to the type of administration intended. For example, in some embodiments, parenteral formulations may contain a sterile aqueous solution or suspension of the conjugate. In some embodiments, compositions for enteral administration may contain an effective amount of phthalocyanine dye conjugate in an aqueous solution or suspension which may optionally contain buffers, surfactants, thixotropic agents and flavoring agents.

[0185] In some embodiments, phthalocyanine dye conjugates (one or more), or conjugates combined with additional therapeutic agents, can be formulated in a pharmaceutically acceptable buffer, e.g., a pharmaceutically acceptable carrier or vehicle. Generally, the pharmaceutically acceptable carrier or vehicle, e.g., those present in the pharmaceutically acceptable buffer, may be any known in the art. Remington's Pharmaceutical Sciences by E.W. Martin, Mack Publishing Co., Easton, Pa., 19th edition (1995), describes compositions and formulations suitable for the delivery of one or more therapeutic compounds. Pharmaceutically acceptable compositions are generally prepared with consideration to regulatory authority or other agency approvals, arranged in accordance with generally accepted pharmacopoeias for use in animals and humans.

[0186] A pharmaceutical composition may include a carrier, such as a diluent, adjuvant, excipient, or vehicle, upon which the compound is administered. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions generally contain a therapeutically effective amount of the compound in a purified form, together with a suitable amount of a carrier to provide a form for appropriate administration to the patient. Such pharmaceutical carriers may be sterile liquids, such as water, and oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water is a typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. The composition may contain, along with the active ingredient, diluents such as lactose, sucrose, dicalcium phosphate, or carboxymethylcellulose; lubricants such as magnesium stearate, calcium stearate, and talc; and binders such as starch, natural rubber such as gum arabic, gelatin, glucose, molasses, polyvinylpyrrolidone, cellulose and its derivatives, povidone, crospovidone, and other such binders known to those skilled in the art. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, and ethanol. The composition may also optionally contain trace amounts of wetting agents, emulsifiers, or pH buffers, such as acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, and other such agents.

[0187] In some embodiments, the pharmaceutical product may be in liquid form, such as a solution, syrup, or suspension. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives, such as suspensions (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats), emulsifiers (e.g., lecithin or gum arabic), non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils), and preservatives (e.g., methyl or propyl-p-hydroxybenzoate or sorbic acid). In some cases, the pharmaceutical product may be presented in lyophilized form for reconstitution with water or another suitable vehicle before use.

[0188] In some embodiments, the properties of the pharmaceutically acceptable buffer or carrier vary depending on the specific mode of administration used. For example, in some embodiments, parenteral formulations may include an injectable fluid as a vehicle, comprising a pharmaceutically and physiologically acceptable fluid, such as water, saline, equilibrium salt solution, aqueous dextrose, or glycerol. In some embodiments, for solid compositions, such as powders, pills, tablets, or capsules, the non-toxic solid carrier may comprise, for example, pharmaceutical-grade mannitol, lactose, starch, or magnesium stearate. In addition to a biologically neutral carrier, the pharmaceutical composition to be administered may, in some embodiments, contain trace amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0189] The compound can be formulated into suitable pharmaceuticals, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations or elixirs for oral administration, as well as transdermal patch preparations and dry powder inhalants. Typically, the compound is formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, 4th edition, 1985, 126). Generally, the form of formulation is a function of the route of administration.

[0190] The composition can be formulated for administration by any route known to those skilled in the art, including intramuscular, intravenous, intradermal, intralesional, intraperitoneal injection, subcutaneous, intratumoral, epidural, nasal, oral, vaginal, rectal, topical, local, ear, inhalation, buccal (e.g., sublingual) and transdermal administration, or any other route. Other modes of administration are also intended. Administration may be local, topical, or systemic, depending on the site of treatment. Local administration to the area requiring treatment can be achieved, for example, by local injection during surgery, for example, by topical application in conjunction with postoperative wound dressing, by injection, using a catheter, using a suppository, or using an implant, for example, but not limited to local injection during surgery, or by topical application in conjunction with postoperative wound dressing.

[0191] Generally, parenteral administration characterized by injection subcutaneously, intramuscularly, intratumorally, intravenously, or intradermally is intended herein. Injectable preparations can be prepared conventionally as liquid solutions or suspensions, solid forms suitable for solutions or suspensions in liquids prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. Furthermore, the pharmaceutical composition to be administered may also contain solvents, such as pH buffers, metal ion salts, or activators in the form of other such buffers. The pharmaceutical composition may also contain other trace amounts of non-toxic adjuncts, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrin. Sustained-release or sustained-release administration systems that maintain a certain level of dose (see, for example, U.S. Patent No. 3,710,795) are also intended herein. The percentage of active compounds contained in such parenteral compositions varies considerably depending on their specific properties, as well as the activity of the compounds and the needs of the target population.

[0192] Injectable preparations are designed for local and systemic administration. Preparations for parenteral administration include sterile solutions prepared for injection, sterile dried soluble products, such as subcutaneous tablets, lyophilized powders prepared to be combined with a solvent immediately before use, sterile suspensions prepared for injection, sterile dried insoluble products, and sterile emulsions prepared to be combined with a vehicle immediately before use. Solutions may be aqueous or non-aqueous. For intravenous administration, suitable carriers include solutions containing physiological saline or phosphate-buffered saline (PBS) and thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, or mixtures thereof.

[0193] Pharmacovigilant carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspensions and dispersants, emulsifiers, chelating agents or sequestering agents, and other pharmaceutically acceptable substances. Examples of aqueous vehicles include sodium chloride injection, Ringer's solution injection, isotonic dextrose injection, sterile water injection, and dextrose and lactated Ringer's solution injection. Non-aqueous parenteral vehicles include hydrogenated oils of plant origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungiostatic concentrates can be added to parenteral preparations packaged in multi-dose containers, and these include phenol or cresol, mercury compounds, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, and benzethonium chloride. The isotonic agent includes sodium chloride and dextrose. The buffer includes phosphoric acid and citrate.

[0194] When administered intravenously, suitable carriers include solutions containing physiological saline or phosphate-buffered saline (PBS) and thickeners and solubilizers, such as glucose, polyethylene glycol, and polypropylene glycol, or mixtures thereof.

[0195] The composition can be formulated for single-dose administration or for multiple-dose administration. The drug can be formulated for direct administration. The composition can be provided as a liquid or lyophilized preparation. If the composition is provided in lyophilized form, it can be restored immediately before use with a suitable buffer, such as sterile saline solution.

[0196] The composition may also be administered sequentially, intermittently, or in the same composition, together with other biologically active agents. Administration may also include controlled-release systems, such as controlled-release formulations and devices, for example, using a pump.

[0197] The most suitable route in any given case varies depending on various factors, such as the nature of the disease, its progression, its severity, and the specific composition used. For example, the composition may be administered systemically, for instance, intravenously. Subcutaneous administration may also be used, although an increased absorption time may be necessary to ensure comparable bioavailability compared to intravenous administration.

[0198] Pharmaceutical compositions can be formulated into dosage forms appropriate for each route of administration. Pharmaceutically and therapeutically active compounds and their derivatives are usually formulated and administered in unit doses or multiple doses. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect in conjunction with the necessary pharmaceutical carrier, vehicle, or diluent. Unit doses include, but are not limited to, tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions and oil-water emulsions containing a suitable amount of the compound or a pharmaceutically acceptable derivative thereof. Unit doses may be contained in ampoules and syringes or in individually packaged tablets or capsules. Unit doses may be administered in fractions or multiples thereof. Multiple doses are multiple identical unit doses packaged in a single container to be administered in separate unit doses. Examples of multiple doses include vials, bottles of tablets or capsules, or pint or gallon bottles. Therefore, multiple dose forms are multiple unit doses that are not separated in the packaging. Generally, dosage forms or compositions can be prepared that contain active ingredients in the range of 0.005% to 100%, with the remainder consisting of a non-toxic carrier. Pharmaceutical compositions can be formulated in dosage forms appropriate for each route of administration.

[0199] The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount that produces the desired pharmacological effect. The exact dose varies depending on the age, weight, and condition of the patient or animal, as is known in the art. Unit dose parenteral preparations are packaged in ampoules, vials, or syringes with needles. The volume of the liquid solution or restored powder preparation containing the pharmaceutically active compound is a function of the disease to be treated and the specific product selected for the package. All preparations for parenteral administration are known in the art and must be sterile to be carried out. In some embodiments, the composition may be provided as a lyophilized powder, which can be restored for administration as a solution, emulsion, and other mixture. They may also be restored and formulated as a solid or gel. Lyophilized powders can be prepared from any of the above solutions.

[0200] Sterile, lyophilized powders can be prepared by dissolving a phthalocyanine dye-targeting molecule conjugate in a buffer solution. The buffer solution may contain excipients that improve the stability of other pharmacological components of the powder or the reconstituted solution prepared from the powder.

[0201] In some embodiments, the desired formulation is provided by subsequent sterile filtration of the solution and subsequent lyophilization under standard conditions known to those skilled in the art. Briefly, the lyophilized powder is prepared by dissolving an excipient, such as dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, or other suitable agent, in a suitable buffer, such as citrate, sodium phosphate, or potassium, or other such buffers known to those skilled in the art. The selected enzyme is then added to the resulting mixture and stirred until dissolved. The resulting mixture is sterile filtered or treated to remove particles and ensure sterility, and then distributed into vials for lyophilization. Each vial may contain a single dose of the compound (1 mg to 1 g, generally 1 to 100 mg, e.g., 1 to 5 mg) or multiple doses. The lyophilized powder can be stored under suitable conditions, e.g., about 4°C to room temperature. Reconstitution of this lyophilized powder using a buffer solution yields a formulation for parenteral administration. The exact amount will vary depending on the indication being treated and the selected compound. Such amounts can be determined empirically.

[0202] In some embodiments, the pH of the composition is between 6 and 10 or approximately between 6 and 10, for example, between 6 and 8 or approximately between 6 and 8, between 6.9 and 7.3 or approximately between 6.9 and 7.3, for example, about pH 7.1. In some embodiments, the pH of the pharmaceutically acceptable buffer is at least or about 5, at least or about 6, at least or about 7, at least or about 8, at least or about 9, or at least or about 10, or 7.1.

[0203] The composition can be formulated for single-dose administration or for multiple-dose administration. The drug can be formulated for direct administration.

[0204] In some embodiments, the compositions provided herein are for direct administration of the provided conjugate in amounts of 0.01 mg or about 0.01 mg to 3000 mg or about 3000 mg, 0.01 mg or about 0.01 mg to 1000 mg or about 1000 mg, 0.01 mg or about 0.01 mg to 500 mg or about 500 mg, 0.01 mg or about 0.01 mg to 100 mg or about 100 mg, 0.01 mg or about 0.01 mg to 50 mg or about 50 mg, 0.01 mg or about 0.01 mg to 10 mg or about 10 mg, 0.01 mg or approximately 0.01 mg to 1 mg or approximately 1 mg, 0.01 mg or approximately 0.01 mg to 0.1 mg or approximately 0.1 mg, 0.1 mg or approximately 0.1 mg to 2000 mg or approximately 2000 mg, 0.1 mg or approximately 0.1 mg to 1000 mg or approximately 1000 mg, 0.1 mg or approximately 0.1 mg to 500 mg or approximately 500 mg, 0.1 mg or approximately 0.1 mg to 100 mg or approximately 100 mg, 0.1 mg or approximately 0.1 mg to 50 mg or approximately 50 mg, 0.1 mg or approximately 0.1 mg to 10 mg or Approximately 10 mg, 0.1 mg or approximately 0.1 mg to 1 mg or approximately 1 mg, 1 mg or approximately 1 mg to 2000 mg or approximately 2000 mg, 1 mg or approximately 1 mg to 1000 mg or approximately 1000 mg, 1 mg or approximately 1 mg to 500 mg or approximately 500 mg, 1 mg or approximately 1 mg to 100 mg or approximately 100 mg, 1 mg or approximately 1 mg to 10 mg or approximately 10 mg, 10 mg or approximately 10 mg to 2000 mg or approximately 2000 mg, 10 mg or approximately 10 mg to 1000 mg or approximately 1000 mg, 10 mg or approximately 10 mg to 50 It is formulated in amounts ranging from 0 mg or approximately 500 mg, 10 mg or approximately 10 mg to 100 mg or approximately 100 mg, 100 mg or approximately 100 mg to 2000 mg or approximately 2000 mg, 100 mg or approximately 100 mg to 1000 mg or approximately 1000 mg, 100 mg or approximately 100 mg to 500 mg or approximately 500 mg, 500 mg or approximately 500 mg to 2000 mg or approximately 2000 mg, 500 mg or approximately 500 mg to 1000 mg or approximately 1000 mg, and approximately 1000 mg to 3000 mg or approximately 3000 mg.In some embodiments, the volume of the composition may be between 0.5 mL and 1000 mL, for example, between 0.5 mL and 100 mL, between 0.5 mL and 10 mL, between 1 mL and 500 mL, between 1 mL and 10 mL, for example, at least or about at least or about 0.5 mL, 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 15 mL, 20 mL, 30 mL, 40 mL, 50 mL, or more. For example, the composition may be formulated for unit dose administration in amounts between 100 mg or about 100 mg and between 500 mg or about 500 mg, or between 200 mg or about 200 mg and between 400 mg or about 400 mg. In some embodiments, the composition is formulated for unit dose administration in amounts of 500 mg or between approximately 500 mg and 1500 mg or approximately 1500 mg, between approximately 800 mg and 1200 mg or approximately 1200 mg, or between approximately 1000 mg and 1500 mg or approximately 1500 mg. In some embodiments, the volume of the composition is 10 mL or between approximately 10 mL and 1000 mL or approximately 1000 mL, or between 50 mL and 500 mL or approximately 500 mL, or the volume of the composition is at least 10 mL, 20 mL, 30 mL, 40 mL, 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, or 1000 mL.

[0205] In some embodiments, the entire contents of the vial of the formulation can be withdrawn for administration and divided into multiple doses for multiple administrations. When withdrawing a certain amount of the drug for administration, the formulation can be further diluted as needed, for example, with water, saline (e.g., 0.9%), or other physiological solution.

[0206] In some embodiments, compositions containing additional therapeutic agents, such as immunomodulators or anticancer agents, are also provided for use in combination with the provided conjugate, according to the embodiment provided. In some aspects, the additional therapeutic agents can be prepared according to known or, for example, the standard formulation guidelines described above. In some embodiments, the immunomodulators, anticancer agents and / or the provided conjugate are formulated as separate compositions. In some embodiments, the immunomodulator is provided as a separate composition from the provided conjugate, and the two compositions are administered separately. In some embodiments, the anticancer agent is provided as a separate composition from the provided conjugate, and the two compositions are administered separately. The compositions can be formulated for parenteral delivery (i.e., for systemic delivery). For example, the compositions or combinations of compositions can be formulated for subcutaneous delivery or intravenous delivery. The provided conjugate and drugs such as immunomodulators and / or anticancer agents can be administered by different routes of administration.

[0207] The composition containing the provided conjugate can be administered locally or systemically, for example, to a subject with a tumor, e.g., cancer, or to a subject that previously had a tumor removed by surgery, using any method known in the art. Specific examples are provided, but those skilled in the art will understand that alternative methods of administering the disclosed agent can be used. Such methods may include, for example, the use of a catheter or implantable pump to provide continuous infusion over a period of several hours to several days to a subject requiring treatment.

[0208] In some embodiments, the conjugate provided is administered by parenteral means, including direct injection or infusion into the tumor, for example. In some embodiments, the conjugate is administered to the tumor by applying the drug to the tumor, for example, by immersing the tumor in a solution containing the conjugate, or by pouring the drug onto the tumor.

[0209] Furthermore, the conjugate can be administered systemically, for example, intravenously, intramuscularly, subcutaneously, intradermally, intraperitoneally, subcutaneously, or orally, to a subject with a tumor, such as cancer.

[0210] In some embodiments, the conjugate can be administered ex vivo by, for example, obtaining cells from a subject, treating such cells with the conjugate along with irradiation, and administering the treated cells to either the same subject or a different subject.

[0211] In some embodiments, the composition contains an average number of dye residues per targeting molecule (e.g., DAR) of 0.5 or about 0.5 to about 1000, for example, 0.5 or about 0.5 to about 100, 0.5 or about 0.5 to about 50, 0.5 or about 0.5 to about 25, 0.5 or about 0.5 to about 10, or 0.5 or about 0.5 to about 5. In some embodiments, the average ratio of dye molecules to targeting molecules in the composition is greater than 0.5 or greater than about 0.5, for example, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or higher. In some embodiments, the ratio of dye molecules to targeting molecules in the composition is 0.5:1, 0.7:1, 0.8:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 25:1, 50:1, 75:1, 100:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1. Or approximately 0.5:1, 0.7:1, 0.8:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 15:1, 20:1, 25:1, 50:1, 75:1, 100:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1 or 1000:1, or between or approximately between any two of these values.

[0212] In some embodiments, when the targeting molecule is a polypeptide, such as an antibody, antigen-binding fragment, or nanobody, the average number of dye molecules per targeting molecule in the composition may be 0.5 or about 0.5 to 5, for example, 0.5 or about 0.5 to 4, for example, 0.5 or about 0.5, 0.6 or about 0.6, 0.7 or about 0.7, 0.8 or about 0.8, 0.9 or about 0.9, 1 or about 1, 2 or about 2, or 3 or about 3. In some embodiments, the average number of dye residues per targeting molecule in the composition is about 3:1. In some embodiments, the average number of dye residues per targeting molecule in the composition is about 4:1. In some embodiments, the average number of dye residues per targeting molecule in the composition is about 2:1. In some embodiments, the average number of dye residues per targeting molecule in the composition is about 1:1. In some embodiments, the average number of pigment residues per targeting molecule in the composition is between approximately 2:1 and approximately 3:1. In some embodiments, the average number of pigment residues per targeting molecule in the composition is between approximately 1:1 and approximately 2:1. In some embodiments, the average number of pigment residues per targeting molecule in the composition is between approximately 1.5:1 and approximately 2:1. In some embodiments, the average number of pigment residues per targeting molecule in the composition is between approximately 3:1 and approximately 4:1. In some embodiments, the average number of pigment residues per targeting molecule in the composition is between approximately 0.5:1 and approximately 1:1.

[0213] Devices and irradiation methods for use with D. conjugates. In some aspects, devices usable with the provided embodiments include light diffusion devices that provide irradiation (in some cases, also called radiation) at wavelengths of light suitable for use with the dye conjugate compositions described herein, e.g., phthalocyanine dye conjugates of formula (X), formula (0), formula (I), or formula (II), and targeting molecules. The irradiation device may include a light source (e.g., a laser) and means for delivering the light to a desired area (e.g., one or more fibers for irradiating an isolated area of ​​a target or an isolated lesion or tumor). Exemplary irradiation devices are described herein by reference, patent numbers US10,295,719, US10,527,771, and US10,416,366. Such devices deliver light to a target area of ​​a target using a light diffusion device containing a non-circular core optical fiber operably connected to a laser. In some embodiments, the core optical fiber is circular and is coiled or bent before interfaced with the light diffusion device. In certain aspects, the device delivers a “top-hat” core irradiance distribution to deliver uniform light to the area being irradiated. Light diffusion devices can be, for example, cylindrical diffusers for use in tumor or tissue radiation. In some embodiments, the light diffusion device is a front diffuser with a lens, and the irradiation is projected through the lens of the front diffuser at the end of the optical fiber. The projected light can be a beam of aligned or dispersed light.

[0214] In some embodiments, the target range, e.g., tumor, vicinity of tumor, lymph node, vicinity of lymph node, is 400 nm or approximately 400 nm to 900 nm or approximately 900 nm, e.g., 500 nm or approximately 500 nm to 900 nm or approximately 900 nm, e.g., 600 nm or approximately 600 nm to 850 nm or approximately 850 nm, e.g., 600 nm or approximately 600 nm to 740 nm or approximately 740 nm, e.g., 660 nm or approximately 660 nm to 740 nm or approximately 740 nm, 660 nm or approximately 660 nm to 710 nm or approximately 710 nm, 660 nm or approximately 66 The light is irradiated with wavelengths within the range of 0nm to 700nm or approximately 700nm, 660nm or approximately 660nm to 685nm or approximately 685nm, 665nm or approximately 665nm to 680nm or approximately 680nm, 670nm or approximately 670nm to 685nm or approximately 685nm, 670nm or approximately 670nm to 690nm or approximately 690nm, 670nm or approximately 670nm to 680nm or approximately 680nm, 680nm or approximately 680nm to 740nm or approximately 740nm, or 690nm or approximately 690nm to 710nm or approximately 710nm. In some embodiments, the target area, e.g., tumor, tumor vicinity, lymph node, lymph node vicinity, or tumor microenvironment, is irradiated with wavelengths of 600 nm or approximately 600 nm to 850 nm or approximately 850 nm, e.g., 660 nm or approximately 660 nm to 740 nm or approximately 740 nm. In some embodiments, the target area, e.g., tumor, tumor vicinity, lymph node, lymph node vicinity, or tumor microenvironment, is irradiated with light of wavelengths of at least approximately 600 nm, 620 nm, 640 nm, 660 nm, 680 nm, 700 nm, 720 nm, or 740 nm, e.g., 670 ± 50 nm or approximately 670 ± 50 nm, or 670 ± 40 nm or approximately 670 ± 40 nm, e.g., approximately 670 nm or approximately 670 nm, or 670 nm or approximately 670 nm. In some embodiments, the target area, such as the tumor, the vicinity of the tumor, the lymph node, the vicinity of the lymph node, or the tumor microenvironment, is irradiated with light of a wavelength of 685 nm or less than 680 nm or approximately 685 nm or less than 680 nm.

[0215] In some embodiments of the methods and uses provided herein, irradiation is carried out using cylindrical diffusion fibers spaced 1.8 ± 0.2 cm or about 1.8 ± 0.2 cm apart, encompassing a diffuser length of 0.5 cm or about 0.5 cm to 10 cm or about 10 cm. In some embodiments, the light irradiation dose is 20 J / cm or about 20 J / cm fiber length to 500 J / cm or about 500 J / cm fiber length. In some embodiments, the tumor is larger than 10 mm or about 10 mm in depth, or is a subcutaneous tumor.

[0216] In some embodiments, the provided method involves irradiating a target area, which is a stromal tumor in the subject, using cylindrical diffusion fibers spaced 1.8±0.2cm or approximately 1.8±0.2cm apart, encompassing a diffuser length of 0.5cm or approximately 0.5cm to 10cm or approximately 10cm, with a light dose of 100 J / cm or approximately 100 J / cm fiber length, or with a fluence rate of 400 mW / cm or approximately 400 mW / cm. In some embodiments, the target area is a tumor greater than 10 mm or approximately 10 mm in depth, or a subcutaneous tumor. In some embodiments, the cylindrical diffusion fibers are placed in a catheter positioned within the tumor at a distance of 1.8±0.2cm or approximately 1.8±0.2cm. In some embodiments, the catheter is optically transparent.

[0217] In some embodiments, the target area, e.g., tumor, tumor vicinity, lymph node, lymph node vicinity, or tumor microenvironment, is at least or about 1 J / cm². 2 For example, at least or about 10 J / cm² 2 , at least or approximately 30 J / cm² 2 , at least or about 50 J / cm² 2 , at least or approximately 75 J / cm² 2 , at least or about 100 J / cm² 2 , at least or approximately 150 J / cm² 2 Or at least or about 500 J / cm² 2 The light dose is irradiated at a dose of . In some embodiments, the irradiation dose is 1 or about 1 to 1 or about J / cm². 2, 1 or approximately 1 to 500 or approximately 500 J / cm² 2 5 or approximately 5-200 or approximately 200 J / cm² 2 , 10 or approximately 10-100 or approximately 100 J / cm 2 10 or approximately 10-50 or approximately 50 J / cm 2 30 or approximately 30-200 or approximately 200 J / cm² 2 30 or approximately 30-150 or approximately 150 J / cm² 2 Or 30 or approximately 30-100 or approximately 100 J / cm² 2 In some embodiments, the target range is at least or about 2 J / cm². 2 , 5J / cm 2 , 10J / cm 2 , 25J / cm 2 50 J / cm 2 75 J / cm 2 , 100 J / cm 2 , 150 J / cm 2 , 200 J / cm 2 300 J / cm² 2 , 400 J / cm 2 or 500 J / cm² 2 It is irradiated with this dose.

[0218] In some embodiments, the target area is a superficial tumor. In some embodiments, the tumor is less than 10 mm thick. In some embodiments, irradiation is performed using a fiber with a microlens tip for surface irradiation. In some embodiments, the light dose is 5 or about 5 J / cm². 2 ~200J / cm 2 Alternatively, approximately 200 J / cm² 2 That is the case.

[0219] In some embodiments, the target area, e.g., tumor, tumor vicinity, lymph node, lymph node vicinity, or tumor microenvironment, is irradiated with a dose of at least or about 1 J / cm fiber length, e.g., at least or about 10 J / cm fiber length, at least or about 50 J / cm fiber length, at least or about 100 J / cm fiber length, at least or about 250 J / cm fiber length, or at least or about 500 J / cm fiber length. In some embodiments, the irradiation dose is 1 or about 1 to 1000 or about 1000 J / cm fiber length, 1 or about 1 to 500 or about 500 J / cm fiber length, 2 or about 2 to 500 or about 500 J / cm fiber length, 50 or about 50 to 300 or about 300 J / cm fiber length, 10 or about 10 to 100 or about 100 J / cm fiber length, or 10 or about 10 to 50 or about 50 J / cm fiber length. In some embodiments, a target area, such as a tumor, the vicinity of a tumor, a lymph node, the vicinity of a lymph node, or the tumor microenvironment, is irradiated with a dose of at least or about 2 J / cm fiber length, 5 J / cm fiber length, 10 J / cm fiber length, 25 J / cm fiber length, 50 J / cm fiber length, 75 J / cm fiber length, 100 J / cm fiber length, 150 J / cm fiber length, 200 J / cm fiber length, 250 J / cm fiber length, 300 J / cm fiber length, 400 J / cm fiber length, or 500 J / cm fiber length.

[0220] In some embodiments, the method provided is 5 or about 5 J / cm 2 ~200 or approximately 200 J / cm² 2 For surface irradiation using a light dose, this includes irradiating a target area, which is a superficial tumor, using a fiber with a microlens tip. In some embodiments, the light dose is 50 or approximately 50 J / cm². 2 That is the case.

[0221] In some embodiments, the irradiation dose after administration of a composition containing a phthalocyanine dye-targeting molecule conjugate is at least or about 1 J / cm² or at least or about 1 J / cm fiber length at a wavelength of 600-800 nm or about 600-800 nm, for example, at least or about 1 J / cm² or at least or about 1 J / cm fiber length at a wavelength of 620-720 nm or about 620-720 nm, or at least or about 10 J / cm at a wavelength of 620-720 nm or about 620-720 nm. 2 Alternatively, a fiber length of at least or about 10 J / cm, and a wavelength of 620-720 nm or at least or about 50 J / cm 2 or at least or about 50 J / cm fiber length, or at least or about 100 J / cm wavelength of 620-720 nm or about 620-720 nm 2 Or the fiber length is at least or about 100 J / cm. In some embodiments, the wavelength is 640-700 nm. In some embodiments, the irradiation dose after administration of the composition containing the phthalocyanine dye-targeting molecule conjugate is at least or about 1.0 J / cm at a wavelength of 670 nm or about 670 nm. 2 Or at least or about 1 J / cm fiber length, or for example, at least or about 10 J / cm wavelength of 670 nm or about 670 nm. 2 Alternatively, at least or about 10 J / cm fiber length, at a wavelength of 670 nm or about 670 nm, at least or about 50 J / cm 2 Or at least or about 50 J / cm fiber length, or at least or about 100 J / cm wavelength of 670 nm or about 670 nm 2 Alternatively, a fiber length of at least or about 100 J / cm, for example, 1.0 to 500 J / cm at a wavelength of 670 nm or about 670 nm. 2 Or a fiber length of 1.0 to 500 J / cm. Exemplary irradiation after administration of the conjugate or composition provided herein is at a wavelength of 620 nm or about 620 nm to 720 nm or about 720 nm, at least or about 1 J / cm2 This also includes irradiating the target area with a dose of at least or approximately 1 J / cm over a fiber length.

[0222] In some embodiments, irradiation is performed at a wavelength of 580 nm or approximately 580 nm to 830 nm or approximately 830 nm, at a rate of 25 or approximately 25 J / cm². 2 ~400 or approximately 400 J / cm² 2 Alternatively, it is carried out with a fiber length of 2 or approximately 2 J / cm to 500 or approximately 500 J / cm. In some embodiments, the target area is irradiated at a wavelength of 670 ± 40 nm. In some embodiments, the target area is irradiated at 50 or approximately 50 J / cm. 2 Alternatively, it is irradiated with a dose of 100 or approximately 100 J / cm over a fiber length.

[0223] In some embodiments, light or laser may be applied to a conjugate, for example, a cell containing a conjugate, for a period of 5 or about 5 seconds to 5 or about 5 minutes. For example, in some embodiments, light or laser is applied for 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 seconds or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 seconds, or within a range between any two of these values, to activate the pigment molecules (one or more) of the conjugate. In some embodiments, light or laser is applied for about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 minutes or more, or about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 minutes, or within a range between any two of these values. In some embodiments, the duration for which light or laser is applied may vary depending, for example, on energy, such as the wattage of the light or laser. For example, light or lasers with lower wattage may be applied for longer periods.

[0224] In some embodiments, light or laser may be applied 30 or about 30 minutes to 96 or about 96 hours after administration of the conjugate. For example, in some embodiments, light or laser may be applied 30, 35, 40, 45, 50 or 55 minutes or about 30, 35, 40, 45, 50 or 55 minutes after administration of the conjugate, or within a range of any two of these values. In some embodiments, light or laser is applied 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours after administration of the conjugate, or approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 hours after administration, or within a range of approximately any two of these values, for example, between 20 or approximately 20 hours and 28 or approximately 28 hours, or approximately 24 hours ± 4 hours. In some embodiments, light or laser may be applied for a period of 1 to 24 hours or about 1 to 24 hours, for example, 1 or about 1 to 12 or about 12 hours, 12 or about 12 to 24 or about 24 hours, 6 or about 6 to 12 or about 12 hours, or longer than 24 or about 24 hours after administration of the conjugate. In some embodiments, light or laser may be applied for 36, 48, 72 or 96 hours or about 36, 48, 72 or 96 hours after administration of the conjugate. In some embodiments, light or laser may be applied 24 hours ± 4 hours or about 24 hours ± 4 hours after administration of the conjugate.

[0225] In some embodiments, the target area, e.g., tumor, tumor vicinity, lymph node, lymph node vicinity, or tumor microenvironment or target, may be irradiated once or more times. Thus, irradiation may be completed on a single day, or it may be repeated over multiple days, at least two or about two different times, three different times, four different times, five different times, or ten different times, using the same or different doses, e.g., irradiation. In some embodiments, repeated irradiation may be performed on the same day, on consecutive days, or every 1-3 days, every 3-7 days, every 1-2 weeks, every 2-4 weeks, every 1-2 months, or at longer intervals. In some embodiments, multiple irradiations, e.g., at least two, at least three, or at least four irradiations, e.g., two, three, four, five, six, seven, eight, nine, or ten separate doses may be administered.

[0226] In some embodiments, the dose or method of irradiation varies depending on the type or morphology of the target area, e.g., tumor, tumor vicinity, lymph node, or lymph node vicinity. For example, in some embodiments, irradiation is performed using a device having a “top-hat” irradiance distribution profile, e.g., as described in publication applications WO2018 / 080952 and US20180239074.

[0227] In some embodiments of the methods and uses provided herein, irradiation is administered after administration of the conjugate. In some embodiments, irradiation or irradiation is performed or achieved between 30 minutes and 96 hours or about 30 minutes and 96 hours after administration of the phthalocyanine dye-targeting molecule conjugate, for example between 30 minutes and 48 hours, 30 minutes and 24 hours or 12 hours and 48 hours after administration of the conjugate, for example, generally at least 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours or longer. In some embodiments, irradiation is performed within approximately 24 hours after administration of the conjugate, or within 24 hours ± 4 hours after administration of the conjugate, or within approximately 20, 21, 22, 23, 24, 24, 26, 27, or 28 hours after administration of the conjugate.

[0228] E. Combination therapy In some embodiments, methods and uses are also provided that include combination therapies and combinations, for example, combinations for use in accordance with combination therapy. In some aspects, the combination includes a conjugate and additional therapeutic agents, for example, immunomodulators or anticancer agents, as provided herein. In some embodiments, the targeting molecule used in the conjugate in such combination therapy is an antibody or antibody fragment that binds to a target molecule linked to a phthalocyanine dye, as provided herein. In some aspects, the combination therapy includes the administration of a conjugate and additional therapeutic agents, for example, immunomodulators, immune checkpoint inhibitors and anticancer agents, therapeutic agents that act on suppressor cells or combinations thereof. In such methods, primary tumors, newly arising tumors, invasive tumor cells and metastatic tumor cells can be sensitized to treatment with additional therapeutic agents, for example, immunomodulators, immune checkpoint inhibitors, therapeutic agents or anticancer agents. In such methods, the growth of primary tumors, newly arising tumors, invasive tumor cells and metastatic tumor cells can be inhibited, reduced or eliminated, and / or the volume of one or more tumors can be reduced.

[0229] Increased susceptibility resulting from such combination treatments may include, but are not limited to, reduced inhibition of tumor growth, reduced tumor cell invasion and / or metastasis, increased tumor cell death, increased systemic immune response, increased novel T cell priming, and intratumor CD8 + Increased T cell diversity, intratumor CD8 + This may include an increase in the number and / or activity of T effector cells, a decrease in the number and / or activity of intratumoral regulatory T cells, a decrease in the number and / or activity of intratumoral bone marrow-derived suppressor cells, a decrease in the number and / or activity of intratumoral tumor-associated fibroblasts or cancer-associated fibroblasts (CAFs), or any combination thereof.

[0230] In some embodiments, the additional therapeutic agent is an anticancer agent. In some embodiments, the anticancer agent may be one or more chemotherapeutic agents, antibody treatments and / or radiotherapeutic agents. In some embodiments, the additional therapeutic agent is an anticancer agent selected from checkpoint inhibitors, immune adjuvants, therapeutic agents that act on suppressor cells, chemotherapeutic agents, radiation and biologics containing anticancer targeting molecules that bind to tumor cells.

[0231] In some aspects, the additional therapeutic agent is an immunomodulator (also called an immune modulating agent), such as an immune checkpoint inhibitor. In some aspects, such combinations are used for the treatment of tumors, lesions, or cancer. In some embodiments, the method involves the administration of an immunomodulator, such as an immune checkpoint inhibitor, before, concurrently with, or after the administration of the provided conjugate.

[0232] In some embodiments, additional therapeutic agents, such as immunomodulators used in such combination therapies as described herein, may include adjuvants, immune checkpoint inhibitors, cytokines, or combinations thereof. Cytokines for use in combination may include, for example, aldethleukin (PROLEUKIN), interferon alpha-2a, interferon alpha-2b (intron A), pegylated interferon alpha-2b (SYLATRON / PEG-intron), IL-15, IL-18, or cytokines targeting the IFNAR1 / 2 pathway or the IL-2 / IL-2R pathway. Adjuvants for use in combination may include, for example, Poly ICLC (HILTONOL / imiquimod), 4-1BB (CD137; TNFRS9), OX40 (CD134), OX40-ligand (OX40L), the Toll-like receptor 2 agonist SUP3, Toll-like receptor TLR3 and TLR4 agonists, adjuvants targeting the Toll-like receptor 7 (TLR7) pathway, other members of the TNFR and TNF superfamily, other TLR2 agonists, TLR3 agonists, and TLR4 agonists.

[0233] In some embodiments, additional therapeutic agents are immune checkpoint inhibitors, which are PD-1 inhibitors, such as small molecules, antibodies, or antigen-binding fragments that inhibit PD-1 activity. Exemplary antibodies targeting PD-1 include, but are not limited to, AB122, AK104, AK105, AMG 404, AMP-224, AMP-514 (MEDI0680), BCD-100, BCD-217, BI 754091, camrelizumab (SHR1210), and semiprimab (LIBTAYO). REGN2810), Cetrerimab (JNJ-63723283), CS1003, CX-188, Dostalrimab (TSR-042), F520, Genolimuzumab (APL-501; GB226, CBT-501), GLS-010, HLX10, HX008, HX009, IBI308, JTX-4014, LZM009, MGA012 (INCMGA0012), MGD013, MGD019, Nivolumab (Opz This includes α-V (BMS-936558), PDR001, pembrolizumab (Keytruda, lambrolizumab, MK-3475), PF-06801591, pidilizumab (CT-011), REGN2810, RO7121661, SCT-I10A, SG001, cintilimab (TYVYT, IBI308), spartalizumab (PDR001), Sym021, tislerizumab (BGB-A317), tripalimab (JS 001), TSR-042 (ANB011), and XmAb20717.

[0234] In some embodiments, additional therapeutic agents are immune checkpoint inhibitors that are PD-L1 inhibitors, such as small molecules, antibodies, or antigen-binding fragments that inhibit PD-L1 activity. Exemplary antibodies that target PD-L1 include, but are not limited to, atezolizumab (Tecentriq, MPDL3280A, RG7446), avelumab (Bavencio, MSB0010718C;M7824), BCD-135, BGB-A333, BMS-936559 (MDX-1105), CBT-502 (TQB-2450), cosivelimab (CK-301), CS1001 (WPB3155), durvalumab ( This includes IMFINZI (MEDI4736), FAZ053, HLX20, INBRX-105, KN035, KN046, LDP, LY3300054, LY3415244, MCLA-145, MSB2311, NM-01, REGN3504, SHR-1316 (HTI-1088), STI-3031 (IMC-001; STI-A1015), TG-1501, and ZKAB001 (STI-A1014).

[0235] In some embodiments, the additional therapeutic agent is an immune checkpoint inhibitor that is a CTLA-4 inhibitor, such as a small molecule, antibody, or antigen-binding fragment that inhibits CTLA-4 activity. In some embodiments, the antibody targeting CTLA-4 is selected from the group consisting of ADG116, ADU-1604, AGEN1181, AGEN1884, AK104, ATOR-1015, BCD-145, BCD-217, BMS-986218, ipilimumab (Yervoy), KN046, MGD019, MK-1308, REGN4659, tremelimumab (tisilimunab, CP-675,206), XmAb20717, and XmAb22841.

[0236] In some embodiments, the additional therapeutic agent is a CD25 inhibitor, such as a small molecule, antibody, or antigen-binding fragment that inhibits CD25 activity. In some embodiments, the anti-CD25 antibody is selected from the group consisting of basiliximab (Symlect), camidanrumab tecillin, daclizumab (Zimbrita; Xenapax), inorimomab, RA8, STI-003, and Xenopax.

[0237] The administration of additional therapeutic agents, such as checkpoint inhibitors, adjuvants, or cytokines, may be administered before, simultaneously with, or after the administration of the provided conjugate. For example, the method may include the steps of administering one or more doses of an immune checkpoint inhibitor, administering a conjugate, and irradiating the target area with light of a suitable wavelength after the administration of the conjugate. The method may also include the steps of administering the conjugate first, irradiating the target area after the administration of the conjugate, and then administering an additional therapeutic agent, such as an immune checkpoint inhibitor, following the administration of the conjugate or following the irradiation step. The method may also include the administration of an additional therapeutic agent, such as an immune checkpoint inhibitor, simultaneously with the administration of the conjugate and following the irradiation step. In some embodiments, additional therapeutic agents, such as immune checkpoint inhibitors, adjuvants, or cytokines, are administered one or more times before the provided conjugate is administered, followed by irradiation of the target area, and then one or more additional doses of the additional therapeutic agents (identical or different additional therapeutic agents) are administered.

[0238] F. Other uses Other methods and uses for the conjugates provided herein are also provided. In some embodiments, the conjugates provided are used for diagnostic, monitoring, or research purposes, such as experimental research. For example, in some embodiments, the conjugates provided are used to visualize or detect target molecules or interactions of interest. Such applications include, but are not limited to, imaging, DNA sequencing, DNA microarrays, immunoblotting (e.g., Western blotting), flow cytometry analysis, protein microarrays, and fluorescence resonance imaging transfer (FRET). In some embodiments, the conjugates provided are used for enzyme activity detection, screening in high-throughput applications, detection of protein interactions (e.g., ligand-receptor interactions), and nucleic acid hybridization.

[0239] For example, in some embodiments, the conjugate provided may be used as an in vitro, in vivo, or ex vivo contrast agent for cells, tissues, or organs in a variety of biomedical applications, including, but not limited to, multi-stage imaging of organs, monitoring of organ function, coronary angiography, fluorescence endoscopy, tumor imaging, laser-guided surgery, photoacoustic and sonofluorescence methods, and other similar methods.

[0240] In some embodiments, the conjugate is administered to a subject for in vivo visualization or detection. In such embodiments, the composition is administered in a dose effective to achieve the desired optical image of a tumor, tissue, or organ. Such doses can vary widely depending on the specific dye compound or conjugate used, the tumor, tissue, or organ to be subjected to the imaging procedure, the imaging equipment used, and other factors. In some embodiments, the conjugate provided is used for the visualization of a disease or condition. The equipment for such visualization is selected to be appropriate for the disease or condition to be visualized by direct microscopic imaging, endoscopic visualization, or 2D or 3D image reconstruction, etc. Exemplary diseases or conditions for which the conjugate provided for visualization can be used include, but are not limited to, diseases or conditions of the eye, skin diseases or conditions, vascular disorders, e.g., atheromas or other vascular abnormalities, abnormalities, diseases and tumors of the oral, bronchial, cervical, and urinary tract, and other tumors, e.g., tumors of the chest or brain.

[0241] In some aspects, the conjugates provided are used for immunofluorescence visualization of formalin-fixed cells or tissues, and for live cell imaging in vitro or ex vivo.

[0242] G. Definition Unless otherwise specified, all technical terms, expressions, and other technical and scientific terms or expressions used herein have the same meaning as those generally understood by those skilled in the art in the field relating to the claimed subject matter. In some cases, terms having a generally understood meaning are defined herein for clarity and / or for easy reference; the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from those generally understood in the art.

[0243] As used herein, the singular forms “a,” “an,” and “the” encompass multiple references unless the context explicitly indicates otherwise. For example, “a” or “an” means “at least one” or “one or more.” The aspects and modifiers described herein are understood to encompass the aspects and modifiers “consisting” and / or “consisting essentially of.”

[0244] Throughout this disclosure, various aspects of the claimed subject matter are presented in scope form. It should be understood that the scope form description is for convenience and brevity only and should not be interpreted as an immutable limitation on the scope of the claimed subject matter. Therefore, the scope description should be considered to encompass all specifically disclosed possible sub-scopes and the individual numerical values ​​within those scopes. For example, where a range of values ​​is provided, it should be understood that each intervening value between the upper and lower limits of that range, as well as any other stated or intervening values ​​within that stated range, are included within the claimed subject matter. These smaller upper and lower limits may independently be encompassed within smaller ranges and, depending on any specifically excluded limits in the stated range, also be included within the claimed subject matter. If the stated range encompasses one or both limits, the range excluding either or both of those encompassed limits is also included within the claimed subject matter. This applies regardless of the width of the range.

[0245] Where used herein, the term “approximately” refers to the normal range of error for each value, which is readily known to those skilled in the art. References to “approximately” values ​​or parameters herein include (and describe) aspects directed toward the value or parameter itself. For example, a description referring to “approximately X” includes a description of “x.”

[0246] As used herein, “conjugate” means a targeting molecule directly or indirectly linked to a phthalocyanine dye of formula (0), formula (I), or formula (II) produced by chemical conjugation, or produced by any other method. For example, a conjugate may refer to a phthalocyanine dye provided herein, directly or indirectly linked to one or more targeting molecules, for example, a polypeptide that binds to or targets a cell surface protein. Targeting molecules may include, for example, proteins, glycoproteins, antibodies, antibody fragments, aphibodies, antigens, antigen-binding fragments, peptides, polypeptides, tissue-homing peptides, small molecules, polymer synthesis molecules, polymer nanoparticles, liposomes, enzyme substrates, hormones, neurotransmitters, cellular metabolites, viral particles, viral capsids, viral nanoparticles, bacterial particles, markers, cells, haptens, avidin, streptavidin, monomeric streptavidin, biotin, carbohydrates, oligosaccharides, polysaccharides, nucleic acids, deoxyribonucleotides, DNA fragments, RNA fragments, aptamers, nucleotide triphosphates, acycloterminator triphosphates, PNA, or chemical parts.

[0247] As used herein, “protein” and “polypeptide” are used synonymously. Proteins may include portions other than amino acids (e.g., they may be glycosylated), or they may be processed or modified. Those skilled in the art will understand that a “protein” may be a complete protein chain produced by a cell (with or without a signal sequence), or it may be a portion thereof. Proteins may sometimes include more than one protein chain, linked, for example, by non-covalent or covalent bonds, for example, by one or more disulfide bonds, or associated by some other means. Polypeptides may contain L-amino acids, D-amino acids, or both, and may contain any of various amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, proteins may include native amino acids, non-native amino acids, synthetic amino acids, and combinations thereof. In some embodiments, proteins may be antibodies, antibody fragments, their biologically active portions, and / or characteristic portions.

[0248] As used herein, “antibody” means a polypeptide comprising at least a light chain or heavy chain immunoglobulin variable region that specifically recognizes and binds to an antigen, such as an epitope of a tumor-specific protein. The antibody comprises a heavy chain and a light chain, each of which is heavy chain variable (V H ) region and light chain variable (V L It has a variable region called the ) region. Overall, V H Region and V LThe region is involved in binding to the antigen recognized by the antibody. The term “antibody” also encompasses intact antibodies and antigen-binding antibody fragments that exhibit antigen-binding ability, e.g., Fab fragments, Fab' fragments, F(ab)'2 fragments, Fab'-SH fragments, single-chain Fv proteins ("scFv"), single-domain antibodies (sdAb), e.g., heavy-chain variable region only (VHH) single-domain antibodies, scFv fragments, and disulfide-stabilized Fv proteins ("dsFv"), diabodies, linear antibodies, and multispecific antibodies formed from antibody fragments. Other antibody fragments or multispecific antibodies formed from antibody fragments include polyvalent scFv, bispecific scFv, or scFv-CH3 dimers. scFv proteins are fusion proteins in which the light-chain variable region and the heavy-chain variable region of an immunoglobulin are linked by a linker, and in dsFv, the chain is mutated to introduce a disulfide bond to stabilize the chain association. The term “antibody” also encompasses genetically modified forms of immunoglobulins, chimeric antibodies, such as humanized mouse antibodies, and heteroconjugate antibodies, such as bispecific antibodies. See also Pierce Catalog and Handbook, 1994–1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J. Immunology, 3rd edition, WH Freeman & Co., New York, 1997.

[0249] As used herein, “antibody-like” molecules include molecules that specifically bind to an antigen but are not structurally related to antibodies. Exemplary antibody-like molecules include, but are not limited to, affibodies, z-domain structures, DARPin, monobodies, antikalin, affin, affimers (e.g., affimer type 1 and affimer type 2 molecules), afitin, alphabodies, antikalin, avimers, finomers, Knitz domain peptides, and nanoclamps that specifically bind to antigens.

[0250] "V HReferences to "VH" or "VH" refer to the variable region of the immunoglobulin heavy chain, encompassing those of Fv, scFv, dsFv, or Fab. L References to "VL" or "VL" refer to the variable region of an immunoglobulin light chain, encompassing those of Fv, scFv, dsFv, or Fab.

[0251] A "monoclonal antibody" is an antibody produced by a single clone of a B lymphocyte or by cells transfected with the light and heavy chain genes of a single antibody. Monoclonal antibodies are produced by methods known to those skilled in the art, for example, by creating hybrid antibody-forming cells from the fusion of myeloma cells with immunosplenic cells. Monoclonal antibodies include humanized monoclonal antibodies.

[0252] "Specifically binding" refers to the ability of an individual antibody to specifically and immunologically react with an antigen, compared to binding to unrelated proteins. For example, a PD-L1 specific conjugate binds substantially only to the PD-L1 protein in vitro or in vivo. As used herein, the term "tumor-specific conjugate" includes tumor-specific antibodies and other agents in their preparations that bind substantially only to tumor-specific proteins.

[0253] "Antibody-dye molecule" or "antibody-dye conjugate" refers to a molecule that includes both an antibody conjugated to a dye molecule provided herein, for example, a tumor-specific antibody. In some examples, the antibody is a humanized antibody (e.g., a humanized monoclonal antibody) that specifically binds to surface proteins on cancer cells.

[0254] "Antigen" refers to a compound, composition, or substance that can stimulate antibody production or a T-cell response in an animal, including a composition (e.g., one containing tumor-specific proteins) injected or absorbed into the animal. Antigens react with products of specific humoral or cellular immunity, including heterologous antigens, e.g., those induced by the disclosed antigen. "Epitope" or "antigenic determinant" refers to a region of an antigen to which B and / or T cells respond. For example, an epitope is a small piece of antigen to which an antibody binds. In one embodiment, T cells respond to an epitope when it is presented together with an MHC molecule. Epitopes can be formed from continuous amino acids or discontinuous amino acids arranged by tertiary folding of proteins. Epitopes formed from continuous amino acids are usually retained upon exposure to denaturing solvents, while epitopes formed by tertiary folding are usually lost upon treatment with denaturing solvents. Epitopes typically contain at least three, more commonly at least five, approximately nine, or approximately eight to ten amino acids in a specific spatial conformation. Methods for determining the spatial conformation of an epitope include, for example, X-ray crystallography and nuclear magnetic resonance.

[0255] Examples of antigens include, but are not limited to, peptides, lipids, carbohydrates, polysaccharides, and nucleic acids containing antigenic determinants, such as those recognized by immune cells. In some cases, antigens include tumor-specific peptides (e.g., those found on the surface of cancer cells) or their immunogenic fragments.

[0256] "Immunomodulators" and "immunomodulatory therapy" refer to therapeutic drugs that modulate the immune system, such as cytokines, adjuvants, and immune checkpoint inhibitors, as well as the use of such drugs and the treatments performed.

[0257] "Immune checkpoint inhibitors" refer to a type of drug that blocks certain proteins produced by certain types of immune system cells, such as T cells and some cancer cells. These proteins help suppress the immune response, preventing T cells from killing cancer cells. When these proteins are blocked, the "brakes" on the immune system are released, allowing T cells to kill cancer cells more effectively. Examples of checkpoint proteins found in T cells or cancer cells include PD-1 / PD-L1 and CTLA-4 / B7-1 / B7-2. Several immune checkpoint inhibitors are used to treat cancer.

[0258] As used herein, a combination refers to any relationship between or among two or more items. A combination may be two or more distinct items, for example, two compositions or two collectibles; a mixture thereof, for example, a single mixture of two or more items; or a variation of any of them. The elements of a combination are generally functionally related or related.

[0259] As used herein, “combination therapy” means a treatment in which a subject is given two or more therapeutic agents, e.g., at least two or at least three therapeutic agents, to treat a single disease. In some embodiments, each therapy may produce an independent pharmacokinetic effect, or together they may produce an additive or synergistic pharmacokinetic effect.

[0260] As used herein, “treating” a subject with a disease or condition means that the symptoms of the subject are partially or completely relieved or remain at rest after treatment. Thus, treatment encompasses prevention, therapy, and / or cure. Prevention means preventing a possible disease and / or preventing the worsening of symptoms or the progression of the disease.

[0261] As used herein, “treatment” means any method by which the symptoms of a condition, disorder or disease or other indication are alleviated or otherwise beneficially altered.

[0262] As used herein, “therapeutic effect” means an effect resulting from a treatment that modifies, usually improves or alleviates, the symptoms of a disease or condition, or cures the disease or condition.

[0263] As used herein, relief of symptoms of a particular disease or disorder by treatment, for example, by administration of a pharmaceutical composition or other therapeutic agent, means any reduction of symptoms that may be caused by or associated with the administration of the composition or therapeutic agent, whether permanent or temporary, persistent or transient.

[0264] As used herein, the term “subject” refers to animals, including mammals, such as humans.

[0265] As used herein, “optional” or “optionally” means that the event or situation described below may or may not occur, and that the description includes both the cases in which such event or situation occurs and the cases in which it does not occur. For example, “a base that may be optionally substituted” means that the base is either unsubstituted or substituted.

[0266] As used herein, “tumor” means an abnormal mass of tissue that results from cells dividing more than they should or failing to die when they should. Tumors can be benign (not cancerous) or malignant (cancerous).

[0267] As used herein, “lesion” refers to an area of ​​abnormal tissue. Lesions may be benign (not cancerous) or malignant (cancerous).

[0268] As used herein, “anticancer agent” refers to any molecule used for treatment to stop or prevent cancer. Examples may include, but are not limited to, small chemical molecules, antibodies, antibody conjugates, immunomodulators, or any combination thereof.

[0269] As used herein, “suppressor cells” or “immunosuppressor cells” refers to cells that can reduce or inhibit the function of immune effector cells, such as CD8+ T effector cells. Examples of suppressor cells may include, but are not limited to, regulatory T cells, M2 macrophages, bone marrow-derived suppressor cells, tumor-associated fibroblasts, or cancer-associated fibroblasts.

[0270] As used herein, “immunosuppressant” refers to a drug that reduces the body’s immune response, thereby reducing the body’s ability to fight infections and other diseases, such as cancer.

[0271] As used herein, “resistant to treatment” means a disease or condition that is not responsive to treatment, and as a result, the treatment is ineffective or does not demonstrate effectiveness in treating the disease or condition.

[0272] As used herein, “systemic immune response” refers to the ability of the immune system in question to respond systemically to an immunological challenge(s) including those associated with tumors, lesions, or cancer. A systemic immune response may include the systemic response of the adaptive and / or innate immune systems in question. It may encompass immune responses across different tissues, including the bloodstream, lymph nodes, bone marrow, spleen, and / or tumor microenvironment, and in some cases, coordinated responses between tissues and organs and various cells, as well as tissue and organ factors.

[0273] As used herein, “local immune response” refers to the immune response in a tissue or organ to an immunological challenge(s), including those associated with tumors, lesions, or cancer. Local immune responses may include the adaptive immune system and / or the innate immune system. Local immunity encompasses immune responses occurring simultaneously in various tissues, including the bloodstream, lymph nodes, bone marrow, spleen, and / or tumor microenvironment.

[0274] As used herein, “protected form” of a reactive group means a specific functional group having a reactive group or the reactive group itself, including hydroxyl, amino, mercapto, and carboxylic acid groups, which is protected by a suitable protecting group using standard techniques known to those skilled in the art and as described herein. Suitable protecting groups for hydroxyls include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, and benzyl. Suitable protecting groups for amino, amidino, and guanidinos include t-butoxycarbonyl and benzyloxycarbonyl. Suitable protecting groups for mercaptos include -C(O)R (wherein R is alkyl, aryl, or aralkyl), p-methoxybenzyl, and trityl. Suitable protecting groups for carboxylic acids include alkyl, aryl, or aralkyl esters. The use of protecting groups is described in detail in Peter GM Wutz, Greene's Protective Groups in Organic Synthesis, 5th edition (2014), John Wiley & Sons, Inc.

[0275] In some embodiments, axial silicon-containing ligands are described as having a conjugateable group. In some embodiments, axial silicon-containing ligands are described as having a reactive group. The terms “conjugateable” and “reactive” as used in this disclosure are synonymous and interchangeable, and no distinction between the two terms should be considered.

[0276] As used herein, the terms “reactive group” and “conjugateable group” are used synonymously and are interpreted as a portion capable of chemically reacting with and linking to a functional group on a different molecule (e.g., a targeting molecule), for example, forming a covalent bond. Typically, a reactive group is an electrophile or nucleophile that can form a covalent bond upon exposure to a corresponding functional group, which is a nucleophile or electrophile, respectively. Alternatively, a reactive group is a photoactivatable group that becomes chemically reactive only after irradiation with light of an appropriate wavelength. Typically, as a result of a conjugation reaction between a dye and a targeting molecule to be conjugated, one or more atoms of reactive group A are incorporated during the novel linkage that attaches the dye to the conjugated targeting molecule.

[0277] In some embodiments, A is a reactive group that reacts with a carboxyl group, amine, or thiol group on the targeting molecule. Suitable reactive groups include, but are not limited to, esters, acyl halides, alkyl halides, anhydrides, carboxylic acids, carbodiimides, carbonates, carbamates, haloacetamides (e.g., iodoacetamide), isocyanates, isothiocyanates, maleimides, NHS esters, phosphoramidites, platinum complexes, sulfonate esters, and thiocyanates, which are activated for optimal adhesion to the targeting molecule. In some embodiments, the reactive group is reactive with a carboxyl group, amine, or thiol group on the targeting molecule. In some embodiments, the reactive group is a sulfhydryl reactive chemical group, such as maleimides, haloacetyls, pyridyl disulfide, aziridine, acryloyl, arylating agents, vinyl sulfones, and pyridyl disulfide. In some embodiments, the reactive group is amine reactive. In some embodiments, the reactive group is an NHS ester.

[0278] As used herein, the “reacted form” of a reactive group means that the reactive group has undergone a chemical reaction and formed a covalent bond with another molecule.

[0279] As used herein, “water-soluble group” refers to a group comprising one or more polar and / or ionic substituents that improve the overall solubility of the molecule in an aqueous medium. Water-soluble groups include, but are not limited to, carboxylate (-CO2) groups, poly(ethylene glycol), sulfonate (-SO3) groups, sulfonyl (-SO2) groups, sulfate (-SO4) groups, hydroxyl (-OH) groups, and phosphate (-OPO3) groups. -2 ) group, phosphonate (-PO3 -2 This includes optionally substituted quaternary nitrogen having a ) group, an amine (-NH2) group, and any counterion for each.

[0280] In certain embodiments, the water-soluble group is a trivalent or tetravalent nitrogen-containing group. In even more specific embodiments, the water-soluble group is a tris-sulfoalkyl or tris-sulfonate quaternary ammonium, a bis-sulfoalkyl or bis-sulfonateamine, or a bis-alkoxypolyethylene glycolamine.

[0281] As used herein, "alkenylene" refers to a straight or branched diunsaturated hydrocarbon chain having 1 to 12 carbon atoms and hydrogen atoms, wherein the unsaturation exists only as double bonds, and these double bonds may be located between any two carbon atoms in the chain, such as ethenylene, propa-1-enylene, and buta-2-enylene. Alkenylene chains may be bonded to the remainder of the molecule by any two carbon atoms in the chain.

[0282] As used herein, the term "alkoxy" refers to a group of formula O(alkyl) unless otherwise specified. Alkoxys may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy.

[0283] The term "alkenyl," as used herein, refers to a linear or branched hydrocarbon chain radical that contains the indicated number of carbon atoms, or, if not, has 2 to 10, 2 to 8, or 2 to 6 carbon atoms, and has one or more carbon-carbon double bonds, which are bonded to the remainder of the molecule by single or double bonds. Alkenyl groups may include, for example, vinyl, allyl, 1-butenyl, and 2-hexenyl. In some embodiments, the alkenyl is a C2-C6 alkenyl.

[0284] The term "alkyl," as used herein, refers to a saturated hydrocarbon chain radical that may be linear or branched, containing the indicated number of carbon atoms, or not having 1 to 10, 1 to 8, 1 to 6, or 1 to 4 carbon atoms, bonded to the remainder of the molecule by single bonds. In certain embodiments, the hydrocarbon chain may optionally be deuterated. For example, C1C6 alkyl indicates that the group may contain 1 to 6 carbon atoms (including both ends). In some embodiments, alkyl is a C1 to C6 alkyl representing a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0285] As used herein, "alkylene" refers to a straight or branched divalent hydrocarbon chain consisting of carbon and hydrogen, containing no unsaturation, and having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, or n-butylene. The alkylene chain may be bonded to the remainder of the molecule by any two carbon atoms within the chain.

[0286] As used herein, the term "alkynyl" refers, unless otherwise specified, to a linear or branched hydrocarbon chain radical containing the indicated number of carbon atoms, or not containing 2 to 10, 2 to 8, or 2 to 6 carbon atoms and having one or more carbon-carbon triple bonds. Alkynyl groups may include, for example, ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In some embodiments, the alkynyl is a C2-C6 alkynyl.

[0287] The term "amino" refers to a radical having the formula -NR'R'' (wherein R' and R'' are independently hydrogen, alkyl, or haloalkyl).

[0288] As used herein, the term "aralkyl" refers, unless otherwise specified, to an alkyl radical in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbon atoms of the alkyl moiety acts as a bonding site to another moiety of the aralkyl group. Examples of "aralkyl" that are not limited to these include the benzyl, 2-phenylethyl, and 3-phenylpropyl groups.

[0289] As used herein, the term "aryl" means any stable monocyclic or bicyclic carbocyclic radical having up to six members in each ring, with at least one ring being aromatic, unless otherwise specified. Examples of aryls include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl.

[0290] As used herein, “arylene” refers to a divalent aryl group having 6 to 14 carbon atoms, which can be bonded to the remainder of the molecule by any two carbon atoms in the carbocyclic group. For example, six-membered arylenes include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene linkers, in which the phenylene bond is in an ortho, meta, or para configuration, respectively.

[0291] The term "aralkylene," as used herein, refers to an aralkyl radical bonded to the rest of the molecule by any two carbon atoms within the moiety, unless otherwise specified. Examples of "aralkylenes" that are not limited to these include the -(C6H4)-(CH2)-, -(CH2)-(C6H4)-(CH2)-, and -(CH2)-(C6H4)- groups. The aryl moiety of an aralkylene group may have 6 to 14 carbon atoms and may be bonded to the rest of the molecule by any two carbon atoms within the aralkylene group. For example, six-membered arylenes include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene linkers, where the phenylene bond is in an ortho, meta, or para configuration, respectively.

[0292] The term "cycloalkyl," as used herein, refers to monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon radicals having the indicated number of ring carbon atoms, or not having 3 to 10 carbon atoms, and being fully saturated or partially unsaturated. Polycyclic cycloalkyls may be fused, cross-linked, or spiro-ring structures. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, and partially unsaturated hydrocarbon rings, such as cyclobutylene, cyclopentene, and cyclohexene. In some embodiments, cycloalkyls are monocyclic C3-C8 cycloalkyls.

[0293] As used herein, "cycloalkylene" refers to a divalent saturated or partially saturated carbocyclic group having 3 to 8 carbon atoms, the remainder of which can be bonded to any two carbon atoms of a cycloalkyl group. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclooctylene.

[0294] The terms “halo,” “halogen,” or “halogenated,” as used herein, refer to any radical of fluorine, chlorine, bromine, or iodine, unless otherwise specified.

[0295] As used herein, the term "haloalkyl" refers to an alkyl radical in which at least one hydrogen atom is replaced by a halogen, unless otherwise specified. In some embodiments, two or more hydrogen atoms (e.g., 2, 3, 4, 5, or 6) are replaced by halogens. In these embodiments, each hydrogen atom may be replaced by the same halogen (e.g., fluoro), or by a combination of different halogens (e.g., fluoro and chloro). "Haloalkyl" also includes alkyl moieties in which all hydrogens are replaced by halogens (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, e.g., trifluoromethyl).

[0296] As used herein, “heteroalkylene” means that at least one carbon atom in the alkylene chain is -NR d ,-O-,-OP(R e )(R f )O-, -S-, -S(O)-, -S(O)2-, -C(O)-, -C(S)- or -C(NOR d )-(wherein, R d is R e and R f Both are either = O or R e and R f One of them is =O, and R e and R f The other one is OR a And R a This refers to an alkylene group as described above, which is replaced by a heteroatom containing an alkyl group as defined herein. In some embodiments, the heteroatom is within the alkylene chain (i.e., the heteroalkylene contains at least one carbon-Z-carbon bond (where Z is -NR) g - and R g is hydrogen or alkyl, -O-, -OP(R e )(R f (including those that are O-, -S-, -S(O)-, or -S(O)2-).

[0297] When used herein, the term "heteroaryl" means, unless otherwise specified, any stable monocyclic or bicyclic aromatic ring radical with up to 10 members, containing at least one heteroatom selected from N, O, S, S(O), and S(O)2 in each ring. Examples of heteroaryls include furan, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indidine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, or naphthyridine.

[0298] The term "heteroaralkyrene," as used herein, refers to a heteroaralkyl radical that is bonded to the rest of the molecule by any two atoms within the moiety, unless otherwise specified. Examples of "heteroaralkyrene" that are not limited to these include the -(heteroarylene)-(CH2)-, -(CH2)-(heteroarylene)-(CH2)-, and -(CH2)-(heteroarylene)- groups. The heteroaryl moiety of a heteroaralkyrene group may have 5 to 10 ring atoms and may be bonded to the rest of the molecule by any two atoms within the heteroaralkyrene group. For example, a heteroaralkyrene group may include a six-membered heteroarylene containing 1,2-pyridine, 1,3-pyridine, and 1,4-pyridine linkers, where the pyridine bond site is in an ortho, meta, or para configuration, respectively.

[0299] As used herein, “heteroarylene” means a divalent radical heteroaryl group containing at least one heteroatom selected from N, O, S, S(O), and S(O)2, wherein the heteroaryl group may be bonded to the remainder of the molecule by any two atoms of the heteroaryl group.

[0300] As used herein, “heterocycloalkylene” means a divalent six-membered saturated or partially saturated heterocyclyl group containing at least one heteroatom selected from N, O, S, S(O), and S(O)2, wherein each carbon atom of the heterocyclyl may be optionally substituted with an oxo, and the heterocyclyl group may be bonded to the remainder of the molecule by any two carbon and / or nitrogen atoms of the heterocycle.

[0301] The terms “heterocyclic,” “heterocyclyl,” or “heterocyclic” as used herein, unless otherwise specified, refer to a stable 4-, 5-, 6-, or 7-membered monocyclic or stable 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocyclic ring structure comprising a carbon atom and at least one non-aromatic (i.e., saturated or partially unsaturated) ring consisting of 1 to 4, preferably up to 3, heteroatoms selected from the group consisting of N, O, and S, wherein the carbon, nitrogen, and sulfur atoms may be optionally oxidized as carbonyl, N-oxide, or sulfoxide / sulfone, respectively, and the nitrogen atom may be optionally quaternized. The heterocyclic ring may be bonded by ring carbon atoms and, if available, by ring nitrogen atoms. The bicyclic heterocyclic ring structure may be fused, bridged, or spiro-bicyclic heterocyclic ring structure (one or more). In some embodiments, the heterocyclyl is monocyclic, having 4 to 7 or 4 to 6 ring atoms, of which 1 or 2 are heteroatoms independently selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl group is bicyclic, in which case the second ring may be an aromatic or non-aromatic ring consisting of a carbon atom and 1 to 4, preferably up to 3, heteroatoms independently selected from the group consisting of N, O, and S, or the second ring may be a benzene ring or a "cycloalkyl" or "cycloalkenyl" as defined herein.Examples of such heterocyclic groups include, but are not limited to, azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazolin, isothiazolidine, isoxazolidine, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidin, thiomorpholine, thiethane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidin, tetrahydro This includes thiopyran, tetrahydrotriazine, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6-azaspiro[3.3]heptane, dihydrobenzofuran, dihydrobenzimidazolyl, dihydrobenzoxazole and dihydrobenzothiazolyl, and their N-oxides or sulfones or sulfoxides.

[0302] As used herein, “metalloid” refers to a chemical element having properties intermediate between typical metals and nonmetals. Metalloids include the chemical elements boron, silicon, germanium, arsenic, antimony, tin, aluminum, zinc, and tellurium. In some embodiments, the metal or metalloid is silicon. In some embodiments, the metal or metalloid is germanium. In some embodiments, the metal or metalloid is aluminum. In some embodiments, the metal or metalloid is tin. In some embodiments, the metal or metalloid is zinc. In some embodiments, the metal or metalloid is tellurium.

[0303] As used herein, in certain embodiments, unless otherwise specified, “optionally substituted alkyl,” “optionally substituted alkylene,” “optionally substituted heteroalkylene,” “optionally substituted alkenylene,” “optionally substituted heteroalkenylene,” and “optionally substituted alkynyl” refer to alkyl, alkylene, heteroalkylene, alkenylene, heteroalkenylene, and alkynyl radicals that are optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, amino, aminoalkyl, sulfonate, and cyano.

[0304] As used herein, in certain embodiments, unless otherwise specified, “optionally substituted cycloalkyl,” “optionally substituted aryl,” “optionally substituted heterocyclyl,” and “optionally substituted heteroaryl” refer to cycloalkyl, aryl, heterocyclyl, and heteroaryl radicals that are optionally substituted with one or more substituents selected from the group consisting of halo, oxo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, haloalkoxyalkyl, amino, aminoalkyl, sulfonate, cyano, and nitro.

[0305] As used herein, “protein” and “polypeptide” are used synonymously. A protein may include portions other than amino acids (e.g., may be glycosylated) or may not be processed or modified. Those skilled in the art will understand that a “protein” may be a complete protein chain (with or without a signal sequence) or a portion thereof, such as those produced by a cell. Those skilled in the art will understand that a protein may sometimes include two or more protein chains linked, for example, by non-covalent or covalent bonds, such as one or more disulfide bonds, or associated by some other means. A polypeptide may contain L-amino acids, D-amino acids, or both, and may contain various amino acid modifications or analogs known in the art. Useful modifications include, for example, terminal acetylation, amidation, and methylation. In some embodiments, a protein may include native amino acids, non-native amino acids, synthetic amino acids, and combinations thereof. In some embodiments, a protein may be an antibody, an antibody fragment, its biologically active portion, and / or characteristic portion.

[0306] Preparation of H. phthalocyanine derivative compounds In some embodiments, the phthalocyanine compounds disclosed herein are prepared by the general synthetic routes described below in Schemes 1 to 3. These schemes are intended to be illustrative to those skilled in the art and are not limiting. Further methods for the synthesis of the phthalocyanine compounds disclosed herein are readily available to those skilled in the art.

[0307] A method for preparing the phthalocyanine compounds disclosed herein is provided in Scheme 1; [ka]

[0308] According to Scheme 1, the compound silicon phthalocyanine dihydroxyd (1-1) is treated with 3-(ethoxydimethylsilyl)propan-1-amine to obtain compound (1-2) which is axially disubstituted. Compound (1-3) is provided by amide coupling of (1-2) with a suitable carboxylic acid derivative. Compound (1-4) is obtained by further amide coupling with the substituted carboxylic acid derivative. The desired product (1-6) is provided by removal of the protecting group of (1-4) and subsequent activation of the resulting carboxylic acid, such as by the formation of its NHS ester.

[0309] A method for preparing the phthalocyanine compounds disclosed herein is provided in Scheme 2: [ka]

[0310] According to the method provided in Scheme 2, compound (2-1) is treated with a substituted carboxylic acid derivative to obtain compound (2-2). Further amide coupling with a suitable carboxylic acid derivative provides compound (2-3).

[0311] The phthalocyanine compounds disclosed herein can also be prepared by the process outlined in Scheme 3. [ka]

[0312] According to Scheme 3, compound (3-1), which is disubstituted in the axial direction, is subjected to reductive alkylation using the corresponding aldehyde to obtain a monosubstituted derivative (3-2). Compound (3-3) is provided by alkylation using a suitable sulfonate-substituted haloalkyl group. The desired product (3-5) is provided by removal of the protecting group of (3-3) and subsequent activation of the resulting carboxylic acid (3-4) by formation of its NHS ester, etc.

[0313] It should be understood that the subject matter is described illustratively, and the technical terms used are intended to be explanatory rather than restrictive. Therefore, it will be understood by those skilled in the art that the solvent state, reaction temperature, volume, and reaction time may vary while still producing the desired compound. Furthermore, those skilled in the art will understand that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, for example, Smith & March, Advanced Organic Chemistry, 5th edition (2001). Such changes and modifications, including but not limited to, those relating to the chemical structure, substituents, derivatives, intermediates, synthesis, formulation, and / or methods of use provided herein, may be made without departing from the spirit and scope thereof. References to U.S. patents and publications herein are incorporated by reference.

[0314] example 1.Chemical synthesis (Example 1) Preparation of 6-((3-(dimethyl((19-((15-methyl-10-oxo-2,5,8-trioxa-11-aza-15-silahexadecane-15-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)silyl)propyl)amino)-6-oxohexanoic acid. Step 1: 3,3'-(((19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole e-19,19-diyl)bis(oxy))bis(dimethylsilanediyl))bis(propan-1-amine): [ka]

[0315] Under a nitrogen atmosphere, 3-aminopropyldimethylethoxysilane (4.2 g, 26.1 mmol) was added to a suspension of silicon(IV) phthalocyanine dihydroxyde (0.5 g, 0.87 mmol) in anhydrous pyridine (40 mL). The resulting mixture was heated at 140 °C for 3 hours. The reaction progress was monitored by TLC with neutral alumina (10% MeOH / CH2Cl2). Once the reaction was complete, the mixture was filtered and the mother liquor was evaporated to dryness under reduced pressure. The resulting residue was suspended in hexane (50 mL), filtered, and further washed with diethyl ether (2 × 10 mL) to obtain the Step 1 intermediate (0.4 g, yield 57%) as a dark blue solid. 1 H-NMR (400 MHz, CDCl3) δ 9.70 (m, 8H), 8.39 (m, 8H), 1.23 (m, 4H), -1.22 (m, 4H), -2.26 (m, 4H), -2.81 (s, 12H).

[0316] Step 2: Methyl 6-((3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-6-oxohexanoate.Dimethylsilyl)propyl)amino)-6-oxohexanoate. [ka]

[0317] Under nitrogen at room temperature, DMAP (catalyst) was added to a solution of 6-methoxy-6-oxohexanoic acid (33 mg, 0.8 equivalents), HOBt (39 mg, 0.96 equivalents), and EDCI (46 mg, 0.96 equivalents) in CH2Cl2 (7 mL). The reaction mixture was stirred for 1.1 hours. This mixture was added dropwise over 24 minutes to a solution of the title compound obtained from step 1 (200 mg, 0.25 mmol) and DIPEA (82 μL, 1.9 equivalents) in CH2Cl2 (23 mL). The reaction mixture was stirred at room temperature for 24 hours. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 aqueous solution (25 mL). The aqueous phase was separated and extracted with CH2Cl2 (3 × 8 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The blue residue was purified by silica gel column chromatography (CombiFlash, 24g column, 0-90% MeOH / CH2Cl2) to obtain the title compound (74 mg, 31% yield). LCMS: 969 (M+23) + .

[0318] Step 3: Methyl 6-((3-(dimethyl((19-((15-methyl-10-oxo-2,5,8-trioxa-11-aza-15-silahexadecane-15-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)silyl)propyl)amino)-6-oxohexanoate. [ka]

[0319] Under nitrogen at room temperature, the solutions of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (14.5 mg, 1.3 equivalents), HOBt (14.5 mg, 1.5 equivalents), and EDCI (17 mg, 1.5 equivalents) in CH2Cl2 (7 mL) were stirred for 1 hour. The solution of the intermediate obtained from step 2 (56 mg, 0.059 mmol) in CH2Cl2 (3 mL) was then used, i Pr2NEt (20 μL, 2 equivalents) was added dropwise. The reaction mixture was stirred at room temperature for 21 hours. The mixture was then diluted with CH2Cl2 (7 mL) and successively washed with 0.1 N HCl (10 mL), NaHCO3 (10 mL), and brine (10 mL). Each aqueous layer was back-extracted with CH2Cl2 (3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CombiFlash 12 g, 0-60% CH2Cl2 / MeOH) to obtain the step 3 intermediate (47 mg, yield 72%) as a solid. 1H NMR (CD2Cl2, 500 MHz) δ 9.68 (m, 8H), 8.39 (m, 8H), 3.67 (s, 3H), 3.63 (s, 2H), 3.51 (m, 2H), 3.47 (m, 1H), 3.45 (m, 2H), 3.34 (m, 1H), 3.31 (m, 2H), 3.13 (s, 3H), 2.31 (dd, J=7.5, 7.5 Hz, 2H), 1.88 (dd, J=7.5, 7.5 Hz, 2H), 1.81 (m, 2H), 1.74 (m, 2H), 1.58 (m, 2H), 1.47 (m, 2H), -1.04 (m, 2H), -1.25 (m, 2H), -2.28 (m, 4H), -2.85 (s, 3H), -2.87 (s, 3H).

[0320] Step 4: 6-((3-(dimethyl((19-((15-methyl-10-oxo-2,5,8-trioxa-11-aza-15-silahexadecane-15-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)silyl)propyl)amino)-6-oxohexanoic acid: 0.01N NaOH (12.5 mL, 3 equivalents) was added dropwise to a solution of the intermediate (46 mg, 0.04 mmol) obtained from Step 3 in THF (19 mL), cooled in an ice / water bath. The reaction mixture was heated to room temperature and stirred for 22 hours. The reaction mixture was diluted with siRNA (20 mL) and washed with saturated aqueous solution of NH₄Cl (15 mL). The aqueous phase was separated and extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The blue residue was purified by silica gel column chromatography (CombiFlash 12 g, 0-60% MeOH / CH₂Cl₂) to obtain the title compound (37.2 mg, yield 82%) as a solid. 1H NMR (CD2Cl2, 500 MHz) δ 9.68 (m, 8H), 8.39 (m, 8H), 3.75 (s, 2H), 3.50 (dd, J=5.5, 2.5 Hz, 2H), 3.45 (m, 4H), 3.29 (dd, J=5.8, 3.8 Hz, 2H), 3.12 (s, 3H), 2.47 (dd, J=6.5, 6.5 Hz, 2H), 2.01 (dd, J=7.0, 7.0 Hz, 2H), 1.85 (m, 2H), 1.68 (m, 6H), -1.08 (m, 2H), -1.31 (m, 2H), -2.23 (m, 2H), -2.29 (m, 2H), -2.85 (s, 3H), -2.86 (s, 3H). LCMS: 1115 (M+23) + .

[0321] (Example 2) Preparation of 2-(2-((3-(dimethyl((19-((15-methyl-10-oxo-2,5,8-trioxa-11-aza-15-silahexadecane-15-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)silyl)propyl)amino)-2-oxoethoxy)acetic acid. Step 1: Synthesis of N-(3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)-2-(2-(2-methoxyethoxy)ethoxy)acetamide. [ka]

[0322] Under nitrogen at room temperature, DMAP (catalyst) was added to a mixture of 2-(2-(2-methoxyethoxy)ethoxy)acetic acid (5 mg, 0.026 mmol), HOBt (4.3 mg, 1 equivalent), and EDCI (5 mg, 1 equivalent) in CH2Cl2 (1.5 mL). The reaction mixture was stirred for 1 hour, and then added dropwise over 15 minutes to a solution of the title compound obtained from Example 1, Step 1 (25 mg, 0.031 mmol) and Pr2NEt (9 μL, 2 equivalents) in CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 24 hours. The mixture was then diluted with CH2Cl2 (3 mL) and washed with saturated aqueous solution of NaHCO3 (5 mL). The aqueous phase was separated and extracted with CH2Cl2 (2 × 3 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The blue residue was purified by silica gel column chromatography (Combiflash Isco, 4g gold column, 0-90% MeOH / CH2Cl2). 1 H-NMR (CD2Cl2, 500 MHz) δ 9.67 (m, 8H), 8.38 (m, 8H), 3.63 (s, 2H), 3.52 (m, 2H), 3.46 (m, 4H), 3.31 (m, 2H), 3.13 (s, 3H), 1.81 (dd, J = 14.0, 7.0, 2H), 1.11 (m, 2H), -1.05 (m, 2H), -1.24 (m, 2H), -2.30 (m, 4H), -2.85 (s, 6H), -2.88 (s, 6H). LCMS: 965 (M+1) + .

[0323] Step 2: Synthesis of 2-(2-((3-(dimethyl((19-((15-methyl-10-oxo-2,5,8-trioxa-11-aza-15-silahexadecane-15-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)silyl)propyl)amino)-2-oxoethoxy)acetic acid: A solution of the intermediate compound obtained from Step 1 (4.5 mg, 0.005 mmol) and diglycolic acid anhydride (2.4 mg, 4.3 equivalents) in DMF (0.5 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with toluene (1 mL) and washed with aqueous NH4Cl solution (1 mL). The aqueous phase was separated and extracted with toluene (3 × 1 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The blue residue was purified by silica gel column chromatography (CombiFlash 4 g, 0-90% MeOH / CH2Cl2) to obtain the title compound (3.5 mg, yield 69%). 1 H NMR (CD2Cl2, 500 MHz) δ 9.60 (m, 8H), 8.24 (m, 8H), 3.68 (bs, 2H), 3.62 (s, 2H), 3.60 (bs, 2H), 3.47 (m, 2H), 3.42 (m, 4H), 3.27 (m, 2H), 1.81 (m, 2H), 1.26 (m, 2H), -1.06 (m, 2H), -1.34 (m, 2H), -2.31 (m, 2H), -2.50 (m, 2H), -2.85 (s, 6H), -3.00 (s, 6H). LCMS: 1080 (M+1) + .

[0324] (Example 3) Preparation of 2-(2-((3-(((19-((11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-21-methyl-16-oxo-2,5,8,15-tetraoxa-11,17-diaza-21-siladocosan-21-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)acetic acid. Step 1: 11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2,5,8-trioxa-11-azatetradecane-14-yl(4-nitrophenyl)carbonate [ka]

[0325] To a solution of 11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2,5,8-trioxa-11-azatetradecane-14-ol (1 g, 2.72 mmol) and TEA (0.75 mL, 5.44 mmol) in dichloromethane (25 mL) cooled to 0°C, 4-nitrophenyl chloroformate (0.821 g, 4.09 mmol) was gradually added over 15 minutes. The reaction mixture was stirred at room temperature for 6 hours. Then, it was poured over water (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude Step 1 intermediate compound (1.8 g), which was used in subsequent steps without further purification.

[0326] Step 2: 11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2,5,8-trioxa-11-azatetradecane-14-yl(3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)carbamate. [ka]

[0327] To a solution of the intermediate compound obtained from Example 1, Step 1 (0.4 g, 0.49 mmol) in THF (8 mL), TEA (0.14 mL, 0.99 mmol) was added. The reaction mixture was cooled to 0°C, and a solution of the title compound obtained from Step 1 (0.26 g, 0.50 mmol) in THF (2 mL) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured over water (30 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography in basic alumina (CH2Cl2, 3% MeOH) to obtain the Step 2 intermediate compound (0.2 g, yield 34%). LCMS: 1199 (M+1) + .

[0328] Step 3: 2-(2-((3-(((19-((11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-21-methyl-16-oxo-2,5,8,15-tetraoxa-11,17-diaza-21-siladocosan-21-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetra Synthesis of aza[2]silacylcycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)acetic acid: At room temperature, 1,4-dioxan-2,6-dione (0.010 g, 0.08 mmol) was added to a solution of the intermediate compound obtained from step 2 (0.08 g, 0.07 mmol) in DMF (2 mL). The reaction mixture was stirred for 30 minutes and then filtered. The filtrate was diluted with ACN and lyophilized. The residue was sequentially triturated with diethyl ether (2 × 3 mL) and hexane (2 × 3 mL) and dried under reduced pressure to obtain the title compound (0.025 g, yield 34%). LCMS: 1314 (M+1) + .

[0329] (Example 4) Preparation of 6-((3-(((19-((11-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-21-methyl-16-oxo-2,5,8,15-tetraoxa-11,17-diaza-21-siladocosan-21-yl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-6-oxohexanoic acid.

[0330] The title compound was synthesized by replacing 1,4-dioxane-2,6-dione with oxepane-2,7-dione in the same manner as in Example 3, Step 3 (15.4 mg, 1.2 equivalents). LCMS: 1326 (M+1) + .

[0331] (Example 5) Preparation of 3-((4-((3-(((19-(((3-(2-(carboxymethoxy)acetamidopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-4-oxobutyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate ammonium

[0332] Step 1: Synthesis of 3-((4-(benzyloxy)-4-oxobutyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0333] At room temperature under a nitrogen atmosphere, a solution of benzyl 4-aminobutanoate hydrochloride (1 g, 4.4 mmol) in DMF (5 mL) was mixed with DIPEA (4 mL, 43.7 mmol), followed by 1,2-oxathione 2,2-dioxide (2.1 g, 43.7 mmol). The reaction mixture was stirred at 150 °C for 16 hours. Upon completion, the reaction mixture was cooled to room temperature and poured over saturated aqueous solution of NaHCO3 (8 mL), and stirred for 1 hour. The mixture was washed with ethyl acetate (2 × 15 mL). Freeze-drying of the aqueous layer yielded a rubbery mass, which was triturated with THF (12 mL) to obtain a sticky solid (8 g). One gram of this crude product was further purified by preparative HPLC to obtain the Step 1 intermediate (310 mg) as its ammonium salt. LCMS: [M+H] + 560

[0334] Step 2: Synthesis of 3-((3-carboxypropyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0335] A stirred solution of the intermediate (310 mg, 0.56 mmol) obtained from Step 1 in methanol:water (1:1, 8 mL) was purged with nitrogen for 5 minutes. 10% palladium carbon was added, and the resulting mixture was stirred under a hydrogen atmosphere for 30 minutes. Once the reaction was complete, the mixture was filtered and washed with methanol:water (1:1, 10 mL). The solvent was removed from the combined filtrate under reduced pressure, and the resulting aqueous phase was freeze-dried to obtain the Step 2 intermediate (271 mg) as a viscous solid. 1 H-NMR (400 MHz, D2O) δ 3.93 (m, 1H), 3.40 - 3.25 (m, 5H), 2.88-2.81 (m, 4H), 2.37 (m, 1H), 2.14-2.02 (m, 4H), 1.91 (bs, 1H), 1.34 (m, 6H), 1.23 (m, 2H). LCMS: [MH] - 468.

[0336] Step 3: 3-((4-((3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-4-oxobutyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0337] At room temperature and under a nitrogen atmosphere, a solution of the intermediate obtained from Step 2 (0.187 g, 0.40 mmol) in DMF (10 mL) was mixed with DIPEA (0.192 g, 1.49 mmol), EDC.HCl (0.143 g, 0.75 mmol), and HOBt (0.114 g, 0.75 mmol). The reaction mixture was stirred for 2 hours, after which the title compound obtained from Example 1, Step 1 (400 mg, 0.5 mmol) was added. The resulting mixture was stirred at room temperature for 48 hours. It was then poured onto water (150 mL). After centrifugation, the precipitate was collected and purified by preparative HPLC to obtain the title compound (30 mg, 5%) as a blue solid. LCMS: [M+H] + 1256

[0338] Step 4: Synthesis of 3-((4-((3-(((19-(((3-(2-(carboxymethoxy)acetamidopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-4-oxobutyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate ammonium: At room temperature under a nitrogen atmosphere, 1,4-dioxan-2,6-dione (2.8 mg, 0.024 mmol) was added to a solution of the intermediate obtained from Step 3 (10 mg, 0.008 mmol) in DMF (2 mL). The reaction mixture was stirred for 5 hours and then subjected to preparative HPLC purification. Appropriate fractions were combined and freeze-dried to obtain the title compound (3.2 mg, 29%) as a blue solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (m, 8H), 8.50 (m, 8H), 7.04 (bs, 9H), 6.82 (s, 2H), 3.92 (m, 3H), 3.62 (s, 3H), 3.02 (m, 3H), 1.87 (m, 7H), 1.75 (m, 3H), 1.58 (m, 11H), -1.15 (m, 4H), -2.35 (m, 4H), -2.92 (s, 12H). MS: [M+H] + 1372.

[0339] (Example 6) 3-((4-((3-(((19-(((3-(6-((λ 5 -Azenoyl)oxy)-6-oxohexanamide)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]-azeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-4-oxobutyl)bis(3-(((λ 5 Preparation of azanail oxysulfonyl propyl ammonia propane-1-sulfonate.

[0340] The title compound was synthesized by replacing 1,4-dioxane-2,6-dione with oxepane-2,7-dione in the same manner as in Example 5, Step 4. LCMS: 1385 (M+1) + .

[0341] (Example 7) Preparation of 2-(2-((3-(((19-((dimethyl(3-(3-(2-sulfonatoethyl)ureido)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate. Step 1: Synthesis of 2-(3-(3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ureido)ethane-1-sulfonate ammonium. [ka]

[0342] Under a nitrogen atmosphere, DIPEA (0.072 g, 0.560 mmol) was added to a stirred solution of the title compound (0.150 g, 0.186 mmol) obtained from Example 1, Step 1 in DCM (10 mL). The reaction mixture was cooled to 0°C, and a solution of tetrabutylammonium 2-(((4-nitrophenoxy)carbonyl)amino)ethane-1-sulfonate (0.079 g, 0.149 mmol) in DCM (3.3 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and triturated using DCM (3 × 5 mL) to obtain the crude material, which was further purified by preparative HPLC. The pure fraction was lyophilized to obtain the intermediate as a blue solid (6 mg, yield 4%). LCMS: [MH] - 954.

[0343] Step 2: Synthesis of 2-(2-((3-(((19-((dimethyl(3-(3-(2-sulfonatoethyl)ureido)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate: At room temperature under a nitrogen atmosphere, 1,4-dioxan-2,6-dione (2.2 mg, 0.0188 mmol) was added to a solution of the intermediate obtained from Step 1 (6 mg, 0.0063 mmol) in DMF (1 mL). The reaction mixture was stirred for 5 hours. Next, it was directly purified by preparative HPLC. Appropriate fractions were combined and freeze-dried to obtain the title compound (2 mg, 29%) as a blue solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (bs, 8H), 8.51 (bs, 8H), 7.06 (bs, 4H), 5.45 (s, 1H), 5.10 (s, 1H), 3.85 (s, 2H), 3.61 (s, 2H), 3.03 LCMS: [MH] - 1070

[0344] (Example 8) Preparation of 2-(2-((3-(((19-(((3-(3-(3-(2,2-disulfonatoethyl)ureido)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate. Step 1: Synthesis of 2-(3-(3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylcycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ureido)ethane-1,1-disulfonic acid tetrabutylammonium. [ka]

[0345] Under an inert atmosphere, at 0°C, a solution of the title compound (0.2 g, 0.25 mmol) obtained from Example 1, Step 1 in CH2Cl2 (20 mL) was prepared, to which DIPEA (0.096 g, 0.75 mmol) and bis(tetrabutyl-λ) in CH2Cl2 (7.5 mL) were added. 5 A solution of (-azanail)2-(((4-nitrophenoxy)carbonyl)amino)ethane-1,1-disulfonate (0.2 mmol) was added sequentially. The reaction mixture was stirred at room temperature for 3 hours. A blue precipitate was formed. The reaction mixture was concentrated under reduced pressure to dryness and washed with CH2Cl2 to obtain the Step 1 intermediate (0.17 g, 45%). LCMS: [MH] - 1034.

[0346] Step 2: Synthesis of 2-(2-((3-(((19-(((3-(3-(3-(2,2-disulfonatoethyl)ureido)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate: Under nitrogen, 1,4-dioxan-2,6-dione (8.7 mg, 0.075 mmol) was added to a stirred solution of the intermediate obtained from Step 1 (38 mg, 0.025 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 2 hours and purified directly by preparative HPLC. Appropriate fractions were combined and freeze-dried to obtain the title compound (4.3 mg, 14%). 1H NMR (400 MHz, DMSO-d6) δ 9.71 (bs, 8H), 8.50 (bs, 8H), 7.51 (bs, 2H), 7.02 (bs, 8H), 5.52 (bs, 2H), 5.25 (bs, 2H), 3.76 (bs, 2H), 1.60 (m, 2H), 1.53 (m, 2H), -1.13 (m, 2H), -1.23 (m, 2H), -2.38 (m, 4H), -2.91 (s, 6H), -2.93 (s, 6H). LCMS: [MH] - 1150.

[0347] (Example 9) Preparation of 6-((3-(((19-(((3-(3-(3-(2,2-disulfonatoethyl)ureido)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-6-oxohexanoate ammonium. At room temperature under a nitrogen atmosphere, adipic anhydride (11 mg, 0.088 mmol) was added to a solution of the intermediate obtained from Example 8, Step 1 (45 mL) in DMF (4.5 mL). The reaction mixture was stirred for 2 hours and purified directly by preparative HPLC. Appropriate fractions were combined and freeze-dried to obtain the title compound (8.5 mg, yield 24%). 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (bs, 8H), 8.49 (bs, 8H), 6.68 (m, 2H), 5.50 (m, 2H), 5.25 (m, 2H), 3.16 (m, 2H), 2.67 (bs, 1H), 2.06 (m, 2H), 1.63 (m, 2H), 1.55 (m, 2H), 1.51 (m, 2H), 1.23 (m, 4H), -1.18 (m, 2H), -1.26 (m, 2H), -2.39 (m, 4H), -2.94 (s, 6H), -2.95 (s, 6H).LCMS: [MH] - 1162.

[0348] (Example 10) 3-((2-((3-(((19-(((3-(6-((λ 5 -Azenoyl)oxy)-6-oxohexanamide)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)bis(3-(((λ 5 Preparation of Azanail Oxysulfonyl Propyl Ammoniopropane-1-Sulfonate Step 1: Synthesis of 3-((2-(benzyloxy)-2-oxoethyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate [ka]

[0349] A suspension of benzylglycinate hydrochloride (0.5 g, 2.5 mmol) in sulfolane (8 mL) was mixed with DIPEA (4.75 mL, 27.3 mmol). The mixture was stirred at room temperature for 15 minutes to obtain a clear solution. 1,2-Oxathiolane 2,2-dioxide (3 g, 24.8 mmol) was added, and the reaction mixture was stirred at 140 °C for 16 hours. The mixture was then cooled to room temperature, diluted with water (15 mL), and washed with DCM (2 × 10 mL). The aqueous layer was separated and freeze-dried to obtain 3.5 g of a sticky solid residue. 900 mg of this crude product was further purified by preparative HPLC to obtain the Step 1 intermediate (400 mg) as a sticky solid. LCMS: 532.7 [M+H] + .

[0350] Step 2: 3-((carboxymethyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0351] A stirred solution of the intermediate obtained from Step 1 (350 mg, 0.66 mmol) in water (10 mL) was purged with N2 for 5 minutes. 10% palladium-carbon was added, and the resulting mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction product was filtered, and the residue was washed with water (5 mL). The combined filtrate was partially distilled under reduced pressure. The remaining solution was freeze-dried to obtain the Step 2 intermediate as a viscous solid. LCMS: 440 [MH] - .

[0352] Step 3: Synthesis of 3-((2-((3-(((19-(((3-(6-methoxy-6-oxohexaemidopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)bis(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0353] Under a nitrogen atmosphere, EDC.HCl (6 mg, 0.03 mmol), HOBt (2.8 mg, 0.02 mmol), and DIPEA (11 μL, 0.06 mmol) were sequentially added to a stirred solution of the intermediate obtained from Step 2 (9 mg, 0.021 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hour, and then added to a solution of the title compound obtained from Example 1, Step 2 (20 mg, 0.02 mmol) in DMF (0.5 mL) at 0°C. The reaction mixture was stirred at room temperature for 8 hours. Water (0.5 mL) was added, and the resulting mixture was freeze-dried. The residue was washed with hexane (5 mL) and diethyl ether (2 × 3 mL) to obtain the Step 3 intermediate (18 mg) as a blue solid, which was used in the next step without further purification. LCMS: 1369 [M] - .

[0354] Step 4: 3-((2-((3-(((19-(((3-(6-((λ 5 -Azenoyl)oxy)-6-oxohexanamide)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)bis(3-(((λ 5Synthesis of Azanail(oxy)sulfonyl)propyl)ammonio)propane-1-sulfonate. To a solution of the intermediate obtained from step 3 (18 mg, 0.01 mmol) in a 1:2 MeOH:H2O mixture (2 mL), K2CO3 (6 mg, 0.04 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction product was directly purified by preparative HPLC (mobile phase: 5 mM ammonium bicarbonate in water + 0.1% NH3; 100% ACN; X-Bridge C18). The selected fractions were combined and lyophilized to obtain the title compound (0.4 mg, yield 3%) as a blue solid. LCMS: 1354 [MH] - .

[0355] (Example 11) 3-((2-((3-(((19-(((3-(2-(2-((λ 5 -Azenoyl)oxy)-2-oxoethoxy)acetamido)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)bis(3-(((λ 5 Preparation of Azanail Oxysulfonyl Propyl Ammoniopropane-1-Sulfonate Step 1: 3,3',3''-((2-((3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)ammonio)tris(propane-1-sulfonic acid)ammonium [ka]

[0356] At 0°C under a nitrogen atmosphere, T3P (50% solution in 0.16 mL of SiO2, 0.25 mmol) and DIPEA (0.11 mL, 0.62 mmol) were sequentially added to a stirred solution of the intermediate obtained from Example 10, Step 2 (54 mg, 0.12 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 hour. A solution of the title compound obtained from Example 1, Step 1 (0.1 g, 0.12 mmol) in DMF (1 mL) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was purified by preparative HPLC (A: 5 mM ammonium bicarbonate in water + 0.1% NH3; B: 100% ACN) to obtain the Step 1 intermediate compound (6 mg, 4%) as a blue solid. LCMS: 1227 [M] -

[0357] Step 2: 3-((2-((3-(((19-(((3-(2-(2-((λ 5 -Azenoyl)oxy)-2-oxoethoxy)acetamido)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethyl)bis(3-(((λ 5 -Azanail)oxy)sulfonyl)propyl)ammonio)propane-1-sulfonate. The title compound was prepared in the same manner as in Example 2, Step 2, by replacing the intermediate compound obtained from Example 2, Step 1 with the intermediate compound obtained from Step 1. The reaction mixture was directly purified by preparative HPLC to obtain the title compound as a blue solid (1.2 mg, 49%). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (m, 8H), 8.51 (m, 8H), 7.03 (bs, 6H), 3.90 (bs, 2H), 3.62 (s, 2H), 3.53 (s, 2H), 3.44 (s, 2H), 2.67-2.61 (m, 4H), 2.34 (m, 8H), 1.83 (bs, 6H), 1.57 (m, 4H), -1.15 (m, 4H), -2.23 (m, 4H), -2.92 (s, 12H). LCMS: 1342 [MH] - .

[0358] (Example 12) Preparation of 3-((6-((λ5-azanail)oxy)-6-oxohexyl)(3-(((λ5-azanail)oxy)sulfonyl)propyl)(3-(((19-(((3-(bis(3-(((λ5-azanail)oxy)sulfonyl)propyl)(3-sulfonatopropyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)propane-1-sulfonate. Step 1: Methyl 6-((3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)hexanoate. [ka]

[0359] To a solution of the intermediate compound obtained from Example 1, Step 1 (0.3 g, 0.37 mmol) in THF (50 mL), a solution of methyl-6-oxohexanoate (0.08 g, 0.56 mmol) in THF (2 mL) and a catalytic amount of AcOH were added. The solution was stirred at room temperature for 1 hour. Then, it was added to a suspension of NaBH(OAc)3 (0.237 g, 1.12 mmol) in THF (10 mL) and stirred for 16 hours. The reaction product was quenched with saturated aqueous solution of NaHCO3 (50 mL) and extracted using DCM (3 × 70 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by basic alumina column chromatography to obtain the Step 1 intermediate (0.10 g, 29%) as a blue solid. LCMS: 933[M+H] +

[0360] Step 2: 3-((3-(((19-((dimethyl(3-((3-sulfonatopropyl)bis(3-sulfopropyl)ammonio)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)(6-methoxy-6-oxohexyl)(3-sulfopropyl)ammonio)propane-1-sulfonate. [ka]

[0361] Under a nitrogen atmosphere, 1,3-propanesultone (0.654 g, 5.4 mmol) and DIPEA (1.4 mL, 8 mmol) were sequentially added to a solution of the intermediate compound obtained from Step 1 (0.10 g, 0.107 mmol) in sulfolane (10 mL), and then irradiated under microwave at 120 °C for 2 hours. The reaction mixture was added dropwise to THF (30 mL) and stirred for 30 minutes. The supernatant was removed. The precipitate was sequentially washed with THF (2 × 10 mL) and dried under reduced pressure to obtain the Step 2 intermediate (0.24 g) as a blue solid. LCMS: 1542 [M] - .

[0362] Step 3: 3-((6-((λ5-azanail)oxy)-6-oxohexyl)(3-(((λ5-azanail)oxy)sulfonyl)propyl)(3-(((19-(((3-(bis(3-(((λ5-azanail)oxy)sulfonyl)propyl)(3-sulfonatopropyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)propane-1-sulfonate. To a solution of the intermediate obtained from step 2 (120 mg, 0.08 mmol) in a 1:2 MeOH:water mixture (5 mL), K2CO3 (32 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and purified directly by preparative HPLC (mobile phase: 5 mM ammonium bicarbonate + 0.1% NH3 in water; 100% ACN; X-Bridge C18). Appropriate fractions were combined and lyophilized to obtain the title compound (23 mg, 18%) as a blue solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.76 (m, 8H), 8.52 (m, 8H), 7.12 (bs, 8H), 3.49 (m, 2H), 3.42 (m, 2H), 2.64 (m, 12H), 2.27 (m, 10H), 1.88 LCMS: 764 [M / 2] - .

[0363] (Example 13) Preparation of 4-((6-((λ5-azanail)oxy)-6-oxohexyl)(4-(((λ5-azanail)oxy)sulfonyl)butyl)(3-(((19-(((3-(bis(4-(((λ5-azanail)oxy)sulfonyl)butyl)(4-sulfonatobutyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)butane-1-sulfonate. Step 1: Sodium 4-iodobutane-1-sulfonate [ka]

[0364] At room temperature, sodium iodide (550 mg, 3.7 mmol) was added to a solution of 1,2-oxathione 2,2-dioxide (0.5 g, 3.7 mmol) in MeOH (5 mL) in a sealed tube. The reaction mixture was heated at 80°C for 6 hours. It was then allowed to cool to room temperature. The precipitate was filtered, washed with cold MeOH (5 mL), and dried under reduced pressure to obtain the Step 1 intermediate (270 mg, 26%) as a white solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 3.33–3.29 (m, 2H), 2.42–2.48 (m, 2H), 1.90–1.83 (m, 2H), 1.71–1.64 (m, 2H).

[0365] Step 2: 4,4',4''-((3-(((19-(((3-((6-methoxy-6-oxohexyl)bis(4-sulfonatobutyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)tris(butane-1-sulfonate)sodium. [ka]

[0366] Under nitrogen, a solution of the intermediate obtained from Step 1 (25 mg, 0.03 mmol) in 3 mL of sulfolane was mixed with the intermediate obtained from Step 1 (0.115 g, 0.4 mmol) and DIPEA (0.093 mL, 0.54 mmol). The reaction mixture was irradiated with microwaves at 120 °C for 4 hours. The reaction mixture was added dropwise to 5 mL of THF and stirred for 30 minutes. The supernatant was removed, and the residue was washed with 2 × 3 mL of THF. The residue was dried under reduced pressure to obtain the crude Step 2 intermediate (50 mg), which was used in subsequent steps without further purification. LCMS: 805 [M / 2-1] -

[0367] Step 3: 4-((6-((λ5-azanail)oxy)-6-oxohexyl)(4-(((λ5-azanail)oxy)sulfonyl)butyl)(3-(((19-(((3-(bis(4-(((λ5-azanail)oxy)sulfonyl)butyl)(4-sulfonatobutyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7 [1,3,5,10]tetraaza[2]silacycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)butane-1-sulfonate: The title compound was prepared in the same manner as in Example 12, Step 3, by replacing the intermediate obtained from Example 12, Step 3 with the intermediate obtained from Step 2 to obtain the title compound (12 mg, 24%) as a blue solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (m, 8H), 8.54 (m, 8H), 7.12 (bs, 8H), 2.40-2.33 (m, 22H), 2.23 (m, 2H), 1.79 (m, 4H), 1.50 (m, 10H), 1.40 (m, 2H), 1.20 (m, 10H), 1.06 (m, 4H), -1.20 (m, 4H), -2.24 (m, 4H), -2.89 (s, 12H). LCMS: 798 [M-1 / 2] - .

[0368] (Example 14) Preparation of 3,3',3''-((3-(((19-(((3-((6-((2,5-dioxopyrrolidine-1-yl)oxy)-6-oxohexyl)bis(3-sulfonatopropyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylcycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)tris(propane-1-sulfonic acid)sodium Step 1: Tetrasodium mono(6-((3-(((19-((dimethyl(3-(tris(3-sulfonatopropyl)ammonio)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)bis(3-sulfonatopropyl)ammonio)hexanoate) [ka]

[0369] Dowex® 50WX8 hydrogen-type resin (4g, 50-100 mesh) was placed on a column and converted to its sodium form by passing a 1N NaCl solution (50mL) through it until the pH of the eluate became neutral. The column was further washed with water to remove excess NaCl. This process was continued until no precipitate was observed during treatment of the eluate with silver nitrate. A solution of the title compound obtained from Example 12 (33mg, 0.02 mmol) in water (3mL) was passed through the column. The blue fraction was collected and freeze-dried to obtain the Step 1 intermediate (29mg, 91%). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (m, 8H), 8.52 (m, 8H), 3.49 (m, 2H), 3.42 (m, 2H), 2.64 (m, 12H), 2.29 (m, 10H), 1.89 (m, 4H), 1.42 (m, 10H), 1.11 (m, 4H), -0.88 (m, 2H), -1.04 (m, 2H), -2.30 (m, 2H), -2.38 (m, 2H), -2.89 (s, 12H). LCMS: 764 [M / 2] - .

[0370] Step 2: 3,3',3''-((3-(((19-(((3-((6-((2,5-dioxopyrrolidine-1-yl)oxy)-6-oxohexyl)bis(3-sulfonatopropyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylcycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)tris(propane-1-sulfonic acid)sodium: In a brown vial, under nitrogen, a solution of the intermediate obtained from Step 1 (1.3 mg) in DMSO (0.3 mL) is prepared by adding DIPEA (32 μL of 0.1 M). DMSO solution (4 equivalents) and N,N'-disuccinimidylcarbonate (64 μL of 0.1 M DMSO solution, 8 equivalents) were added sequentially. The resulting mixture was stirred overnight at room temperature. The reaction product was diluted with DMF (0.3 mL), filtered through a 0.45 μm filter, and added dropwise over 20 minutes to vigorously stirred MTBE (5 mL). The reaction vial was washed with DMF (0.2 mL). A blue precipitate was formed. The suspension was allowed to settle, and the clear supernatant was removed. MTBE (2.5 mL) was added, and this process was repeated twice. The residue after the final wash was dried under reduced pressure to obtain the title compound (0.5 mg, 37%). LCMS: 812 [M-1 / 2] - .

[0371] (Example 15) Preparation of 2-(2-((3-(((19-(((3-(4-(bis(3-sulfonatopropyl)ammonio)butanamide)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate. Step 1: 3-((4-(benzyloxy)-4-oxobutyl)(3-sulfopropyl)ammonio)propane-1-sulfonate [ka]

[0372] At room temperature under a nitrogen atmosphere, a solution of benzyl 4-aminobutanoate hydrochloride (1 g, 4.4 mmol) in DMF (5 mL) was mixed with DIPEA (4 mL, 17.5 mmol), followed by 1,2-oxathione 2,2-dioxide (2.1 g, 44 mmol). The reaction mixture was stirred at 100 °C for 16 hours. It was then cooled to room temperature and treated with saturated aqueous solution of NaHCO3 (8 mL), and stirred for 1 hour. The mixture was washed with ethyl acetate (2 × 15 mL). The aqueous layer was freeze-dried to obtain the residue, which was triturated with THF (12 mL). Of the 3 grams of crude product, 1 gram was further purified by preparative HPLC to obtain the Step 1 intermediate (260 mg). LCMS: 438 [M+H] +

[0373] Step 2: 3-((3-carboxypropyl)(3-sulfopropyl)ammonio)propane-1-sulfonate [ka]

[0374] A solution of the intermediate obtained from Step 1 (260 mg, 0.59 mmol) in a methanol:water mixture (6 mL, 1:1) was purged with nitrogen for 5 minutes. 10% palladium carbon (140 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered, and the residue was washed with methanol:water (10 mL, 1:1). The combined filtrate was partially rotavaped and freeze-dried to obtain the Step 2 intermediate (210 mg). 1 H-NMR (400 MHz, heavy water) δ 3.25 - 3.21 (m, 4H), 3.09 - 3.13 (m, 2H), 2.86 (t, J = 7.2 Hz, 4H), 2.27 (t, J = 6.9 Hz, 2H), 2.04 (m, 4H), 1.85 (m, 2H). MS: 348 [M+H] +

[0375] Step 3: 3-((4-((3-(((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-4-oxobutyl)(3-sulfopropyl)ammonio)propane-1-sulfonate [ka]

[0376] At room temperature under a nitrogen atmosphere, HOBt (57 mg, 0.37 mmol), DIPEA (96 mg, 0.75 mmol), and EDC.HCl (71 mg, 0.37 mol) were added to a solution of the intermediate obtained from Step 2 (69 mg, 0.18 mmol) in DMF (4 mL). The reaction mixture was stirred for 2 hours, followed by the addition of the title compound obtained from Example 1, Step 1 (0.200 g, 0.25 mmol). The reaction was stirred at room temperature for 48 hours. The contents were poured onto water (100 mL). The precipitate was separated by centrifugation to obtain 210 mg of crude material, which was purified by preparative HPLC to obtain the Step 3 intermediate (10 mg, 4%) as a blue solid. LCMS: 1134 [M+H] +

[0377] Step 4: 2-(2-((3-(((19-(((3-(4-(bis(3-sulfonatopropyl)ammonio)butanamide)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)amino)-2-oxoethoxy)ammonium acetate: The title compound was prepared in the same manner as in Step 2 of Example 2, by replacing the intermediate obtained from Step 1 of Example 2 with the intermediate obtained from Step 3 (8 mg, 0.007 mmol) to obtain the title compound (3.2 mg, 35%) as a blue solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (bs 8H), 8.52 (bs, 8H), 6.82 (m, 2H), 3.98 (s, 2H), 3.64 (s, 2H), 3.12 (m, 3H), 1.89 (m, 7H), 1.77 (m, 2H), 1.59 (m, 8H), -1.15 (m, 4H), -2.34 (m, 4H), -2.92 (s, 12H). LCMS: 1248 [MH] - .

[0378] (Example 16) Preparation of 4,4',4''-((3-(((19-(((3-((6-((2,5-dioxopyrrolidine-1-yl)oxy)-6-oxohexyl)bis(4-sulfonatobutyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylcycloundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)tris(butane-1-sulfonic acid)sodium Step 1: 6-((3-(((19-((dimethyl(3-(tris(4-sulfonatobutyl)ammonio)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)bis(4-sulfonatobutyl)ammonio)sodium hexanoate [ka]

[0379] The title compound (34 mg, 88%) was prepared in the same manner as in Example 14, Step 1, by replacing Example 12 with Example 13 (38 mg, 0.02 mmol). 1H NMR (400 MHz, DMSO-d6) δ 9.77 (m, 8H), 8.54 (m, 8H), 2.39-2.33 (m, 22H), 2.21 (m, 2H), 1.79 (m, 4H), 1.50 (m, 10H), 1.39 (m, 2H), 1.18 (m, 10H), 1.05 (m, 4H), -1.20 (m, 4H), -2.24 (m, 4H), -2.89 (s, 6H), -2.90 (s, 6H). LCMS: 799 [M / 2] -

[0380] Step 2: 4,4',4''-((3-(((19-(((3-((6-((2,5-dioxopyrrolidine-1-yl)oxy)-6-oxohexyl)bis(4-sulfonatobutyl)ammonio)propyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[1]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)dimethylsilyl)propyl)ammonio)tris(butane-1-sulfonic acid)sodium [ka]

[0381] The title compound (0.0005 mmol) was prepared by replacing the title compound obtained from Step 1 (1.4 mg, 0.0008 mmol) with the title compound obtained from Step 1 (1.4 mg, 0.0008 mmol) in the same manner as in Step 2 of Example 14. LCMS: 847 [M-1 / 2]-

[0382] (Example 17) Preparation of 2-((19-((dimethyl(3-(tris(4-sulfonatobutyl)ammonio)propyl)silyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)-2-methyl-6,6-bis(4-sulfonatobutyl)-9,12,15-trioxa-6-aza-2-silaoctadecane-6-ium-18-ate sodium Step 1: 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoic acid [ka]

[0383] 2.0 g, 7.2 mmol of tert-butyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate was dissolved in 20 mL of trifluoroacetic acid at 0°C. The reaction mixture was stirred at room temperature for 16 hours. Upon completion, the solvent was removed under reduced pressure to obtain the crude title compound, which was used in subsequent steps without further purification.

[0384] Step 2: Methyl 3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate [ka]

[0385] At room temperature, concentrated H2SO4 (0.3 mL) was added to a solution of the title compound (1.5 g, 6.7 mmol) obtained from Step 1 in MeOH (20 mL). The solution was stirred at 60°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography using neutral alumina to obtain the title compound (1.1 g, 69%) in liquid form. ¹H NMR (400 MHz, D2O) δ 3.69 (m, 2H), 3.60-3.56 (m, 15H), 2.57 (m, 2H).

[0386] Step 3: Methyl 3-(2-(2-(2-oxoethoxy)ethoxy)ethoxy)propanoate [ka]

[0387] Under nitrogen, a solution of the title compound obtained from step 2 (0.9 g, 3.8 mmol) in dichloromethane (5 mL) was added to a stirred solution of dess-martin periodinane (4.04 g, 9.5 mmol) and pyridine (0.92 mL, 11.4 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 4 hours. Upon completion, the reaction mixture was diluted with dichloromethane (5 mL) and treated with a saturated solution of NaHCO3 (5 mL) and a 10% solution of Na2S2O3 (5 mL). The resulting mixture was stirred at room temperature for 30 minutes and extracted with dichloromethane (3 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography in neutral alumina to obtain the title compound (0.45 g, 50%), which was rapidly used in the next step. LCMS: 235 [M+1] +

[0388] Step 4: Methyl 2-((19-(((3-aminopropyl)dimethylsilyl)oxy)-19H-6,11-(azeno)-17,21-(azeno[3]episoindroazeno)benzo[7,8][1,3,5,10]tetraaza[2]silacylundecino[4,3-a:11,1-a']diisoindole-19-yl)oxy)-2-methyl-9,12,15-trioxa-6-aza-2-silacotadecane-18-oate. [ka]

[0389] At room temperature, a stirring solution of the title compound (200 mg, 0.25 mmol) obtained from Step 1 of Example 1 was added to THF (100 mL) to a stirring solution of the title compound (72 mg, 0.3 mmol) obtained from Step 3 in THF (2 mL), followed by a catalytic amount of AcOH (15 mg / mL solution of AcOH in 0.1 mL of THF, 0.025 mmol). The solution was stirred at room temperature for 1 hour, and then added to a suspension of NaBH(OAc)3 (0.16 g, 0.75 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 4 hours. The reaction contents were poured onto saturated NaHCO3 aqueous solution (50 mL) and extracted using DCM (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with ba...

Claims

1. Conjugates including the following: i) Targeting molecules; and ii) Compounds of formula (I): 【Chemistry 1】 or its salts, stereoisomers, or tautomers: In equation (I), M is Si; X is 【Chemistry 2】 ； And, Y is 【Transformation 3】 ； And, R １ and R ２ Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl; R ３ , R ４ or R ５ is selected from substituent (a) or substituent (b); (a) R ３ is hydrogen, -L[[ID= 3]] ３ -H, -L ３ -A or -L ３ -Z; R ４ is, -L ４ -H, -(NH) ｍ -L ４ -A, -(NH) ｍ -L ４ -Z, -(O) ｍ -L ４ -A or -(O) ｍ -L ４ -Z is; and R ５ is, -L ５ -H or -L ５ -A is; (b) R ３ is, -L ３ -H or -L ３ -A is; R ４ is, -L ４ -H, -(NH) ｍ -L ４ -A or -(O) ｍ -L ４ -A and R ３ and R ４ It is connected by a bond, -L ４ -Forms heterocyclines substituted with A; R ５ is, -L ５ -H or -L ５ -A is; However, R ３ , R ４ and R ５ At least one of them is a group containing A; A is a reactive group or a protected form thereof that is capable of forming a covalent bond with the thiol, hydroxyl, carboxyl, or amino group of the targeting molecule, R ６ and R ７ Each of these is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl. R ８ , R ９ or R １０ is selected from substituent (a) or substituent (b); (a) R ８ is hydrogen, -L ８ -H or -L ８ -Z is; R ９ is, -L ９ -H, -(NH) ｎ -L ９ -Z or -(O) ｎ -L ９ -Z is; and R １０ is, -L １０ -Z is; (b) R ８ and R ９ It is connected by a bond, -L ９ -Z is substituted to form a heterocycline, R １０ is, -L １０ -H or -L １０ -Z is; However, R ８ , R ９ and R １０ At least one of these is a group containing Z; Z is a water-soluble group comprising one or more polar or ionic substituents selected from the following: carboxylate (-CO ２ ), poly(ethylene glycol), sulfonate (-SO ３ H) group, sulfonyl (-SO ２ H) group, sulfate (-SO ４ ) group, hydroxyl (-OH) group, phosphate (-OPO) ３ H) group, phosphonate (-PO ３ H) group, amine (-NH ２ ) groups and quaternary nitrogen; these groups may each be optionally substituted with A or L'-A; L １ and L ２ Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkyl, or optionally substituted heterocycline; L ３ , L ４ , L ５ , L ８ , L ９ and L １０ Each of these is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene, wherein the carbon atoms of the alkylene, heteroalkylene, alkenylene, heteroalkenylene, cycloalkylene, heterocyclene, arylene, aralkylene, heteroaralkylene, or optionally substituted heteroarylene may be further optionally substituted with Z, and each nitrogen atom of the heteroalkylene or heteroalkenylene may be optionally substituted with one or two L'-Z; Each L' is independently an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted cycloalkylene, optionally substituted heterocyclene, optionally substituted arylene, optionally substituted aralkylene, optionally substituted heteroaralkylene, or optionally substituted heteroarylene; a is either 0 or 1, b is either 0 or 1, c is either 0 or 1, d is either 0 or 1. m is either 0 or 1. n is either 0 or 1, However, if b is 1, then a is 0, If d is 1, then c is 0, If m is 1, then b is 1, If n is 1, then c is 1; furthermore, R ６ and R ７ Both are methyl, L ２ If is propylene, c is 1 and d is 0, then L ８ , L ９ and L １０ These are not propylene; Furthermore, the targeting molecule is covalently bonded to the compound of formula (I).

2. L １ and L ２ are each independently optionally substituted C １－１０ alkylene, optionally substituted hetero C １－１０ alkylene, optionally substituted C ２－１０ alkenylene, or hetero C ２－１０ alkenylene, the conjugate according to claim 1.

3. L １ and L ２ are each independently C ２－４ alkylene, hetero C ２－４ alkylene, optionally substituted C ２－４ alkenylene, or optionally substituted hetero C ２－４ alkenylene, the conjugate according to claim 1.

4. L １ and L ２ Each of these can be arbitrarily substituted in C ２－４ The conjugate according to claim 1, wherein the conjugate is alkylene.

5. The conjugate according to claim 1, wherein A is independently selected from the following: -C(O)OR １１ ; -NR １２ R １３ ; -NHC(O)R １４ ; -C(O)R １５ ; -OR １６ ; -SR １６ ; -OOS(O) 2 R １７ ; -OP(OR １８ )(NR １９ R ２０ ); -N=C=O; -N=C=S; -S-C≡N; -SO 2 -F; -SO 2 -Cl; -SO 2 -Br; -S-SR ２１ , or Five-membered or six-membered dioxo-substituted heterocyclyls; Each R １１ R is independently hydrogen, alkyl, haloalkyl, alkenyl, heterocyclyl, aryl, or heteroaryl, and each R １１ These are 1 to 5 halos, -SO 3 H and -SO 2 It may be independently and arbitrarily substituted by 1 to 5 groups selected from F; Each R １２ These are independently hydrogen, alkyl, or haloalkyl; Each R １３ Each R is independently an aryl or heteroaryl, and each R １３ Hello, -SO 3 H and -SO 2 It may be independently and arbitrarily substituted by 1 to 5 groups selected from F; or arbitrarily, R １２ and R １３ It may form a cyclic imide together with the bonded nitrogen; Each R １４ is an optionally substituted haloalkyl or optionally substituted aralkyl; Each R １５ These are independently, and each is independently a halo, heterocyclyl, and -SO 3 － or -SO ２ It is an aryl that may be arbitrarily substituted with 1 to 5 groups of F; Each R １６ Each is an aryl group which may be independently substituted with 1 to 5 groups which are independently halo or heterocyclyl groups; Each R １７ Each of these is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, and each of the heterocyclyl, aryl, or heteroaryl is independently a halo, -SO ３ H, -SO ２ F and -C(O)OR ｃ It may be optionally replaced by 1 to 5 elements selected from; Each R ｃ These are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl, ； R １８ , R １９ and R ２０ Each of these is independently an optionally substituted alkyl or optionally substituted haloalkyl; R ２１ It is a heteroaryl compound.

6. The conjugate according to claim 1, wherein A is selected from the group consisting of the following: 【Chemistry 4】 - NHC(O)R １４ -COOH and -OSO 2 R １７ ; In the formula, each R ｘ and R ｙ R is independently hydrogen or a halo, ｚ is hydrogen or -SO 3 It is H; R １４ is an optionally substituted haloalkyl or optionally substituted aralkyl; Each R １７ These are independently optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. Here, the heterocyclyl, aryl, or heteroaryl is independently selected, halo, -SO 3 H, -SO 2 F, and -C(O)OR ｃ It may be arbitrarily substituted with 1 to 5 groups consisting of and Each R c is independently an optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl, or optionally substituted aryl.

7. The conjugate according to claim 1, wherein Z is selected from the following: -C(O)OH, -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ C(O)OH、 -(CH ２ CH ２ O) ｖ (CH ２ ) ｐ C(O)OH、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ OR ２２ 、 -(CH ２ CH ２ O) ｖ (CH ２ ) ｐ OR ２２ 、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ SR ２２ 、 -(CH ２ CH ２ O) ｖ (CH ２ ) ｐ SR ２２ 、 -O(CH ２ ) ｖ N[(CH ２ CH ２ O) ｎ CH ２ CH ２ OR ２２ ] ｔ、 -(CH) ２ ) ｑ (OCH ２ CH ２ ) ｖ N[(CH] ２ CH ２ O) ｗ CH ２ CH ２ OR ２２ ] ｔ 、 -(CH ２ CH ２ O) ｍ (CH ２ ) ｐ N[(CH ２ CH ２ O) ｗ CH ２ CH ２ OR ２２ ] ｔ 、 -NH ２ 、 -(CH ２ ) ｑ N[(CH ２ CH ２ O) ｖ CH ２ CH ２ OR ２２ ] ｔ 、 -(CH ２ ) ｑ NR ｂ [(CH ２ CH ２ O) ｗ CH ２ CH ２ OR ２２ ] ｕ 、 -(CH ２ ) ｑ N[(CH ２ ) ｐ (OCH) ２ CH ２ ) ｖ OR ２２ ] ｔ 、 -(CH ２ ) ｑ N[(CH ２ ) ｐ SO ３ H] ｔ 、 -(CH ２ ) ｑ NR ｂ [(CH ２ ) ｐ SO ３ H] ｕ 、 -(CH ２ ) ｑ NR ｂ (CH ２ ) ｐ CH(SO ３ H) ２ 、 -(CH ２ ) ｑ N[(CH ２ ) ｐ S(O) ｕ OH] ｔ 、 -(CH) ２ ) ｑ N[(CH] ２ ) ｐ OSO ３ H] ｔ 、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ SO ３ H、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ S (O) ｕ Oh, -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ OSA ３ H、 -SO ３ H、 -CH(SO ３ H) ２ 、 —OSO ３ H -S(O) ｕ OH、 -P(O)(OH) ２ 、 -CH(P(O)(OH) ２ ) ２ 、 -(CH ２ ) ｑ N[(CH ２ ) ｐ P(O)(OH) ２ ] ｔ 、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ P(O)(OH) ２ 、 --(CH ２ - ｑ NN[(CH ２ - ｐ OP(O)(OH) ２ - ｔ 、 -OP(O)(OH) ２ 、 -(CH ２ ) ｑ (OCH) ２ CH ２ ) ｖ (CH) ２ ) ｑ P(O)(OH) ２ 、 -(CH ２ ) ｑ N[(CH ２ ) ｐ P(O)(OH) ２ ] ｔ 、 -P(O)(OH) ２ Glutamate, aspartate, histidine, 1,3-β-glucan, 1,4-β-glucan; however, Each R ２２ These are independently alkyl, haloalkyl, cycloalkyl, or aryl. Each R ｂ These are independently hydrogen, alkyl, heteroalkylene, haloalkyl, or cycloalkyl, Each of v, w, and p is an integer between 1 and 10, independently. Each q is an independent integer between 0 and 10. t is 2 or 3, u is either 1 or 2.

8. The conjugate according to claim 1, wherein a and c are 0 and b and d are 1.

9. The conjugate according to claim 1, wherein a and c are 1 and b and d are 0.

10. The conjugate according to claim 1, wherein X is selected from the following: 【Transformation 5】 。

11. The conjugate according to claim 1, wherein Y is selected from the following: 【Transformation 6】 。

12. Z may be optionally substituted with A or L'-A in sulfonates (-SO 3 H) group; L' is an alkylene that may be independently substituted, a heteroalkylene that may be independently substituted, an alkenylene that may be independently substituted, or a heteroalkenylene that may be independently substituted. The conjugate according to claim 1.

13. R ６ and R ７ The alkyl group may be optionally substituted; R ３ , R ４ or R ５ However, the substituent (a) is selected from the following: (a) R ３ is hydrogen, -L ３ -H, -L ３ -A or -L ３ -Z is; R ４ is, -L ４ -H, -(NH) ｍ -L ４ -A, -(NH) ｍ -L ４ -Z, -(O) ｍ -L ４ -A or -(O) ｍ -L ４ -Z is; and R ５ is, -L ５ -H or -L ５ -A is; moreover, R ８、 R ９ or R １０ However, the substituent (a) is selected from the following: (a) R ８ is hydrogen, -L ８ -H, or -L ８ -Z is; R ９ is, -L ９ -H, -(NH)n-L ９ -Z, or -(O)n-L ９ -Z is; and R １０ is, -L １０ -Z is The conjugate according to claim 1.

14. The conjugate according to claim 1, wherein the compound of formula (I) is selected from the following group of compounds: 【Transformation 7】 【Transformation 8】

15. The compound of formula (I) 【Chemistry 9】 The conjugate according to claim 1.

16. The compound of formula (I) 【Chemistry 10】 The conjugate according to claim 1.

17. The conjugate according to claim 1, wherein the targeting molecule comprises a peptide, protein, antibody or fragment thereof, antigen or fragment thereof, aphibody, virus particle or virus capsid, bacterial particle, nucleic acid or fragment thereof, or any combination thereof.

18. The conjugate according to claim 17, wherein the targeting molecule comprises a protein, a peptide, or an antibody or a fragment thereof.

19. The conjugate according to claim 17, wherein the antibody or antigen-binding antibody fragment comprises cetuximab, basiliximab, daclizumab, trastuzumab, panitumumab, or an antigen-binding fragment thereof.

20. The conjugate according to claim 17, wherein the targeting molecule is a peptide or small molecule that binds to EGFR, HER2, CD25, PD-1, PD-L1, or CTLA-4.

21. The conjugate according to claim 1, wherein the targeting molecule binds to CD25 but does not substantially block IL-2 signaling.

22. The conjugate according to claim 1, wherein the conjugate has a compound-to-targeting molecule ratio of approximately 5:1, 4:1, 3:1, 2:1, or 1:

1.

23. The conjugate according to claim 1, wherein the conjugate has a compound-to-targeting molecule ratio between approximately 1:1 to 5:1, 1.5:1 to 4:1, 1.5:1 to 3.5:1, 1.5:1 to 3:1, or approximately 2:1 to 3:

1.

24. The conjugate according to claim 1, wherein the compound of formula (I) has maximum absorption at wavelengths between approximately 600 nm and 800 nm, approximately 620 nm and 720 nm, approximately 640 nm and 700 nm, approximately 640 nm and 680 nm, or approximately 660 nm and 680 nm.

25. The conjugate according to claim 1, wherein the compound of formula (I) has maximum absorption at a wavelength of 680 nm or less.

26. A pharmaceutical composition comprising a conjugate according to any one of claims 1 to 25 and a pharmaceutically acceptable excipient.

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