Inhibitors of prostate specific membrane antigens and uses thereof

Abstract

Provided herein are compounds of Formula (I), pharmaceutical compositions comprising the compounds, and methods of using the compounds or pharmaceutical compositions to diagnose or treat a disease or condition, such as a disease or condition characterized by overexpression of prostate specific membrane antigen (PSMA). # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to International Patent Application No. PCT / CN2023 / 118176, filed on September 12, 2023, and International Patent Application No. PCT / CN2024 / 092402, filed on May 10, 2024, the entire contents of each of which are incorporated herein by reference. Technical field

[0003] Provided herein are certain compounds that inhibit prostate - specific membrane antigen (PSMA), pharmaceutical compositions comprising such compounds, and methods of using such compounds or pharmaceutical compositions to diagnose or treat a disease or disorder, such as a disease or disorder characterized by overexpression of PSMA. Background art

[0004] Prostate cancer is the second most common male malignancy and the most prevalent cancer in the male reproductive system (Rawla 2019). It accounted for 3.8% of all cancer - related deaths in men in 2018. According to GLOBOCAN data, it is estimated that 1.4 million people were diagnosed with prostate cancer globally in 2020, and the number of new cases will exceed one million in 2040 (Deo et al. 2022). Despite high 5 - year survival rates thanks to early detection and intervention, approximately 62 out of every 100,000 men still develop metastatic castration - resistant prostate cancer (mCRPC), which is the advanced stage of prostate cancer (Thurin et al. 2020). CRPC is highly lethal and the median overall survival (OS) is less than 2 years (Khoshkar et al. 2022). Thus, there is a huge unmet medical need.

[0005] More than 80% of prostate cancer patients highly express prostate - specific membrane antigen (PSMA), which is a type II 750 - amino - acid transmembrane protein, also known as folate hydrolase I or glutamate carboxypeptidase II (O′Keefe et al. 2018). It cleaves the terminal carboxy - glutamate from both γ - linked folylpolyglutamates and the neuronal dipeptide N - acetylaspartylglutamate (NAAG). Although PSMA is expressed at low levels in the brain, saliva, kidney, and small intestine, its expression level in prostate cancer is increased 100 - to 1000 - fold (Heston 1997). Nevertheless, PSMA is positively correlated with the Gleason score and cancer aggressiveness and remains highly expressed in CRPC, making it an ideal target for diagnosis and therapy.

[0006] Multiple modalities are being developed for the treatment of prostate cancer based on PSMA targeting, including but not limited to prodrugs, antibody-drug conjugates, cellular immunotherapy, photodynamic therapy, image-guided surgery, ultrasound-mediated nanobubble disruption (Wang et al. 2022). Among them, PSMA-targeted radiotheranostics has been proven to be feasible. Pluvicto (lutetium Lu 177 vipivotide tetraxetan) and Locametz (gallium Ga-68 gozetotide) were approved in 2022 for PSMA-positive mCRPC therapy and as a positron emission tomography (PET) diagnostic agent for PSMA-positive lesions, respectively. The median OS for patients treated with Pluvicto was 15.3 months, 4 months longer than the standard of care (SOC). Approximately one-third (30%) of patients with evaluable disease at baseline showed an overall response according to the RECIST 1.1 criteria when treated with Pluvicto plus SOC, compared with 2% with SOC alone (Sartor et al. 2021). The modest improvement in median OS and response rate indicates that ligands with higher safety margins are needed and that more tumor lesions need to be guided to absorb and have longer retention times, ultimately leading to better clinical outcomes.

[0007] PSMA-targeted therapies may also be clinically beneficial for cancers other than prostate cancer. PSMA has been found to have elevated expression levels in adenoid cystic carcinoma ( 2 Wang et al. 2022), salivary gland duct carcinoma (Terroir et al. 2023), sarcoma (Kleiburg et al. 2022), etc. Some PSMA radioligand therapies have been explored in clinical settings or used for adjuvant therapy (Wang et al. 2022, Terroir et al. 2023), but the true medical benefits still need to be validated in larger cohorts and better-designed studies.

[0008] In summary, PSMA-targeted therapies, whether used alone or in combination with other treatment options, have important value for the treatment and diagnosis of PSMA-positive cancers. SUMMARY OF THE INVENTION

[0009] In one embodiment, the present invention provides a compound of formula (I):

[0010]

[0011] or a stereoisomer, mixture of stereoisomers, tautomer or pharmaceutically acceptable salt thereof, wherein L 1 to L 4 , X, Y, G 1 , G 2 , G 3 , ring W, ring A, R2 n, P 1 L and Z are as defined herein or elsewhere.

[0012] Also provided herein is a complex formed from a compound provided herein and a divalent or trivalent metal cation.

[0013] Also provided herein is a pharmaceutical composition comprising a compound provided herein or a complex provided herein and a pharmaceutically acceptable excipient.

[0014] Also provided herein is a method of treating or diagnosing prostate specific membrane antigen (PSMA)-positive cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein or a complex provided herein.

[0015] Also provided herein is a method of detecting a cell or tissue expressing prostate specific membrane antigen (PSMA), the method comprising (i) contacting a cell or tissue expressing PSMA with a compound provided herein or a complex provided herein, and (ii) applying one or more imaging methods to detect the cell or tissue. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 Showing in the LnCAP xenograft mouse model 177 the in vivo tumor uptake of 177 Lu]Lu-E8 compared to the reference compound

[0017] Figure 2 Showing in the 22Rv1 mouse model 177 the in vivo tumor uptake of 177 Lu]Lu-E7 and 177 Lu]Lu-E8 compared to the reference compound

[0018] Figure 3 Showing the inhibition of tumor growth (tumor volume) by escalating doses (103 μCi, 198 μCi or 516 μCi) of 177 Lu]Lu-E8 compared to saline and the reference compound 177 Lu]Lu-PSMA-617 (201 μCi or 512 μCi) in the LnCAP CDX xenograft mouse model.

[0019] Figure 4 Showing compared to saline and the reference compound 177Compared with Lu-PSMA-617 (201 μCi or 512 μCi), the inhibitory effect of escalating doses (103 μCi, 198 μCi or 516 μCi) of 177 Lu-Lu-E8 on tumor growth (tumor weight). Detailed implementation mode

[0020] It should be understood that the present application provided herein is not limited to the specific methods, protocols and reagents described herein, as these may vary. It should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the scope of the present invention provided herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0021] Several documents are cited throughout this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether above or below, is hereby incorporated by reference in its entirety. If there is a conflict between the definitions or teachings of such incorporated references and the definitions or teachings set forth in this specification, the text of this specification shall prevail.

[0022] Definitions

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In one embodiment, unless otherwise specified, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", edited by Leuenberger, H.G.W, Nagel, B. and Klbl, H. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland.

[0024] As used herein and in this specification and the appended claims, unless the context clearly indicates otherwise, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents.

[0025] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" shall be interpreted as specifying the presence of the stated feature or component mentioned, but not excluding the presence or addition of one or more features or components or groups thereof. Additionally, the terms "comprising" and "including" are intended to include the instances covered by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide a more specific embodiment of the present invention.

[0026] As used herein, the term "or" shall be interpreted as an inclusive "or", which means either or any combination. Thus, "A, B or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B and C". Exceptions to this definition will only occur when the combination of elements, functions, steps or acts are mutually exclusive in some way.

[0027] As used herein, the phrase "and / or" as used in phrases such as "A and / or B" is intended herein to include both A and B; A or B; A (alone); and B (alone). Similarly, the phrase "and / or" as used in phrases such as "A, B and / or C" is intended to cover each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0028] As used herein and unless otherwise specified, the term "alkyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is saturated. In one embodiment, the alkyl has, for example, one to twenty-four carbon atoms (C1-C 24 alkyl), four to twenty carbon atoms (C4-C 20 alkyl), six to sixteen carbon atoms (C6-C 16 alkyl), six to nine carbon atoms (C6-C9 alkyl), one to fifteen carbon atoms (C1-C 15 alkyl), one to twelve carbon atoms (C1-C 12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl) and is attached to the remainder of the molecule by a single bond. Examples of alkyl include but are not limited to methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless otherwise specified, the alkyl is optionally substituted.

[0029] As used herein and unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing one or more carbon-carbon double bonds. The term "alkenyl" also encompasses groups having "cis" and "trans" configurations, or alternatively, "E" and "Z" configurations, as understood by one of ordinary skill in the art. In one embodiment, the alkenyl has, for example, two to twenty-four carbon atoms (C2-C 24 alkenyl), four to twenty carbon atoms (C4-C 20 alkenyl), six to sixteen carbon atoms (C6-C 16 alkenyl), six to nine carbon atoms (C6-C9 alkenyl), two to fifteen carbon atoms (C2-C 15 alkenyl), two to twelve carbon atoms (C2-C 12 alkenyl), two to eight carbon atoms (C2-C8 alkenyl), or two to six carbon atoms (C2-C6 alkenyl) and is attached to the remainder of the molecule by a single bond. Examples of alkenyl include, but are not limited to, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like. Unless otherwise specified, the alkenyl is optionally substituted.

[0030] As used herein and unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain group consisting only of carbon and hydrogen atoms and containing one or more carbon-carbon triple bonds. In one embodiment, the alkynyl has, for example, two to twenty-four carbon atoms (C2-C 24 alkynyl), four to twenty carbon atoms (C4-C 20 alkynyl), six to sixteen carbon atoms (C6-C 16 alkynyl), six to nine carbon atoms (C6-C9 alkynyl), two to fifteen carbon atoms (C2-C 15 alkynyl), two to twelve carbon atoms (C2-C 12 alkynyl), two to eight carbon atoms (C2-C8 alkynyl), or two to six carbon atoms (C2-C6 alkynyl) and is attached to the remainder of the molecule by a single bond. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like. Unless otherwise specified, the alkynyl is optionally substituted.

[0031] As used herein and unless otherwise specified, the term "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms and which is saturated. The cycloalkyl can include fused ring systems, bridged ring systems, or spiro ring systems. In one embodiment, the cycloalkyl has, for example, 3 to 15 ring carbon atoms (C3-C 15 cycloalkyl), 3 to 10 ring carbon atoms (C3-C 10cycloalkyl) or 3 to 8 ring carbon atoms (C3-C8 cycloalkyl). The cycloalkyl is connected to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like. Unless otherwise specified, the cycloalkyl is optionally substituted.

[0032] As used herein and unless otherwise specified, the term "heteroalkyl" refers to a saturated straight or branched carbon chain that is interrupted one or more times with the same or different heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. Examples of heteroalkyls include, but are not limited to, -O-CH3, -S-CH3, -CH2-O-CH3, -CH2-O-C2H5, -CH2-S-CH3, -CH2-S-C2H5, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-S-CH3, -C2H4-S-C2H5, and the like. Unless otherwise specified, the heteroalkyl is optionally substituted.

[0033] As used herein and unless otherwise specified, the term "heterocyclic group" refers to a non-aromatic group monocyclic or polycyclic moiety containing one or more (e.g., one, one or two, one to three or one to four) heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. The heterocyclic group can be attached to the main structure at any heteroatom or carbon atom. The heterocyclic group can be monocyclic, bicyclic, tricyclic, tetracyclic or other polycyclic ring systems, wherein the polycyclic ring system can be a fused ring system, a bridged ring system or a spiro ring system. The heterocyclic group polycyclic ring system can include one or more heteroatoms in one or more rings. The heterocyclic group can be saturated or partially unsaturated. A saturated heterocycloalkyl can be referred to as "heterocycloalkyl". A partially unsaturated heterocycloalkyl can be referred to as "heterocycloalkenyl" if the heterocyclic group contains at least one double bond, or as "heterocycloalkynyl" if the heterocyclic group contains at least one triple bond. In one embodiment, the heterocyclic group has, for example, 3 to 18 ring atoms (3-membered to 18-membered heterocyclic group), 4 to 18 ring atoms (4-membered to 18-membered heterocyclic group), 5 to 14 ring atoms (5-membered to 14-membered heterocyclic group), 5 to 18 ring atoms (5-membered to 18-membered heterocyclic group), 4 to 8 ring atoms (4-membered to 8-membered heterocyclic group) or 5 to 8 ring atoms (5-membered to 8-membered heterocyclic group). Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer within the given range; for example, "3 to 18 ring atoms" means that the heterocyclic group can consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, 8 ring atoms, 9 ring atoms, 10 ring atoms, etc. (up to and including 18 ring atoms). Examples of heterocyclic groups include, but are not limited to, imidazolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, isoxazolidinyl, isothiazolidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl and piperidinyl. Examples of heterocyclic groups also include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8-diaza-spiro[4,5]decyl, 1,7-diaza-spiro[4,5]decyl, 1,6-diaza-spiro[4,5]decyl, 2,8-diaza-spiro[4,5]decyl, 2,7-diaza-spiro[4,5]decyl, 2,6-diaza-spiro[4,5]decyl, 1,8-diaza-spiro[5,4]decyl, 1,7-diaza-spiro[5,4]decyl, 2,8-diaza-spiro[5,4]decyl, 2,7-diaza-spiro[5,4]decyl, 3,8-diaza-spiro[5,4]decyl, 3,7-diaza-spiro[5,4]decyl, 1-azo-7,11-dioxo-spiro[5,5]undecyl, 1,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. Unless otherwise specified, the heterocyclic group is optionally substituted.

[0034] As used herein and unless otherwise specified, the term "aryl" refers to a monocyclic aromatic group and / or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, aryl has 6 to 20 ring carbon atoms (C 6-20 aryl), 6 to 18 ring carbon atoms (C 6-18 aryl), 6 to 14 ring carbon atoms (C 6-14 aryl) or 6 to 10 ring carbon atoms (C 6-10 aryl). Examples of aryl include but are not limited to phenyl, naphthyl, fluorenyl, azulyl, anthryl, phenanthryl, pyrenyl, biphenyl and terphenyl. The term "aryl" also refers to bicyclic, tricyclic or other polycyclic hydrocarbon rings, wherein at least one of the rings is aromatic and the other rings may be saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, dihydroindenyl or tetrahydronaphthyl (tetralinyl). Unless otherwise specified, aryl is optionally substituted.

[0035] As used herein and unless otherwise specified, the term "heteroaryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more (e.g., one, one or two, one to three or one to four) heteroatoms independently selected from O, S and N. Heteroaryl can be attached to the main structure at any heteroatom or carbon atom. In certain embodiments, heteroaryl has 5 to 20, 5 to 15 or 5 to 10 ring atoms. The term "heteroaryl" also refers to bicyclic, tricyclic or other polycyclic rings, wherein at least one of the rings is aromatic and the other rings may be saturated, partially unsaturated or aromatic, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S and N. Examples of monocyclic heteroaryl include but are not limited to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl include but are not limited to indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, isobenzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridyl, furanopyridyl, thiophenopyridyl, dihydroisoindolyl and tetrahydroquinolinyl. Examples of tricyclic heteroaryl include but are not limited to carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl and xanthenyl. Unless otherwise specified, heteroaryl is optionally substituted.

[0036] As used herein and unless otherwise specified, the term "alkylene" or "alkylene chain" refers to a straight or branched polyvalent (e.g., divalent or trivalent) hydrocarbon chain that consists only of carbon and hydrogen and that connects the remainder of the molecule to a group (or groups) and is saturated. In one embodiment, the alkylene has, for example, from one to twenty-four carbon atoms (C1-C 24 alkylene), from one to fifteen carbon atoms (C1-C 15 alkylene), from one to twelve carbon atoms (C1-C 12 alkylene), from one to eight carbon atoms (C1-C8 alkylene), from one to six carbon atoms (C1-C6 alkylene), from two to four carbon atoms (C2-C4 alkylene), or from one to two carbon atoms (C1-C2 alkylene). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene glycol, n-butylene, and the like. An alkylene chain is connected to the remainder of the molecule via a single bond and to the group via a single bond. The connection points of the alkylene chain to the remainder of the molecule and to the group can be achieved via one carbon or any two (or more) carbons within the chain. Unless otherwise specified, the alkylene chain is optionally substituted.

[0037] As used herein and unless otherwise specified, the term "alkynylene" is a polyvalent (e.g., divalent or trivalent) alkynyl group; the term "cycloalkylene" is a polyvalent (e.g., divalent or trivalent) cycloalkyl group; the term "heteroalkylene" is a polyvalent (e.g., divalent or trivalent) heteroalkyl group; the term "arylene" is a polyvalent (e.g., divalent or trivalent) aryl group; and the term "heteroarylene" is a polyvalent (e.g., divalent or trivalent) heteroaryl group. Other "ylene" terms can be similarly constructed from the corresponding "yl" terms.

[0038] It should be understood that if appropriate based on the valence of the group, the term "group" as used herein includes and can be replaced by the corresponding term "ylene". For example, when the ring portion of a compound provided herein is described as a heteroalkyl group, if the ring portion is polyvalent (e.g., divalent or trivalent), i.e., it is connected to multiple parts of the compound, the ring portion is also a heteroalkylene group.

[0039] As used herein and unless otherwise specified, the term "aralkyl" refers to an alkyl moiety substituted with an aryl group. One example is benzyl. As used herein and unless otherwise specified, the term "heteroaralkyl" refers to an alkyl moiety substituted with a heteroaryl group. Unless otherwise specified, terms for other similar components can be similarly constructed.

[0040] When a group described herein is referred to as "substituted", the group can be substituted by any suitable one or more substituents. Illustrative examples of substituents include, but are not limited to, the substituents seen in the exemplary compounds and embodiments provided herein, and: halogen atoms such as F, Cl, Br, or I; cyano; oxo group (=O); hydroxy (-OH); alkyl; alkenyl; alkynyl; cycloalkyl; aryl; -(C=O)OR'; -O(C=O)R'; -C(=O)R'; -OR'; -S(O) x R'; -S-SR'; -C(=O)SR'; -SC(=O)R'; -NR'R'; -NR'C(=O)R'; -C(=O)NR'R'; -NR'C(=O)NR'R'; -OC(=O)NR'R'; -NR'C(=O)OR'; -NR'S(O) x NR'R'; -NR'S(O) x R' and -S(O) x NR'R', where: R' is independently H, C1-C 15 alkyl or cycloalkyl each time it appears, and x is 0, 1, or 2. In some embodiments, the substituent is C1-C 12 alkyl. In other embodiments, the substituent is cycloalkyl. In other embodiments, the substituent is a halogen group such as fluorine. In other embodiments, the substituent is an oxo group. In other embodiments, the substituent is a hydroxy group. In other embodiments, the substituent is an alkoxy group (-OR'). In other embodiments, the substituent is a carboxyl group. In other embodiments, the substituent is an amino group (-NR'R').

[0041] As used herein and unless otherwise specified, the term "optional" or "optionally" (e.g., optionally substituted) means that the subsequently described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "optionally substituted alkyl" means that the alkyl may or may not be substituted and the description includes both substituted alkyl and unsubstituted alkyl.

[0042] As used herein and unless otherwise specified, the term "halogen group" or "halogen" refers to a halogen residue selected from the group consisting of F, Cl, Br, and I.

[0043] As used herein and unless otherwise specified, the term "linker" refers to any chemically suitable linker. In one embodiment, the linker does not cleave or cleaves only slowly under physiological conditions. In one embodiment, the linker does not contain a recognition sequence for a protease or other recognition structure for a degrading enzyme. In one embodiment, when the compounds provided herein are administered systemically to allow broad access to all compartments of the body and the compounds provided herein are then enriched at any location in the body where the tumor is located, the linker is selected such that it does not cleave or cleaves only slowly in the blood. In one embodiment, if less than 50% of the linker cleaves within 2 hours after administration of the compound to a human patient, it is considered to cleave slowly. Suitable linkers include, but are not limited to, optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amine, ether, thioether phosphine, aminophosphate, formamide, ester, imidoester, amidine, thioester, sulfonamide, 3-thiopyrrolidine-2,5-dione, carbamate, urea, guanidine, thiourea, disulfide, oxime, hydrazine, hydrazide, hydrazone, diaza bond, triazole, triazoline, tetrazine, platinum complex, and amino acids or combinations thereof. In one embodiment, the linker comprises 1,4-piperazine, 1,3-propane, and phenol ether or combinations thereof.

[0044] The linker can also be a cleavable linker, such as a peptidyl motif cleaved by cathepsin. Any suitable linker cleavable by cathepsin can be used. Some suitable cleavable peptide linkers are described in Peterson et al., Bioconjugate Chem., 1998. For example, suitable cleavable linkers include optionally substituted NO2Tyr-Gln-Gly-Val-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Asn-Gly-Thr-Gly-Phe-Lys(aminobenzoyl), NO2Tyr-Ser-Val-Val-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Val-Gln-Ser-Ala-Phe, polyVal-Gln-Phe-Val, NO2Tyr-Gly-Val-Phe-Gln-Phe, NO2Tyr-Gly-Thr-Val-Ala-Phe-Lys(aminobenzoyl), NO2Tyr-Ala-Thr-Ala-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Ser-Val-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Gly-Gln-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Gln-Ser-Val-Gly-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Thr-Val-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Val-Ala-Gly-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Ser-Thr-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Ala-Ala-Gly-Thr-Phe-Lys(aminobenzoyl), NO2Tyr-Val-Ala-Gln-Phe, NO2Tyr-Gln-Gly-Val-Gly-Phe-Lys(aminobenzoyl), NO2Tyr-Val-Asn-Asn-Asn-Phe-Lys(aminobenzoyl), NO2Tyr-Ala-Ser-Ala-Asn-Phe-Lys(aminobenzoyl), NO2Tyr-Phe-Gln-Thr-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Ala-Ala-Ala-Ser-Phe-Lys(aminobenzoyl), NO2Tyr-Gln-Tyr-Ser-Gly-Phe-Lys(aminobenzoyl),NO2Tyr-Ala-Ala-Thr-Ala-Phe-Lys(benzoyl), NO2Tyr-Ala-Thr-Gln-Phe-Phe-Lys(benzoyl), NO2Tyr-Gln-Ser-Ala-Ser-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Ser-Phe-Phe-Lys(benzoyl), NO2Tyr-Thr-Ala-Gly-Ala-Phe-Lys(benzoyl), NO2Tyr-Ala-Thr-Thr-Phe-Phe-Lys(benzoyl), NO2Tyr-Ala-Ser-Gly-Ser-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Thr-Phe-Phe-Lys(benzoyl), NO2Tyr-Gly-Ala-Ala-Gly-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys(benzoyl), NO2Tyr-Ala-Ala-Thr-Gly-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys(benzoyl), NO2Tyr-Gln-Thr-Val-Gly-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Gln-Phe-Phe-Lys(benzoyl), NO2Tyr-Ala-Ser-Ala-Gly-Phe-Lys(benzoyl), NO2Tyr-Gly-Gln-Ser-Phe-Phe-Lys(benzoyl), NO2Tyr-Thr-Ser-Ala-Thr-Phe-Lys(benzoyl), NO2Tyr-Gly-Thr-Val-Ala-Phe-Lys(benzoyl), NO2Tyr-Thr-Ala-Gln-Ala-Phe-Lys(benzoyl), NO2Tyr-Gly-Val-Ala-Ala-Phe-Lys(benzoyl), NO2Tyr-Val-Ala-Ser-Ala-Phe-Lys(benzoyl), NO2Tyr-Gln-Gly-Ser-Phe-Phe-Lys(benzoyl), NO2Tyr-Thr-Ala-Thr-Asn-Phe-Lys(benzoyl), NO2Tyr-Ala-Thr-Ser-Phe-Phe-Lys(benzoyl), NO2Tyr-Thr-Gly-Val-Gly-Phe-Lys(benzoyl)NO2Tyr-Gly-Thr-Ala-Phe-Phe-Lys(aminobenzoyl), NO2Tyr-Gln-Val-Ala-Gly-Phe-Lys(aminobenzoyl), NO2Tyr-Gly-Ser-Ala-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Val-Ala-Ala-Gln-Phe-Lys(aminobenzoyl), NO2Tyr-Gln-Thr-Ala-Thr-Phe-Lys(aminobenzoyl), NO2Tyr-Thr-Gly-Tyr-Thr-Phe-Lys(aminobenzoyl), NO2Tyr-Ser-Ala-Gly-Thr-Phe-Lys(aminobenzoyl), NO2Tyr-Val-Tyr-Tyr-Val-Phe, NO2Tyr-Ala-Ser-Tyr-Gly-Phe, Z-Phe-Lys-PABC, Z-Phe-Lys, Z-Val-Lys-PABC, Z-Ala-Lys-PABC, Phe-Phe-Lys-PABC, D-Phe-Phe-Lys-PABC, D-Ala-Phe-Lys-PABC, Gly-Phe-Lys-PABC, Ac-Phe-Lys-PABC, HCO-Phe-Lys-PABC, Phe-Lys-PABC, Z-Lys-PABC, Z-Val-Cit-PABC, Z-Val-Cit, Z-Phe-Cit-PABC, Z-Leu-Cit-PABC, Z-Ile-Cit-PABC, Z-Trp-Cit-PABC, Z-Phe-Arg(NO2)-PABC and Z-Phe-Arg(Ts)-PABC.,

[0045] As used herein and unless otherwise specified, the term "amino acid" refers to any organic acid containing one or more amino substituents, such as α-amino acids, β-amino acids or γ-amino acids, derivatives of aliphatic carboxylic acids. In the polypeptide notation used herein, for example Xaa1Xaa2Xaa3Xaa4Xaa5, where Xaa1 to Xaa5 are each and independently selected from amino acids as defined, according to standard usage and convention, the left-hand direction is the amino-terminal direction and the right-hand direction is the carboxyl-terminal direction.

[0046] As used herein and unless otherwise specified, the term "conventional amino acid" refers to the twenty naturally occurring amino acids and encompasses all stereoisomeric isotypes, i.e., their D,L-amino acids, D-amino acids, and L-amino acids. These conventional amino acids may also be referred to herein by their conventional three-letter or single-letter abbreviations, and their abbreviations follow conventional usage (see, e.g., Immunology-A Synthesis, 2nd ed., eds. E.S. Golub and D.R. Gren, Sinauer Associates, Sunderland Mass. (1991)).

[0047] As used herein and unless otherwise specified, the term "non-conventional amino acid" refers to non-natural amino acids or chemical amino acid analogs, such as α,α-disubstituted amino acids, N-alkyl amino acids, homosteric amino acids, dehydro amino acids, aromatic amino acids (other than phenylalanine, tyrosine, and tryptophan), and o-aminobenzoic acid, m-aminobenzoic acid, or p-aminobenzoic acid. Non-conventional amino acids also include compounds having amine and carboxyl functional groups separated in a 1,3 or greater substitution pattern, such as β-alanine, γ-aminobutyric acid, Freidinger lactam, bicyclic dipeptide (BTD), aminomethylbenzoic acid, and other compounds known in the art. Statine-like bioisosteres, hydroxyethylene bioisosteres, reduced amide bond bioisosteres, thioamide bioisosteres, urea bioisosteres, carbamate bioisosteres, thioether bioisosteres, vinyl bioisosteres, and other amide bond bioisosteres known in the art may also be used. The use of analogs or non-conventional amino acids can improve the stability and biological half-life of the added peptides because the analogs or non-conventional amino acids are more resistant to degradation under physiological conditions. Those skilled in the art will appreciate the similar types of substitutions that can be made. A non-limiting list of non-conventional amino acids that can be used as suitable structural units for peptides and their standard abbreviations (in parentheses) are as follows: α-aminobutyric acid (Abu), L-N-methylalanine (Nmala), α-amino-α-methylbutyrate (Mgabu), L-N-methylarginine (Nmarg), aminocyclopropane (Cpro), L-N-methylasparagine (Nmasn), formyl L-N-methylaspartic acid (Nmasp), aminoisobutyric acid (Aib), L-N-methylcysteine (Nmcys), aminonorbornane (Norb), L-N-methylglutamine (Nmgln), formyl L-N-methylglutamic acid (Nmglu), cyclohexylalanine (Chexa), L-N-methylhistidine (Nmhis), cyclopentylalanine (Cpen), L-N-methylisoleucine (Nmile), L-N-methylleucine (Nmleu), L-N-methyllysine (Nmlys), L-N-methylmethionine (Nmmet), L-N-methylnorleucine (Nmnle), L-N-methylnorvaline (Nmnva), L-N-methylornithine (Nmorn), L-N-methylphenylalanine (Nmphe), L-N-methylproline (Nmpro), L-N-methylserine (Nmser), L-N-methylthreonine (Nmthr), L-N-methyltryptophan (Nmtrp), D-ornithine (Dorn), L-N-methyltyrosine (Nmtyr), L-N-methylvaline (Nmval), L-N-methylethylglycine (Nmetg), L-N-methyl-tert-butylglycine (Nmtbug).L-Norleucine (NIe), L-Norvaline (Nva), α-Methylaminobutyrate (Maib), α-Methyl-γ-aminobutyrate (Mgabu), D-α-Methylalanine (Dmala), α-Methylcyclohexylalanine (Mchexa), D-α-Methylarginine (Dmarg), α-Methylcyclopentylalanine (Mcpen), D-α-Methylasparagine (Dmasn), α-Methyl-α-naphthylalanine (Manap), D-α-Methylaspartate (Dmasp), α-Methylpenicillamine (Mpen), D-α-Methylcysteine (Dmcys), N-(4-Aminobutyl)glycine (NgIu), D-α-Methylglutamine (Dmgln), N-(2-Aminoethyl)glycine (Naeg), D-α-Methylhistidine (Dmhis), N-(3-Aminopropyl)glycine (Norn), D-α-Methylisoleucine (Dmile), N-Amino-α-methylbutyrate (Nmaabu), D-α-Methyleucine (Dmleu), α-Naphthylalanine (Anap), D-α-Methyllysine (Dmlys), N-Benzylglycine (Nphe), D-α-Methylmethionine (Dmmet), N-(2-Carbamoylethyl)glycine (NgIn), D-α-Methylornithine (Dmorn), N-(Carbamoylmethyl)glycine (Nasn), D-α-Methylphenylalanine (Dmphe), N-(2-Carboxyethyl)glycine (NgIu), D-α-Methylproline (Dmpro), N-(Carboxymethyl)glycine (Asp), D-α-Methylserine (Dmser), N-Cyclobutylglycine (Ncbut), D-α-Methylthreonine (Dmthr), N-Cycloheptylglycine (Nchep), D-α-Methyltryptophan (Dmtrp), N-Cyclohexylglycine (Nchex), D-α-Methyltyrosine (Dmty), N-Cyclodecylglycine (Ncdec), D-α-Methylvaline (Dmval), N-Cyclododecylglycine (Ncdod), D-N-Methylalanine (Dnmala), N-Cyclooctylglycine (Ncoct), D-N-Methylarginine (Dnmarg), N-Cyclopropylglycine (Nepro), D-N-Methylasparagine (Dnmasn), N-Cycloundecylglycine (Ncund), D-N-Methylaspartate (Dnmasp), N-(2,2-Diphenylethyl)glycine (Nbhm), D-N-Methylcysteine (Dnmcys), N-(3,3-Diphenylpropyl)glycine (Nbhe), D-N-Methylglutamine (Dnmgln), N-(3-Guanidinopropyl)glycine (Narg), D-N-Methylglutamate (Dnmglu),N-(1-Hydroxyethyl)glycine (Ntbx), D-N-methylhistidine (Dnmhis), N-(hydroxyethyl)glycine (Nser), D-N-methylisoleucine (Dnmile), N-(imidazolylethyl)glycine (Nhis), D-N-methyleucine (Dnmleu), N-(3-indolylethyl)glycine (Nhtrp), D-N-methyllysine (Dnnilys), N-methyl-γ-aminobutyrate (Nmgabu), N-methylcyclohexylalanine (Nmchexa), D-N-methylmethionine (Dnmmet), D-N-methylornithine (Dnmorn), N-methylcyclopentylalanine (Nmcpen), N-methylglycine (Nala), D-N-methylphenylalanine (Dnmphe), N-methylaminoisobutyrate (Nmaib), D-N-methylproline (Dnmpro), N-(1-methylpropyl)glycine (Nile), D-N-methylserine (Dnmser), N-(2-methylpropyl)glycine (Nleu), D-N-methylthreonine (Dnmthr), D-N-methyltryptophan (Dnmtrp), N-(1-methylethyl)glycine (Nval), D-N-methyltyrosine (Dnmtyr), N-methyl-naphthylalanine (Nmanap), D-N-methylvaline (Dnmval), N-methylpenicillamine (Nmpen), γ-aminobutyric acid (Gabu), N-(p-hydroxyphenyl)glycine (Nhtyr), L- / -butylglycine (Tbug), N-(sulfidomethyl)glycine (Ncys), L-ethylglycine (Etg), penicillamine (Pen), L-homophenylalanine (Hphe), L-α-methylalanine (Mala), L-α-methylarginine (Marg), L-α-methylasparagine (Masn), L-α-methylaspartate (Masp), L-α-methyl-tert-butylglycine (Mtbug), L-α-methylcysteine (Mcys), L-methylethylglycine (Metg), L-α-methylglutamine (MgIn), L-α-methylglutamate (MgIu), L-α-methylhistidine (Mhis), L-α-methylhomophenylalanine (Mhphe), L-α-methylisoleucine (Mile), N-(2-methylthioethyl)glycine (Nmet), L-α-methyleucine (Mleu), L-α-methyllysine (Mlys), L-α-methylmethionine (Mmet), L-α-methylnorleucine (MnIe), L-α-methylnorvaline (Mnva), L-α-methylornithine (Mom), L-α-methylphenylalanine (Mphe), L-α-methylproline (Mpro), L-α-methylserine (Mser), L-α-methylthreonine (Mthr),L-α-methyltryptophan (Mtrp), L-α-methyltyrosine (Mtyr), L-α-methylvaline (Mval), L-N-methylhomophenylalanine (Nmhphe), N-(N-(2,2-diphenylethyl)carbamoylmethyl)glycine (Nnbhm), N-(N-(3,3-diphenylpropyl)-carbamoylmethyl)glycine (Nnbhe), 1-carboxy-1-(2,2-diphenyl-ethylamino)cyclopropane (Nmbc), L-o-methylserine (Omser), L-o-methylhomoserine (Omhser).

[0048] As used herein and unless otherwise specified, the term "radioactive moiety" refers to a molecular assembly that carries a radionuclide. The nuclide is bound by covalent or coordination bonds that are stable under physiological conditions.

[0049] As used herein and unless otherwise specified, the term "fluorescent isotope" refers to an isotope that emits electromagnetic radiation after excitation by electromagnetic radiation of a shorter wavelength.

[0050] As used herein and unless otherwise specified, the term "radioactive isotope" refers to a radioactive isotope of an element (included in the term "radionuclide") that emits α-radiation, β-radiation, and / or γ-radiation.

[0051] As used herein and unless otherwise specified, the term "radiopharmaceutical" refers to a bioactive compound modified with a radioactive isotope. In particular, an embedding substance can be used to deliver radioactivity in the immediate vicinity of DNA (e.g., 131 I).

[0052] As used herein and unless otherwise specified, the terms “chelating agent” or “chelator” are used interchangeably and refer to a molecule, typically an organic molecule and typically a Lewis base, having two or more unshared electron pairs available for donation to a metal ion. The metal ion is typically coordinated to the chelating agent through two or more electron pairs. The term “chelating atom” refers to an atom that provides an unshared electron pair available for donation to a metal ion. The terms “bidentate chelating agent,” “tridentate chelating agent,” “tetradentate chelating agent,” “hexadentate chelating agent,” and “octadentate chelating agent” refer to chelating agents having two, three, four, six, and eight electron pairs, respectively, that are readily available for simultaneous donation to a metal ion coordinated through the chelating agent. In one embodiment, the chelating agent has 3 or 4 nitrogen chelating atoms. In one embodiment, the chelating agent further has 3 or 4 oxygen-containing groups containing oxygen chelating atoms. In one embodiment, the oxygen-containing group is carboxylic acid (−COOH) or phosphonic acid (−PO3H2) or a derivative thereof. Typically, the electron pairs of the chelating agent form coordination bonds with a single metal ion; however, in certain instances, the chelating agent may form coordination bonds with more than one metal ion, where various binding modes are possible.

[0053] As used herein and unless otherwise specified, when a “chelating agent” is part of a compound provided herein (e.g., the chelating agent Z in a compound of formula (I) provided herein), it refers to the chelating agent moiety of the complete chelating agent molecule (even when using the chemical name or abbreviation of the complete molecule). As used herein and unless otherwise specified, the “chelating moiety” of a complete chelating agent molecule refers to a partial structure of the complete chelating agent molecule, and the partial structure has the same or substantially the same chelating atoms as the complete chelating agent molecule. For example, DOTA typically refers to the complete molecule of 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid. As used herein and unless otherwise specified, the “chelating moiety” of DOTA refers to a partial structure of DOTA that has the same or substantially the same chelating atoms as DOTA, such as the following partial structure:

[0054]

[0055] Upon viewing the structures of the compounds provided herein, one of ordinary skill in the art will be able to know the points of attachment of the chelating moiety to the remainder of the compound. In one embodiment, the point of attachment for the chelating agents provided herein is on a chelating agent atom (such as a nitrogen atom). In one embodiment, the point of attachment for the chelating agents provided herein is on a carbon atom from an alkylene group attached to the chelating atom. In one embodiment, the point of attachment for the chelating agents provided herein is on a ring carbon atom (such as a ring carbon atom of a pyridine ring) from a ring containing the chelating atom. In one embodiment, the chelating moiety provided herein is generated by removing an -OH group from an acid group or a derivative thereof. For example, in one embodiment, the point of attachment is on the carbon atom of a carboxylic acid (-COOH) after removing the -OH group; in another embodiment, the point of attachment is on the phosphorus atom of a phosphonic acid (-PO3H2) after removing the -OH group. Non-limiting points of attachment are also depicted in the chelating agent structures in Table 1.

[0056] As used herein and unless otherwise specified, the term "fluorescent dye" refers to a compound that emits visible or infrared light after excitation by electromagnetic radiation of a shorter and suitable wavelength. One of ordinary skill in the art will understand that each fluorescent dye has a predetermined excitation wavelength.

[0057] As used herein and unless otherwise specified, the term "contrast agent" refers to a compound that increases the contrast of a structure or fluid in medical imaging. Enhancement is achieved by absorbing electromagnetic radiation or altering the electromagnetic field.

[0058] As used herein and unless otherwise specified, the term "paramagnetic" refers to paramagnetism induced by unpaired electrons in a medium. If an external magnetic field is applied, a paramagnetic substance induces a magnetic field. Different from diamagnetism, the direction of the induced field is the same as the external field, and different from ferromagnetism, the field is maintained in the absence of an external field.

[0059] As used herein and unless otherwise specified, the term "nanoparticle" as used herein refers to a particle having a diameter size between 1 nanometer and 100 nanometers, such as a spherical particle. Depending on the composition, nanoparticles may have evaluable magnetic, optical, or physico-chemical properties. Additionally, surface modification can be achieved for many types of nanoparticles.

[0060] As used herein and unless otherwise specified, "pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Suitable pharmaceutically acceptable salts of the compounds provided herein include acid addition salts, which can be formed, for example, by mixing a solution of choline or its derivative with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compounds provided herein carry an acidic moiety, suitable pharmaceutically acceptable salts thereof can include alkali metal salts (such as sodium or potassium salts); alkaline earth metal salts (such as calcium or magnesium salts); and salts formed with suitable organic ligands (such as ammonium, quaternary ammonium and amine cations formed using counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyl sulfonates and aryl sulfonates).Illustrative examples of pharmaceutically acceptable salts include, but are not limited to: acetates, adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, butyrates, calcium edetate, camphorates, camphorsulfonates, carbonates, chlorides, citrates, cinnamates, cyclopentanepropionates, digluconates, dihydrochlorides, dodecyl sulfates, edetates, ethanedisulfonates, estolates, esulfonates, ethane sulfonates, formates, fumarates, gluceptates, glucoheptonates, gluconates, glutamates, glycerophosphates, glycol benzoates, hemisulfates, heptanoates, hexanoates, hexylresorcinates, hydrabamine, hydrobromides, hydrochlorides, hydroiodides, 2-hydroxyethane sulfonates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, mandelates, mesylates, methanesulfonates, methanesulfonylates, mucates, 2-naphthalenesulfonates, naphthalenesulfonates, nicotinates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, pectates, persulfates, 3-phenylpropionates, phosphates / diphosphates, picrates, pivalates, polygalacturonates, propionates, salicylates, stearates, sulfates, subacetates, succinates, tannates, tartrates, theophylline chlorides, toluenesulfonates, triethiodides, undecanoates, valerates, etc. (see, e.g., Berge, S.M. et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds provided herein contain both basic and acidic functional groups that allow the compound to be converted into a base addition salt or an acid addition salt.

[0061] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (e.g., solubility in polar solvents), but for the purposes provided herein, the salts are equivalent to the parent form of the compound in other respects.

[0062] In addition to the desalted form, the present invention also provides compounds in the form of prodrugs. The prodrugs of the compounds are readily subject to chemical change under physiological conditions to provide the compounds. A prodrug is an active or inactive compound which, following administration of the prodrug to a patient, is chemically modified via physiological actions in the body (e.g., hydrolysis, metabolism, etc.) to the compounds provided herein. In addition, a prodrug can be converted to the compounds provided herein by chemical or biochemical means in an ex vivo environment. For example, when a prodrug is placed in a transdermal patch reservoir together with a suitable enzyme, the prodrug can be slowly converted to the compounds provided herein. The suitability and techniques involved in the manufacture and use of prodrugs are known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek Drug Metabolism Reviews 16.5 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of masking the carboxylate anion include various esters, such as alkyl (e.g., methyl, ethyl) esters, cycloalkyl (e.g., cyclohexyl) esters, aralkyl (e.g., benzyl, p-methoxybenzyl) esters, and alkoxycarbonyloxyalkyl (e.g., pivaloyloxymethyl) esters. Amines have been masked as derivatives substituted with arylcarbonyloxymethyl, which are cleaved by esterases in the body to release the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). In addition, drugs containing acidic NH groups (e.g., imidazole, imide, indole, etc.) have been masked with N-acyloxymethyl (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxyl groups have been masked as esters and ethers. EP 0 039 051 (Sloan and Little, April 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation, and uses.

[0063] As used herein and unless otherwise specified, the term "isomer" refers to different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Atropisomers" are stereoisomers that are hindered from rotating about a single bond. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion may be referred to as a "racemic" mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry may be assigned according to the Cahn-Ingold-Prelog R-S system. When a compound is an enantiomer, the stereochemistry at each chiral carbon may be designated as R or S. A resolved compound of unknown absolute configuration may be named (+) or (-), depending on the direction (right or left) in which it rotates plane-polarized light at the wavelength of the sodium D line. However, the signs (+) and (-) of the optical rotation are not related to the absolute configuration R and S of the molecule. Certain compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- according to the absolute stereochemistry at each asymmetric atom. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible isomers, including racemic mixtures, substantially optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared, for example, using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0064] As used herein and unless otherwise specified, the term "enantiomeric purity" or "enantiomer purity" refers to a qualitative or quantitative measure of a purified enantiomer. The enantiomeric purity of the compounds described herein may be described by enantiomeric excess (ee), which indicates the extent to which a sample contains one enantiomer in greater amounts than the other. The ee of a racemic mixture is 0%, while that of a single, completely pure enantiomer is 100%. Examples of enantiomeric purity include an ee of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%. Similarly, "diastereomeric purity" may be described by diastereomeric excess (de), which indicates the extent to which a sample contains one diastereomer in greater amounts than the other.

[0065] As used herein and unless otherwise specified, the term "substantially purified enantiomer" refers to a compound in which one enantiomer has been enriched relative to the other. In one embodiment, the other enantiomer represents less than about 20%, less than about 10%, less than about 5%, or less than about 2% of the enantiomer.

[0066] "Stereoisomers" may also include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof. In certain embodiments, the compounds described herein are separated into the E isomer or the Z isomer. In other embodiments, the compounds described herein are a mixture of the E isomer and the Z isomer.

[0067] As used herein and unless otherwise specified, the term "tautomer" refers to one of two or more structural isomers that readily interconvert from one isomeric form to another and exist in equilibrium. If tautomers are possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, prototropic tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization. Valence tautomers include some reorganization of bonding electrons for interconversion. A specific example of keto-enol tautomerization is the tautomerism between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example is the tautomerization of 2-pyridone and 2-hydroxypyridine.

[0068] The compounds provided herein can be synthesized according to one or more of the methods / examples provided herein. It should be noted that general procedures can be presented as they relate to the preparation of compounds with unspecified stereochemistry. However, such procedures are generally applicable to those compounds with specific stereochemistry, such as where the stereochemistry of a group is (S) or (R). Additionally, compounds having one stereochemistry (e.g., (R)) can generally be used to produce compounds having the opposite stereochemistry (i.e., (S)) using well-known methods (e.g., by transformation).

[0069] Certain compounds provided herein have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, and individual isomers are intended to be encompassed within the scope of this application.

[0070] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. For example, the compounds can be radiolabeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of this application.

[0071] As used herein and unless otherwise specified, the term "pharmaceutical composition" refers to a substance and / or combination of substances used for the identification, prevention or treatment of a tissue condition or disease. The pharmaceutical composition is formulated to be suitable for administration to a patient for the prevention and / or treatment of a disease. In addition, a pharmaceutical composition is a combination of an active agent and a carrier (inert or active) that renders the composition suitable for therapeutic use. The pharmaceutical composition may be formulated for oral, parenteral, topical, inhaled, rectal, sublingual, transdermal, subcutaneous or vaginal routes of administration depending on its chemical and physical properties. The pharmaceutical composition includes solids, semi-solids, liquids, transdermal therapeutic systems (TTS). Solid compositions are selected from the group consisting of tablets, coated tablets, powders, granules, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also included are liquid compositions selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous administration, solutions for infusion or solutions of the carrier systems provided herein. The semi-solid compositions provided herein include emulsions, suspensions, creams, lotions, gels, spheres, buccal tablets and suppositories.

[0072] As used herein and unless otherwise specified, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.

[0073] As used herein and unless otherwise specified, the term "carrier" or "excipient" as used herein refers to a diluent, adjuvant, excipient or vehicle administered with a therapeutic agent. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils (including oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.). When a pharmaceutical composition is administered intravenously, the saline solution is the carrier. A saline solution and aqueous dextrose and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. When necessary, the composition may also contain small amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0074] As used herein and unless otherwise specified, the term "cytotoxicity" refers to the depletion, elimination, and / or killing of target cells. As used herein and unless otherwise specified, the term "cytotoxic agent" refers to an agent that has cytotoxic and / or cytostatic effects on cells. The term is intended to include chemotherapeutic agents and toxins, such as enzymatically active toxins and fragments thereof from bacteria, fungi, plants, or animals. As used herein and unless otherwise specified, the term "cytostasis" refers to the inhibition of cell proliferation. As used herein and unless otherwise specified, the term "cytostatic agent" refers to an agent that has cytostatic effects on cells, thereby inhibiting the growth and / or expansion of a particular cell subset.

[0075] As used herein and unless otherwise specified, the term "cytokine" refers to small proteins (about 5 to 20 kDa) that participate in autocrine signaling, paracrine signaling, and endocrine signaling as immunomodulators. Cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors, but generally do not include hormones or growth factors.

[0076] As used herein and unless otherwise specified, the term "immunomodulatory molecule" refers to a substance that stimulates or inhibits the immune system and can help the body fight cancer, infection, or other diseases. Specific immunomodulatory molecules can be monoclonal antibodies, cytokines, and vaccines, which affect specific parts of the immune system.

[0077] As used herein and unless otherwise specified, the term "amphiphilic substance" refers to a compound that has both hydrophilic and lipophilic properties. Common amphiphilic substances are phospholipids, cholesterol, glycolipids, fatty acids, bile acids, saponins, pediocin, local anesthetics, Ab proteins, and antimicrobial peptides.

[0078] As used herein and unless otherwise specified, the terms "protein" and "polypeptide" are used interchangeably herein and refer to any peptide-bonded chain of amino acids, regardless of length or post-translational modification. In one embodiment, the amino acids are any of the amino acids provided herein. The proteins provided herein (including protein derivatives, protein variants, protein fragments, protein segments, protein epitopes, and protein domains) can be further modified by chemical modification. This means that such chemically modified polypeptides contain other chemical groups in addition to the 20 naturally occurring amino acids. Examples of such other chemical groups include (but are not limited to) glycosylated amino acids and phosphorylated amino acids. Chemical modification of a polypeptide can provide advantageous properties compared to the parent polypeptide, such as one or more of the following: enhanced stability, increased biological half-life, or increased water solubility.

[0079] As used herein and unless otherwise specified, the terms "nucleic acid" and "polynucleotide" are used interchangeably herein and refer to polymeric or oligomeric macromolecules or biomacromolecules that are essential for all known forms of life. Nucleic acids, including DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), are made up of monomers called nucleotides. Most naturally occurring DNA molecules consist of two complementary biopolymer strands that coil around each other to form a double helix. DNA strands are also called polynucleotides composed of nucleotides. Each nucleotide contains a nitrogenous nucleobase, as well as a monosaccharide sugar called deoxyribose or ribose, and a phosphate group. Naturally occurring nucleobases include guanine (G), adenine (A), thymine (T), uracil (U), or cytosine (C). Nucleotides are joined to each other in the chain by covalent bonds between the sugar of one nucleotide and the phosphate of another nucleotide, resulting in an alternating sugar-phosphate backbone. If the sugar is deoxyribose, the polymer is DNA. If the sugar is ribose, the polymer is RNA. Generally, polynucleotides are formed via phosphodiester bonds between individual nucleotide monomers. As used herein and unless otherwise specified, the term "nucleic acid" includes (but is not limited to) ribonucleic acid (RNA), deoxyribonucleic acid (DNA), and mixtures thereof (e.g., RNA-DNA hybrids (within one strand)), as well as cDNA, genomic DNA, recombinant DNA, cRNA, and mRNA. Nucleic acids can consist of entire genes or portions thereof, and nucleic acids can also be miRNA, siRNA, piRNA, or shRNA. miRNA are short ribonucleic acid (RNA) molecules that are on average 22 nucleotides in length but can be longer, and are found in all eukaryotic cells (i.e., plants, animals, and some viruses), and play a role in the transcriptional and post-transcriptional regulation of gene expression. miRNA are post-transcriptional regulators that bind to complementary sequences in target messenger RNA transcripts (mRNA), typically causing translational repression and gene silencing. Small interfering RNA (siRNA), sometimes called short interfering RNA or silencing RNA, are short ribonucleic acid (RNA) molecules that are between 20 and 25 nucleotides in length. They are associated with the RNA interference (RNAi) pathway, in which they interfere with the expression of specific genes. Short hairpin RNA (shRNA) or small hairpin RNA (shRNA) are artificial RNA molecules that can be used to silence the expression of target genes via RNA interference (RNAi). Expression of shRNA in cells is typically achieved by delivery of plasmids or via viral or bacterial vectors. piRNA are also short RNAs that typically contain 26 to 31 nucleotides and their name is derived from the so-called piwi proteins to which they bind. Nucleic acids can also be artificial nucleic acids. Artificial nucleic acids include polyamides or peptide nucleic acids (PNA), morpholinos, and locked nucleic acids (LNA), as well as glycol nucleic acids (GNA) and threose nucleic acids (TNA). Each of these nucleic acids differs from naturally occurring DNA or RNA in the modification of the molecular backbone.Nucleic acids can be synthesized, for example, chemically, for example according to the phosphotriester method (see, for example, Uhlmann, E. and Peyman, A. (1990) Chemical Reviews, 90, 543-584).

[0080] As used herein and unless otherwise specified, the term "viral structural protein" (VSP) refers to a viral capsid protein (VCP) or a viral envelope glycoprotein (VEG). As used herein and unless otherwise specified, the term "viral capsid protein" (VCP) refers to the structural viral capsid protein of a virus. In one embodiment, the virus is a double-stranded DNA virus, a single-stranded DNA virus, a double-stranded RNA virus, a single-stranded RNA virus, an antisense single-stranded RNA virus, a single-stranded RNA retrovirus, a double-stranded RNA retrovirus. The VCP can comprise the major capsid protein of an adeno-associated virus (AAV).

[0081] As used herein and unless otherwise specified, the term "viral envelope glycoprotein" (VEG) refers to a viral protein that is part of the viral envelope. The viral envelope typically derives from a portion of the host cell membrane, for example containing phospholipids, and additionally contains, for example, viral glycoproteins that help the virus evade the immune system. Enveloped viruses include DNA viruses such as Herpesvirus, Poxvirus, and Hepadnavirus; RNA viruses such as Flavivirus, Togavirus, Coronavirus, Hepatitis D, Orthomyxovirus, Paramyxovirus, Rhabdovirus, Bunyavirus, Filovirus, and Retrovirus. In one embodiment, the viral envelope glycoprotein is derived from any of these viruses.

[0082] As used herein and unless otherwise specified, the term "liposome" refers to a single- or multi-layered (e.g., 2, 3, 4, 5, 6, 7, 8, 9, and 10 layers) lipid structure that encapsulates an aqueous interior, depending on the number of lipid membranes formed. Lipids capable of forming liposomes include all substances having fatty or fat-like properties. Such lipids contain extended non-polar residues (X) and typically contain water-soluble, polar, hydrophilic residues (Y), which can be characterized by the following basic formula

[0083] X-Yn

[0084] where n is equal to or greater than zero. Lipids with n = 0 are referred to as "non-polar lipids", while lipids with n>1 are referred to as "polar lipids". In one embodiment, the lipids that can form the lipids in the liposomes provided herein are selected from the group consisting of: glycerides, glycerophospholipids, sulfur lipids, sphingolipids, phospholipids, isoprenolides, steroids, stearins, sterols, and carbohydrates-containing lipids.

[0085] Virus-like particles (VLPs) are multimers of VSPs (e.g., VCPs and / or VEPs) that do not contain polynucleotides but otherwise have viral characteristics, such as binding to cell surface receptors, internalizing with the receptor, being stable in the blood, and / or containing glycoproteins, etc. VLPs are generally assembled from multimers of VCPs and / or VEPs, especially VCPs. VLPs are known in the art and are produced from a variety of viruses, including Parvoviridae (e.g., adeno-associated virus), Retroviridae (e.g., HIV), Flaviviridae (e.g., hepatitis C virus), and bacteriophages (e.g., QP, AP205).

[0086] It should be noted that if there is a difference between the depicted structure and the name of the structure, more consideration is given to the depicted structure.

[0087] Compound

[0088] In one embodiment, the present disclosure provides a compound of formula (I):

[0089]

[0090] or a stereoisomer, mixture of stereoisomers, tautomer, or pharmaceutically acceptable salt thereof, wherein:

[0091] X is O, S, or NH;

[0092] Each Y is independently -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H2, -OPO3H2, or

[0093] L 1 is an optionally substituted C1-C6 alkylene group, wherein one or two -CH2- groups in the alkylene group are independently optionally replaced by: -NHC(=O)-*, -C(=O)NH-*, -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, or -NH-, where * refers to the direction towards the Y adjacent to L 1 adjacent;

[0094] L 2 is an optionally substituted C1-C6 alkylene, wherein one or two -CH2- in the alkylene are independently optionally replaced by: -O-, -S-, C3-C6 cycloalkylene, C3-C6 cycloalkenylene or a 3- to 6-membered heteroalkylene;

[0095] L 3 is -(C=O)-NR 1 -*, -NR 1 -(C=O)-*, -C(=O)-, -O-, -S-, -S-S-, -S-CH2-S-, -S(=O)-, -S(O)2-, NR 1 -, -NR 1 -(C=O)-NR 1 -, -C(=O)-NR 1 -C(=O)-, -OC(=O)-NR 1 -*, -NR 1 C(=O)O-*, -OC(=S)-NR 1 -*, -NR 1 C(=S)O-*, -(C=O)-(a 3- to 10-membered optionally substituted N-containing ring)-* or -(a 3- to 10-membered optionally substituted N-containing ring)-(C=O)-*, where * refers to the direction towards L 2 ;

[0096] L 4 is an optionally substituted C1-C6 alkylene;

[0097] G 1 is absent, -O-, -S-, -NR 4 -, -NR 4 -(C=O)-*, -(C=O)-NR 4 -*, or an optionally substituted C2-C6 alkylene, wherein one or more -CH2- in the alkylene are independently replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 4 -, -(C=O)-NR 4 -*, or -NR 4 -(C=O)-*, where * refers to the direction towards L 4 ;

[0098] G 2 and G 3 each independently is absent, -O-, -S-, -NR 1 -, -NR1 -(C=O)-*, -(C=O)-NR 1 -*, -NR 1 -(C=S)-* or an optionally substituted C1-C6 alkylene, wherein one or more -CH2- in said alkylene are independently optionally replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 1 、-(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards G 1 of;

[0099] R 4 is H or an optionally substituted C1-C6 alkyl; or R 4 and G 2 the NR 1 together with an intervening atom form a 5- to 12-membered heterocyclic ring;

[0100] P 1 is absent, NR 8 、C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C 14 cycloalkyl or 5- to 14-membered heterocyclic; wherein said aryl, heteroaryl, cycloalkyl and heterocyclic are independently optionally substituted;

[0101] R 8 is independently H or an optionally substituted C1-C6 alkyl;

[0102] Ring W is a 5- to 10-membered heteroaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl or 5- to 14-membered heterocyclic;

[0103] Ring A is a C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C 14 cycloalkyl or 5- to 14-membered heterocyclic;

[0104] Each R 1 is independently H or an optionally substituted C1-C6 alkyl;

[0105] Each R 2independently OH, halogen, oxo, C1-C6 alkyl, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, wherein each alkyl is independently optionally substituted with one or more OH, oxo or halogen;

[0106] when valence allows, n is an integer from 0 to 6;

[0107] L is absent or a linker; and

[0108] Z is a radioactive moiety, chelator, fluorescent dye, contrast agent, cell growth inhibitor or cytotoxic agent, cytokine, immunomodulatory molecule, amphiphile, nucleic acid, viral structural protein, protein or biotin.

[0109] As described herein, one or more -CH2- in an alkylene group (e.g., L 1 , L 2 , G 1 , G 2 and G 3 ) can optionally be replaced by a ring moiety provided herein. When this group is a C1 alkylene group and -CH2- (i.e., C1 alkylene) is replaced by a ring moiety, this group becomes the ring moiety itself.

[0110] In one embodiment, P 1 is absent. In one embodiment, P 1 is NR 8 . In one embodiment, P 1 is NH. In one embodiment, P 1 is optionally substituted C6-C 10 aryl. In one embodiment, P 1 is optionally substituted 5- to 10-membered heteroaryl. In one embodiment, P 1 is optionally substituted C3-C 14 cycloalkyl. In one embodiment, P 1 is optionally substituted 5- to 14-membered heterocyclic group. In one embodiment, the aryl, heteroaryl, cycloalkyl and heterocyclic groups, and their optional substituents are as described in ring B and R 2 , i.e., P 1 corresponds to ring W optionally substituted with n R 2 as described herein.

[0111] In one embodiment, G 1 is absent. In one embodiment, G 1 is -O-. In one embodiment, G 1is -S-. In one embodiment, G 1 is -NR 4 -. In one embodiment, G 1 is -NH-. In one embodiment, G 1 is an optionally substituted C2-C6 alkylene, wherein one or more -CH2- in the alkylene are independently replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 4 , -(C=O)-NR 4 -* or -NR 4 -(C=O)-*, where * refers to the direction towards L 4 . In one embodiment, the C2-C6 alkylene of G 1 is unsubstituted.

[0112] In one embodiment, the compound is a compound of formula (II-A), (II-B), (II-C) or (II-D):

[0113]

[0114]

[0115] or a stereoisomer, mixture of stereoisomers, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0116] Ring B is a C6-C 10 aryl, 5- to 10-membered heteroaryl, C3-C 14 cycloalkyl or 5- to 14-membered heterocyclic group;

[0117] Each R 2 is independently OH, halogen, oxo, C1-C6 alkyl, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, wherein each alkyl is independently optionally substituted by one or more OH, oxo or halogen; and

[0118] When the valence allows, each n is an integer from 0 to 6.

[0119] In one embodiment, R 8 is H. In one embodiment, R 8 is C1-C6 alkyl. In one embodiment, R 8 is C1-C3 alkyl. In one embodiment, R 8 is methyl. In one embodiment, R 8is ethyl. In one embodiment, the alkyl group in R 8 is unsubstituted. In one embodiment, the alkyl group in R 8 is substituted. In one embodiment, the alkyl group in R 8 is substituted by one or more halogens, oxo groups, hydroxyl groups or C1-C6 alkoxy groups.

[0120] In one embodiment, L 4 is -(CH2) 0-3 CH(R 3 )(CH2) 0-3 -, or R 4 is -(CH2) 1-3 -R 3a wherein R 3 is C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C3-C8 cycloalkyl or -(CH2) 0-3 -R 3a wherein each R 3a is independently C6-C 20 aryl, C3-C 14 cycloalkyl, 3- to 14-membered heterocyclic group or 5- to 20-membered heteroaryl, and wherein the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic group or heteroaryl in R 3 or R 3a is optionally substituted by one or more of the following groups: halogen, OH, C1-C6 alkyl, C6-C 10 aryl, C6-C 10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclic group, C6-C 10 aryloxy, C6-C 10 cycloalkyloxy or 5- to 10-membered heteroaryloxy.

[0121] In one embodiment, ring A is C6-C 10 aryl. In one embodiment, ring A is C6-C8 aryl. In one embodiment, ring A is phenyl. In one embodiment, ring A is naphthyl.

[0122] In one embodiment, ring A is 5- to 10-membered heteroaryl. In one embodiment, ring A is 5- to 8-membered heteroaryl. In one embodiment, ring A is 5-membered heteroaryl. In one embodiment, ring A is 6-membered heteroaryl. In one embodiment, ring A is a 5- or 6-membered heteroaryl containing one or more nitrogen, oxygen or sulfur ring atoms.

[0123] In one embodiment, ring A is C3-C 14Cycloalkyl. In one embodiment, ring A is C3-C 12 Cycloalkyl. In one embodiment, ring A is C5-C 12 Cycloalkyl. In one embodiment, ring A is C3-C8 cycloalkyl. In one embodiment, ring A is C3 cycloalkyl. In one embodiment, ring A is C4 cycloalkyl. In one embodiment, ring A is C5 cycloalkyl. In one embodiment, ring A is C6 cycloalkyl. In one embodiment, ring A is C7 cycloalkyl. In one embodiment, ring A is C8 cycloalkyl. In one embodiment, ring A is C9 cycloalkyl. In one embodiment, ring A is C 10 Cycloalkyl. In one embodiment, ring A is C 11 Cycloalkyl. In one embodiment, ring A is C 12 Cycloalkyl. In one embodiment, ring A is C 13 Cycloalkyl. In one embodiment, ring A is C 14 Cycloalkyl. In one embodiment, the cycloalkyl is a fused, bridged or spiro cycloalkyl. In one embodiment, the cycloalkyl is a monocyclic cycloalkyl.

[0124] In one embodiment, ring A is a fused C6-C 14 Cycloalkyl. In one embodiment, ring A is a fused C6-C 12 Cycloalkyl. In one embodiment, ring A is a fused C6-C 10 Cycloalkyl. In one embodiment, ring A is a bridged C8 cycloalkyl. In one embodiment, ring A is a bridged C5-C 14 Cycloalkyl. In one embodiment, ring A is a bridged C5-C 12 Cycloalkyl. In one embodiment, ring A is a bridged C5-C 10 Cycloalkyl. In one embodiment, ring A is a spiro C6-C 14 Cycloalkyl. In one embodiment, ring A is a spiro C6-C 12 Cycloalkyl. In one embodiment, ring A is a spiro C6-C 10 Cycloalkyl.

[0125] In one embodiment, ring A is a monocyclic C3-C8 cycloalkyl. In one embodiment, ring A is cyclopropyl. In one embodiment, ring A is cyclobutyl. In one embodiment, ring A is cyclopentyl. In one embodiment, ring A is cyclohexyl.

[0126] In one embodiment, ring A is a 5- to 14-membered heterocyclic group. In one embodiment, ring A is a 5- to 12-membered heterocyclic group. In one embodiment, ring A is a 5- to 10-membered heterocyclic group. In one embodiment, ring A is a 5-membered heterocyclic group. In one embodiment, ring A is a 6-membered heterocyclic group. In one embodiment, ring A is a 7-membered heterocyclic group. In one embodiment, ring A is an 8-membered heterocyclic group. In one embodiment, ring A is a 9-membered heterocyclic group. In one embodiment, ring A is a 10-membered heterocyclic group. In one embodiment, ring A is an 11-membered heterocyclic group. In one embodiment, ring A is a 12-membered heterocyclic group. In one embodiment, ring A is a 13-membered heterocyclic group. In one embodiment, ring A is a 14-membered heterocyclic group. In one embodiment, ring A is a 5- to 14-membered N-containing heterocyclic group. In one embodiment, ring A is a 5- to 10-membered N-containing heterocyclic group. In one embodiment, the heterocyclic group is a fused, bridged or spiro heterocyclic group. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group.

[0127] In one embodiment, ring A is a fused, bridged or spiro C5-C 12 cycloalkyl group. In one embodiment, ring A is a fused, bridged or spiro 5- to 12-membered heterocyclic group. In one embodiment, ring A is a fused C 10 aryl group. In one embodiment, ring A is a fused 9- or 10-membered heteroaryl group.

[0128] In one embodiment, ring A is a fused 6- to 14-membered heterocyclic group. In one embodiment, ring A is a fused 6- to 12-membered heterocyclic group. In one embodiment, ring A is a fused 6- to 10-membered heterocyclic group. In one embodiment, ring A is a bridged 5- to 14-membered heterocyclic group. In one embodiment, ring A is a bridged 5- to 12-membered heterocyclic group. In one embodiment, ring A is a bridged 5- to 10-membered heterocyclic group. In one embodiment, ring A is a spiro 6- to 14-membered heterocyclic group. In one embodiment, ring A is a spiro 6- to 12-membered heterocyclic group. In one embodiment, ring A is a spiro 6- to 10-membered heterocyclic group.

[0129] In one embodiment, ring A is a monocyclic 3- to 8-membered heterocyclic group. In one embodiment, ring A is a monocyclic 3- to 8-membered nitrogen-containing heterocyclic group. In one embodiment, ring A is a monocyclic 3- to 6-membered heterocyclic group. In one embodiment, ring A is a monocyclic 5- or 6-membered nitrogen-containing heterocyclic group.

[0130] In one embodiment, ring A is where the connection to the left is in the direction towards Z.

[0131] In one embodiment, ring A is cyclohexyl. In one embodiment, ring A is azetidinyl. In one embodiment, ring A is pyrrolidinyl. In one embodiment, ring A is piperidinyl. In one embodiment, ring A is azepanyl. In one embodiment, ring A is azocanyl. In one embodiment, ring A is piperazinyl. In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In one embodiment, ring A is In these embodiments, the connection to the left is in the direction of Z.

[0132] In one embodiment, L 1 is a C1-C6 alkylene. In one embodiment, L 1 is methylene. In one embodiment, L 1 is ethylene. In one embodiment, L 1 is a C3 alkylene. In one embodiment, L 1 is a C4 alkylene. In one embodiment, L 1 is a C5 alkylene. In one embodiment, L 1 is a C6 alkylene. In one embodiment, L 1 is an unsubstituted C1-C6 alkylene. In one embodiment, L 1 is a C1-C6 alkylene substituted with one or more halogens, oxo groups, hydroxyl groups or C1-C6 alkoxy groups. In one embodiment, L 1 is a C1-C6 alkylene substituted with one or more halogens (e.g., substituted with one or more F).

[0133] In one embodiment, L 1 is a C1-C6 alkylene, wherein one or two -CH2- in the alkylene are independently optionally replaced by: -NHC(=O)-*, -C(=O)NH-*, -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-* or -NH-, where * refers to the direction towards Y adjacent to L 1 In one embodiment, L 1 is a C1-C6 alkylene, and wherein L 1One of the -CH2- in it is replaced by the following: -NHC(=O)-*, -C(=O)NH-*, -O-, -S-, -S(=O)2- or -S(=O)-, where * refers to the direction towards Y adjacent to L 1 In one embodiment, L 1 is a C1-C6 alkylene group, and one of the -CH2- in L 1 is replaced by -NHC(=O)-*, where * refers to the direction towards Y adjacent to L 1 the direction.

[0134] In one embodiment, L 1 is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-NHC(=O)-, -CH2CH2-NHC(=O)-, -CH2CH2CH2-NHC(=O)-, -CH(OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2-, -CH(OH)CH2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -CH2OCH2-, -CH2SCH2-, -CH(OH)CH2CH2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-O-C(CH3)2-, -CH2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-S-C(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2-, -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -C(=O)NH-CH2-, -NHC(=O)-CH2CH2-, -C(=O)NH-CH(CH3)-, -NHC(=O)-CH2CH2CH2- or -C(=O)NH-C(CH3)2-.

[0135] In one embodiment, L 1 is -CH2CH2-. In one embodiment, L 1is -CH2CH2CH2-. In one embodiment, L 1 is -CH2CH2-NHC(=O)-. In one embodiment, L 1 is -CH2-NHC(=O)-.

[0136] In one embodiment, L 2 is a C1-C6 alkylene group. In one embodiment, L 2 is a straight-chain C1-C6 alkylene group. In one embodiment, L 2 is a methylene group. In one embodiment, L 2 is an ethylene group. In one embodiment, L 2 is a C3 alkylene group. In one embodiment, L 2 is a C4 alkylene group. In one embodiment, L 2 is -CH2CH2CH2CH2-. In one embodiment, L 2 is a C5 alkylene group. In one embodiment, L 2 is a C6 alkylene group. In one embodiment, L 2 is a straight-chain C1-C6 alkylene group. In one embodiment, L 2 is an unsubstituted C1-C6 alkylene group. In one embodiment, L 2 is a C1-C6 alkylene group substituted with one or more halogens, oxo groups, hydroxyl groups, or C1-C6 alkoxy groups.

[0137] In one embodiment, L 2 is a C1-C6 alkylene group, wherein one or two -CH2- in the alkylene group are replaced by -O-. In one embodiment, one or two -CH2- in the alkylene group (L 2 ) are replaced by -S-. In one embodiment, one -CH2- in the alkylene group (L 2 ) is replaced by a C3-C6 cycloalkylene group. In one embodiment, one -CH2- in the alkylene group (L 2 ) is replaced by a C3-C6 cycloalkenylene group. In one embodiment, one -CH2- in the alkylene group (L 2 ) is replaced by a 3- to 6-membered heteroalkylene group.

[0138] In one embodiment, L 3 is -(C=O)-NR 1 -*. In one embodiment, L 3 is -(C=O)-NH-*. In one embodiment, L 3 is -NR 1 -(C=O)-*. In one embodiment, L 3is -NH-(C=O)-*. In one embodiment, L 3 is -C(=O)-. In one embodiment, L 3 is -O-. In one embodiment, L 3 is -S-. In one embodiment, L 3 is -S-S-. In one embodiment, L 3 is -S-CH2-S-. In one embodiment, L 3 is -S(=O)-. In one embodiment, L 3 is -S(O)2-. In one embodiment, L 3 is NR 1 . In one embodiment, L 3 is NH. In one embodiment, L 3 is -NR 1 -(C=O)-NR 1 . In one embodiment, L 3 is -C(=O)-NR 1 -C(=O)-. In one embodiment, L 3 is -OC(=O)-NR 1 -*. In one embodiment, L 3 is -NR 1 C(=O)O-*. In one embodiment, L 3 is -OC(=S)-NR 1 -*. In one embodiment, L 3 is -NR 1 C(=S)O-*. In one embodiment, L 3 is In one embodiment, L 3 is In one embodiment, L 3 is -(C=O)-(3 - to 10 - membered optionally substituted N - containing ring)-*. In one embodiment, L 3 is -(C=O)-(3 - to 8 - membered optionally substituted N - containing ring)-*. In one embodiment, L 3 is -(C=O)-(5 - or 6 - membered optionally substituted N - containing ring)-*. In one embodiment, L 3 is -(3 - to 10 - membered optionally substituted N - containing ring)-(C=O)-*. In one embodiment, L 3 is -(3 - to 8 - membered optionally substituted N - containing ring)-(C=O)-*. In one embodiment, L 3is -(5- or 6-membered optionally substituted N-containing ring)-(C=O)-*. In these embodiments, * refers to the direction towards L 2 The direction of.

[0139] In one embodiment, L 4 is -(CH2) 0-3 CH(R 3 )(CH2) 0-3 -. In one embodiment, L 4 is -(CH2) 0-3 CH(R 3 )(CH2) 0-3 -, where R 3 is C1-C 20 alkyl, C2-C 20 alkenyl, C2-C 20 alkynyl, C3-C8 cycloalkyl or -(CH2) 0-3 -R 3a , where R 3a is C6-C 20 aryl, C3-C 14 cycloalkyl, 3- to 14-membered heterocyclic group or 5- to 20-membered heteroaryl, and where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic group or heteroaryl in R 3 or R 3a is optionally substituted by one or more of the following groups: halogen, OH, C1-C6 alkyl, C6-C 10 aryl, C6-C 10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclic group, C6-C 10 aryloxy, C6-C 10 cycloalkyloxy or 5- to 10-membered heteroaryloxy. In one embodiment, L 4 is -(CH2) 0-3 CH(CH2R 3a )(CH2) 0-3 -. In one embodiment, L 4 is -CH(R 3 )-. In one embodiment, L 4 is -CH(R 3 )-, and R 3 is -(CH2) 0-3 -R 3a . In one embodiment, L 4 is -CH(R 3 )-, and R 3 is -(CH2) 1-3 -R 3a . In one embodiment, L 4is -CH(R 3 )-, and R 3 is -CH2-R 3a .

[0140] In one embodiment, L 4 is a C1-C6 alkylene group. In one embodiment, L 4 is a methylene group. In one embodiment, L 4 is an ethylene group. In one embodiment, L 4 is a C3 alkylene group. In one embodiment, L 4 is a C4 alkylene group. In one embodiment, L 4 is a C5 alkylene group. In one embodiment, L 4 is a C6 alkylene group. In one embodiment, L 4 is an unsubstituted C1-C6 alkylene group.

[0141] In one embodiment, R 1 is H. In one embodiment, R 1 is a C1-C6 alkyl group. In one embodiment, R 1 is a C1-C3 alkyl group. In one embodiment, R 1 is a methyl group. In one embodiment, R 1 is an ethyl group. In one embodiment, the alkyl group in R 1 is unsubstituted. In one embodiment, the alkyl group in R 1 is substituted. In one embodiment, R 1 is a C1-C6 alkyl group optionally substituted by one or more of the following groups: OH, halogen, oxo group, In one embodiment, R 1 is

[0142] In one embodiment, each R 2 is independently OH, halogen, oxo group, C1-C6 alkyl group, -O-(C1-C6 alkyl group), -S-(C1-C6 alkyl group), -NH2, -NH-(C1-C6 alkyl group) or -N(C1-C6 alkyl group)2, and each of the C1-C6 alkyl groups is independently and optionally substituted by one or more OH, oxo group or halo groups. In one embodiment, each R 2 is independently OH, oxo group, halogen, -NH2 or C1-C6 alkyl group.

[0143] In one embodiment, n is 0 (i.e., R 2is non-existent). In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5. In one embodiment, n is 6. In one embodiment, when there is more than one n, each n is independent, that is, each of them can be the same or different. In one embodiment, each n is independently 0, 1 or 2.

[0144] In one embodiment, R 3 is C1-C 20 alkyl. In one embodiment, R 3 is C1-C 16 alkyl. In one embodiment, R 3 is C1-C 12 alkyl. In one embodiment, R 3 is C1-C6 alkyl.

[0145] In one embodiment, R 3 is C2-C 20 alkenyl. In one embodiment, R 3 is C2-C 16 alkenyl. In one embodiment, R 3 is C2-C 12 alkenyl. In one embodiment, R 3 is C2-C6 alkenyl.

[0146] In one embodiment, R 3 is C2-C 20 alkynyl. In one embodiment, R 3 is C2-C 16 alkynyl. In one embodiment, R 3 is C2-C 12 alkynyl. In one embodiment, R 3 is C2-C6 alkynyl.

[0147] In one embodiment, R 3 is C3-C8 cycloalkyl. In one embodiment, R 3 is C 3-6 cycloalkyl. In one embodiment, R 3 is cyclopropyl. In one embodiment, R 3 is cyclobutyl. In one embodiment, R 3 is cyclopentyl. In one embodiment, R 3 is cyclohexyl.

[0148] In one embodiment, R 3 is -(CH2) 0-3 -R3a 。In one embodiment, R 3 is -(CH2) 1-3 -R 3a 。In one embodiment, R 3 is -CH2R 3a 。In one embodiment, R 3 is -CH2CH2R 3a 。In one embodiment, R 3 is -CH2CH2CH2R 3a 。In one embodiment, R 3 is -(C2-C6 alkenyl)-R 3a 。In one embodiment, R 3 is (Z)-CH2-CH=CH-R 3a 。In one embodiment, R 3 is (E)-CH2-CH=CH-R 3a 。

[0149] In one embodiment, R 3a is C6-C 20 aryl. In one embodiment, R 3a is C6-C 18 aryl. In one embodiment, R 3a is C6 aryl. In one embodiment, R 3a is C 10 aryl. In one embodiment, R 3a is C 14 aryl. In one embodiment, R 3a is C 18 aryl. In one embodiment, R 3a contains one or more phenyl groups. In one embodiment, R 3a is phenyl. In one embodiment, R 3a is pyridyl. In one embodiment, R 3a is biphenyl. In one embodiment, R 3a is bipyridyl. In one embodiment, R 3a is anthryl. In one embodiment, R 3a is acridinyl. In one embodiment, R 3a is acenaphthylenyl. In one embodiment, R 3a is indenyl. In one embodiment, R 3a is phenanthryl. In one embodiment, R 3a is propylene naphthyl. In one embodiment, R 3a is benzophenanthryl. In one embodiment, R 3ais naphthyl. In one embodiment, R 3a is tetracenyl. In one embodiment, R 3a is chrysenyl. In one embodiment, R 3a is pyrenyl.

[0150] In one embodiment, R 3a is C3-C 14 cycloalkyl. In one embodiment, R 3a is C3-C 10 cycloalkyl. In one embodiment, R 3a is C3-C6 cycloalkyl. In one embodiment, R 3a is C3 cycloalkyl. In one embodiment, R 3a is C4 cycloalkyl. In one embodiment, R 3a is C5 cycloalkyl. In one embodiment, R 3a is C6 cycloalkyl. In one embodiment, R 3a is C7 cycloalkyl. In one embodiment, R 3a is C8 cycloalkyl. In one embodiment, the cycloalkyl is a fused, bridged or spiro cycloalkyl. In one embodiment, the cycloalkyl is a monocyclic cycloalkyl.

[0151] In one embodiment, R 3a is a 3- to 14-membered heterocyclic group. In one embodiment, R 3a is a 5- to 14-membered heterocyclic group. In one embodiment, R 3a is a 5- to 12-membered heterocyclic group. In one embodiment, R 3a is a 5- to 10-membered heterocyclic group. In one embodiment, R 3a is a 5-membered heterocyclic group. In one embodiment, R 3a is a 6-membered heterocyclic group. In one embodiment, R 3a is a 7-membered heterocyclic group. In one embodiment, R 3a is an 8-membered heterocyclic group. In one embodiment, R 3a is a 9-membered heterocyclic group. In one embodiment, R 3a is a 10-membered heterocyclic group. In one embodiment, R 3a is an 11-membered heterocyclic group. In one embodiment, R 3a is a 12-membered heterocyclic group. In one embodiment, R 3a is a 13-membered heterocyclic group. In one embodiment, R 3a is a 14-membered heterocyclic group. In one embodiment, R 3ais an N-containing heterocyclic group having 5 to 14 members. In one embodiment, R 3a is an N-containing heterocyclic group having 5 to 10 members. In one embodiment, the heterocyclic group is a fused, bridged or spiro heterocyclic group. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group.

[0152] In one embodiment, R 3a is a heteroaryl having 5 to 20 members. In one embodiment, R 3a is a heteroaryl having 5 to 18 members. In one embodiment, R 3a is a heteroaryl having 5 to 12 members. In one embodiment, R 3a is a heteroaryl having 5 to 8 members. In one embodiment, R 3a is a 5-membered heteroaryl. In one embodiment, R 3a is a 6-membered heteroaryl. In one embodiment, R 3a is a 9-membered heteroaryl. In one embodiment, R 3a is a 10-membered heteroaryl. In one embodiment, R 3a is a 14-membered heteroaryl. In one embodiment, R 3a is a 16-membered heteroaryl. In one embodiment, R 3a is a 18-membered heteroaryl. In one embodiment, the heteroaryl contains one or more nitrogen, oxygen or sulfur ring atoms. In one embodiment, the heteroaryl is a fused heteroaryl. In one embodiment, the heteroaryl is a monocyclic heteroaryl. In one embodiment, the heteroaryl contains one or more pyridine rings.

[0153] In one embodiment, R 3a is unsubstituted. In one embodiment, R 3a is substituted. In one embodiment, R 3a is substituted by one or more halogens, OH, C1-C6 alkyl, C6-C 10 aryl, C6-C 10 cycloalkyl, C6-C 10 aryloxy or a 3- to 8-membered heterocyclic group. In one embodiment, R 3a is substituted by one or more C6-C 10 aryl, C6-C 10 cycloalkyl or a 3- to 8-membered heterocyclic group, and wherein each aryl, cycloalkyl and heterocyclic group is independently optionally substituted by one or more halogens, OH or C1-C6 alkyl. In one embodiment, R 3a is substituted by one or more phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl or imidazolyl. In one embodiment, R 3a is substituted by one or more halogens, OH or C1-C6 alkyl.

[0154] In one embodiment, R 3a is C6-C 20 aryl, 5- to 20-membered heteroaryl or 3- to 14-membered heterocyclic group, wherein the aryl, heteroaryl and heterocyclic group are optionally substituted by one or more halogen, OH, C1-C6 alkyl, C6-C 10 aryl, C6-C 10 cycloalkyl, C6-C 10 aryloxy or 3- to 8-membered heterocyclic group. In one embodiment, R 3a is phenyl, pyridyl, biphenyl, bipyridyl, anthryl, acridinyl, acenaphthylenyl, indenyl, phenanthryl, propylene naphthyl, benzophenanthryl, naphthyl, condensed tetraphenyl, yl or pyrenyl, wherein R 3a is optionally substituted by one or more halogen, OH or C1-C6 alkyl.

[0155] In one embodiment, R 3a is

[0156] In one embodiment, R 3a is In one embodiment, R 3a is

[0157] In one embodiment, R 4 is H. In one embodiment, R 4 is C1-C6 alkyl. In one embodiment, R 4 is methyl. In one embodiment, R 4 is ethyl. In one embodiment, R 4 is C3 alkyl. In one embodiment, R 4 is C4 alkyl. In one embodiment, R 4 is C5 alkyl. In one embodiment, R 4 is C6 alkyl. In one embodiment, the alkyl in R 4 is unsubstituted. In one embodiment, the alkyl in R 4 is substituted. In one embodiment, the alkyl in R 4 is substituted by R 3a In one embodiment, R 4 is -(CH2) 1-3 -R 3a In one embodiment, R 4 is -CH2-R 3a In one embodiment, R 4 is -CH2CH2-R3a .

[0158] In one embodiment, R 4 and G 2 's NR 1 together with the intervening atom form a 5- to 12-membered heterocyclic group ring. In one embodiment, R 4 and G 2 's NR 1 together with the intervening atom form a 5- to 8-membered heterocyclic group ring. In one embodiment, The moiety is

[0159] In one embodiment, the compound is a compound of formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F) or (III-G):

[0160]

[0161]

[0162] or a stereoisomer, mixture of stereoisomers, tautomer or pharmaceutically acceptable salt thereof, wherein:

[0163] R 3a is C6-C 20 aryl, C3-C 14 cycloalkyl, 3- to 14-membered heterocyclic group or 5- to 20-membered heteroaryl, and wherein R 3 or R 3a 's alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclic group or heteroaryl is optionally substituted with one or more of the following groups: halogen, OH, C1-C6 alkyl, C6-C 10 aryl, C6-C 10 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclic group, C6-C 10 aryloxy, C6-C 10 cycloalkyloxy or 5- to 10-membered heteroaryloxy.

[0164] In one embodiment, the carbon atom connected to -CH2R 3a has an S-configuration. In one embodiment, the carbon atom connected to -CH2R 3a has an R-configuration.

[0165] In one embodiment, the compound is a compound of formula (III-A'), (III-B'), (III-C'), (III-D'), (III-E'), (III-F') or (III-G'):

[0166]

[0167]

[0168] or a tautomer or a pharmaceutically acceptable salt thereof.

[0169] In one embodiment, X is O. In one embodiment, X is S. In one embodiment, X is NH.

[0170] In one embodiment, Y is -CO2H. In one embodiment, Y is -SO2H. In one embodiment, Y is -SO3H. In one embodiment, Y is -OSO3H. In one embodiment, Y is -PO2H. In one embodiment, Y is -PO3H2. In one embodiment, Y is -OPO3H2. In one embodiment, Y is In one embodiment, all Ys are COOH. In one embodiment, only one Y is COOH. In one embodiment, only two Ys are COOH. In one embodiment, each of the Ys is different.

[0171] In one embodiment, when the carbon connected to Y is a chiral center, it has an S-configuration. In one embodiment, when the carbon connected to Y is a chiral center, it has an R-configuration. In one embodiment, the carbon connected to -Y and -L 2 has an S-configuration. In one embodiment, the carbon connected to -Y and -L 1 -Y has an S-configuration.

[0172] In one embodiment, the compound is a compound of formula (IV-A1), (IV-A2), (IV-B1), (IV-B2), (IV-C1) or (IV-C2):

[0173]

[0174] or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein a and b are each independently an integer from 1 to 5.

[0175] In one embodiment, the compound is a compound of formula (IV-A1′), (IV-A2′), (IV-B1′), (IV-B2′), (IV-1l′) or (IV-C2′):

[0176]

[0177] or a tautomer or a pharmaceutically acceptable salt thereof, wherein a and b are each independently an integer from 1 to 5.

[0178] In one embodiment, a is 1. In one embodiment, a is 2. In one embodiment, a is 3. In one embodiment, a is 4. In one embodiment, a is 5. In one embodiment, b is 1. In one embodiment, b is 2. In one embodiment, b is 3. In one embodiment, b is 4. In one embodiment, b is 5.

[0179] In one embodiment, ring B is a 5- to 10-membered heteroaryl. In one embodiment, ring B is a 5- to 8-membered heteroaryl. In one embodiment, ring B is a 5- or 6-membered heteroaryl. In one embodiment, ring B is a 5- or 6-membered heteroaryl containing one or more N, O, or S atoms on the ring. In one embodiment, ring B is a 5-membered nitrogen-containing heteroaryl. In one embodiment, ring B is a 5-membered sulfur-containing heteroaryl. In one embodiment, ring B is a 5-membered oxygen-containing heteroaryl. In one embodiment, ring B is a 6-membered nitrogen-containing heteroaryl. In one embodiment, ring B is a 6-membered oxygen-containing heteroaryl. In one embodiment, ring B is a 6-membered sulfur-containing heteroaryl.

[0180] In one embodiment, ring B is an oxadiazole ring. In one embodiment, ring B is an oxazole ring. In one embodiment, ring B is an isoxazole ring. In one embodiment, ring B is a triazole ring. In one embodiment, ring B is an imidazole ring. In one embodiment, ring B is a pyrazole ring. In one embodiment, ring B is a pyridine ring. In one embodiment, ring B is a pyrimidine ring. In one embodiment, ring B is a pyrazine ring. In one embodiment, ring B is a pyridazine ring. In one embodiment, ring B is a thiadiazole ring. In one embodiment, ring B is a thiazole ring. In one embodiment, ring B is an isothiazole ring. In one embodiment, ring B is a pyridone ring. In one embodiment, ring B is a pyrazinone ring.

[0181] In one embodiment, ring B is wherein the connection to the left is in the direction of Z.

[0182] In one embodiment, ring B is In one embodiment, ring B is In one embodiment, ring B is In one embodiment, ring B is In one embodiment, ring B is In one embodiment, ring B is In these embodiments, the connection to the left is in the direction of Z.

[0183] In one embodiment, Ring B is C6-C 10 aryl. In one embodiment, Ring B is phenyl.

[0184] In one embodiment, Ring B is C3-C 14 cycloalkyl. In one embodiment, Ring B is C3-C 10 cycloalkyl. In one embodiment, Ring B is C3-C6 cycloalkyl. In one embodiment, Ring B is cyclopropyl. In one embodiment, Ring B is cyclobutyl. In one embodiment, Ring B is cyclopentyl. In one embodiment, Ring B is cyclohexyl. In one embodiment, the cycloalkyl is a fused, bridged or spiro cycloalkyl. In one embodiment, the cycloalkyl is a monocyclic cycloalkyl.

[0185] In one embodiment, Ring B is a 3- to 14-membered heterocyclic group. In one embodiment, Ring B is a 5- to 14-membered heterocyclic group. In one embodiment, Ring B is a 5- to 12-membered heterocyclic group. In one embodiment, Ring B is a 5- to 10-membered heterocyclic group. In one embodiment, Ring B is a 3-membered heterocyclic group. In one embodiment, Ring B is a 4-membered heterocyclic group (e.g., azetidinyl). In one embodiment, Ring B is a 5-membered heterocyclic group (e.g., pyrrolidinyl). In one embodiment, Ring B is a 6-membered heterocyclic group (e.g., piperidinyl). In one embodiment, Ring B is a 7-membered heterocyclic group. In one embodiment, Ring B is an 8-membered heterocyclic group. In one embodiment, the heterocyclic group is an N-containing heterocyclic group. In one embodiment, the heterocyclic group is a fused, bridged or spiro heterocyclic group. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group.

[0186] In one embodiment, G 2 is absent. In one embodiment, G 2 is -O-. In one embodiment, G 2 is -S-. In one embodiment, G 2 is NR 1 . In one embodiment, G 2 is -NR 1 -(C=O)-*. In one embodiment, G 2 is -(C=O)-NR 1 -*. In one embodiment, G 2 is NH. In one embodiment, G 2 is -NHC(=O)-*. In one embodiment, G 2 is -(C=O)-NH-*. In one embodiment, G 2 is -NR 1 -(C=S)-*. In these embodiments, * refers to the direction towards NR4 direction.

[0187] In one embodiment, G 2 is a C1-C6 alkylene group. In one embodiment, G 2 is a methylene group. In one embodiment, G 2 is an ethylene group. In one embodiment, G 2 is a C3 alkylene group. In one embodiment, G 2 is a C4 alkylene group. In one embodiment, G 2 is a C5 alkylene group. In one embodiment, G 2 is a C6 alkylene group. In one embodiment, G 2 is an unsubstituted C1-C6 alkylene group. In one embodiment, G 2 is a C1-C6 alkylene group substituted with one or more halogens, oxo groups, hydroxy groups or C1-C6 alkoxy groups.

[0188] In one embodiment, G 2 is a C1-C6 alkylene group, wherein one or two -CH2- in the alkylene group are independently replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 1 , -(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 . In one embodiment, G 2 is a C1-C3 alkylene group, wherein one of the -CH2- in the alkylene group is independently replaced by: -O-, -S-, NR 1 , -(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 . In one embodiment, G 2 is a C1-C3 alkylene group, wherein one of the -CH2- in the alkylene group is replaced by: NH, -C(=O)NH-*, -NHC(=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 .

[0189] In one embodiment, G 2 is absent, -O-, -NH-, -NHC(=O)-*, -NR1 -(C═S)-* or an unsubstituted C1-C6 alkylene, where * refers to the direction towards NR 4 In one embodiment, G 2 is C1-C6 alkylene, where one or both of the -CH2- in G 2 are replaced by: -O-, -S-, -S(═O)2-, -S(═O)-, -C(═O)-, -C(═O)O-*, -OC(═O)-*, -NH-, -(C═O)-NH-*, -NH-(C═O)-* or -NR 1 -(C═S)-*, where * refers to the direction towards NR 4 In one embodiment, G

[0190] In one embodiment, G 3 is absent. In one embodiment, G 3 is -O-. In one embodiment, G 3 is -S-. In one embodiment, G 3 is NR 1 In one embodiment, G 3 is -NR 1 -(C═O)-*. In one embodiment, G 3 is -(C═O)-NR 1 -*. In one embodiment, G 3 is NH. In one embodiment, G 3 is -NHC(═O)-*. In one embodiment, G 3 is -(C═O)-NH-*. In one embodiment, G 3 is -NR 1 -(C═S)-*. In these embodiments, * refers to the direction towards NR 4 In one embodiment, G

[0191] In one embodiment, G 3 is C1-C6 alkylene. In one embodiment, G 3 is methylene. In one embodiment, G 3 is ethylene. In one embodiment, G 3 is C3 alkylene. In one embodiment, G 3 is C4 alkylene. In one embodiment, G 3 is C5 alkylene. In one embodiment, G 3 is C6 alkylene. In one embodiment, G 3 is unsubstituted C1-C6 alkylene. In one embodiment, G 3is a C1-C6 alkylene group substituted by one or more halogens, oxo groups, hydroxyl groups or C1-C6 alkoxy groups. In one embodiment, G 3 is -CH2-. In one embodiment, G 3 is -CH2CH2-. In one embodiment, G 3 is -CH2CH2CH2-.

[0192] In one embodiment, G 3 is a C1-C6 alkylene group, wherein one or two -CH2- in the alkylene group are independently replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 1 , -(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 In one embodiment, G 3 is a C1-C3 alkylene group, wherein one of the -CH2- in the alkylene group is independently replaced by: -O-, -S-, NR 1 , -(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 In one embodiment, G 3 is a C1-C3 alkylene group, wherein one of the -CH2- in the alkylene group is replaced by: NH, -C(=O)NH-*, -NHC(=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 In one embodiment, G

[0193] In one embodiment, G 3 is absent, -O-, -NH-, -NHC(=O)-*, -NR 1 -(C=S)-* or an unsubstituted C1-C6 alkylene group, where * refers to the direction towards NR 4 In one embodiment, G 3 is a C1-C6 alkylene group, wherein G 3One or both of the -CH2- are replaced by the following: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -NH-, -(C=O)-NH-*, -NH-(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards NR 4 direction.

[0194] In one embodiment, ring B is phenyl and G 3 is -NR 1 -(C=S)-*. In one embodiment, (ring B)-G 3 is

[0195] In one embodiment, G 2 and G 3 are both absent.

[0196] In one embodiment, ring W is a 5- to 10-membered heteroaryl. In one embodiment, ring W is a 5- to 8-membered heteroaryl. In one embodiment, ring W is a 5- or 6-membered heteroaryl. In one embodiment, ring W is a 5- or 6-membered heteroaryl containing one or more N, O or S atoms on the ring. In one embodiment, ring W is a 5-membered nitrogen-containing heteroaryl. In one embodiment, ring W is a 5-membered sulfur-containing heteroaryl. In one embodiment, ring W is a 5-membered oxygen-containing heteroaryl. In one embodiment, ring W is a 6-membered nitrogen-containing heteroaryl. In one embodiment, ring W is a 6-membered oxygen-containing heteroaryl. In one embodiment, ring W is a 6-membered sulfur-containing heteroaryl.

[0197] In one embodiment, ring W is an oxadiazole ring. In one embodiment, ring W is an oxazole ring. In one embodiment, ring W is an isoxazole ring. In one embodiment, ring W is a triazole ring. In one embodiment, ring W is an imidazole ring. In one embodiment, ring W is a pyrazole ring. In one embodiment, ring W is a pyridine ring. In one embodiment, ring W is a pyrimidine ring. In one embodiment, ring W is a pyrazine ring. In one embodiment, ring W is a pyridazine ring. In one embodiment, ring W is a thiadiazole ring. In one embodiment, ring W is a thiazole ring. In one embodiment, ring W is an isothiazole ring. In one embodiment, ring W is a pyridone ring. In one embodiment, ring W is a pyrazinone ring.

[0198] In one embodiment, ring W is where the connection to the left is in the direction towards Z.

[0199] In one embodiment, ring W is a C3-C8 cycloalkyl group. In one embodiment, ring W is a C3-C6 cycloalkyl group. In one embodiment, ring W is a cyclopropyl group. In one embodiment, ring W is a cyclobutyl group. In one embodiment, ring W is a cyclopentyl group. In one embodiment, ring W is a cyclohexyl group.

[0200] In one embodiment, ring W is a C3-C8 cycloalkenyl group. In one embodiment, ring W is a C3-C6 cycloalkenyl group. In one embodiment, ring W is a cyclopropene. In one embodiment, ring W is a cyclobutene. In one embodiment, ring W is a cyclopentene. In one embodiment, ring W is a cyclohexene. In one embodiment, ring W is

[0201] In one embodiment, ring W is a 5- to 14-membered heterocyclic group. In one embodiment, ring W is a 5- to 12-membered heterocyclic group. In one embodiment, ring W is a 5- to 10-membered heterocyclic group. In one embodiment, ring W is a 5-membered heterocyclic group. In one embodiment, ring W is a 6-membered heterocyclic group. In one embodiment, ring W is a 7-membered heterocyclic group. In one embodiment, ring W is an 8-membered heterocyclic group. In one embodiment, the heterocyclic group is a nitrogen-containing heterocyclic group. In one embodiment, the heterocyclic group is a fused, bridged or spiro heterocyclic group. In one embodiment, the heterocyclic group is a monocyclic heterocyclic group. In one embodiment, ring W is In one embodiment, ring W is

[0202] In one embodiment, is In one embodiment, is In one embodiment, is In these embodiments, the connection to the left is in the direction of Z.

[0203] In one embodiment, ring W is a C3-C8 cycloalkyl group and ring A is a C3-C 14 cycloalkyl group. In one embodiment, ring W is a C3-C6 cycloalkyl group and ring A is a C3-C 10 cycloalkyl group. In one embodiment, ring W is a C3-C6 cycloalkyl group and ring A is a bridged C5-C 10 cycloalkyl group. In one embodiment, ring W is a C3-C6 cycloalkyl group and ring A is

[0204] In one embodiment, ring W is a C3-C8 cycloalkenyl group and ring A is a C3-C 14Cycloalkyl. In one embodiment, ring W is a C3-C6 cycloalkenyl, and ring A is a C3-C 10 Cycloalkyl. In one embodiment, ring W is a C3-C6 cycloalkenyl, and ring A is a bridged C5-C 10 Cycloalkyl. In one embodiment, ring W is a C3-C6 cycloalkenyl, and ring A is In one embodiment, is and ring A is

[0205] In one embodiment, ring W is a 5- to 10-membered heteroaryl, and ring A is a C3-C 14 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heteroaryl, and ring A is a C3-C 10 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heteroaryl, and ring A is a bridged C5-C 10 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heteroaryl, and ring A is

[0206] In one embodiment, ring W is a 5- to 14-membered heterocyclic group, and ring A is a C3-C 14 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heterocyclic group, and ring A is a C3-C 10 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heterocyclic group, and ring A is a bridged C5-C 10 Cycloalkyl. In one embodiment, ring W is a 5- to 6-membered heterocyclic group, and ring A is

[0207] In one embodiment (of any of the formulas provided herein in which both ring A and ring B are present), ring B is a 5- to 10-membered heteroaryl, and ring A is a C3-C 14 Cycloalkyl. In one embodiment, ring B is a 5- to 6-membered heteroaryl, and ring A is a C3-C 10 Cycloalkyl. In one embodiment, ring B is a 5- to 6-membered heteroaryl, and ring A is a bridged C5-C 10 Cycloalkyl. In one embodiment, ring B is a 5- to 6-membered heteroaryl, and ring A is In one embodiment, at least one of ring A and ring B is not phenyl. In one embodiment, ring B is phenyl, and ring A is In one embodiment, ring B is and ring A is

[0208] In one embodiment, P 1(or ring B, when applicable) is a 5- to 6-membered heteroaryl, ring A is a bridged C5-C 10 cycloalkyl, and ring W is a C3-C6 cycloalkenyl. In one embodiment, P 1 (or ring B, when applicable) is Ring A is and is In one embodiment, P 1 (or NR 8 , when applicable) is NH, ring A is a bridged C5-C 10 cycloalkyl, and ring W is a C3-C6 cycloalkenyl. In one embodiment, P 1 (or NR 8 , when applicable) is NH, ring A is and is

[0209] In one embodiment, L is absent. In one embodiment, L is a linker.

[0210] In one embodiment, L is a C1-C 12 alkylene. In one embodiment, L is a C1-C6 alkylene. In one embodiment, L is a methylene. In one embodiment, L is an ethylene. In one embodiment, L is a C3 alkylene. In one embodiment, L is a C4 alkylene. In one embodiment, L is a C5 alkylene. In one embodiment, L is a C6 alkylene. In one embodiment, L is an unsubstituted C1-C 12 alkylene. In one embodiment, L is a C1-C alkylene substituted with one or more halogens, oxo groups, hydroxyl groups or C1-C6 alkoxy groups 12 alkylene. In one embodiment, L is -(CH2) 1-6 -. In one embodiment, L is -CH2-. In one embodiment, L is -CH2CH2-. In one embodiment, L is -CH2CH2CH2-.

[0211] In one embodiment, L comprises or is a C1-C 12 alkylene, wherein one or more -CH2- in the alkylene are independently replaced by: -NHC(=O)-*, -C(=O)NH-*, -NHC(=S)-*, -C(=S)NH-*, -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-* or -NH-, where * refers to the direction towards P 1The direction. In one embodiment, L comprises an optionally C1-C6 alkylene group, wherein one or more of the -CH2- groups in said alkylene group are independently replaced by: -NHC(=O)-*, -C(=O)NH-*, -NHC(=S)-*, -C(=S)NH-*, -O-, -S or -NH-, where * refers to the direction towards P 1 The direction. In one embodiment, one or more non-terminal -CH2- groups in the alkylene group of L are independently replaced by the groups provided herein. In one embodiment, in addition to or independent of said one or more non-terminal -CH2- groups, the terminal -CH2- group connecting Z and / or the terminal -CH2- group connecting P 1 The terminal -CH2- groups are independently replaced by the groups provided herein.

[0212] In one embodiment, L comprises or is -(CH2) 0-5 -NHC(=O)-(CH2) 0-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -NHC(=O)-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -C(=O)NH-(CH2) 0-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -C(=O)NH-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -O-(CH2) 0-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -O-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -NHC(=S)-(CH2) 0-5 -*. In one embodiment, L comprises or is -(CH2) 0-5 -NHC(=S)-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 1-5 -NHC(=O)-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 1-5 -C(=O)NH-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2)1-5-O-(CH2) 1-5 -*. In one embodiment, L comprises or is -(CH2) 1-5-NHC(=S)-(CH2) 1-5 -*. In these embodiments, * refers to the direction towards P 1 The direction of.

[0213] In one embodiment, L comprises or is a peptide comprising 1 to 5 amino acids. In one embodiment, L comprises or is a peptide comprising 2 to 4 amino acids. In one embodiment, the amino acids are conventional amino acids. In one embodiment, L is a cleavable peptide (e.g., by cathepsin).

[0214] In one embodiment, L is -(CH2) 0-6 -(Xaa 1 ) 1-5 -(CH2) 0-6 -*. In one embodiment, L(L) is -(CH2) 0-6 -(Xaa 1 )1-(CH2) 0-6 -*. In one embodiment, L(L) is -(CH2) 0-6 -(Xaa 1 )2-(CH2) 0-6 -*. In one embodiment, L(L) is -(CH2) 0-6 -(Xaa 1 )3-(CH2) 0-6 -*. In one embodiment, L(L) is -(CH2) 0-6 -(Xaa 1 )4-(CH2) 0-6 -*. In one embodiment, L(L) is -(CH2) 0-6 -(Xaa 1 )5-(CH2) 0-6 -*. In one embodiment, L(L) is -(Xaa 1 ) 1-5 -*. Xaa 1 is an amino acid having the formula -N(R 8 )R 9 C(=O)-*; each R 8 is independently H or optionally substituted C1-C6 alkyl; and each R 9 is independently C1-C 20 alkylene, wherein one or more -CH2- in said alkylene are independently optionally replaced by: C3-C 14 cycloalkylene, C3-C 14 cycloalkenylene, C6-C 10An arylene, a 5- to 14-membered heteroalkylene group, or a 5- to 10-membered heteroarylene group; wherein the alkylene, cycloalkylene, cycloalkenylene, arylene, and heteroarylene groups are each independently optionally substituted; or R 8 and R 9 , or R 8 and R 9 together with the nitrogen to which it is attached forms a 5- to 12-membered optionally substituted heterocyclic group. In these embodiments, * refers to the direction towards P 1 .

[0215] In one embodiment, P 1 is NR 8 , and L is absent. In one embodiment, P 1 is NR 8 , L is absent, and Z is a chelating moiety resulting from the removal of the -OH group from an acid group or its derivative. In one embodiment, P 1 is ring B, and L is -(CH2) 1-6 .

[0216] In one embodiment, the compound is a compound of formula (V-A1), (V-A2), (V-A3), (V-B1), (V-B2), (V-B3), (V-C1), (V-C2), or (V-C3):

[0217]

[0218]

[0219]

[0220] or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 6.

[0221] In one embodiment, the compound is a compound of formula (V-A1′) or formula (V-B1′):

[0222]

[0223] or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

[0224] In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment, p is 2. In one embodiment, p is 3. In one embodiment, p is 4. In one embodiment, p is 5. In one embodiment, p is 6.

[0225] In one embodiment, Z is a radioactive moiety. In one embodiment, the radioactive moiety is a fluorescent isotope, a radioactive isotope, or a radiopharmaceutical. In one embodiment, the radioactive moiety is a radioactive isotope suitable for diagnostic use. In one embodiment, the radioactive moiety is a radioactive isotope suitable for therapeutic use. In one embodiment, the radioactive moiety is a radioactive isotope suitable for medical imaging or radiotherapy. In one embodiment, the radioactive moiety is selected from the group consisting of: isotopes that emit α-radiation, isotopes that emit β-radiation, isotopes that emit γ-radiation, isotopes that emit Auger electrons, isotopes that emit X-rays, and isotopes that emit fluorescence.

[0226] In one embodiment, the radioactive moiety is a complex formed by a radioactive isotope of a metal cation and a chelating agent. In one embodiment, the radioactive moiety is a complex formed by a cation selected from the following and a chelating agent provided herein: 177 Lu, Al 18 F, 203 Pb, 212 Pb, 51 Cr, 67 Ga, 68 Ga, 89 Zr, 111 In, 99m Tc, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 64 Cu, 67 Cu, 188 Re, 186 Re,198 Au, 225 Ac, 227 Th or 199 Ag. In one embodiment, the radioactive moiety is a complex formed by a cation selected from the following and a chelating agent provided herein: 177 Lu, 68 Ga, 90 Y, Al 18 F, 203 Pb, 212 Pb, 64 Cu or 225 Ac. In one embodiment, the radioactive moiety is a complex formed by 177 the cation of Lu and a chelating agent provided herein. In one embodiment, the radioactive moiety is a complex formed by 68 the cation of Ga and a chelating agent provided herein. In one embodiment, the chelating agent is the chelating agent provided in Table 1.

[0227] As used herein and unless otherwise specified, when a chemical name or abbreviation refers to a complete molecule, the chelating agent is the chelating moiety of the complete molecule. In one embodiment, the point of attachment of the chelating moiety is on a chelating atom (e.g., a nitrogen atom). In one embodiment, the point of attachment of the chelating moiety is on a carbon atom from an alkylene group attached to the chelating atom. In one embodiment, the point of attachment of the chelating moiety is on a ring carbon atom from a ring containing the chelating atom (e.g., a ring carbon atom of a pyridine ring).

[0228] In one embodiment, the radioactive moiety is 177 Lu-DOTA, 177 Lu-DOTAGA, 68 Ga-DOTA, 90 Y-DOTA, Al 18 F-NOTA, 2 03 Pb-TCMC, 212 Pb-PSC, 203 Pb-PSC, 212 Pb-TCMC, 64 Cu-DOTA or 225 the metal chelating moiety of Ac-DOTA. In one embodiment, the radioactive moiety is 177 Lu-DOTA. In one embodiment, the radioactive moiety is 177 Lu-DOTAGA. In one embodiment, the radioactive moiety is 68 Ga-DOTA.

[0229] In one embodiment, the radioactive moiety comprises 11 C,18 F, 72 As, 72 Se, 123 I, 124 I, 131 I or 211 At.

[0230] In one embodiment, Z is a fluorescent dye. In one embodiment, the fluorescent dye is xanthene, acridine, oxazine, cyanine, styryl dye, coumarin, porphine, metal-ligand complex, fluorescent protein, nanocrystal, perylene, boron-dipyrromethene or phthalocyanine, or a conjugate or combination thereof.

[0231] In one embodiment, Z is a chelating agent. A wide variety of chelating agents have been reported, such as Banerjee et al. (Banerjee et al., Dalton Trans, 2005, 24: 3886), Price et al. (Chem Soc Rev, 2014, 43: 260), Wadas et al. (Chem Rev, 2010, 110: 2858), and U.S. Patent Nos. 5,367,080, 5,367,080, 5,364,613, 5,021,556, 5,075,099 and 5,886,142, the entire contents of each of which are incorporated herein by reference. In one embodiment, the chelating agent is a linear chelating agent. In one embodiment, the chelating agent is a cyclic agent. In one embodiment, the chelating agent is a macrocyclic chelating agent. In one embodiment, the chelating agent is a nitrogen-containing macrocyclic chelating agent. In one embodiment, the chelating agent is a tetrapyridine chelating agent, an N3S chelating agent, an N2S2 chelating agent or an N4 chelating agent.

[0232] In one embodiment, the chelating agent is capable of binding to a radioactive moiety. In one embodiment, the binding is by ionic, covalent, dipole or ion-dipole interactions. In one embodiment, the chelating agent binds directly to the radioactive moiety. In one embodiment, the chelating agent binds indirectly to the radioactive moiety (e.g., through a linker).

[0233] In one embodiment, the chelating agent comprises one or more amines (e.g., primary, secondary, or tertiary amines). In one embodiment, the chelating agent comprises one or more epoxy atoms. In one embodiment, the chelating agent comprises one or more ring nitrogen atoms. In one embodiment, the chelating agent comprises two ring nitrogen atoms. In one embodiment, the chelating agent comprises three ring nitrogen atoms. In one embodiment, the chelating agent comprises four ring nitrogen atoms. In one embodiment, the chelating agent comprises one or more carboxylic acids. In one embodiment, the chelating agent comprises two carboxylic acids. In one embodiment, the chelating agent comprises three carboxylic acids. In one embodiment, the chelating agent comprises four carboxylic acids. In one embodiment, the chelating agent comprises two or more ring nitrogen atoms and two or more carboxylic acids.

[0234] In one embodiment, the chelating agent is a tetradentate chelating agent. In one embodiment, the chelating agent is a hexadentate chelating agent. In one embodiment, the chelating agent is an octadentate chelating agent. In one embodiment, the chelating agent comprises an optionally substituted 8- to 20-membered nitrogen-containing heterocyclic group.

[0235] In one embodiment, the chelating agent is a chelating agent that forms a complex with a divalent or trivalent metal cation. In one embodiment, the chelating agent is the following (chelating moiety): 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1-(pentanedioic acid)-4,7,10-triacetic acid (DOTAGA), 2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetamide (TCMC), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N′,N′,N″-pentaacetic acid (DTPA), bis-(carboxymethylimidazole)glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC). In one embodiment, the chelating agent is DOTA, NOTA, EDTA, DTPA, TETA, DO3A, PCTA, or desferrioxamine.

[0236] In one embodiment, the chelating agent is the chelating moiety of any of the following: AAZTA, BAT, CDTA, DTA, CyEDTA, EDTMP, DTPMP, CyDTPA, Cy2DTPA, DTPA-MA, DTPA-BA, BOPA, NTA, NOC, NOTP, CY-DTA, DTCBP, CTA, cyclam, CB-Cyclam, cyclen, TETA, sarcophagine, CPTA, TEAMA, Cyclen, DATA, DFO, DATA(M), DATA(P), DATA(Ph), DATA(PPh), DEDPA, H4octapa, H2dedpa, H5decapa, H2azapa, H2CHX-DEDPA, DFO, DFO-Chx-MAL, DFO-p-SCN, DFO-1AC, DFO-BAC, p-SCN-Bn-DFO, DFO-pPhe-NCS, DFO-HOPO, DFC, diphosphine, DOTAGA, DOTA-MFCO, DOTAM, DOTAM-monoacid, DOTA-MA, DOTA-pNB, DOTA-4AMP, nitro-DOTA, nitro-PA-DOTA, p-NCS-Bz-DOTA, PA-DOTA, DOTA-NCS, DOTA-NHS, CB-DO2A, PCTA, p-NH2-Bn-PCTA, p-SCN-Bn-PCTA, p-SCN-Bn-DOTA, DOTMA, NB-DOTA, H4NB-DOTA, H4TCE-DOTA, HOPO, 3,4,3-(Li-1,2-HOPO), TREN(Me-3,2-HOPO), TCE-DOTA, DOTP, DOTMP, DOTEP, DOTMPE, F-DOTPME, DOTPP, DOTBzP, DOTA-monoamide, DOXP, p-NCS-DOTA, p-NCS-PADOTA, p-NCS-TRITA, TRITA, TETA, 3p-C-DEPA, 3p-C-DEPA-NCS, p-NH2-BN-OXO-DO3A, p-SCN-BN-TCMC, TCMC, 4-aminobutyl-DOTA, azido-monoamide-DOTA, BCN-DOTA, butyne-DOTA, BCN-DOTA-GA, DOA3P, DO2a2p, DO2A (trans-H2do2a), DO3A, DO3A-thiol, DO3AtBu-N-(2-aminoethyl)acetamide, DO3TMP-monoamide, DO2AP, CB-DO2A, C3B-DO2A, HP-DO3A, DOTA-NHS-ester, maleimide-DOTA-GA,Maleimido-monoamide-DOTA, maleimido-DOTA, NH2-DOTA-GA, NH2-PEG4-DOTA-GA, GA, p-NH2-Bn-DOTA, p-NO2-Bn-DOTA, p-SCN-Bn-DOTA, p-SCN-Bz-DOTA, TA-DOTA, TA-DOTA-GA, OTTA, DOXP, TSC, FSC, DTC, DTCBP, PTSM, ATSM, H2ATSM, H2PTSM, Dp44mT, DpC, Bp44mT, QT, Hybrid thiosemicarbazone-benzothiazole, Thiosemicarbazone-styryl acridine tetradentate ligand H2L2-4, HBED, HBED-CC, dmHBED, dmEHPG, HBED-un, SHBED, Br-Me2HBED, BPCA, HEHA, BF-HEHA, deferiproue, THP, HYNIC (2-hydrazinonicotinamide), NHS-HYNIC, HYNIC-Kp-DPPB, HYNIC-Ko-DPPB, (HYNIC)(tricine)2, (HYNIC)(EDDA)Cl, p-EDDHA, AIM, AIMA, IAMB, MAMA, MAMA-DGal, MAMA-MGal, MAMA-DA, MAMA-HAD, PSC, macropa, macropaquin, macroquin-SO3, Crown, MAG3B, NODAGA, SCN-Bz-NOTA-R, NOT-P(NOTMP), NOTAM, p-NCS-NOTA, TACN, TACN-TM, NETA, NETA-monoamine, p-SCN-PhPr-NE3TA, C-NE3TA-NCS, C-NETA-NCS, 3p-C-NETA, NODASA, NOPO, NODA, NODA-MPAA, NO2A, N-benzyl-NODA, C-NOTA, BCNOT-monoamine, Maleimido-monoamide-NOTA, NO2A-azide, NO2A-butyne, NO2AP, NO3AP, N-NOTA, oxo-DO3A, p-NH2-Bn-NOTA, p-NH2-Bn-oxo-DO3A, p-NO2-Bn-cyclen, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, TRAP, PEPA, BF-PEPA, pycup, pycup2A, pycup1AlBn, pycup2Bn, SarAr-R, DiAmSar, AmBaSar-R, siamSar, Sar, Tachpyr, tachpyr-(6-Me), TAM A, TAM B, TAME,TAME-Hex, THP-Ph-NCS, THP-NCS, THP-TATE, NTP, H3THP, THPN, CB-TE2A, PCB-TE1A1P, TETA-NHS, CPTA, CPTA-NHS, CB-TE1K1P, CB-TE2A, TE2A, H2CB-TE2A, TE2P, CB-TE2P, MM-TE2A, DM-TE2A, 2C-TETA, 6C-TETA, BAT, BAT-6, NHS-BAT ester, SSBAT, CHX-A″-DTPA, SCN-CHX-A-DTPA-P, SCN-TETA, TMT-amine, p-BZ-HTCPP, H4pyPa, H4octox, p-NO2-Bn-neunpa, p-SCN-Bn-H4neunpa, TTHA, tBu4pypa-C7-NHS, H4heunpa, H2macropa, BT-DO3A, DO3A-Nprop, DO3AP, DOTPMB, DOTAMAE, DOTAMAP, Do3AMBu, DEPA, p-No2-Bn-PCTA, symPC2APA, symPCA2PA, asymPC2APA, asymPCA2PA, 99m Tc(CO)3-chelate, N x S 4-x (N4, N2S2, N3S) or MeO-DOTA-NCS. In one embodiment, the chelate is DOTA, DOTAGA, NOPO, PCTA, NOTA, NODAGA, NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, CHX-A″-DTPA, DFO, Macropa, Crown, DOTAM (also known as TCMC), PSC, HOPO, HEHA, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N x S 4-x (N4, N2S2, N3S), Hynic, 99mTc(CO)3-chelator or its analog. In one embodiment, the chelator is DOTA, DOTAGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA, NODAGA, NODA-MPAA, HBED, CB-TE2A, DFO, THP or N4. In one embodiment, the chelator is DOTA, DOTAGA, NOPO, PCTA, DOTAM, PSC, Macropa, Crown, NOTA or NODAGA. In one embodiment, the chelator is DOTA, NOPO, PCTA, Macropa or Crown.The structures of chelating agents are known in the art and have been reported, for example, in U.S. Patent Nos. 4,885,363, 5,720,934, 5,367,080, 5,364,613, 5,021,556, 5,075,099, and 5,886,142; Li et al., Nucl Med Biol, 2001, 28:145; Eisenwiener et al., Bioconjug Chem, 2002, 13:530; Brechbiel et al., Bioconjug Chem, 1991, 2:187; Price et al., Chem Soc Rev, 2014, 43:260; Schwartz et al., Bioconjug Chem, 1991, 2:333; Nock et al., J Nucl Med, 2005, 46:1727; McAuley et al., Canadian J Chem, 1989, 67:1657; Donlias et al., Free Radic Biol Med, 2003, 35:719; Pfister et al., EJNMMI Res, 2015, 5:74; Cusnir et al., Int J Mol Sci, 2017, 18; Demoin et al., Nucl Med Biol, 2016, 43:802; Thiele et al., Angew Chem Int Ed, 2017, 56:14712; Price et al., Chem Soc Rev, 2014, 43:260; Allott et al., Chem Commun (Camb), 2017, 53:8529; Tomesello et al., Molecules, 2017, 22:1282; Ma et al., Dalton Trans, 2015, 44:4884; Babich et al., J Nucl Med, 1993, 34:1964; Babich et al., Nucl Med Biol, 1995, 22:25; and WO 2022 / 123462, the entire contents of each of the documents cited above are incorporated herein by reference.

[0237] In one embodiment, the chelating agent (Z) has the structure in Table 1.

[0238] Table 1.

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] In one embodiment, Z is In one embodiment, Z is In one embodiment, Z-L-P 1 -G 3 (or a subformula thereof) is In one embodiment, Z-L-P 1 -G 3 (or a subformula thereof) is

[0245] In one embodiment, Z is a contrast agent. In one embodiment, the contrast agent comprises a paramagnetic agent. In one embodiment, the paramagnetic agent comprises paramagnetic nanoparticles.

[0246] In one embodiment, Z is a cell growth inhibitor and / or a cytotoxic agent. In one embodiment, the cell growth inhibitor and / or cytotoxic agent is selected from the group consisting of: alkylating agents, antimetabolites, antibiotics, epothilones, nuclear receptor agonists and antagonists, antiandrogens, antiestrogens, platinum compounds, hormones and antihormones, inhibitors of interferons and cell cycle-dependent protein kinases (CDKs), inhibitors of cyclooxygenase and / or lipoxygenase, biological fatty acids and fatty acid derivatives (including prostaglandins and leukotrienes), inhibitors of protein kinases, inhibitors of protein phosphatases, inhibitors of lipid kinases, platinum coordination complexes, ethylenimines, methylmelamines, triazines, vinca alkaloids, pyrimidine analogs, purine analogs, alkyl sulfonates, folic acid analogs, anthracendiones, substituted ureas, methylhydrazine derivatives such as acediasulfone, aclarubicine, α-amanitin, ambazone, aminoglutethimide, L-asparaginase, monomethyl auristatin E, azathioprine, bleomycin, busulfan, calcium folinate, carboplatin, capecitabine, carmustine, celecoxib, chlorambucil, cis-platin, cladribine, cyclophosphamide, cytarabine, dacarbazine, actinomycin d, dapsone, daunorubicin, dibrompropamidine, diethylstilbestrole, docetaxel, dolastatin 10 and 15, doxorubicin, enediynes, epirubicin, epothilone B, epothilone D, estramucin phosphate, estrogen, ethinylestradiole, etoposide, flavopiridol, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, fosfestrol, furazolidone, gemcitabine,Gonadotropin-releasing hormone analogs, hexamethylmelamine, hydroxyurea, hydroxymethylnitrofurantoin, hydroxyprogesterone caproat, hydroxyurea, idarubicin, idoxuridine, ifosfamide, interferon a, irinotecan, leuprolide, lomustine, lurtotecan, mafenide sulfate olamide, methyl bis(chloroethyl)amine, medroxyprogesterone acetate, megestrol acetate, melphalan, mepacrine, mercaptopurine, methotrexate, metronidazole, mitomycin C, mitopodozide, mitotane, mitoxantrone, mithramycin, nalidixic acid, nifuratel, nifuroxazide, nifuralazine, nifurtimox, nimustine, ninorazole, nitrofurantoin, nitrogen mustard, oleomucin, oxolinic acid, pentamidine, pentostatin, phenazopyridine, phthalylsulfathiazole, pipobroman, prednimustine, prednisone, preussin, procarbazine, pyrimethamine, raltitrexed, rapamycin, rofecoxib, rosiglitazone, salazosulfapyridine, acriflavinium chloride, semustineStreptozocine, sulfacarbamide, sulfacetamide, sulfachlopyridazine, sulfadiazine, sulfadicramide, sulfadimethoxine, sulfaethidole, sulfafurazole, sulfaguanidine, sulfaguanole, sulfamethizole, sulfamethoxazole, cotrimoxazole, sulfamethoxydiazine, sulfamethoxypyridazine, sulfamoxole, sulfanilamide, sulfaperin, sulfaphenazole, sulfathiazole, sulfisomidine, staurosporin, tamoxifen, taxol, teniposide, tertiposide, testosterone lactone, testosterone propionate, thioguanine, thiotepa, tinidazole, topotecan, triaziquone, treosulfan, trimethoprim, trofosfamide, UCN - 01, vinblastine, vincristine, vindesine, vinblastine, vinorelbine, and zorubicin, or their corresponding derivatives or analogs and combinations thereof.

[0247] In one embodiment, the cell growth inhibitor and / or cytotoxic agent is selected from the group consisting of doxorubicin, α - amanitin, and monomethyl auristatin E. In one embodiment, Z is doxorubicin.

[0248] In one embodiment, Z is a cytokine. In one embodiment, the cytokine is a chemokine molecule. In one embodiment, the chemokine molecule is selected from the group consisting of CXCL9, CXCL10, and CX3CL1. In one embodiment, Z is CXCL9. In one embodiment, Z is CXCL10. In one embodiment, Z is CX3CL1.

[0249] In one embodiment, Z is an immunomodulatory molecule. In one embodiment, the immunomodulatory molecule is selected from the group consisting of: CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL17, CX3CL1, CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27, CCL28, interleukin-2, interferon α, and interferon γ. In one embodiment, the immunomodulatory molecule is selected from the group consisting of CXCL3, interleukin-2, and CCL8. In one embodiment, Z is interleukin-2.

[0250] In one embodiment, Z is an amphiphilic substance. In one embodiment, the amphiphilic substance is selected from the group consisting of: lipids, phospholipids, and other highly lipophilic moieties conjugated to polar groups (such as ammonium ions or inositol trisphosphate). In one embodiment, the lipids are selected from the group consisting of: glycolipids, prenol lipids, sterol lipids, glycerolipids, polyketides, and fatty acids, and the phospholipids are selected from the group consisting of: plasmalogens, sphingomyelins, phosphatidates, and phosphoinositols. In one embodiment, the amphiphilic substance is a lipid or a phospholipid. In one embodiment, the amphiphilic substance is N - polyethylene glycolated 1,2 - distearoyl glycerol - 3 - phosphoethanolamine. In one embodiment, Z is a lipid. In one embodiment, Z is a phospholipid. In one embodiment, Z is N - polyethylene glycolated 1,2 - distearoyl glycerol - 3 - phosphoethanolamine.

[0251] In one embodiment, Z is a nucleic acid. In one embodiment, the nucleic acid is selected from the group consisting of DNA, RNA, siRNA, mRNA, PNA, and cDNA. In one embodiment, the nucleic acid encodes the cytokines and / or immunomodulatory molecules provided herein. In one embodiment, the nucleic acid is siRNA or PNA.

[0252] In one embodiment, Z is a viral structural protein. In one embodiment, the viral structural protein has a virus selected from the group consisting of:

[0253] (i) double-stranded DNA viruses, such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae;

[0254] (ii) single-stranded DNA viruses, such as Anelloviridae, Inoviridae, Parvoviridae;

[0255] (iii) double-stranded RNA viruses, such as Reoviridae;

[0256] (iv) single-stranded RNA viruses, such as Coronaviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae;

[0257] (v) antisense single-stranded RNA viruses, such as Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bornaviridae;

[0258] (vi) single-stranded RNA retroviruses, such as Retroviridae;

[0259] (vii) double-stranded DNA retroviruses, such as Caulimoviridae, Hepadnaviridae.

[0260] In one embodiment, a viral capsid protein (VCP), such as VCP, is derived from a virus selected from the group consisting of: double-stranded DNA viruses, such as Myoviridae, Siphoviridae, Podoviridae, Herpesviridae, Adenoviridae, Baculoviridae, Papillomaviridae, Polydnaviridae, Polyomaviridae, Poxviridae; single-stranded DNA viruses, such as Anelloviridae, Inoviridae, Parvoviridae; double-stranded RNA viruses, such as Reoviridae; single-stranded RNA viruses, such as Coronaviridae, Picornaviridae, Caliciviridae, Togaviridae, Flaviviridae, Astroviridae, Arteriviridae, Hepeviridae; negative-sense single-stranded RNA viruses, such as Arenaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Bunyaviridae, Orthomyxoviridae, Bornaviridae; single-stranded RNA retroviruses, such as Retroviridae; double-stranded DNA retroviruses, such as Caulimoviridae, Hepadnaviridae. In one embodiment, the VCP is from the family Parvoviridae, such as from adeno-associated virus. In one embodiment, the VCP is human AAV, bovine AAV, goat AAV, avian AAV, canine parvovirus (CPV), murine parvovirus; minute virus of mice (MVM); parvovirus B19 (B19); parvovirus H1 (H1); human bocavirus (HBoV); feline panleukopenia virus (FPV); or goose parvovirus (GPV). In one embodiment, the VCP is from certain AAV-serotypes, such as AAV-1, AAV-2, AAV-2-AAV-3 hybrid, AAV-3a, AAV-3b, AAV-4, AAV-5, AAV-6, AAV-6.2, AAV-7, AAV-8, AAV-9, AAV-10, AAVrh.10, AAV-11, AAV-12, AAV-13 or AAVrh32.33. In one embodiment, the VCP is AAV-2 or a variant thereof capable of assembling into a VLP.

[0261] In one embodiment, Z is a protein. In one embodiment, the protein is selected from the group consisting of membrane-bound proteins and non-binding proteins. Examples of proteins include (but are not limited to) CEA, CA19-9, macrophage migration inhibitory factor (MIF), interleukin 8 (IL-8), AXL, MER, and c-MET.

[0262] In one embodiment, Z is biotin. In one embodiment, provided herein is a liposome comprising a compound provided herein, wherein Z is an amphiphilic substance.

[0263] The liposomes provided herein can be of various types, such as those described by Alavi et al., Adv Pharm Bull, 2017. In one embodiment, the liposomes provided herein are stealth liposomes. Stealth liposomes are known in the art and are reviewed, for example, by Immordino et al., Int J Nanomedicine, 2006.

[0264] The liposomes provided herein can be positively charged, negatively charged or neutral liposomes. The charge of the liposome is determined by the lipid composition and is the average of all the charges of the lipids contained in the liposome. For example, a mixture of negatively charged phospholipids and cholesterol will produce negatively charged liposomes.

[0265] In one embodiment, the lipids / phospholipids used in the liposome include (but are not limited to) glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, thioesters, sphingolipids, phospholipids, prenyllipids, steroids, stearins, sterols and carbohydrates-containing lipids.

[0266] In one embodiment, the negatively charged lipids / phospholipids are selected from the group consisting of phosphatidylserine (PS), phosphatidylglycerol (PG) and phosphatidic acid (PA). PS and PG are collective terms for lipids sharing similar phosphatidylserine and phosphatidylglycerol head groups, respectively. However, many different non-polar residues can be attached to these head groups. Thus, PS and PG isolated from different natural sources are substantially different in terms of the length, composition and / or chemical structure of the attached non-polar residues, and naturally occurring PS and PG are generally mixtures of PS and PG with different non-polar residues.

[0267] In one embodiment, the PS used in the liposomes provided herein is selected from the group consisting of: palmitoyl oleoyl phosphatidylserine, palmitoyl linoleoyl-phosphatidylserine, palmitoyl arachidoyl phosphatidylserine, palmitoyl docosahexaenoyl-phosphatidylserine, stearoyl oleoyl phosphatidylserine, stearoyl linoleoyl phosphatidylserine, stearoyl-arachidoyl phosphatidylserine, stearoyl docosahexaenoyl phosphatidylserine, dioctanoyl phosphatidylserine, dilauroyl phosphatidylserine, dimyristoyl phosphatidylserine, diphytanoyl phosphatidylserine, di(heptadecanoyl) phosphatidylserine, dioleoyl-phosphatidylserine, dipalmitoyl phosphatidylserine, distearoyl phosphatidylserine, dilinoleoyl-phosphatidylserine, dicrotonoyl phosphatidylserine, di(docosahexaenoyl)-phosphatidylserine, PS from brain, and PS from soy; in one embodiment, it is dioleoyl phosphatidylserine.

[0268] In one embodiment, the PG used in the liposomes provided herein is selected from the group consisting of: palmitoyl oleoyl phosphatidylglycerol, palmitoyl-linoleoyl phosphatidylglycerol, palmitoyl arachidoyl phosphatidylglycerol, palmitoyl-docosahexaenoyl phosphatidylglycerol, stearoyl oleoyl phosphatidylglycerol, stearoyl-linoleoyl phosphatidylglycerol, stearoyl arachidoyl phosphatidylglycerol, stearoyl docosahexaenoyl phosphatidylglycerol, dioctanoyl phosphatidylglycerol, dilauroyl phosphatidylglycerol, di(heptadecanoyl) phosphatidylglycerol, diphytanoyl-phosphatidylglycerol, dimyristoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, dielaidoyl phosphatidyl-glycerol, distearoyl phosphatidylglycerol, dioleoyl phosphatidylglycerol, dilinoleoyl-phosphatidylglycerol, diarachidoyl phosphatidylglycerol, docosahexaenoyl phosphatidyl-glycerol, and PG from eggs; in one embodiment, it is dioleoyl phosphatidylglycerol.

[0269] Similar to PS and PG, PE is also a general term for lipids sharing a phosphatidylethanolamine head group. In one embodiment, PE is selected from the group consisting of: palmitoyl oleoyl phosphatidylethanolamine, palmitoyl linoleoyl phosphatidylethanolamine, palmitoyl arachidonyl phosphatidylethanolamine, palmitoyl docosahexaenoyl phosphatidylethanolamine, stearoyl oleoyl phosphatidylethanolamine, stearoyl linoleoyl phosphatidylethanolamine, stearoyl arachidonyl phosphatidylethanolamine, stearoyl docosahexaenoyl phosphatidylethanolamine, dilauroyl phosphatidylethanolamine, dimyristoyl phosphatidylethanolamine, diphytanoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, di(heptadecanoyl) phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dielaidoyl phosphatidylethanolamine, diarachidonyl phosphatidylethanolamine, docosahexaenoyl phosphatidylethanolamine, PE from bacteria, PE from heart, PE from brain, PE from liver, PE from eggs, and PE from soybeans, and in one embodiment, is 1,2-diacyl-sn-glycero-3-PE, 1-acyl-2-acyl-sn-glycero-3-PE, 1,2-dipalmitoyl-PE, and / or 1,2-dilauroyl-sn-glycero-3-PE (DLPE).

[0270] The liposomes provided herein may comprise at least one other component selected from the group consisting of adjuvants, additives, and auxiliary substances. In one embodiment, the adjuvants are selected from the group consisting of: unmethylated DNA, such as unmethylated DNA containing CpG dinucleotides (CpG motifs), said CpG dinucleotides such as CpG ODNs (CPG PTO ODNs) having a phosphorothioate (PTO) backbone or CpG ODNs (CpG PO ODNs) having a phosphodiester (PO) backbone; bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA), lipopolysaccharide (LPS), muramyl dipeptide, and derivatives thereof; synthetic lipopeptide derivatives, such as ParmCys; lipoarabinomannan; peptidoglycan; zymosan; heat shock proteins (HSPs), such as HSP70; dsRNA and synthetic derivatives thereof, such as PolyEpolyC; polycationic peptides, such as poly-L-arginine; paclitaxel; fibronectin; flagellin; imidazoquinoline; cytokines having adjuvant activity, such as GM-CSF, interleukin-(IL-)2, IL-6, IL-7, IL-18, type I and type II interferons (such as interferon-γ), TNF-α; 25-dihydroxyvitamin D3 (calcitriol); synthetic oligopeptides, such as peptides presenting MHCII; gel-like precipitates of aluminum hydroxide (alum). In one embodiment, the adjuvants that may be comprised in the liposomes provided herein are selected from the group consisting of: unmethylated DNA, such as unmethylated DNA containing CpG dinucleotides (CpG motifs), said CpG dinucleotides such as CpG ODNs (CPG PTO ODNs) having a phosphorothioate (PTO) backbone or CpG ODNs (CpG PO ODNs) having a phosphodiester (PO) backbone; bacterial products from the outer membrane of Gram-negative bacteria, such as monophosphoryl lipid A (MPLA); and synthetic lipopeptide derivatives, such as ParmCys.

[0271] As used herein and unless otherwise specified, the term "additive" encompasses substances that stabilize any component of the liposome or the liquid medium, such as, for example, antioxidants, free radical scavengers, and the like. In one embodiment, the stabilizers are selected from the group consisting of: α-tocopherol or carbohydrates, such as glucose, sorbitol, sucrose, maltose, trehalose, lactose, cellubiose, raffmose, maltotriose, or dextran. The stabilizers may be comprised in the lipid membrane of the liposome, inside the liposome, and / or within the liquid medium surrounding the liposome.

[0272] The liposomes provided herein can have a diameter between 10 and 1000 nm. In one embodiment, it has a diameter between 30 and 800 nm, between 40 and 500 nm, between 50 and 300 nm, or between 100 and 200 nm. The diameter of the liposomes can be affected, for example, by extruding the liposome composition through a screen or mesh having a known pore size. This method and other methods of controlling the size of liposomes are known in the art and are described, for example, in Mayhew et al., (1984) Biochim. Biophys. Acta 775: 169-174 or Olson et al., (1979) Biochim. Biophys. Acta 557: 9-23.

[0273] In one embodiment, the liposomes or mixtures of liposomes provided herein are contained in a liquid medium. As used herein and unless otherwise specified, the term "liquid medium" includes all biocompatible, physiologically acceptable liquids and liquid compositions, such as FLO, saline solutions, and buffer solutions (such as, for example, PBS, Ringer's solution, etc.).

[0274] In one embodiment, the liposomes are loaded with a substance selected from the group consisting of pharmaceuticals and nucleic acids.

[0275] In one embodiment, the liposome-loaded agent is a cell growth inhibitor and / or cytotoxic agent provided herein. In one embodiment, the liposome-loaded nucleic acid is the nucleic acid provided herein. A variety of methods in the art can be used to load liposomes with a given therapeutic agent. In one embodiment, the therapeutic agent is admixed with the lipid components during liposome formation. Other passive loading methods include dehydration-rehydration (Kirby and Gregoriadis (1984) Biotechnology 2:979), reverse-phase evaporation (Szoka and Papahadjopoulos (1978) Proc. Natl. Acad. Sci. USA 75:4194), or detergent depletion (Milsmann et al., (1978) Biochim. Biophys. Acta 512:147-155). Other methods for encapsulating therapeutic agents include so-called "remote loading" or "active loading", in which, due to gradients, such as a pH or salt gradient between the outside and inside of preformed liposomes, the therapeutic agent is transported into the liposomes along the gradient (see, e.g., Cheung et al., (1998) Biochim. Biophys. Acta 1414:205-216; Cullis et al., (1991) Trends Biotechnol. 9:268-272; Mayer et al., (1986) Chem. Phys. Lipids 40:333-345).

[0276] In one embodiment, the compound is a compound in Table 2 or Table 2A, or a stereoisomer, mixture of stereoisomers, tautomer, or pharmaceutically acceptable salt thereof.

[0277] Table 2.

[0278]

[0279]

[0280] Table 2A.

[0281]

[0282] In one embodiment, the compounds provided herein are single diastereomers. In one embodiment, the compounds provided herein are mixtures of diastereomers. In one embodiment, the compounds provided herein have a diastereomeric excess (de) of at least about 50%, at least about 80%, or at least about 90%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 95%, at least about 97%, at least about 99%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 99.5%. In one embodiment, the compounds provided herein have a diastereomeric excess of at least about 99.9%.

[0283] In one embodiment, the compounds provided herein are used as diagnostic agents. In one embodiment, the compounds provided herein are used as therapeutic agents. In one embodiment, the compounds provided herein are used as theranostic agents.

[0284] In one embodiment, a complex is provided herein that is formed from a compound provided herein and a metal cation. In one embodiment, when Z is a chelating agent, a complex is formed.

[0285] In one embodiment, the metal cation is a divalent or trivalent metal cation. In one embodiment, the metal cation is the cation of Cr, Ga, In, Tc, Re, La, Yb, Sm, Ho, Y, Pm, Dy, Er, Lu, Sc, Pr, Gd, Bi, Ru, Pd, Rh, Sb, Ba, Hg, Eu, Tl, Pb, Cu, Re, Au, Ac, Th, or Ag. In one embodiment, the metal cation is the cation of Ga. In one embodiment, the metal cation is the cation of Lu.

[0286] In one embodiment, the metal cation is 51 Cr, 67 Ga, 68 Ga, 89 Zr, 111 In, 99m Tc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y, 90 Y, 149 Pm, 165 Dy, 169 Er, 177 Lu, 47 Sc,142 Pr, 159 Gd, 212 Bi, 213 Bi, 97 Ru, 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 Ba, 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 Tl, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 198 Au, 225 Ac, 227 Th or 199 a cation of Ag. In one embodiment, the metal cation is 68 a cation of Ga. In one embodiment, the metal cation is 177 a cation of Lu. In one embodiment, the metal cation is 177 Lu 3+ . In one embodiment, the metal cation is 68 Ga 3+ . In one embodiment, the metal cation is 111 In 3+ . In one embodiment, the metal cation is 99m Tc 4+ . In one embodiment, the metal cation is 90 Y 3+ . In one embodiment, the metal cation is 203 Pb 2+ . In one embodiment, the metal cation is 212 Pb 2+ . In one embodiment, the metal cation is 64 Cu 2+ . In one embodiment, the metal cation is 225 Ac 3+ .

[0287] In one embodiment, provided herein are specifically any complexes formed from the compounds in Table 2 or Table 2A and the metal cations provided herein. In one embodiment, provided herein are specifically any complexes formed from the compounds in Table 2 or Table 2A and 177 Lu 3+Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 68 Ga 3+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 111 In 3+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 99m Tc 4+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 90 Y 3+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 203 Pb 2+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 212 Pb 2+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 64 Cu 2+ Any complex formed. In one embodiment, provided herein are specifically any complexes formed by the compounds in Table 2 or Table 2A and 225 Ac 3+ Any complex formed.

[0288] In one embodiment, the complex is a complex in Table 3, or a stereoisomer, a mixture of stereoisomers, a tautomer, or a pharmaceutically acceptable salt thereof.

[0289] Table 3.

[0290]

[0291]

[0292] As used herein and unless otherwise specified, the → and --- shown in the structures provided herein are for the sole purpose of illustrating the possible chelation between a compound and a metal cation. It does not mean that chelation necessarily occurs as indicated by → and ---. It does not mean that chelation cannot occur between other atoms of the compound and the metal cation.

[0293] In one embodiment, without being bound by a particular theory, the compounds or complexes provided herein exhibit suitable cellular uptake in PSMA-transfected cells and tumor uptake in PSMA-positive tumors. In one embodiment, without being bound by a particular theory, the compounds or complexes provided herein exhibit effective PSMA enzyme inhibition, good tumor uptake, and / or retention. In one embodiment, without being bound by a particular theory, small animal PET / CT or SPECT / CT depicts tumor volumes with high tumor / blood and tumor / kidney ratios and long-term tumor retention, and causes complete tumor inhibition in in vivo efficacy studies.

[0294] In one embodiment, the complexes provided herein are used as diagnostic agents. In one embodiment, the complexes provided herein are used as therapeutic agents. In one embodiment, the complexes provided herein are used as theranostic agents.

[0295] Pharmaceutical Compositions and Methods of Use

[0296] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound provided herein or a complex provided herein and a pharmaceutically acceptable excipient.

[0297] In one embodiment, the present disclosure provides a virus-like particle (VLP) comprising a compound provided herein, wherein Z is a viral structural protein. In one embodiment, the virus-like particle is loaded with a substance selected from the group consisting of a medicament and a nucleic acid. In one embodiment, the medicament loaded in the virus-like particle is a cell growth inhibitor and / or a cytotoxic agent provided herein. In one embodiment, the nucleic acid loaded in the virus-like particle is a nucleic acid provided herein.

[0298] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound provided herein, a liposome provided herein, or a virus-like particle provided herein and a pharmaceutically acceptable excipient.

[0299] As used herein and unless otherwise specified, a PSMA-positive disease or disorder (e.g., PSMA-positive cancer) refers to a disease or disorder (e.g., cancer) characterized by elevated expression (e.g., overexpression) of PSMA. In one embodiment, the elevated expression is compared to, for example, a healthy subject. In one embodiment, PSMA positivity is determined by a method provided herein (e.g., using a compound or complex provided herein), or by a method known in the art, including methods approved by the US FDA (e.g., IHC staining, PSMA imaging).

[0300] In one embodiment, provided herein is a method for diagnosing a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject a diagnostically effective amount of a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein. In one embodiment, the compound provided herein, the complex provided herein, or the pharmaceutical composition provided herein is used for diagnosing a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject.

[0301] In one embodiment, provided herein is a method for treating a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein. In one embodiment, the compound provided herein or the pharmaceutical composition provided herein is used for treating a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject.

[0302] In one embodiment, provided herein is a method for treating or diagnosing cancer. In one embodiment, provided herein is a method for treating PSMA-positive cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, a complex described herein, or a pharmaceutical composition described herein. In one embodiment, provided herein is a method for diagnosing PSMA-positive cancer, the method comprising administering to a subject in need thereof a diagnostically effective amount of a compound described herein, a complex described herein, or a pharmaceutical composition described herein.

[0303] In one embodiment, provided herein is a method for treating a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein. In one embodiment, the compound provided herein, the liposome provided herein, the virus-like particle (VLP) provided herein, or the pharmaceutical composition provided herein is used for treating a disease or disorder characterized by overexpression of prostate-specific membrane antigen (PSMA) in a subject.

[0304] In one embodiment, the administration is intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, or intrasternal administration. In one embodiment, the administration is intravenous administration.

[0305] In one embodiment, the disease is cancer. In one embodiment, the cancer disease is PSMA-positive cancer. PSMA expression has been detected in various cancers (e.g., Rowe et al., 2015, Annals of Nuclear Medicine 29:877-882; Sathekge et al., 2015, Eur J Nucl Med Mol Imaging 42:1482-1483; Verburg et al., 2015, Eur J Nucl Med Mol Imaging 42:1622-1623; and Pyka et al., J Nucl Med November 19, 2015 jnumed.115.164442), the entire content of each of which is incorporated herein by reference. In one embodiment, the cancer is prostate cancer, kidney cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain cancer, melanoma, neuroendocrine tumor, ovarian cancer, adenoid cystic carcinoma, salivary gland duct carcinoma, or sarcoma. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is adenoid cystic carcinoma. In one embodiment, the cancer is salivary gland duct carcinoma. In one embodiment, the cancer is sarcoma.

[0306] In one embodiment, the subject is an animal. In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0307] Also provided herein is a method of detecting a cell or tissue that expresses prostate-specific membrane antigen (PSMA), the method comprising (i) contacting the cell or tissue that expresses PSMA with a compound or complex described herein, and (ii) applying one or more imaging methods to detect the cell or tissue. In one embodiment, the imaging method includes positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), computed tomography (CT), scintigraphy imaging, luminescence imaging, or fluorescence imaging, or a combination thereof.

[0308] In one embodiment, the cell or tissue that expresses PSMA comprises prostate cells or tissue, spleen cells or tissue, or kidney cells or tissue.

[0309] In one embodiment, the detection is performed in vivo. In one embodiment, the detection is performed ex vivo. In one embodiment, the detection is performed in vitro.

[0310] In one embodiment, the present disclosure provides a kit comprising a compound provided herein, a complex provided herein, or a pharmaceutical composition provided herein, and instructions for diagnosing or treating a disease or disorder provided herein. In one embodiment, the present disclosure provides a kit comprising a compound provided herein, a complex provided herein, a liposome provided herein, a virus-like particle (VLP) provided herein, or a pharmaceutical composition provided herein, and instructions for treating a disease or disorder.

[0311] It should be understood that any embodiment of the compounds provided herein as set forth above, and any particular substituents and / or variables in the compounds provided herein as set forth above, may be independently combined with other embodiments and / or substituents and / or variables of other compounds to form embodiments not specifically set forth above. Additionally, in cases where a list of substituents and / or variables is provided for any particular group or variable, it should be understood that each individual substituent and / or variable may be deleted from a particular embodiment and / or claim, and the remaining list of substituents and / or variables shall be considered to be within the scope of the embodiments provided herein.

[0312] It should be understood that in this specification, combinations of substituents and / or variables of the depicted formulas are only permitted when such combinations result in stable compounds.

[0313] Examples

[0314] Certain embodiments of the invention are illustrated by the following non-limiting examples.

[0315] Preparation Methods

[0316] Preparative HPLC Purification Method 1

[0317] The compound was purified on a Shimadzu LC-20AP and UV detector. The column used was a Shim-pack GISC18 (250*20) mm, 10 μm. The column flow rate was 15 mL / min. Mobile phases (A) 0.1% TFA / water and (B) acetonitrile were used. Purification was carried out using a linear gradient of 5% to 35% (B) acetonitrile for 20 or 30 minutes. UV spectra were recorded at 220 nm and 254 nm.

[0318] Preparative HPLC Purification Method 2

[0319] The compound was purified on a Shimadzu LC-20AP and UV detector. The column used was Shim-pack GISC18 (250*20) mm, 10 μm. The column flow rate was 15 mL / min. The mobile phases used were (A) 0.1% NH3 / water and (B) acetonitrile. Purification was carried out using a linear gradient of 5% to 35% (B) acetonitrile for 20 or 30 minutes. The UV spectra were recorded at 220 nm and 254 nm.

[0320] Preparative HPLC purification method 3

[0321] The compound was purified on a Shimadzu LC-20AP and UV detector. The column used was Shim-pack GISC18 (250*20) mm, 10 μm. The column flow rate was 15 mL / min. The mobile phases used were (A) 0.1% NH4HCO3 / water and (B) acetonitrile. Purification was carried out using a linear gradient of 2% to 35% (B) acetonitrile for 25 or 30 minutes. The UV spectra were recorded at 220 nm and 254 nm.

[0322] Preparation method

[0323] The compounds provided herein can be prepared using reactions and techniques known in the art and the reactions and techniques described herein.

[0324] Preparation of intermediates

[0325] D1: Tri-tert-butyl 2,2′,2″-(10-(2-hydrazino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0326]

[0327] Step 1

[0328] At 0 °C, D1-2 (33.5 mL, 232.00 mmol) was added to a solution of D1-1 (10.00 g, 58.00 mmol), sodium acetate (19.05 g, 232.00 mmol) and tetrabutylammonium bromide (430.00 mg, 1.34 mmol) in DMA (N,N-dimethylacetamide) (84 mL). The mixture was stirred overnight at 25 °C under a N2 atmosphere. The reaction mixture was diluted with 330 mL of water, the pH was adjusted to 8.8 - 9.0 with sodium carbonate solution, filtered and washed with water (20 mL × 2). The filter cake was added to 90 mL of ethanol, heated to 45 °C to obtain a clear solution, to which 270 mL of water was added, stirred at room temperature for 2 hours, and filtered. The filter cake was washed with water (20 mL × 2) and dried to obtain D1-3 (26.80 g, 52.10 mmol, yield: 90.0%) as a white solid. LC-MS (ESI) m / z: 515 [M+H] + 。

[0329] Step 2

[0330] At 0 °C, K2CO3 (6.71 g, 48.60 mmol) and D1-4 (5.95 mL, 53.40 mmol) were added to a solution of D1-3 (25.00 g, 48.60 mmol) in ACN (acetonitrile) (250 mL). The mixture was stirred at 25 °C under N2 for 10 hours. The reaction mixture was filtered and evaporated to dryness to obtain the crude product D1-5 (25.00 g, crude) as a colorless oil. LC-MS (ESI) m / z: 601 [M+H] + 。

[0331] Step 3

[0332] Hydrazine hydrate (239 mL, 4.16 mol) was added to a solution of D1-5 (25.00 g, 41.60 mmol) in EtOH (ethanol) (750 mL). The mixture was stirred at 80 °C under N2 for 2 days. The resulting mixture was evaporated under reduced pressure to obtain a crude product, which was purified by flash chromatography to obtain compound D1 (13.60 g, 23.18 mmol, yield: 47.7%, over two steps) as a white solid. LC-MS (ESI) m / z: 587 [M+H] + 。

[0333] D2: (((S)-6-((S)-2-Amino-3-(naphthalen-2-yl)propanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)carbamoyl)-L-glutamic acid di-tert-butyl ester

[0334]

[0335] Step 1

[0336] To a solution of D2-1 (25.00 g, 85.00 mmol) in DCM (dichloromethane) (260 mL) at 0 °C was added TEA (triethylamine) (47 mL, 338.00 mmol) and N,N-dimethylpyridin-4-amine (413.00 mg, 3.38 mmol). Then, a solution of bis(1H-imidazol-1-yl)methanone (15.07 g, 93.00 mmol) in DCM (85 mL) was added dropwise over a period of 30 minutes. The mixture was stirred at 25 °C under N2 for 16 h. The reaction was quenched with saturated NaHCO3 (aqueous solution). The aqueous layer was extracted with DCM (250 mL × 2). The combined organic layers were washed with brine (500 mL × 1), dried over Na2SO4, filtered and concentrated to give a crude product, which was dissolved in DCM (410 mL), followed by the addition of D2-2 (22.79 g, 61.10 mmol) and DIEA (N,N-diisopropylethylamine) (47.4 mL, 272.00 mmol). The mixture was stirred at 25 °C under N2 for 16 h. The reaction was quenched with 1.0 mol / L HCl (aqueous solution). The aqueous layer was extracted with DCM (500 mL × 2). The combined organic layers were washed with brine (500 mL × 1). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product, which was purified by flash chromatography to give compound D2-3 (30.00 g, 48.20 mmol, yield: 71.1%) as a colorless oil. LC-MS (ESI) m / z: 622 [M+H] + 。

[0337] Step 2

[0338] To a solution of D2-3 (25.00 g, 40.20 mmol) in MeOH (methanol) (150 mL) was added 10% wet Pd / C (2.50 g). The mixture was stirred at 25 °C under H2 for 12 h. The suspension was filtered through a pad of diatomaceous earth and washed with MeOH (50 mL × 2). The combined filtrates were concentrated to dryness to give D2-4 (16.80 g, 34.50 mmol, yield: 86.0%). LC-MS (ESI) m / z: 488 [M+H] + 。

[0339] Step 3

[0340] To a solution of D2-5 (2.00 g, 5.72 mmol) in DMF (N,N-dimethylformamide) (20 mL) was added DIEA (4.00 mL, 22.90 mmol), D2-4 (2.79 g, 5.72 mmol), and T3P (1-propane phosphonic acid cyclic anhydride) (5.88 mL, 11.45 mmol). The mixture was stirred at 25 °C under N2 for 8 h. The reaction was quenched with H2O (50 mL). The aqueous layer was extracted with EA (ethyl acetate) (200 mL × 2). The combined organic layers were washed with saturated NaCl (aqueous solution) (150 mL × 1), dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to give D2-6 (1.60 g, 1.95 mmol, yield: 34.1%). LC-MS (ESI) m / z: 819 [M+H] + 。

[0341] Step 4

[0342] To a solution of D2-6 (1.60 g, 1.95 mmol) in MeOH (32 mL) was added 10% wet Pd / C (0.16 g). The mixture was stirred at 25 °C under H2 for 12 h. The suspension was filtered through a Celite pad and washed with MeOH (20 mL × 2). The combined filtrates were concentrated to dryness to give D2 (1.00 g, 1.46 mmol, yield: 74.7%). LC-MS (ESI) m / z: 685 [M+H] + 。

[0343] D3: 4-(((tert-butoxycarbonyl)amino)methyl)bicyclo[2.2.2]octane-1-carboxylic acid

[0344]

[0345] Step 1

[0346] To a solution of D3-1 (20.00 g, 94.00 mmol) in ACN (300 mL) was added Boc2O (32.80 mL, 141.00 mmol), pyridine (4.57 mL, 56.50 mmol), and NH4HCO3 (52.10 g, 660.00 mmol). The mixture was stirred at 25 °C under N2 for 3 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness to give the crude product, which was purified by silica gel column chromatography to give D3-2 as a white solid (18.00 g, 85.00 mmol, yield: 90.0%). LC-MS (ESI) m / z: 212 [M+H] + 。

[0347] Step 2

[0348] To a solution of D3-2 (25.20 g, 119.00 mmol) in DCM (250 mL) at 0 °C was added Burgess reagent (N-(triethylammoniumsulfonyl)carbamate) (85.00 g, 358.00 mmol). The mixture was stirred at 25 °C under N2 for 16 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give D3-3 (21.80 g, 113.00 mmol, yield: 95.0%) as a white solid. LC-MS (ESI) m / z: 194 [M+H] + 。

[0349] Step 3

[0350] To a solution of D3-3 (21.80 g, 113.00 mmol) in MeOH (400 mL) were added PtO2 (2.56 g, 11.28 mmol) and Boc2O (di-tert-butyl dicarbonate) (39.30 mL, 169.00 mmol). The mixture was stirred at 40 °C under H2 for 48 h. The reaction mixture was filtered and the cake was washed with MeOH (50 mL). Then the filtrate was evaporated under reduced pressure to give a crude product, which was quenched with water (200 mL) and extracted with EA (250 mL). The combined organic layers were washed with brine (250 mL × 3), dried over Na2SO4, filtered and concentrated to give D3-4 (28.80 g, 97.00 mmol, yield: 86.0%) as a white solid. LC-MS (ESI) m / z: 298 [M+H] + 。

[0351] Step 4

[0352] To a solution of D3-4 (32.00 g, 108.00 mmol) in MeOH (150 mL) and H2O (150 mL) was added NaOH (12.91 g, 323.00 mmol). The mixture was stirred at 50 °C under N2 for 24 h. Then the mixture was evaporated under reduced pressure to give an aqueous layer, which was extracted with EA (100 mL × 2). The pH of the aqueous layer was adjusted to 2 with HCl (2N). The resulting mixture was filtered and the cake was evaporated to dryness to give D3 (28.30 g, 100.00 mmol, yield: 93.0%) as a white solid. LC-MS (ESI) m / z: 284 [M+H] + 。

[0353] D4: Di-tert-butyl (S)-2-(3-((S)-6-((S)-2-amino-3-(anthracen-9-yl)propanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)hexanedioate

[0354]

[0355] Step 1

[0356] At 0 °C, tert-butyl acetate (6 mL, 12.41 mmol) and boron trifluoride diethyl etherate (6.3 mL, 49.70 mmol) were added to a 0 °C solution of D4-1 (2.00 g, 12.41 mmol) in THF (10 mL). The mixture was stirred at 28 °C under N2 for 2 days. The reaction was quenched with aqueous NaOH (1 N, 20 mL). The aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give D4-2 (600.00 mg, 12.19 mmol, yield: 17.7%) as a yellow oil. LC-MS (ESI) m / z: 274 [M+H] + 。

[0357] Step 2

[0358] To a solution of D4-2 (1.36 g, 4.96 mmol) in THF (15 mL) were added DIEA (1.73 mL, 9.92 mmol), D4-3 (2.56 g, 5.95 mmol), and DMAP (0.06 g, 0.50 mmol). The mixture was stirred at 25 °C under N2 for 2 hours. The reaction was quenched with H2O (50 mL). The aqueous layer was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give D4-4 (2.02 g, 3.18 mmol, yield: 64.1%) as a colorless oil. LC-MS (ESI) m / z: 636 [M+H] + 。

[0359] Step 3

[0360] A mixture of D4-4 (1.40 g, 2.20 mmol) and 10% wet Pd / C (0.23 g) in MeOH (20 mL) was degassed under vacuum and purged with H2 three times. The mixture was stirred at 18 °C under a H2 atmosphere for 16 hours. The reaction mixture was filtered and evaporated to dryness to give a crude product, which was purified by silica gel column chromatography to give D4-5 (791.00 mg, 1.58 mmol, yield: 71.6%) as a yellow oil. LC-MS (ESI) m / z: 502 [M+H] + 。

[0361] Step 4

[0362] To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(anthracen-9-yl)propanoic acid (2.70 g, 5.54 mmol) in DMF (30 mL) was added HATU (3.16 g, 8.31 mmol), DIEA (3.87 mL, 22.15 mmol) and D4-5 (2.78 g, 5.54 mmol). The mixture was stirred at 30 ° C under N2 for 2 hours. The reactant was quenched with saturated NH4Cl (50 mL). The aqueous layer was extracted with EA (125 mL×2). The combined organic layers were washed with brine (200 mL×1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D4-6 (3.70 g, 3.81 mmol, yield: 68.9%) as a yellow oil. LC-MS (ESI) m / z: 971 [M+H] + .

[0363] Step 5

[0364] To a solution of D4-6 (5.00 g, 5.15 mmol) in DCM (40 mL) was added piperidine (10 mL). The mixture was stirred at 32 ° C under N2 for 2 hours. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give D4 (2.70 g, 3.60 mmol, yield: 70.0%) as a yellow solid. LC-MS (ESI) m / z: 749 [M+H] + .

[0365] D5: (4S,8S,15S)-15-amino-16-(anthracen-9-yl)-1,6,14-trioxo-2,5,7,13-tetraazahexadecane-1,4,8-tricarboxylic acid tri-tert-butyl ester

[0366]

[0367] Step 1

[0368] To a solution of D5-1 (5.00 g, 39.40 mmol) in DCM (119 mL) was added t-BuOH (2-methylpropan-2-ol) (2.92 g, 39.40 mmol) at 0° C. The mixture was stirred at 0° C. under N2 for 2 hours. The mixture was then evaporated under reduced pressure to give D5-2 (5.70 g, crude) as a yellow oil, which was used directly in the next step without any further purification.

[0369] Step 2

[0370] To a solution of D5-2 (5.59 g, 34.00 mmol) in DCM (10 mL) was added (S)-tert-butyl 3-amino-2-(((benzyloxy)carbonyl)amino)propanoate (5.00 g, 16.99 mmol) and TEA (9.47 mL, 67.90 mmol). The mixture was stirred at 25 °C under N2 for 4 h. The resulting mixture was quenched with water (100 mL) and extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D5-3 (5.07 g, 12.00 mmol, yield: 30.5%, over two steps) as a yellow oil. LC-MS (ESI) m / z: 423 [M+H] + 。

[0371] Step 3

[0372] To a solution of D5-3 (5.60 g, 13.26 mmol) in MeOH (70 mL) was added 10% Pd / C (1.41 g, 13.26 mmol). The mixture was stirred at 25 °C under H2 for 12 h. The resulting mixture was filtered and evaporated to dryness to give D5-4 (3.36 g, crude) as a colorless oil. LC-MS (ESI) m / z: 289 [M+H] + 。

[0373] Step 4

[0374] To a solution of N6-((benzyloxy)carbonyl)-L-lysine tert-butyl ester (12.27 g, 36.50 mmol) in anhydrous DCM (158 mL) at -10 °C was added dropwise a solution of triphosgene (3.80 g, 12.81 mmol) and TEA (20.34 mL, 146.00 mmol) in anhydrous DCM (210 mL) over 1 h. The reaction mixture was stirred at -10 °C for 2 h and then a solution of D5-4 (10.52 g, 36.50 mmol) and TEA (10.17 mL, 73.00 mmol) in anhydrous DCM (316 mL) was added over 30 min. The reaction was stirred for an additional 3 h. The reaction was quenched with water (200 mL) and extracted with DCM (300 mL × 2). The combined organic layers were washed with brine (800 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by reverse-phase silica gel column chromatography, eluting with ACN / H2O (0.1% FA) to give D5-5 (6.37 g, 9.79 mmol, yield: 77.0%) as a yellow oil. LC-MS (ESI) m / z: 651 [M+H] + 。

[0375] Step 5

[0376] A mixture of D5-5 (2.53 g, 3.89 mmol) and 10% Pd / C (0.41 g, 0.39 mmol) in MeOH (40 mL) was degassed and purged with H2 three times. The mixture was stirred at 35 °C under a H2 atmosphere for 2 h. The resulting mixture was filtered and evaporated to dryness to give D5-6 (2.14 g, crude). LC-MS (ESI) m / z: 517 [M+H] + .

[0377] Step 6

[0378] To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(anthracen-9-yl)propanoic acid (2.00 g, 4.10 mmol) in DMF (10 mL) at 25 °C was added D5-6 (2.23 g, 4.31 mmol), 2-chloro-1-methylpyridinium iodide (1.36 g, 5.33 mmol) and DIEA (2.87 mL, 16.41 mmol). The mixture was stirred at 25 °C under N2 for 16 h. The resulting mixture was quenched with H2O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D5-7 as a yellow oil (2.10 g, 2.13 mmol, yield: 51.9%). LC-MS (ESI) m / z: 986 [M+H] + .

[0379] Step 7

[0380] To a solution of D5-7 (2.00 g, 2.03 mmol) in DCM (16 mL) was added piperidine (4 mL, 40.40 mmol). The mixture was stirred at 25 °C under N2 for 1 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give D5 as a yellow solid (602.00 mg, 0.79 mmol, yield: 38.9%). LC-MS (ESI) m / z: 764 [M+H] + .

[0381] D6: (((S)-1-(tert-butoxy)-6-((S)-2-((2-ethoxy-3,4-dioxobut-1-en-1-yl)amino)-3-(naphthalen-2-yl)propanamido)-1-oxohexan-2-yl)carbamoyl)-L-glutamic acid di-tert-butyl ester

[0382]

[0383] To a solution of D2 (500.00 mg, 0.73 mmol) in DMF (5 mL) was added 3,4 - diethoxycyclobut - 3 - ene - 1,2 - dione (186.00 mg, 1.10 mmol) and DIEA (0.51 mL, 2.92 mmol). The mixture was stirred at 25 °C under N2 for 4 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D6 (660.00 mg, crude) as a colorless oil. LC - MS (ESI) m / z: 809 [M + H] + 。

[0384] D7: tert - butyl ((4 - aminobicyclo[2.2.2]octan - 1 - yl)methyl)carbamate

[0385]

[0386] Step 1

[0387] To a solution of D3 (1.00 g, 3.53 mmol) in toluene (10 mL) was added benzyl alcohol (0.38 g, 3.53 mmol), diphenyphosphoryl azide (0.77 g, 3.18 mmol) and triethylamine (1.071 g, 10.59 mmol). The mixture was stirred at 100 °C under N2 for 12 h. The reaction was quenched with water (20 mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D7 - 1 (1.01 g, 2.60 mmol, yield: 73.7%) as a yellow oil. LC - MS (ESI) m / z: 389 [M + H] + 。

[0388] Step 2

[0389] To a solution of D7 - 1 (1.01 g, 2.60 mmol) in MeOH (10 mL) was added 10% wet Pd / C (0.28 g). The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at room temperature under a H2 atmosphere for 12 h. The reaction mixture was filtered and evaporated to dryness to give D7 (670.00 mg, crude) as a colorless oil. LC - MS (ESI) m / z: 255 [M + H] + 。

[0390] D8: Benzyl tert-butyl bicyclo[2.2.2]octane-1,4-diyl dicarbamate

[0391]

[0392] Step 1

[0393] To a solution of D3-1 (8.00 g, 37.70 mmol) in toluene (64 mL) was added benzyl alcohol (3.92 mL, 37.70 mmol), diphenylphosphoryl azide (12.18 mL, 56.50 mmol) and TEA (13.13 mL, 94.00 mmol). The mixture was stirred at 90 °C under N2 for 16 h. The reaction was quenched with H2O (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (100 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D8-1 (8.50 g, 26.80 mmol, yield: 71.1%) as a yellow solid. LC-MS (ESI) m / z: 318 [M+H]+.

[0394] Step 2

[0395] To a solution of D8-1 (8.50 g, 26.8 mmol) in THF (50 mL) and water (50 mL) was added NaOH (3.21 g, 80 mmol). The mixture was stirred at 60 °C under N2 for 12 h. Then the mixture was evaporated under reduced pressure to give the crude product, which was then quenched with H2O (50 mL). The aqueous layer was extracted with EA (50 mL × 2). The pH of the aqueous phase was adjusted to 2 with 2N HCl to give a white suspension, which was then filtered. The filter cake was dried in vacuo to give D8-2 (8.00 g, 26.40 mmol, yield: 98.5%) as a white solid. LC-MS (ESI) m / z: 304 [M+H]+ + 。

[0396] Step 3

[0397] To a solution of D8-2 (1.00 g, 3.30 mmol) in t-BuOH (15 mL) was added Boc2O (2.76 mL, 11.87 mmol), TEA (0.55 mL, 3.96 mmol), and diphenyphosphoryl azide (0.96 g, 3.96 mmol). The mixture was stirred at 80 °C under N2 for 16 h. The reaction was quenched with water (10 mL). The aqueous layer was extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D8 (1.01 g, 2.70 mmol, yield: 82.1%) as a yellow oil. LC-MS (ESI) m / z: 375 [M+H] + 。

[0398] D9: Tris(tert-butyl) 2,2′,2″-(10-((5-(4-aminobicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0399]

[0400] Step 1

[0401] To a solution of D8-2 (0.80 g, 2.64 mmol) in DMF (10 mL) was added HATU (1.50 mg, 3.96 mmol), DIEA (1.38 mL, 7.91 mmol), and D1 (1.70 mg, 2.90 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The reaction was quenched with H2O (10 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with brine (150 mL × 1), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D9-1 (1.80 g, 2.06 mmol, yield: 78.2%) as a yellow oil. LC-MS (ESI) m / z: 872 [M+H] + 。

[0402] Step 2

[0403] To a solution of D9-1 (2.00 g, 2.29 mmol) in MeCN (20 mL) at 0 °C was added TsCl (4-methylbenzenesulfonyl chloride) (1.31 g, 6.88 mmol) and DIEA (2.00 mL, 11.47 mmol). The mixture was stirred at 40 °C under N2 for 5 h. The resulting mixture was concentrated to give a crude product, which was purified by preparative HPLC (0.1% TFA / water: ACN = 2:1) to afford D9-2 (0.33 g, 0.39 mmol, yield: 16.9%) as a yellow oil. LC-MS (ESI) m / z: 854 [M+H] + 。

[0404] Step 3

[0405] To a solution of D9-2 (0.33 g, 0.39 mmol) in THF (10 mL) was added 10% Pd / C (41.1 mg). The mixture was stirred at 26 °C under H2 for 16 h. The resulting mixture was filtered and evaporated to dryness to afford D9 (0.26 g, 0.36 mmol, yield: 93.5%) as a yellow oil. LC-MS (ESI) m / z: 720 [M+H] + 。

[0406] D10: Tris(tert-butyl) 2,2′,2″-(10-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0407]

[0408] Step 1

[0409] To a solution of D8 (0.40 g, 1.07 mmol) in TFA (1 mL) was added DCM (4.00 mL). The mixture was stirred at 25 °C under N2 for 2 h. Then the mixture was evaporated under reduced pressure to give crude D10-1 (0.30 g, 1.09 mmol) as a yellow solid. LC-MS (ESI) m / z: 275 [M+H] + 。

[0410] Step 2

[0411] To a solution of D10-1 (0.30 g, 1.09 mmol) in DMF (4.0 mL), 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (689.00 mg, 1.20 mmol), HATU (624.00 mg, 1.64 mmol) and DIEA (0.76 mL, 4.37 mmol) were added. The mixture was stirred at 25 °C under N2 for 2 hours. The resulting mixture was quenched with water (10 mL) and extracted with EA (10 mL×2). The combined organic layers were washed with brine (10 mL×1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography to give D10-2 (792.00 mg, 0.96 mmol, yield: 87.0%) as a yellow oil. LC-MS (ESI) m / z: 829 [M+H] + .

[0412] Step 3

[0413] To a solution of D10-2 (790.00 mg, 0.95 mmol) in MeOH (20 mL) was added 10% wet Pd / C (101.00 mg). The mixture was stirred at 25 °C under H2 for 4 hours. The reaction mixture was filtered and concentrated in vacuo to give D10 (650.00 mg, 0.94 mmol, yield: 98.9%) as a colorless oil. LC-MS (ESI) m / z: 695 [M+H] + .

[0414] D112, 2′,2″-(10-((5-((1r,4r)-4-aminocyclohexyl)-1,3,4-oxadiazol-2-yl)methyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate tri-tert-butyl

[0415]

[0416] Step 1

[0417] To a solution of D11-1 (700.00 mg, 1.19 mmol) in DMF (14 mL) was added DIEA (0.83 mL, 4.77 mmol), HATU (544.00 mg, 1.43 mmol) and D1 (523.00 mg, 1.43 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The reaction was quenched with water (10 mL) and extracted with EA (25 mL × 2). The combined organic layers were washed with brine (25 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D11-2 (500.00 mg, 0.54 mmol, yield: 44.9%) as a yellow oil. LC-MS (ESI) m / z: 934 [M+H] + 。

[0418] Step 2

[0419] To a solution of D11-2 (500.00 mg, 0.54 mmol) in MeCN (8 mL) was added TsCl (204.00 mg, 1.07 mmol), DIEA (0.28 mL, 1.61 mmol). The mixture was stirred at 40 °C under N2 for 16 h. The reaction was quenched with water (5 mL) and extracted with EA (25 mL × 2). The combined organic layers were washed with brine (25 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give D11-3 (160.00 mg, 0.18 mmol, yield: 32.6%) as a yellow solid. LC-MS (ESI) m / z: 916 [M+H] + 。

[0420] Step 3

[0421] To a solution of D11-3 (140.00 mg, 0.15 mmol) in DCM (1 mL) was added piperidine (0.50 mL, 5.05 mmol). The mixture was stirred at 25 °C under N2 for 2 h. Then the mixture was evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography to give D11 (63.00 mg, 0.09 mmol, yield: 59.4%) as a yellow solid. LC-MS (ESI) m / z: 694 [M+H] + 。

[0422] D12: Di-tert-butyl 2,2′-(4-(2-amino-2-oxoethyl)-10-(2-((4-aminobicyclo[2.2.2]octan-1-yl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate

[0423]

[0424] Step 1

[0425] At 0 °C, add Na2CO3 (146.00 mg, 1.37 mmol) and benzyl 2-bromoacetate (0.16 ml, 1.00 mmol) to a solution of D12-1 (500.00 mg, 1.25 mmol) in ACN (5 ml). Stir the mixture under a N2 atmosphere at 25 °C for 2 h. Filter the reaction mixture, and concentrate and purify the filtrate to obtain D12-2 (246.00 mg, 0.49 mmol, yield: 35.9%) as a yellow oil. LC-MS (ESI) m / z: 549 [M+H] + 。

[0426] Step 2

[0427] At 23 °C, add K2CO3 (124.00 mg, 0.90 mmol) and 2-bromoacetamide (93.00 mg, 0.67 mmol) to a solution of D12-2 (246.00 mg, 0.45 mmol) in ACN (3 ml). After addition, stir the mixture under N2 at 23 °C for 2 h. Quench the reaction mixture by adding H2O (20 mL) and extract with EA (50 mL×2). Wash the combined organic layers with brine (50 mL), dry over Na2SO4, filter, and concentrate to obtain the crude product D12-3 (306.00 mg, crude). LC-MS (ESI) m / z: 606 [M+H] + 。

[0428] Step 3

[0429] At 25 °C, add 10% wet Pd / C (61.50 mg) to a solution of D12-3 (350.00 mg, 0.58 mmol) in MeOH (30 mL), and stir the mixture under a H2 atmosphere (15 psi) at 25 °C for 2 h. Filter the resulting mixture and evaporate the filtrate to dryness to obtain the crude product D12-4 (289.00 mg, 0.56 mmol, yield: 96.9%) as a yellow oil. LC-MS (ESI) m / z: 516 [M+H] + 。

[0430] Step 4

[0431] To a solution of D12-4 (280.00 mg, 0.54 mmol) in DMF (3 mL) was added D10-1 (164.00 mg, 0.60 mmol), HATU (310.00 mg, 0.82 mmol), and DIEA (0.38 mL, 2.17 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The resulting mixture was quenched with water (10 mL) and extracted with EA (25 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D12-5 (382.00 mg, 0.50 mmol, yield: 92.6%) as a colorless oil. LC-MS (ESI) m / z: 772 [M+H] + 。

[0432] Step 5

[0433] To a solution of D12-5 (430.00 mg, 0.56 mmol) in MeOH (10 mL) was added 10% wet Pd / C (43.00 mg), and the mixture was stirred at 25 °C under a H2 atmosphere for 2 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give a crude product. D12 (289.00 mg, 0.45 mmol, yield: 80.4%) as a colorless oil. LC-MS (ESI) m / z: 638 [M+H] + 。

[0434] D13: Di-tert-butyl 2,2′-(4-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate

[0435]

[0436] To a solution of D12-1 (5.00 g, 12.48 mmol) in ACN (100 mL) at 60 °C was slowly added K2CO3 (6.90 g, 49.9 mmol) and 2-bromoacetamide (2.58 g, 18.72 mmol) in ACN (50 mL). The mixture was stirred at 60 °C under N2 for 16 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by reverse-phase chromatography, eluting with ACN / H2O (0.1% FA) to give D13 (0.80 g, 1.75 mmol, yield: 14.0%) as an off-white solid. LC-MS (ESI) m / z: 458 [M+H] + 。

[0437] D14: Di-tert-butyl 2,2′-(4-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate

[0438]

[0439] Step 1:

[0440] To a solution of D14-1 (10.00 g, 48.90 mmol) in MeOH (50 mL) was added hydrazinium hydroxide (49.9 mL, 1.03 mol). The mixture was stirred at 25 °C under N2 for 5 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give D14-2 (4.30 g, 21.04 mmol, yield: 43.0%) as a white solid. LC-MS (ESI): 205 [M+H] + 。

[0441] Step 2:

[0442] To a solution of D8-2 (2.00 g, 6.59 mmol) in DMF (20 mL) was added DIEA (3.45 mL, 19.78 mmol), HATU (5.01 g, 13.19 mmol) and D14-2 (1.35 g, 6.59 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The reaction was quenched with H2O (50 mL) and extracted with EA (150 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D14-3 (yield: 3 g, 6.13 mmol) as a white solid. LC-MS (ESI): 490 [M+H] + 。

[0443] Step 3:

[0444] To a solution of triphenylphosphine (2.14 g, 8.17 mmol) and I2 (2.07 g, 8.17 mmol) in DCM (100 mL) at 0 °C was added TEA (2.85 mL, 20.42 mmol) and D14-3 (2.00 g, 4.08 mmol). The mixture was stirred at 25 °C under N2 for 2 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give D14-4 (1.4 g, 2.97 mmol, yield: 72.7%) as a white solid. LC-MS (ESI): 472 [M+H] + 。

[0445] Step 4:

[0446] To a solution of D14-4 (1.40 g, 2.97 mmol) in THF (50 mL) was added TBAF (tetrabutylammonium fluoride) (5.94 mL, 5.94 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The reaction was quenched with H2O (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give D14-5 as a white solid (0.90 g, 2.52 mmol, yield: 85.0%). LC-MS (ESI): 358 [M+H] + 。

[0447] Step 5:

[0448] To a solution of D14-5 (0.90 g, 2.52 mmol) in THF (10 mL) at 0 °C was added TEA (1.05 mL, 7.55 mmol) and MsCl (0.29 mL, 3.78 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The reaction was quenched with H2O (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product D14-6 (1.10 g, 2.53 mmol, yield: 100%). LC-MS (ESI): 436 [M+H] + 。

[0449] Step 6:

[0450] To a solution of D14-6 (1.10 g, 2.53 mmol) in ACN (20 mL) was added D13 (0.80 g, 1.77 mmol) and K2CO3 (1.05 g, 7.58 mmol). The mixture was stirred at 60 °C under N2 for 16 h. Then the mixture was evaporated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give D14-7 as a yellow oil (1.1 g, 1.38 mmol, yield: 54.6%). LC-MS (ESI): 797 [M+H] + 。

[0451] Step 7:

[0452] To a solution of D14-7 (1.10 g, 1.38 mmol) in THF (30 mL) was added 10% wet Pd / C (0.18 g, 0.14 mmol) and 10% wet Pd(OH)2 / C (0.19 g, 0.14 mmol). The mixture was stirred at 25 °C under a H2 balloon for 16 h. The resulting mixture was filtered and evaporated under reduced pressure to give the crude product D14 as a yellow oil (0.91 g, 1.38 mmol, yield: 100%). LC-MS (ESI): 663 [M+H] + .

[0453] E1: (((S)-1-Carboxy-5-((S)-2-((3,4-dioxo-2-((4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)bicyclo[2.2.2]oct-1-yl)amino)cyclobut-1-ene-1-yl)amino)-3-(naphthalen-2-yl)propanamido)pentyl)carbamoyl)-L-glutamic acid (Method A)

[0454]

[0455] Step 1

[0456] To a solution of D7 (47.2 mg, 0.19 mmol) in THF (0.50 mL) was added D6 (50.00 mg, 0.06 mmol) and DIEA (0.04 mL, 0.25 mmol). The mixture was stirred at 50 °C under N2 for 4 h. The reaction was quenched with water (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give E1-1 as a white solid (14.00 mg, 0.01 mmol, yield: 22.3%). LC-MS (ESI) m / z: 1017 [M+H] + .

[0457] Step 2

[0458] To a solution of E1-1 (14.00 mg, 0.01 mmol) in DCM (0.50 mL) was added TFA (0.50 mL). The mixture was stirred at 25 °C under N2 for 4 h. Then the mixture was evaporated under reduced pressure to give the crude E1-2 as a white solid (11.00 mg). LC-MS (ESI) m / z: 749 [M+H] + .

[0459] Step 3

[0460] To a solution of E1-2 (110.00 mg, 0.15 mmol) in DMF (1 mL) was added DOTA-PNP (2,2′,2″-(10-(2-(4-nitrophenoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid) (85.00 mg, 0.16 mmol) and DIEA (0.10 mL, 0.59 mmol). The mixture was stirred under N2 at room temperature for 4 h. The resulting mixture was concentrated to give a crude material, and the crude material was purified by preparative HPLC (method 3) to give the title compound E1 (6.00 mg, 4.87 μmol, yield: 3.3%) as a white solid. LC-MS (ESI) m / z: 1135 [M+H] + 。 1 1H NMR (400 MHz, D2O) δ 7.81 (td, J = 8.7, 6.1 Hz, 3H), 7.64 (s, 1H), 7.48 (ddd, J = 7.3, 5.0, 1.8 Hz, 2H), 7.34 (dd, J = 8.5, 1.7 Hz, 1H), 4.87 (dd, J = 9.4, 5.5 Hz, 1H), 3.99 (dd, J = 8.3, 5.0 Hz, 1H), 3.92 (dd, J = 8.3, 4.7 Hz, 1H), 3.77 (d, J = 8.2 Hz, 3H), 3.66 (p, J = 6.6 Hz, 1H), 3.52 (s, 2H), 3.48 - 3.33 (m, 10H), 3.22 - 3.01 (m, 12H), 2.89 (s, 2H), 2.29 (dd, J = 8.7, 7.1 Hz, 2H), 2.07 - 1.93 (m, 1H), 1.90 - 1.75 (m, 1H), 1.67 - 1.54 (m, 7H), 1.54 - 1.33 (m, 9H), 1.19 (dt, J = 15.4, 6.6 Hz, 2H).

[0461] E2: (S)-2-(3-((S)-5-((S)-3-(anthracen-9-yl)-2-((3,4-dioxo-2-((4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)bicyclo[2.2.2]octan-1-yl)amino)cyclobut-1-ene-1-yl)amino)propanamido)-1-carboxypentyl)ureido)adipic acid (Method B)

[0462]

[0463] Step 1

[0464] To a solution of 3,4 - diethoxycyclobut - 3 - ene - 1,2 - dione (0.92 mL, 6.19 mmol) in THF (15 mL) was added TEA (1.036 mL, 7.43 mmol) and D7 (630.00 mg, 2.48 mmol). The mixture was stirred under N2 at room temperature for 3 h. The resulting mixture was concentrated to give a crude product, and the crude product was purified by silica gel column chromatography to give E2 - 1 (750.00 mg, 1.98 mmol, yield: 80.0%) as a colorless oil. LC - MS (ESI) m / z: 379 [M + H] + 。

[0465] Step 2

[0466] To a solution of E2 - 1 (100.00 mg, 0.13 mmol) in THF (0.5 mL) was added DIEA (0.093 mL, 0.534 mmol) and D4 (50.50 mg, 0.13 mmol). The mixture was stirred under N2 at 70 °C for 48 h. The reaction was quenched with H2O (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, and the crude product was purified by silica gel column chromatography to give E2 - 2 (68.00 mg, 0.063 mmol, yield: 47.1%) as a yellow oil. LC - MS (ESI) m / z: 1081 [M + H] + 。

[0467] Step 3

[0468] A solution of E2 - 2 (68.00 mg, 0.063 mmol) in DCM (1 mL) and TFA (1 mL) was stirred under N2 at 25 °C for 2 h. The reaction mixture was concentrated to give E2 - 3 (48.00 mg, 0.059 mmol, yield: 93.6%) as a yellow oil. LC - MS (ESI) m / z: 813 [M + H] + 。

[0469] Step 4

[0470] To a solution of E2 - 3 (49.00 mg, 0.060 mmol) in DMF (0.5 mL) was added TEA (0.042 mL, 0.31 mmol) and DOTA - PNP (31.70 mg, 0.060 mmol). The mixture was stirred under N2 at 25 °C for 5 h. The crude product was purified by preparative HPLC (method 3) to give E2 (9.50 mg, 7.60 μmol, yield: 12.6%) as a white solid. LC - MS (ESI) m / z: 1199 [M + H]+ . 1 1H NMR (400 MHz, D2O) δ 8.46 (s, 1H), 8.34 - 8.23 (m, 2H), 8.09 - 7.99 (m, 2H), 7.66 - 7.42 (m, 4H), 4.95 - 4.83 (m, 1H), 4.27 - 4.18 (m, 1H), 4.13 - 4.06 (m, 1H), 4.06 - 3.96 (m, 2H), 3.89 - 3.71 (m, 4H), 3.55 - 3.51 (m, 2H), 3.47 - 3.33 (m, 11H), 3.26 - 3.17 (m, 2H), 3.16 - 3.04 (m, 8H), 2.97 - 2.89 (m, 2H), 2.27 - 2.19 (m, 2H), 1.93 - 1.86 (m, 1H), 1.76 - 1.67 (m, 2H), 1.62 - 1.51 (m, 9H), 1.49 - 1.37 (m, 7H), 1.32 - 1.22 (m, 2H).

[0471] E3: (4S, 8S, 15S)-16-(Anthracen-9-yl)-15-((3,4-dioxocyclobut-1-en-1-yl)amino)-1,6,14-trioxo-2,5,7,13-tetraazacyclohexadecane-1,4,8-tricarboxylic acid (Method C)

[0472]

[0473] Step 1

[0474] To a solution of E2-1 (407.00 mg, 1.08 mmol) in toluene (5 mL) was added DIEA (0.75 mL, 4.30 mmol) and methyl (S)-2-amino-3-(anthracen-9-yl)propionate hydrochloride (340.00 mg, 1.08 mmol). The mixture was stirred at 70 °C under N2 atmosphere for 16 h. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography to give E3-1 (500.00 mg, 0.82 mmol, yield: 76.0%) as a white solid. LC-MS (ESI) m / z: 612 [M + H] + .

[0475] Step 2

[0476] At 0 °C, LiOH (19.57 mg, 0.82 mmol) and H2O2 (0.08 mL, 0.82 mmol) were added to a solution of E3-1 (250.00 mg, 0.41 mmol) in THF (3 mL) and water (1 mL). The mixture was stirred at 30 °C under a N2 atmosphere for 4 hours. The reaction was quenched with an aqueous Na2S2O3 solution (5 mL) at 0 °C, and then the pH was adjusted to 5 with 1 N HCl. The aqueous layer was extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product E3-2 (240.00 mg, 0.40 mmol) as a yellow solid. LC-MS (ESI) m / z: 598 [M+H] + 。

[0477] Step 3

[0478] To a solution of E3-2 (100.00 mg, 0.17 mmol) in DMF (2 mL) were added D5-6 (104.00 mg, 0.20 mmol), HATU (63.60 mg, 0.17 mmol), and DIEA (0.03 mL, 0.17 mmol). The mixture was stirred at room temperature under N2 for 1 hour. The reaction mixture was quenched with water (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography to give E3-3 (72.00 mg, 0.07 mmol, yield: 39.3%) as a colorless oil. LC-MS (ESI) m / z: 1097 [M+H] + 。

[0479] Step 4

[0480] To a solution of E3-3 (72.00 mg, 0.07 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol). The mixture was stirred at 30 °C under N2 for 1 hour. The mixture was evaporated under reduced pressure to give the crude E3-4 (55.00 mg, 0.07 mmol) as a brown oil. LC-MS (ESI) m / z: 828 [M+H] + 。

[0481] Step 5

[0482] To a solution of E3-4 (55.00 mg, 0.07 mmol) in DMF (1 mL) and water (0.3 mL) was added DOTA-PNP (52.40 mg, 0.10 mmol) and DIEA (0.05 mL, 0.27 mmol). The mixture was stirred under N2 at room temperature for 2 h. The resulting mixture was concentrated to give the crude material, which was purified by preparative HPLC (Method 1) to give the title compound E3 (27.00 mg, 0.02 mmol, yield: 33.3%) as a white solid. LC-MS (ESI) m / z: 1214 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 8.49 - 8.39 (m, 2H), 8.19 - 8.11 (m, 2H), 8.07 - 8.01 (m, 3H), 7.76 (s, 1H), 7.56 - 7.45 (m, 4H), 6.42 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 5.08 - 4.96 (m, 1H), 4.33 - 4.20 (m, 1H), 4.06 - 3.88 (m, 2H), 3.78 - 3.67 (m, 3H), 3.62 (s, 6H), 3.44 - 3.38 (m, 2H), 3.21 - 3.12 (m, 4H), 3.06 - 2.96 (m, 10H), 2.93 - 2.89 (m, 2H), 2.85 - 2.77 (m, 2H), 2.75 - 2.65 (m, 2H), 1.83 - 1.70 (m, 6H), 1.51 - 1.40 (m, 6H), 1.36 - 1.24 (m, 2H), 0.96 - 0.77 (m, 4H).

[0483] E4: (S)-2-(3-((S)-5-((S)-3-(Anthracen-9-yl)-2-((3,4-dioxo-2-((4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)bicyclo[2.2.2]octan-1-yl)amino)cyclobut-1-ene-1-yl)amino)propanamido)-1-carboxypentyl)ureido)adipic acid (Method D)

[0484]

[0485] Step 1

[0486] To a solution of D10 (150.00 mg, 0.22 mmol) in THF (1 mL) was added 3,4 - diethoxycyclobut - 3 - ene - 1,2 - dione (44.10 mg, 0.26 mmol), DIEA (0.15 mL, 0.86 mmol). The mixture was stirred at 25 °C under N2 for 4 h. The reaction was quenched with water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give E4 - 1 (149.00 mg, 0.18 mmol, yield: 84.3%) as a colorless oil. LC - MS (ESI) m / z: 819 [M + H] + 。

[0487] Step 2

[0488] To a solution of E4 - 1 (140.00 mg, 0.17 mmol) in EtOH (1.5 mL) was added D4 (90.00 mg, 0.12 mmol), TEA (0.071 mL, 0.51 mmol). The mixture was stirred at 70 °C under N2 for 16 h. The reaction was quenched with water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give E4 - 2 (54.00 mg, 0.035 mmol, yield: 20.8%) as a yellow oil. LC - MS (ESI) m / z: 1522 [M + H] + 。

[0489] Step 3

[0490] A solution of E4 - 2 (54.00 mg, 0.035 mmol) in TFA (0.5 mL), triisopropylsilane (0.013 mL, 0.035 mmol) and water (0.013 mL, 0.72 mmol) was stirred at 25 °C under N2 for 16 h. The resulting mixture was concentrated to give a crude material, which was purified by preparative HPLC (method 3) to give the title compound E4 (3.00 mg, 2.44 μmol, yield: 6.9%) as a white solid. LC - MS (ESI) m / z: 1185 [M + H] + 。 11H NMR (400 MHz, D2O) δ 8.56 (s, 1H), 8.38 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H), 7.87 - 7.58 (m, 4H), 4.98 - 4.95 (m, 1H), 4.29 (d, J = 11.7 Hz, 2H), 4.21 - 4.11 (m, 3H), 4.08 - 4.04 (m, 1H), 3.87 (s, 1H), 3.71 - 3.58 (m, 2H), 3.56 - 3.42 (m, 4H), 3.42 - 3.31 (m, 2H), 3.19 (d, J = 28.4 Hz, 5H), 3.12 - 3.03 (m, 1H), 2.96 - 2.65 (m, 5H), 2.46 - 2.18 (m, 5H), 2.06 - 1.93 (m, 5H), 1.84 - 1.67 (m, 7H), 1.64 - 1.54 (m, 4H), 1.54 - 1.43 (m, 2H), 1.42 - 1.24 (m, 5H).

[0491] E6: (((S)-1-Carboxy-5-((S)-2-((3,4-dioxo-2-((4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)bicyclo[2.2.2]oct-1-yl)amino)cyclobut-1-ene-1-yl)amino)-3-(naphthalen-2-yl)propanamido)pentyl)carbamoyl)-L-glutamic acid (Method A)

[0492]

[0493] Step 1:

[0494] To a solution of D10 (103.00 mg, 0.15 mmol) in EtOH (0.5 ml) was added DIEA (0.086 ml, 0.49 mmol) and D6 (100.00 mg, 0.12 mmol). The mixture was stirred at 80 °C under N2 for 20 h. The reaction was quenched with H2O (5 mL). The aqueous layer was extracted with EA (5 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give the title compound E6-1 as a yellow oil (150.00 mg, 0.10 mmol, yield: 83.0%). LC-MS (ESI) m / z: 1458 [M + H] + .

[0495] Step 2:

[0496] E6-1 (100.00 mg, 0.069 mmol) was stirred in a solution of TFA (0.95 mL), TIPS (0.025 mL) and water (<0.025 mL) at 25 °C under N2 for 12 h. The resulting mixture was concentrated to give the crude material, which was purified by preparative HPLC (Method 1) to afford the title compound E6 as a white solid (10.00 mg, 8.84 μmol, yield: 12.9%). LC-MS (ESI) m / z: 1121.51 [M+H] + 。 1 1H NMR (400 MHz, D2O) δ 7.99 - 7.19 (m, 7H), 5.04 - 4.88 (m, 1H), 4.34 - 4.23 (m, 1H), 4.13 - 4.04 (m, 1H), 4.00 - 3.59 (m, 8H), 3.56 - 2.87 (m, 19H), 2.58 - 2.45 (m, 2H), 2.31 - 2.08 (m, 2H), 2.09 - 1.67 (m, 13H), 1.68 - 1.48 (m, 2H), 1.41 - 1.03 (m, 4H).

[0497] E7: (S)-2-(3-((S)-5-((S)-3-(Anthracen-9-yl)-2-((3,4-dioxido-2-((4-(5-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)-1,3,4-oxadiazol-2-yl)bicyclo[2.2.2]octan-1-yl)amino)cyclobut-1-ene-1-yl)amino)propanamido)-1-carboxypentyl)ureido)adipic acid

[0498]

[0499] Step 1:

[0500] To a solution of 3,4-diethoxycyclobut-3-ene-1,2-dione (0.134 mL, 0.90 mmol) in THF (8 mL) was added D9 (260.00 mg, 0.36 mmol) and TEA (0.15 mL, 1.08 mmol). The mixture was stirred at 27 °C under N2 for 12 h. The resulting mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to afford the title compound as a yellow oil (280.00 mg, 0.33 mmol, 92% yield). LC-MS (ESI) m / z: 843.9 [M+H] + 。

[0501] Step 2:

[0502] To a solution of D4 (100.00 mg, 0.13 mmol) in THF (0.5 mL) was added TEA (0.074 mL, 0.534 mmol) and E7-1 (113.00 mg, 0.13 mmol). The mixture was stirred at 50 °C under N2 for 2 days. The resulting mixture was quenched with H2O (5 mL). The aqueous layer was extracted with EA (2 mL). The organic layer was washed with brine (1 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound E7-2 (71.00 mg, 0.046 mmol, 34.4% yield). LC-MS (ESI) m / z: 1546.2 [M+H] + .

[0503] Step 3:

[0504] A solution of E7-2 (71.00 mg, 0.046 mmol) in TFA (0.95 mL), TIPS (0.025 mL) and water (0.025 mL) was stirred at 25 °C under N2 for 12 h. The resulting mixture was concentrated to give a residue, which was purified by preparative HPLC (Method 3) to give the title compound E7 as a white solid (23.00 mg, 0.019 mmol, 40.5% yield). LC-MS (ESI) m / z: 1209.9 [M+H] + . 1 1H NMR (400 MHz, D2O) δ 8.51 (s, 1H), 8.35 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.73 - 7.53 (m, 4H), 4.98 - 4.87 (m, 1H), 4.36 (s, 2H), 4.25 - 4.17 (m, 1H), 4.12 - 4.04 (m, 3H), 3.99 - 3.85 (m, 4H), 3.65 - 3.37 (m, 10H), 3.31 - 3.22 (m, 2H), 3.20 - 2.94 (m, 8H), 2.31 - 2.23 (m, 2H), 2.10 - 1.96 (m, 6H), 1.88 - 1.56 (m, 12H), 1.48 - 1.41 (m, 2H), 1.36 - 1.30 (m, 2H).

[0505] The following compounds were prepared using procedures similar to those described in the examples above. As will be appreciated by those skilled in the art, these similar examples may involve variations in the general reaction conditions. The method column indicates the preparation method described above for preparing the compound.

[0506]

[0507]

[0508]

[0509]

[0510]

[0511] E17 and E18: (((1S)-1-carboxy-5-(3-(naphthalen-2-yl)-2-((5-(4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)methyl)bicyclo[2.2.2]octan-1-yl)-1,3,4-oxadiazol-2-yl)amino)propanamido)pentyl)carbamoyl)-L-glutamic acid (Method E)

[0512]

[0513] Step 1

[0514] Stir a mixture of D3 (1.00 g, 3.53 mmol) and CDI (1.14 g, 7.06 mmol) in THF (15 ml) at 25 °C for 1 hour. Thereafter, add the mixture to hydrazine·H2O (0.554 ml, 17.64 mmol) and stir the mixture at 25 °C for an additional 1 hour. Wash the reaction mixture with H2O (10 mL × 3) and extract with ethyl acetate (10 mL x 3). Concentrate the combined organic layers in vacuo to give E17-1 (1.20 g, 4.03 mmol, 114% yield) as a colorless oil. LCMS (ESI): [M+H] + = 298.20.

[0515] Step 2

[0516] Add E17-2 (0.771 g, 3.36 mmol) to a mixture of triphosgene (0.998 g, 3.36 mmol) in DCM (15 mL). Stir the mixture at 25 °C for 1 hour and then add E17-1 (1.00 g, 3.36 mmol) to the mixture and stir it for an additional 1 hour. Concentrate the reaction mixture to give a crude product, which is purified by silica gel column chromatography to give E17-3 (900 mg, 1.484 mmol, 44.1% yield) as a white solid. LCMS (ESI): [M+H] + = 553.20

[0517] Step 3

[0518] To a mixture of E17-3 (500 mg, 0.905 mmol), TEA (0.252 ml, 1.809 mmol) in DCM (3 ml) was added Ts-Cl (259 mg, 1.357 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography to give E17-4 (300 mg, 0.905 mmol, 47.6% yield) as a white solid. LCMS (ESI): [M+H] + = 535.10

[0519] Step 4

[0520] A solution of E17-4 (200 mg, 0.374 mmol) and LiOH (8.96 mg, 0.374 mmol) in MeOH (2 ml) and water (1 ml) was stirred at 25 °C for 3 h. The mixture was adjusted to pH = 5 with HCl (1 M) and extracted with EA (10 mL×2). The combined organic layers were washed with brine (10 mL×1), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product E17-5 (150 mg, 0.288 mmol, 77% yield). LCMS (ESI) [M+H] + = 521.20

[0521] Step 5

[0522] To a solution of E17-5 (150 mg, 0.288 mmol) in DMF (2 ml) was added HATU (131 mg, 0.346 mmol), DIEA (0.101 ml, 0.576 mmol) and D5-6 (155 mg, 0.317 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (Biotage flash), eluting with DCM:MeOH = 20 / 1, collected and concentrated in vacuo to give E17-6 (170 mg, 0.141 mmol, 48.8% yield) as a colorless oil. LCMS (ESI): [M+H] + = 990.40

[0523] Step 6

[0524] A mixture of E17-6 (170 mg, 0.172 mmol) in TFA (3 ml) was stirred at 25 °C for 5 h. The mixture was concentrated to give crude E17-7 (100 mg, 0.139 mmol, 81% yield). LCMS (ESI): [M+H] + = 722.30。

[0525] Step 7

[0526] To a solution of E17 - 7 (100 mg, 0.139 mmol) in DMSO (5 ml) was added DIEA (0.048 ml, 0.278 mmol) and DOTA - PNP (72.8 mg, 0.139 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated to give a crude product, and the crude product was purified by preparative HPLC (Method 3) to give the first eluate in the form of isomer 1E17 as a white solid (8 mg, 7.08 μmol, 5.11% yield) and the second eluate in the form of isomer 2E18 (5 mg, 0.044 mmol, 32.0% yield).

[0527] E17: LCMS (ESI): [M + 2H] 2+ / 2 = 554.80. 1 H NMR (400 MHz, DMSO - d6) δ ppm 8.05 - 8.20 (m, 1H) 7.82 (br.s., 4H) 7.46 (br.s., 3H) 7.11 - 7.26 (m, 1H) 6.60 - 6.71 (m, 1H) 6.22 - 6.39 (m, 2H) 4.17 - 4.34 (m, 2H) 3.98 - 4.16 (m, 3H) 3.61 - 3.68 (m, 3H) 2.86 - 3.06 (m, 14H) 2.71 - 2.81 (m, 3H) 2.22 - 2.37 (m, 5H) 1.97 - 2.08 (m, 4H) 1.68 - 1.78 (m, 5H) 1.40 - 1.53 (m, 8H) 1.25 (br.s., 6H) 0.85 - 0.90 (m, 2H).

[0528] E18: LCMS (ESI): [M + 2H] 2+ / 2 = 554.80. 1 H NMR (400 MHz, DMSO - d6) δ ppm 11.23 - 13.48 (m, 6H) 8.67 - 8.93 (m, 1H) 8.16 (br.s., 1H) 7.72 - 7.95 (m, 4H) 7.32 - 7.59 (m, 3H) 6.34 (d, J = 8.33 Hz, 2H) 4.21 - 4.42 (m, 2H) 3.93 - 4.20 (m, 3H) 3.61 (br.s., 8H) 3.07 - 3.22 (m, 7H) 2.76 - 3.06 (m, 10H) 2.57 - 2.76 (m, 2H) 2.26 (dd, J = 15.31, 7.79 Hz, 6H) 1.81 - 2.03 (m, 2H) 1.51 - 1.79 (m, 7H) 1.10 - 1.51 (m, 9H).

[0529] E21: (4S,8S,15S)-15-((3,4-dioxo-2-((4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)bicyclo[2.2.2]oct-1-yl)amino)cyclobut-1-ene-1-yl)amino)-16-(naphthalen-2-yl)-1,6,14-trioxo-2,5,7,13-tetraazacyclohexadecane-1,4,8-tricarboxylic acid (Method E)

[0530]

[0531] Step 1:

[0532] To a solution of E21-1 (800.00 mg, 0.98 mmol) in EtOH (8 ml) was added DIEA (0.51 ml, 2.93 mmol) and E21-2 (224.00 mg, 0.98 mmol). The mixture was stirred at 70 °C under N2 for 8 h. The resulting mixture was concentrated to give a crude product, which was purified by flash chromatography to give the title compound E21-3 (527.00 mg, 0.53 mmol, yield: 53.8%) as a yellow solid. LC-MS (ESI) m / z: 1002 [M+H] + .

[0533] Step 2:

[0534] To a solution of E21-3 (500.00 mg, 0.50 mmol) in THF (5 ml) at 0 °C was added 1N NaOH (1.00 ml, 1.00 mmol). The mixture was stirred at room temperature under N2 for 4 h. Then the mixture was evaporated under reduced pressure to give the title compound E21-4 (520.00 mg, 0.53 mmol, crude) as a yellow solid. LC-MS (ESI) m / z: 988 [M+H] + .

[0535] Step 3:

[0536] To a solution of E21-4 (350.00 mg, 0.35 mmol) in DMF (3 mL) was added DIEA (0.31 mL, 1.77 mmol), E21-5 (183.00 mg, 0.35 mmol) and HATU (269.00 mg, 0.71 mmol). The mixture was stirred for 2 h at room temperature under N2. The resulting mixture was quenched with saturated NH4Cl (aqueous solution). The aqueous layer was extracted with EA (25 mL). The combined organic layers were washed with saturated NaHCO3 (aqueous solution) (50 mL×1). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound E21-6 (155.00 mg, 0.10 mmol, 29.4% yield). LC-MS (ESI) m / z: 1487 [M+H] + 。

[0537] Step 4:

[0538] A solution of E21-6 (100.00 mg, 0.07 mmol) in TFA (0.95 mL), TIPS (0.025 mL) and water <0.025 mL) was stirred at 25 °C under N2 for 5 h. The resulting mixture was concentrated to give the crude material, which was purified by preparative HPLC (Method 3) to give the title compound E21 as a pale yellow solid (25.00 mg, 0.02 mmol, yield: 32.0%). LC-MS (ESI) m / z: 1150 [M+H] + 。 1 1H NMR (400 MHz, D2O) δ 7.77 - 7.69 (m, 3H), 7.55 (s, 1H), 7.45 - 7.36 (m, 2H), 7.27 - 7.23 (m, 1H), 4.82 - 4.75 (m, 1H), 4.13 - 4.03 (m, 1H), 3.86 - 3.64 (m, 5H), 3.52 - 3.40 (m, 2H), 3.37 - 3.23 (m, 13H), 3.16 - 2.95 (m, 11H), 1.87 - 1.76 (m, 6H), 1.73 - 1.60 (m, 6H), 1.56 - 1.48 (m, 1H), 1.44 - 1.23 (m, 3H), 1.14 - 1.02 (m, 2H).

[0539] E22: (4S,8S,15S)-16-(anthracen-9-yl)-1,6,14-trioxo-15-((6-((4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)bicyclo[2.2.2]octan-1-yl)amino)pyrimidin-4-yl)amino)-2,5,7,13-tetraazapentadecan-1,4,8-tricarboxylic acid (Method F)

[0540]

[0541] Step 1:

[0542] To a solution of E22-2 (2.00 g, 8.41 mmol) in DMF (20 mL) was added K2CO3 (3.49 g, 25.20 mmol) and E22-1 (2.02 g, 8.41 mmol). The mixture was stirred at 80 °C under N2 for 10 h. The resulting mixture was quenched with H2O (20 mL). The aqueous layer was extracted with EA (100 mL × 2). The combined organic layers were washed with brine (200 mL × 1), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography to give the title compound E22-3 (1.10 g, 2.77 mmol, yield: 32.9%) as a white solid. LC-MS (ESI) m / z: 397 [M+H] + .

[0543] Step 2:

[0544] To a solution of E22-3 (0.50 g, 1.26 mmol) in 1,4-dioxane (5 mL) was added (S)-ethyl 2-amino-3-(anthracen-9-yl)propionate (0.37 g, 1.26 mmol), tBuBrettPhos Pd G6 TES (0.11 g, 0.13 mmol) and potassium tert-butoxide (0.42 g, 3.78 mmol). The mixture was stirred at 110 °C under N2 for 1 h. The reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EA (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography to give the title compound E22-4 (210.00 mg, 0.36 mmol, yield: 28.7%) as a yellow solid. LC-MS (ESI) m / z: 582 [M+H] + .

[0545] Step 3:

[0546] To a solution of E22-4 (100.00 mg, 0.17 mmol) in DCM (1 mL) was added 1,4-dioxane containing HCl (1.07 mL, 4.30 mmol). The mixture was stirred at 25 °C under N2 for 2 h. The mixture was then evaporated under reduced pressure to give the title compound E22-5 (80.00 mg, 0.15 mmol, crude). LC-MS (ESI) m / z: 482 [M+H] + 。

[0547] Step 3:

[0548] To a solution of E22-5 (150.00 mg, 0.31 mmol) in DMF (1 mL) was added DIEA (0.21 ml, 1.25 mmol), D5-6 (241.00 mg, 0.47 mmol) and T3P (0.37 mL, 0.62 mmol). The mixture was stirred at 50 °C under N2 for 1 h. The crude product was purified by a C18 reverse-phase column to give the title compound E22-6 (110.00 mg, 0.11 mmol, yield: 36.0%) as a yellow solid. LC-MS (ESI) m / z: 980 [M+H] + 。

[0549] Step 4:

[0550] To a solution of E22-7 (61.40 mg, 0.11 mmol) in DMF (0.2 mL) was added DIEA (0.08 mL, 0.43 mmol), HATU (81.00 mg, 0.21 mmol) and E22-6 (105.00 mg, 0.11 mmol). The mixture was stirred at 25 °C under N2 for 1 h. The reaction was quenched with H2O (10 mL). The aqueous layer was extracted with EA (5 mL×4). The combined organic layers were washed with brine (25 mL×3), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography to give the title compound E22-8 (75.00 mg, 0.05 mmol, yield: 45.6%) as a yellow solid. LC-MS (ESI) m / z: 1535 [M+H] + 。

[0551] Step 4:

[0552] To E22-8 (75.00 mg, 0.05 mmol) were added TFA (0.6 mL), TIPS (0.02 mL), and water (0.02 mL). The mixture was stirred at 25 °C under N2 for 16 h. The mixture was then evaporated under reduced pressure to give a crude product. The compound was purified by preparative HPLC (Method 3) to give the title compound E22 (6.00 mg, 4.83 μmol, yield: 9.9%) as a white solid. LC-MS (ESI) m / z: 1198 [M+H] + 。 1 H NMR (400 MHz, D2O) δ 8.33 - 8.08 (m, 2H), 7.94 - 7.68 (m, 3H), 7.61 - 7.05 (m, 6H), 4.34 - 4.17 (m, 2H), 4.01 - 3.68 (m, 5H), 3.64 - 3.46 (m, 6H), 3.41 - 3.23 (m, 9H), 3.18 - 2.90 (m, 10H), 2.04 - 1.73 (m, 8H), 1.65 - 1.44 (m, 6H), 1.32 - 1.09 (m, 3H), 0.94 - 0.63 (m, 2H).

[0553] E23: (((S)-1-Carboxy-5-((S)-3-(naphthalen-2-yl)-2-((4-((4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)bicyclo[2.2.2]octan-1-yl)amino)-1,3,5-triazin-2-yl)amino)propanamido)pentyl)carbamoyl)-L-glutamic acid (Method G)

[0554]

[0555] Step 1:

[0556] To a solution of E23-1 (500.00 mg, 0.72 mmol) in ACN (20 mL) were added E23-2 (265.00 mg, 1.44 mmol) and Na2CO3 (229.00 mg, 2.16 mmol). The mixture was stirred at 10 °C under N2 for 12 h. The resulting mixture was concentrated to give a crude product, and the crude product was purified by flash chromatography to give the title compound E23-3 (111.00 mg, 0.13 mmol, yield: 18.3%) as a yellow solid. LC-MS (ESI): 842 [M+H] + 。

[0557] Step 2:

[0558] To a solution of E23-3 (100.00 mg, 0.12 mmol) in DMF (1 ml) was added D2 (81.00 mg, 0.12 mmol) and DIEA (0.062 ml, 0.36 mmol). The mixture was stirred at 100 °C under N2 for 2 h. The reaction was quenched with H2O (3 mL). The aqueous layer was extracted with EA (5 mL×2). The combined organic layers were washed with brine (5 mL×1), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography to give the title compound E23-4 (51.00 mg, 0.034 mmol, yield: 28.8%) as a colorless oil. LC-MS (ESI): 1491 [M+H] + 。

[0559] Step 3:

[0560] To a solution of E23-4 (51.00 mg, 0.034 mmol) in MeOH (2 ml) was added 10% wet Pd / C (3.64 mg, 0.034 mmol). The mixture was stirred at 60 °C under H2 for 12 h. The resulting mixture was filtered and concentrated to give the title compound E23-5 (12.00 mg, 0.034 mmol, yield: 24.1%) as a white solid. LC-MS (ESI): 1457 [M+H] + 。

[0561] Step 4:

[0562] To a solution of E23-5 (5.00 mg, 3.43 μmol) in TFA (0.95 ml) was added TIPS (0.025 ml) and water (0.025 ml). The mixture was stirred at 25 °C under N2 for 1 h. Then the resulting mixture was concentrated to give a residue, which was purified by preparative HPLC (method 3) to give the title compound E23 (0.60 mg, 0.48 μmol, yield: 14.1%) as a white solid. LC-MS (ESI): 1120 [M+H] + 。 11H NMR (400 MHz, D2O) δ 7.97 - 7.70 (m, 5H), 7.50 - 7.35 (m, 3H), 4.00 - 3.95 (m, 1H), 3.87 - 3.81 (m, 1H), 3.73 - 3.67 (m, 2H), 3.38 - 3.21 (m, 9H), 3.15 - 2.92 (m, 12H), 2.76 - 2.59 (m, 4H), 2.31 - 2.19 (m, 4H), 1.89 - 1.81 (m, 12H), 1.55 - 1.45 (m, 2H), 1.26 - 1.22 (m, 2H), 1.19 - 1.17 (m, 2H), 1.04 - 0.98 (m, 2H).

[0563] The following compounds were prepared using procedures similar to those described in the examples above. As will be appreciated by those skilled in the art, these similar examples may involve variations of the general reaction conditions. The Method column indicates the preparation methods described above for preparing the compounds.

[0564]

[0565]

[0566] Naalad enzyme assay

[0567] A fluorescence-based assay was used to determine the inhibition of Naalad enzyme activity. Briefly, a solution containing 40 μM of the substrate N-acetyl-Asp-Glu (Sigma-Aldrich) and the compound at a concentration ranging from 0.15 nM to 1000 nM was mixed in equal volume with 0.4 μg / mL of recombinant human PSMA (rhPSMA, Sino Biological) in assay buffer (50 mM HEPES, 100 mM NaCl, pH 7.5). The enzyme reaction was carried out by incubating at 37 °C for one hour and then the reaction was stopped by heating at 95 °C for 5 minutes. A solution of 15 mM ortho-phthalaldehyde (Sigma-Aldrich) was added to all vials and incubated at ambient temperature for 10 minutes. The reaction solution was loaded onto a 96-well flat-bottom clear black microplate (Corning) and read using a microplate reader (Tecan) at excitation and emission wavelengths of 330 and 450 nm, respectively. The data was analyzed by the single-point total binding regression algorithm of GraphPad Prism (GraphPad Software).

[0568] Example <![CDATA[IC 50 (nM)]]> Example <![CDATA[IC 50 (nM)]]> PSMA-617 2.4 E14 1.7 HTK03149 1.6 E15 0.8 E1 3.3 E16 3.5 E2 4.0 E17 3.5 E3 1.2 E18 3.7 E4 1.4 E20 1.8 E5 3.0 E21 1.5 E6 1.5 E22 4.9 E7 2.1 E24 8.6 E8 1.6 E25 23.1 E9 1.0 E26 9.5 E10 1.7 E27 26.6 E11 10.0 E28 2.1 E12 0.9 E13 1.7

[0569] PSMA-617 has the following structure:

[0570]

[0571] HTK03149 (described in WO 2020 / 252598) has the following structure:

[0572]

[0573] Radiochemistry

[0574] 177 Lu labeling: The precursor was mixed with 177 a stock solution of LuCl3 (Isotopia) at a molar ratio of 5:1 to 10:1 in a solution (pH 4.76) containing 0.41 mg / mL sodium acetate and 0.3 mg / mL glacial acetic acid, or 4.37 mg / ml sodium acetate and 1 mg / ml gentisic acid. The mixture was then incubated at 70 °C for 30 minutes.

[0575] 68Ga labeling: Elute with 0.05 M HCl from 68 Ge / 68 a Ga generator (Isotope Technologies Garching) to obtain 68 a GaCl3 solution (1.0 mL, 370 MBq). After incubating 20 μg of the precursor with 20 mCi 68 GaCl3 at 95 °C for 20 minutes, the 68 Ga-labeled compound was prepared in sodium acetate buffer (1 M, pH 4.2). Quality standards: RCP > 98% (iTLC), specific activity > 0.75 mCi / μg, and activity > 1 mCi / ml.

[0576] 212 Pb / 203 Pb labeling: The standard protocol can be found in WO 2021 / 154921A1, which is incorporated herein by reference.

[0577] 225 Ac labeling: The standard protocol can be found in WO2023 / 191839A2, which is incorporated herein by reference.

[0578] Radiochemical purity (RCP) determination.

[0579] The RCP was measured by radio-iTLC. Briefly, the 177Compounds labeled with Lu were spotted on iTLC-silica chromatographic paper (Agilent) and developed in a mobile phase of 0.05 M citric acid / sodium citrate (pH 4.0). The developed bands were scanned with a radio iTLC scanner (Echert & Ziegler) or cut into 10 equal slices and the activity was measured by a γ-counter (Zonkia). The RCP acceptance criterion was ≥90%.

[0580] Cell uptake assay

[0581] LNCaP (ATCC) cells were cultured in RPMI 1640 medium (Gibco) containing 10% fetal bovine serum (FBS) (Gibco) in a humidified incubator at 37.0 °C in 5% carbon dioxide (CO2). One day before the experiment, 2x10 5 LNCaP cells / well were seeded in 24-well plates. 7.4 KBq (200 nCi) of 177 Lu-labeled compound was added to each well and then incubated for different durations in a 37 °C, 5% CO2 incubator. At each time point, the supernatant, cell membrane fraction, and intracellular fraction were collected. The cell membrane fraction was recovered by incubating the cells with a buffer (pH 2.7) containing 50 mM glycine and 100 mM NaCl at 37 °C for 10 minutes, while the intracellular fraction was recovered from cells treated with 1 M NaOH. The activity of the 177 Lu-labeled compound in each fraction was detected by a γ-counter.

[0582]

[0583] * Presents the intracellular fraction at each time point

[0584] ** Presents the cell membrane fraction at each time point

[0585] Biodistribution in LnCAP or 22RV1 CDX tumor mouse models

[0586] LnCAP and 22RV1 CDX xenograft tumor models were generated by subcutaneously inoculating 5x10 6 cells / site in male SCID or nude mice (Vital River), respectively. Animals were housed according to IACUC guidelines and had free access to food and water. When the tumor size reached approximately 0.2 - 0.3 cm 3 , the animals were used for biodistribution studies. Approximately 1.10 - 1.85 MBq of 177 Lu]Lu-E7, 177 Lu]Lu-E8 or 177Lu]Lu-PSMA-617. At each time point, the animals were sacrificed and tissues were collected, weighed, and radioactivity measurements were performed using a gamma counter. The radioactivity in the tissues was presented as %ID / g (percentage of injected dose per gram). The data are shown in Tables 4 to 6, Figure 1 and Figure 2 in.

[0587] Table 4. 177 Lu]Lu-E8, 177 Lu]Lu-E7 and 177 Lu]Lu-PSMA-617 tissue biodistribution.

[0588]

[0589]

[0590]

[0591] Table 5. 177 Lu]Lu-E8 and 177 Lu]Lu-PSMA-617 tissue biodistribution.

[0592]

[0593]

[0594] Table 6A. 177 Lu]Lu-E8 tumor uptake AUC (%ID / g.hr) and T / NT (tumor / non-tumor) ratio in the LnCAP (A) tumor model

[0595]

[0596] Table 6B. 177 Lu]Lu-E8 tumor uptake AUC (%ID / g.hr) and T / NT (tumor / non-tumor) ratio in the 22Rv1 tumor model

[0597]

[0598] Study on the tumor suppression efficacy of 177 Lu]Lu-E8 in the LnCAP tumor model

[0599] Method. The LnCAP CDX xenograft mouse model was generated as described above. When the average tumor volume reached 300 mm 3For in vivo efficacy studies, animals were used. The animals were randomly divided into six groups (G1 to G6), with 8 animals / group, and were given normal saline as vehicle control, 7.4 and 18.5 MBq 177 Lu]Lu-PSMA-617, or 3.7, 7.4 and 18.5 MBq 177 Lu]Lu-E8. Tumor volume was measured and recorded twice a week. When the average tumor volume in the vehicle group reached more than 1000 mm 3 , the animals were euthanized and tumor tissues were collected and weighed. Tumor inhibitory efficacy was evaluated based on tumor volume or tumor weight at the end point.

[0600] Results. As Figure 4 shown in 177 Figure 5, 177 Lu]Lu-E8 inhibited tumor growth in a dose-dependent manner and was more significant than

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Claims

1. A compound of formula (I): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein: X is O, S or NH; Each Y is independently -CO2H, -SO2H, -SO3H, -OSO3H, -PO2H, -PO3H2, -OPO3H2 or L 1 is an optionally substituted C1-C6 alkylene group, wherein one or two -CH2- groups in the alkylene group are independently optionally replaced by -NHC(=O)-*, -C(=O)NH-*, -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-* or -NH-, wherein * refers to a group facing toward L 1 The adjacent Y direction; L 2 is an optionally substituted C1-C6 alkylene group, wherein one or two -CH2- groups in the alkylene group are independently optionally replaced by: -O-, -S-, C3-C6 cycloalkylene group, C3-C6 cycloalkenylene group, or 3- to 6-membered heterocyclylene group; L 3 -(C=O)-NR 1 -*, -NR 1 -(C=O)-*, -C(=O)-, -O-, -S-, -SS-, -S-CH2-S-, -S(=O)-, -S(O)2-, NR 1 、-NR 1 -(C=O)-NR 1 -、-C(=O)-NR 1 -C(=O)-, -OC(=O)-NR 1 -*, -NR 1 C(=O)O-*、-OC(=S)-NR 1 -*, -NR 1 C(=S)O-*, -(C=O)-(3- to 10-membered optionally substituted N-containing ring)-*, or -(3- to 10-membered optionally substituted N-containing ring)-(C=O)-*, wherein * refers to the direction toward L 2 direction; L 4 is an optionally substituted C1-C6 alkylene group; G 1 Absent, -O-, -S-, -NR 4 -、-NR 4 -(C=O)-*, -(C=O)-NR 4 -*, or an optionally substituted C2-C6 alkylene group, wherein one or more -CH2- in the alkylene group is independently replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 4 、-(C=O)-NR 4 -* or -NR 4 -(C=O)-*, where * refers to the direction toward L 4 direction; G 2 and G 3 Each independently represents absence, -O-, -S-, -NR 1 -、-NR 1 -(C=O)-*, -(C=O)-NR 1 -*, -NR 1 -(C=S)-*, or an optionally substituted C1-C6 alkylene group, wherein one or more -CH2- in the alkylene group is independently optionally replaced by: -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, NR 1 、-(C=O)-NR 1 -*, -NR 1 -(C=O)-* or -NR 1 -(C=S)-*, where * refers to the direction towards G 1 direction; R 4 is H or an optionally substituted C1-C6 alkyl group; or R 4 and G 2 NR 1 Together with the intervening atoms, they form a 5- to 12-membered heterocyclyl ring; P 1 Does not exist, NR 8 、C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C 14 Cycloalkyl or 5- to 14-membered heterocyclyl; wherein the aryl, heteroaryl, cycloalkyl and heterocyclyl are independently optionally substituted; R 8 is independently H or optionally substituted C1-C6 alkyl; Ring W is a 5- to 10-membered heteroaryl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkenyl group, or a 5- to 14-membered heterocyclyl group; Ring A is C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C 14 Cycloalkyl or 5- to 14-membered heterocyclic group; Each R 1 is independently H or optionally substituted C1-C6 alkyl; Each R 2 is independently OH, halogen, oxo, C1-C6 alkyl, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, wherein each alkyl is independently optionally substituted with one or more OH, oxo or halogen; When valence permits, n is an integer from 0 to 6; L is absent or a linker; and Z is a radioactive moiety, a chelating agent, a fluorescent dye, a contrast agent, a cytostatic or cytotoxic agent, a cytokine, an immunomodulatory molecule, an amphiphilic substance, a nucleic acid, a viral structural protein, a protein, or biotin.

2. The compound of claim 1, wherein G 1 is O.

3. The compound of claim 1, wherein G 1 NR 4 .

4. The compound according to claim 1, which is a compound of formula (II-A), (II-B), (II-C) or (II-D): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein: Ring B is C6-C 10 Aryl, 5- to 10-membered heteroaryl, C3-C 14 Cycloalkyl or 5- to 14-membered heterocyclic group; Each R 2 is independently OH, halogen, oxo, C1-C6 alkyl, -O-(C1-C6 alkyl), -S-(C1-C6 alkyl), -NH2, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, wherein each alkyl is independently optionally substituted with one or more OH, oxo or halogen; and Each n is an integer from 0 to 6 when valence permits.

5. The compound according to any one of claims 1 to 4, wherein L 4 -(CH2) 0-3 CH(R 3 )(CH2) 0-3 -, or R 4 -(CH2) 1-3 -R 3a , where R 3 C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C3-C8 cycloalkyl or -(CH2) 0-3 -R 3a , where each R 3a Independently C6-C 20 Aryl, C3-C 14 cycloalkyl, 3- to 14-membered heterocyclyl, or 5- to 20-membered heteroaryl, and wherein R 3 or R 3a The alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl or heteroaryl in the 10 Aryl, C6-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclic group, C6-C 10 Aryloxy, C6-C 10 The group is substituted with a cycloalkyloxy group or a 5- to 10-membered heteroaryloxy group.

6. The compound of claim 5, wherein L 4 -(CH2)0-3CH(CH2R 3a )(CH2) 0-3 -.

7. A compound as described in any one of claims 1 to 6, wherein G 2 NR 1 or O.

8. A compound as described in any one of claims 1 to 6, wherein G 2 is non-existent or unsubstituted C1-C6 alkylene.

9. The compound of any one of claims 1 to 6, wherein G 2 is a C1-C6 alkylene group, wherein G 2 One or two of the -CH2- in the sequence are replaced by -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -NH-, -(C=O)-NH-*, -NH-(C=O)-*, or -NR 1 -(C=S)-*, where * refers to the direction towards G 1 direction.

10. The compound of claim 1, wherein the compound is a compound of formula (III-A), (III-B), (III-C), (III-D), (III-E), (III-F) or (III-G): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein: R 3a C6-C 20 Aryl, C3-C 14 cycloalkyl, 3- to 14-membered heterocyclyl, or 5- to 20-membered heteroaryl, and wherein R 3 or R 3a The alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl or heteroaryl in the 10 Aryl, C6-C 10 Cycloalkyl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclic group, C6-C 10 Aryloxy, C6-C 10 The group is substituted with a cycloalkyloxy group or a 5- to 10-membered heteroaryloxy group.

11. The compound of any one of claims 1 to 10, wherein G 3 is non-existent or unsubstituted C1-C6 alkylene.

12. The compound of any one of claims 1 to 10, wherein G 3 is a C1-C6 alkylene group, wherein G 3 One or more -CH2- in the formula (a) is replaced by -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-*, -NH-, -(C=O)-NH-*, -NH-(C=O)-*, or -NR 1 -(C=S)-*, where * refers to the direction towards G 1 direction.

13. A compound as described in any one of claims 1 to 12, wherein L 1 It is an unsubstituted C1-C6 alkylene group, or a C1-C6 alkylene group substituted by one or more halogen groups.

14. The compound of any one of claims 1 to 12, wherein L 1 is C1-C6 alkylene, and wherein L 1 One of the -CH2- in the above is replaced by -NHC(=O)-*, -C(=O)NH-*, -O-, -S-, -S(=O)2- or -S(=O)-, wherein * refers to the direction toward L. 1 adjacent to the Y direction.

15. The compound of any one of claims 1 to 12, wherein L 1 For -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2-NHC(=O)-, -CH2CH2-NHC(=O)-, -CH2CH2CH2-NHC(=O)-, -CH( OH)-, -CHF-, -CF2-, -CH(CH3)-, -C(CH3)2-, -CH2CH(OH)-, -CH2CHF-, -CHFCH2-, -CF2CH2-, -CH2CF2- , -CH(OH)CH2-, -CH2CH(OH)CH2-, -CH2CHFCH2-, -(CH2)2CH(OH)-, -(CH2)2CHF-, -CH2OCH2-, -CH2SC H2-, -CH(OH)CH2CH2-, -CH(CH3)-O-CH2-, -C(CH3)2-O-CH2-, -CH2-O-CH(CH3)-, -CH2-OC(CH3)2-, -C H2-S(O)-CH2-, -CH2-S(O)2-CH2-, -CH(CH3)-S-CH2-, -C(CH3)2-S-CH2-, -CH2-S-CH(CH3)-, -CH2-S C(CH3)2-, -CH(CH3)-S(O)-CH2-, -C(CH3)2-S(O)-CH2-, -CH2-S(O)-CH(CH3)-, -CH2-S(O)-C(CH3)2- , -CH(CH3)-S(O)2-CH2-, -C(CH3)2-S(O)2-CH2-, -CH2-S(O)2-CH(CH3)-, -CH2-S(O)2-C(CH3)2-, -C( =O)NH-CH2-, -NHC(=O)-CH2CH2-, -C(=O)NH-CH(CH3)-, -NHC(=O)-CH2CH2CH2- or -C(=O)NH-C(CH3)2-.

16. The compound of any one of claims 1 to 15, wherein L 2 It is a straight chain C1-C6 alkylene group.

17. The compound of claim 16, wherein L 2 It is -CH2CH2CH2CH2-.

18. A compound as described in any one of claims 1 to 17, wherein L 3 -(C=O)-NR 1 -* or -NR 1 -(C=O)-*, where * refers to the direction toward L 2 direction.

19. The compound of any one of claims 1 to 18, wherein X is O.

20. The compound of any one of claims 1 to 19, wherein all Y are COOH.

21. The compound of any one of claims 1 to 12, which is a compound of formula (IV-A1), (IV-A2), (IV-B1), (IV-B2), (IV-C1) or (IV-C2): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein a and b are each independently an integer of 1 to 5.

22. The compound of claim 21, wherein the compound is a compound of formula (V-A1), (V-A2), (V-A3), (V-B1), (V-B2), (V-B3), (V-C1), (V-C2) or (V-C3): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 6.

23. The compound according to claim 21 or 22, which is a compound of formula (V-A1′) or (V-B1′): or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof, wherein p is an integer from 0 to 6.

24. The compound of any one of claims 1 to 23, wherein ring W is a 5- to 10-membered heteroaryl group.

25. The compound as claimed in claim 24, wherein ring W is a 5-membered or 6-membered nitrogen-containing heteroaryl group.

26. The compound of any one of claims 1 to 23, wherein ring W is C3-C8 cycloalkenyl.

27. The compound of claim 26, wherein ring W is cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl.

28. The compound as claimed in any one of claims 1 to 23, wherein ring W is a 5- to 8-membered heterocyclyl.

29. The compound as claimed in claim 28, wherein ring W is a 5-membered or 6-membered nitrogen-containing heterocyclic group.

30. A compound as described in any one of claims 1 to 23, wherein for The connection to the left side is in the Z direction.

31. The compound of any one of claims 4 to 30, wherein ring B is a 5-membered or 6-membered heteroaryl.

32. The compound as claimed in claim 31, wherein Ring B is a 5-membered or 6-membered nitrogen-containing heteroaryl group.

33. The compound of claim 32, wherein ring B is The connection to the left side is in the Z direction.

34. The compound of any one of claims 1 to 33, wherein ring A is a fused, bridged or spiro C5-C 12 Cycloalkyl, fused, bridged or spiro 5- to 12-membered heterocyclic group, fused C 10 Aryl, or condensed 9-membered or 10-membered heteroaryl.

35. The compound of claim 34, wherein ring A is The connection to the left side is in the Z direction.

36. The compound of any one of claims 1 to 33, wherein ring A is a monocyclic C3-C8 cycloalkyl, or a monocyclic 3- to 6-membered heterocyclyl.

37. A compound as described in any one of claims 5 to 36, wherein R 3a C6-C 20 aryl, 5- to 20-membered heteroaryl or 3- to 14-membered heterocyclyl, wherein the aryl, heteroaryl and heterocyclyl are optionally substituted with one or more halogen, OH, C1-C6 alkyl, C6-C 10 Aryl, C6-C 10 Cycloalkyl, C6-C 10 The aryloxy group or a 3- to 8-membered heterocyclic group is substituted.

38. The compound of claim 37, wherein R 3a Phenyl, pyridyl, biphenyl, bipyridyl, anthracenyl, acridinyl, acenaphthenyl, indenyl, phenanthryl, propylene naphthyl, triphenylenyl, naphthyl, condensed tetraphenyl, or pyrene, where R 3a Optionally substituted with one or more halogen, OH or C1-C6 alkyl.

39. The compound of claim 37, wherein R 3a for 40. The compound of claim 39, wherein R 3a for 41. A compound as described in any one of claims 1 to 40, wherein R 1 For H.

42. A compound as described in any one of claims 1 to 40, wherein R 1 is C1-C6 alkyl, optionally substituted with one or more OH, halogen, oxo, replace.

43. A compound as described in any one of claims 1 to 42, wherein R 4 For H.

44. A compound as described in any one of claims 1 to 40, wherein R 4 and G 2 NR 1 Together with the intervening atoms they form a 5- to 8-membered heterocyclyl ring.

45. A compound as described in any one of claims 1 to 44, wherein each R 2 are independently OH, oxo, halogen, NH2 or C1-C6 alkyl.

46. ​​The compound of any one of claims 1 to 45, wherein each n is independently 0, 1 or 2.

47. A compound as described in any one of claims 1 to 46, wherein L is absent.

48. A compound as described in any one of claims 1 to 46, wherein L is a linker.

49. The compound of claim 48, wherein L comprises or is an optionally substituted C1-C 12 Alkylene, wherein one or more -CH2- in the alkylene is independently optionally replaced by: -NHC(=O)-*, -C(=O)NH-*, -NHC(=S)-*, -C(=S)NH-*, -O-, -S-, -S(=O)2-, -S(=O)-, -C(=O)-, -C(=O)O-*, -OC(=O)-* or -NH-, wherein * refers to the direction toward P 1 direction.

50. The compound of claim 49, wherein the linker is -(CH2) 1-6 -.

51. The compound of any one of claims 1 to 50, wherein Z is a radioactive moiety.

52. The compound of claim 51, wherein the radioactive moiety is a fluorescent isotope, a radioisotope, or a radiopharmaceutical.

53. The compound of claim 51, wherein the radioactive moiety is selected from the group consisting of an alpha-emitting isotope, a beta-emitting isotope, a gamma-emitting isotope, an Auger electron-emitting isotope, an X-ray-emitting isotope, and a fluorescent-emitting isotope.

54. The compound of claim 51, wherein the radioactive moiety is a complex formed by a radioisotope of a metal cation and a chelating agent.

55. The compound of claim 51, wherein the radioactive moiety is a complex formed by the following cation and a chelating agent in Table 1: 177 Lu, A1 18 F. 203 Pb, 212Pb, 51Cr, 67 Ga, 68 Ga, 89 Zr, 11 In, 99m Tc, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y. 90 Y. 149 Pm, 165 Dy, 169 2. 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 97 Such as 109 Pd, 105 Rh, 101 mRh, 119 Sb, 128 8. 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 T1, 64 Cu, 67 Cu, 188 Re, 186 Re, 198 Au, 225 Ac, 227 Th or 199 Ag.

56. The compound of claim 51, wherein the radioactive moiety is a metal chelating moiety: l77 Lu-DOTA, 177 Lu-DOTAGA, 68 Ga-DOTA, 90 Y-DOTA、A1 18 F-NOTA, 203 Pb-TCMC, 212 Pb-PSC, 203 Pb-PSC, 212 Pb-TCMC, 64 Cu-DOTA or 225 Ac-DOTA.

57. The compound of claim 51, wherein the radioactive moiety comprises 11 C. 18 F. 72 As, 72 Se, 123 I. 124 I. 131 I or 211 At.

58. A compound as described in any one of claims 1 to 50, wherein Z is a fluorescent dye.

59. The compound of claim 58, wherein the fluorescent dye is a xanthene, an acridine, an oxazine, a cyanine, a styryl dye, a coumarin, a porphine, a metal-ligand complex, a fluorescent protein, a nanocrystal, a perylene, a boron-dipyrromethene, or a phthalocyanine, or a conjugate or combination thereof.

60. The compound of any one of claims 1 to 50, wherein Z is a chelating agent.

61. The compound of claim 60, wherein the chelator is a tetradentate chelator, a hexadentate chelator, or an octadentate chelator.

62. The compound of claim 60 or 61, wherein the chelator comprises an optionally substituted 8- to 20-membered nitrogen-containing heterocyclic group.

63. The compound of claim 60, wherein the chelating agent is a chelating moiety of 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1-(pentanedioic acid)-4,7,10-triacetic acid (DOTAGA), 2-[4,7,10-tris(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetamide (TCMC), triethylenetetramine (TETA), iminodiacetic acid, diethylenetriamine-N,N,N′,N′,N″-pentaacetic acid (DTPA), bis(-(carboxymethylimidazole)glycine, or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

64. The compound of claim 60, wherein the chelator is a chelator in Table 1.

65. The compound of any one of claims 1 to 50, wherein Z is a contrast agent.

66. The compound of claim 65, wherein the contrast agent comprises a paramagnetic agent.

67. A compound of Table 2 or Table 2A, or a stereoisomer, mixture of stereoisomers, tautomer or pharmaceutically acceptable salt thereof.

68. A complex formed by a compound of any one of claims 1 to 50, 60 to 64, or 67 and a metal cation.

69. The complex of claim 68, wherein the metal cation is a cation of Cr, Ga, In, Tc, Re, La, Yb, Sm, Ho, Y, Pm, Dy, Er, Lu, Sc, Pr, Gd, Bi, Ru, Pd, Rh, Sb, Ba, Hg, Eu, Tl, Pb, Cu, Re, Au, Ac, Th or Ag.

70. The complex of claim 68, wherein the metal cation is 51 Cr, 67 Ga, 68 Ga, 89 Zr, 111 In, 99 mTc, 186 Re, 188 Re, 139 La, 140 La, 175 Yb, 153 Sm, 166 Ho, 88 Y. 90 Y. 149 Pm, 165 Dy, 169 2. 177 Lu, 47 Sc, 142 Pr, 159 Gd, 212 Bi, 213 Bi, 97 Such as 109 Pd, 105 Rh, 101m Rh, 119 Sb, 128 8. 197 Hg, 151 Eu, 153 Eu, 169 Eu, 201 T1, 203 Pb, 212 Pb, 64 Cu, 67 Cu, 198 Au, 225 Ac, 227 Th or 199 The cation of Ag.

71. The complex of claim 70, wherein the metal cation is 177 Lu 3+ , 68 Ga 3+ , 111 In 3+ , 99m Tc 4+ , 90 Y 3+ , 203 Pb 2+ , 212 Pb 2+ , 64 Cu 2+ or 225 Ac 3+ .

72. A complex of Table 3, or a stereoisomer, a mixture of stereoisomers, a tautomer or a pharmaceutically acceptable salt thereof.

73. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 67 or a complex as claimed in any one of claims 68 to 72 and a pharmaceutically acceptable excipient.

74. A method of treating or diagnosing prostate specific membrane antigen (PSMA) positive cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 67, a complex of any one of claims 68 to 72, or a pharmaceutical composition of claim 73.

75. The method of claim 74, wherein the cancer is prostate cancer, kidney cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neuroendocrine tumor, ovarian cancer, adenoid cystic carcinoma, salivary duct carcinoma, or sarcoma.

76. The method of claim 75, wherein the cancer is prostate cancer.

77. A method for detecting a cell or tissue expressing prostate specific membrane antigen (PSMA), the method comprising (i) contacting the PSMA expressing cell or tissue with a compound of any one of claims 1 to 67, a complex of any one of claims 68 to 72, or a pharmaceutical composition of claim 73, and (ii) applying one or more imaging methods to detect the cell or tissue.

78. The method of claim 77, wherein the imaging method comprises positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), computed tomography (CT), scintigraphic imaging, luminescence imaging, or fluorescence imaging, or a combination thereof.

79. The method of claim 77 or 78, wherein the PSMA-expressing cells or tissues comprise prostate cells or tissues, spleen cells or tissues, or kidney cells or tissues.

80. The method of any one of claims 77 to 79, wherein the detecting is performed in vivo, ex vivo or in vitro.

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