PSMA-targeted PSMA-parpi conjugate and preparation method therefor and use thereof

Abstract

Provided are a PSMA-targeted PSMA-PARPi conjugate and a preparation method therefor and the use thereof. The conjugate directionally transfers a compound to a tumor site by means of a PSMA-mediated active targeting effect to reduce the lethality of the conjugate for healthy cells and normal tissue, thereby improving the selectivity for prostate tumors and improving the anti-tumor effects. The present invention solves the problem of the occurrence of peripheral adverse reactions in the clinical use of PARP, improves the safety window, and provides a new bifunctional molecular targeted drug for the clinical treatment of solid tumors such as prostate cancer. The PSMA-PARPi conjugate has a general formula as shown in:

Description

PSMA-PARPi conjugates targeted by PSMA, as well as preparation methods and applications thereof Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to a compound, a preparation method and an application thereof, and specifically relates to a PSMA-targeted PSMA-PARPi conjugate, a preparation method and an application thereof. The present invention is a compound with anti-tumor activity targeting prostate cancer, a preparation method and an application thereof. Background Art

[0002] Prostate cancer (PCa) is a solid malignancy with the highest incidence among men worldwide and the second-highest mortality rate in Western countries. Treatment options for early-stage, localized prostate cancer include radical prostatectomy and external beam radiotherapy. For advanced or metastatic PCa, androgen deprivation therapy is more appropriate. However, most tumors eventually progress to castration-resistant prostate cancer (CRPC) or metastatic castration-resistant prostate cancer (mCRPC). mCRPC is the final stage of PCa progression and the leading cause of mortality. Once progressing to mCRPC, patients have only cytotoxic chemotherapy options such as paclitaxel, abiraterone acetate, enzalutamide, or radium-223 dichloride to prolong survival. However, most conventional chemotherapeutic agents suffer from poor selectivity, significant side effects, and drug resistance, resulting in poor clinical efficacy and poor quality of life for patients. Therefore, the search for novel targeted anti-tumor drugs for prostate cancer is of great clinical value and significance.

[0003] Olaparib is the first PARP inhibitor approved for prostate cancer. It has inhibitory activity against PARP1, PARP2, and PARP3 in vitro and in vivo. PARP1, 2, and 3 are involved in the DNA damage repair process, of which PARP1 is the most abundant isoform in the PARP family and plays a key role in the signaling and repair of DNA damage. After DNA damage caused by cell activity, chemicals, or ionizing radiation, PARP1 is rapidly activated, recognizes and binds to DNA single-strand breaks (SSBs), catalyzes the breakdown of nicotinamide adenine dinucleotide (NAD) into ADP-ribose and nicotinamide, and then transfers the ADP-ribose units to synthesize poly (ADP-ribose) (PAR) chains. By reducing the affinity between PARP1 and DNA, PARP1 is disengaged from DNA and then guides DNA single-strand repair, which is a key process in the DNA base excision repair pathway. Olaparib inhibits PARP enzyme activity and increases the formation of PARP-DNA complexes, resulting in the inability to repair tumor cell DNA, thereby disrupting cell division and leading to apoptosis. Olaparib is currently FDA-approved for the treatment of ovarian, breast, pancreatic, and prostate cancers, making it the first approved PARP inhibitor. However, this class of drugs has poor tissue selectivity and often results in myelosuppressive toxicities, including neutropenia, thrombocytopenia, and severe anemia, with anemia being the most common. Approximately 45% of patients receiving Olaparib discontinue treatment due to various adverse reactions, and 22% have their dose reduced due to adverse reactions. The most common adverse reactions leading to treatment discontinuation are anemia (25%) and thrombocytopenia (6%), and the most common adverse reaction leading to dose reduction is anemia (16%). Approximately 18% of patients discontinue treatment due to various serious adverse reactions, with anemia being the most common adverse reaction leading to discontinuation (7%). Although PARP inhibitors have demonstrated promising efficacy in a variety of malignancies, these limitations limit their further development and clinical application.

[0004] Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein located on the surface of prostate epithelial cells. It is overexpressed on the surface of the vast majority of prostate cancer cells, while normal cells express it only at very low levels. PSMA expression levels increase with increasing prostate tumor grade. Domestic and international researchers have designed antibody, peptide, and small molecule targeting modules for PSMA. Antibody-drug conjugates have entered the clinical stage. Currently, the FDA has approved PSMA-targeting radioactive elements 68Ga, 177Lu, and 18F as PET / CT imaging agents for prostate cancer. These agents demonstrate good selectivity and targeting for prostate tumors and possess excellent specific affinity for PSMA.

[0005] Summary of the Invention

[0006] One of the objects of the present invention is to provide a PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof, which is a compound having the structural formula I and formula II. The PSMA-PARPi conjugate comprises a bifunctional conjugate as shown below:

[0007] Linkers include diacids of different lengths, alkyl chains, disulfides, amides, carbamates, heterocyclic alkyl groups, alkoxycarbonyl groups, alkylamino groups, natural or unnatural amino acids, etc., specifically general formula I and general formula II.

[0008] X=CH2, NH, O;

[0009] Y = carbonyl, CH2;

[0010] n=an integer of 0-10 (preferably 1-5);

[0011] R1=H, alkyl, heteroalkyl, or aromatic group having 1-10 carbon atoms, wherein the alkyl group is preferably methyl, isopropyl, cyclopropyl, or isobutyl, the heteroalkyl group is preferably hydroxymethyl, and the aromatic group is preferably phenyl;

[0012] R2=H, alkyl group with 1-5 carbon atoms, wherein the alkyl group is preferably methyl;

[0013] * is R configuration or S configuration.

[0014] Furthermore, the present invention is selected from the following compounds:

[0015] (((S)-1-carboxy-5-(5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5-oxopentanamido)pentyl)carbamoyl)-L-glutamic acid (CQ-01),

[0016] (11S,15S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,5,13-trioxo-2-oxa-6,12,14-triazaheptadecan-11,5,17-tricarboxylic acid (CQ-02),

[0017] (14S,18S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,8,16-trioxo-4,5-dithio-9,15,17-triazaeicosane-14,18,20-tricarboxylic acid (CQ-03),

[0018] (((S)-1-carboxy-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid (CQ-04),

[0019] (((S)-1-carboxy-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzamido)pentyl)carbamoyl)-L-glutamic acid (CQ-05),

[0020] (((S)-1-carboxy-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carboxamido)pentyl)carbamoyl)-L-glutamic acid (CQ-06),

[0021] (11S,15S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,5,13-trioxy-2,6,12,14-tetraazaheptadecan-11,5,17-tricarboxylic acid (CQ-07),

[0022] (12S,16S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,6,14-trioxo-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (CQ-08),

[0023] (((S)-1-carboxy-5-(8-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-8-oxooctylamido)pentyl)carbamoyl)-L-glutamic acid (CQ-09),

[0024] (((S)-1-carboxy-5-(3-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)propionamido)pentyl)carbamoyl)-L-glutamic acid (CQ-10),

[0025] (3S,7S)-25-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5,13,18,25-tetraoxo-4,6,12,17-tetraazapentacosane-1,3,7-tricarboxylic acid (CQ-11),

[0026] (3S,7S,18S)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid (CQ-12),

[0027] (3S,7S,18R)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid (CQ-13),

[0028] (2S,13S,17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-methyl-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid (CQ-14),

[0029] (13S,17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-3-methyl-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid (CQ-15),

[0030] (((S)-1-carboxy-5-(4-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)cyclopropyl)amino)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid (CQ-16),

[0031] (((S)-1-carboxy-5-(4-(2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethyl)amino)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid (CQ-17),

[0032] (2S,13S,17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-(hydroxymethyl)-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid (CQ-18),

[0033] (5S,16S,20S)-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-7,10,18-trioxo-2-thio-6,11,17,19-tetraazadocosa-16,22-tricarboxylic acid (CQ-19),

[0034] (3S,7S,18S)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-20-methyl-5,13,16-trioxo-4,6,12,17-tetraazaphthalic acid-1,3,7-tricarboxylic acid (CQ-20),

[0035] (3S,7S,18S,19R)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazacyclohexane-1,3,7-tricarboxylic acid (CQ-21),

[0036] (2S,13S,17S)-2-benzyl-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid (CQ-22),

[0037] (2R,13S,17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,4,7,15-tetraoxo-2-phenyl-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid (CQ-23),

[0038] (3S,7S)-21-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5,13,6,21-tetraoxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid (CQ-24),

[0039] (6S,17S,21S)-1-amino-6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-1,8,11,19-tetraoxo-2,7,12,18,20-pentaazatriazine-17,23-tricarboxylic acid (CQ-25),

[0040] (((S)-1-carboxy-5-(4-(S)-2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbonyl)pyrrolidin-1-yl)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid (CQ-26).

[0041] The compounds of the present invention are pharmaceutically acceptable salts, which are salts formed by reacting the compounds with inorganic acids or organic acids. The pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, phosphates, acetates, propionates, butyrates, oxalates, tartrates, methanesulfonates, p-toluenesulfonates, fumarates, taurates, citrates, or succinates.

[0042] A second object of the present invention is to provide a method for preparing the compounds of Formula I and Formula II or their pharmaceutically acceptable salts, the method comprising the following steps:

[0043] The reaction is carried out in an organic solvent at -20°C to 200°C, wherein the organic solvent is an ether, alcohol, alkane, aromatic hydrocarbon, ketone, alkyl halide, amide, nitrile, ester or a mixture thereof containing 1-20 carbon atoms, or various proportions thereof; the catalyst is 4-dimethylaminopyridine (DMAP); the condensing agent is O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU); the deprotecting agent is trifluoroacetic acid (TFA), palladium on carbon (Pd / C), concentrated hydrochloric acid or piperidine; and the base used is DIPEA, TEA, lithium hydroxide or sodium hydroxide.

[0044] The definitions of the substituents are the same as those in the above general formula I and general formula II.

[0045] A third object of the present invention is to provide the use of compounds of Formula I and Formula II or pharmaceutically acceptable salts thereof in preparing an anti-prostate tumor cell model.

[0046] A fourth object of the present invention is to provide the use of compounds of formula I and formula II in preparing an anti-prostate tumor nude mouse model.

[0047] A fifth object of the present invention is to provide the use of the compounds of formula I and formula II or their pharmaceutically acceptable salts in the preparation of anti-prostate tumor drugs.

[0048] A sixth object of the present invention is to provide a pharmaceutical composition comprising:

[0049] (i) compounds of Formula I and Formula II or pharmaceutically acceptable salts thereof; and

[0050] (ii) a pharmaceutically acceptable carrier, diluent or excipient.

[0051] A seventh object of the present invention is to provide a method for preventing and / or treating prostate tumors, comprising the steps of administering compounds of Formula I and Formula II or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention to a subject in need.

[0052] In another preferred embodiment, the prostate tumor includes primary prostate tumor and metastatic prostate tumor.

[0053] In another preferred embodiment, the prostate tumor includes hormone-sensitive prostate tumor and hormone-resistant prostate tumor.

[0054] In another preferred embodiment, the hormone-resistant prostate tumor includes castration-resistant prostate cancer (CRPC).

[0055] In another preferred example, the castration-resistant prostate cancer (CRPC) includes metastatic castration-resistant prostate cancer (mCRPC).

[0056] In another preferred embodiment, the prostate tumor includes prostate tumors of various stages in the TNM staging system and prostate tumors of various stages in the four-stage classification system.

[0057] In another preferred embodiment, the prostate tumor is a PSMA-positive prostate tumor.

[0058] This invention designs and synthesizes for the first time a series of PARP inhibitors specifically targeting prostate cancer, solves the occurrence of peripheral adverse reactions in the clinical use of PARP, improves the safety window, and provides a new type of bifunctional molecular targeted drug for the clinical treatment of solid tumors such as prostate cancer.

[0059] Compared with the prior art, the present invention is beneficial in that:

[0060] Provided is a PSMA-targeted anti-tumor compound, PSMA-PARPi. In vivo and in vitro experimental results confirm that the compound provided by the invention has good anti-proliferation effect and PSMA selectivity on PSMA-positive prostate tumor cells LNCaP, C4-2B and 22RV1 cells, and is superior to Olaparib in both selectivity for PSMA-positive tumor cells and safety for normal prostate epithelial cells. In the 22RV1 nude mouse model of prostate cancer, the compound has better anti-tumor effect than Olaparib after oral gavage at an equimolar dose. After administration of the compound provided by the present invention, there was no significant decrease in the lymphocyte count of mice, while the lymphocyte count in the Olaparib group decreased. The results indicate that the compound provided by the present invention has better safety than Olaparib. This solves the problem of the non-selectivity of PARP inhibitors in clinical use leading to the occurrence of peripheral adverse reactions, increases the safety window, and provides a new type of dual-functional molecular targeted drug for the treatment of solid tumors such as prostate cancer.

[0061] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1: PSMA competitively inhibits the in vitro anti-tumor activity of CQ-04 and CQ-16.

[0063] Figure 2: Routine blood tests at the endpoint of CQ-04 treatment in the 22RV1 nude mouse model.

[0064] Figure 3: Body weight changes in 22RV1 nude mouse model treated with CQ-04.

[0065] Figure 4: Changes in tumor volume after treatment with CQ-04 in the 22RV1 nude mouse tumor model.

[0066] Figure 5: Anti-tumor effect of CQ-16 in 22RV1 nude mouse model.

[0067] the term

[0068] In order that the present disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning given below.

[0069] As used herein, the term "alkyl" includes straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0070] Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers (or conformers)): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, etc. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformers) are all within the scope of the present invention.

[0071] As used herein, the term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversion via proton migration, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion via reorganization of some of the bonding electrons.

[0072] Unless otherwise specified, all compounds mentioned in this application are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (i.e., racemates). In all compounds of this application, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0073] In the present application, the term "conjugate" generally refers to a compound prepared by one or more chemical reactions of the compounds of the present application, or connected to each other through one or more connecting structures such as a bridge, a spacer, or a connecting part.

[0074] In this application, the term "pharmaceutically acceptable carrier" generally refers to a carrier for administering therapeutic agents, such as antibodies or polypeptides, genes, and other therapeutic agents (such as the conjugates of the present invention or pharmaceutically acceptable salts thereof). The term refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition and can be administered without excessive toxicity. Suitable carriers can be large, slowly metabolized macromolecules, such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polyamino acids, amino acid copolymers, lipid aggregates, and inactivated viral particles. These carriers are well known to those skilled in the art. Pharmaceutically acceptable carriers in therapeutic compositions may include liquids, such as water, saline, glycerol, and ethanol. Auxiliary substances, such as wetting agents or emulsifiers, pH buffer substances, etc., may also be present in these carriers.

[0075] The term "about" can refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined.

[0076] The term "administering" refers to the physical introduction of the conjugate of the present invention or a pharmaceutically acceptable salt thereof into a subject using any of a variety of methods and delivery systems known to those skilled in the art, including intravenous, intratumoral, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example, by injection or infusion.

[0077] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining specific embodiments with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application. DETAILED DESCRIPTION

[0078] The present invention will be further described in detail below with reference to the accompanying drawings and examples, but the embodiments of the present invention are not limited thereto. Without departing from the above-mentioned technical ideas of the present invention, various substitutions and changes can be made according to common technical knowledge and customary means in the field, and all should be included in the scope of the present invention.

[0079] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If the manufacturers of the reagents or instruments are not specified, they can be purchased from regular channels.

[0080] The structures of the compounds were confirmed by nuclear magnetic resonance and high-resolution mass spectrometry. 1 H-NMR and 13 C-NMR was measured using a Bruker 500 MHz NMR instrument with TMS as the internal standard. LC-HRMS was performed using an Agilent 1290 HPLC-6224 liquid chromatography-mass spectrometer. Melting points were determined using a Buchi M565 melting point apparatus. Column chromatography was performed using 200–300 mesh silica gel.

[0081] Example 1

[0082] Synthesis of PSMA-B

[0083] Triphosgene (2.9 g, 10 mmol) was added to a 500 mL three-necked flask and dissolved in 50 mL of dry dichloromethane. The mixture was stirred in an ice bath. A solution of PSMA-SM2 (9.1 g, 27 mmol) and DIPEA (10.4 mL, 60 mmol) in 50 mL of dichloromethane was slowly added dropwise to the 500 mL three-necked flask and stirred in an ice bath for 2.5 hours. A solution of PSMA-SM1 (8.0 g, 27 mmol) and DIPEA (10.4 mL, 60 mmol) in 50 mL of dichloromethane was added dropwise to the 500 mL three-necked flask. The mixture was stirred at room temperature for 12 hours. LC-MS monitoring revealed the disappearance of the starting material. The mixture was washed three times with 200 mL of 1 M hydrochloric acid, 200 mL of saturated sodium bicarbonate, and 200 mL of saturated brine in an ice bath. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using ethyl acetate and petroleum ether to obtain 10.1 g of colorless, transparent oily substance, PSMA-B, with a yield of 61%. MS (ESI + ): m / z found: 622.3685, calculated: 622.3704 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.39–7.28(m,5H),5.41–5.33(m,2H),5.10(q,J=12.3Hz,2H),4.35(dtd,J=19.7,8.0,4.7Hz, 2H),3.17(dp,J=17.1,6.7Hz,2H),2.35–2.20(m,2H),1.85–1.68(m,2H),1.44(s,18H),1.43(s,9H),1.26(t,J=7.2Hz,2H),0.89–0.85(m,2H).

[0084] Synthesis of PSMA-C

[0085] 3.1 g of PSMA-B was added to a 250 mL three-necked flask and dissolved in 30 mL of anhydrous methanol. 0.62 g of 5% Pd / C was added, and the atmosphere was replaced with hydrogen three times before stirring at room temperature overnight. LC-MS monitoring revealed the disappearance of the starting material. The mixture was filtered through celite, and the filter cake was washed with 100 mL of methanol. The mixture was concentrated to a constant weight without further purification, yielding 2.4 g of colorless, transparent oily PSMA-C (98% yield). MS (ESI + ): m / z found: 488.3330, calculated: 488.3319 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ5.15(dd,J=8.1,3.7Hz,2H),4.34(td,J=7.9,4.8Hz,2H),2.73–2.64(m,2H),2.39–2.23(m,2H),2.07(ddd d,J=14.2,9.4,6.4,5.2Hz,2H),1.91–1.72(m,2H),1.68–1.53(m,2H),1.52(s,2H),1.48–1.45(s,18H),1.44(s,9H),1.36–1.24(m,2H).

[0086] Synthesis of tBuDUPA

[0087] 1.774g PSMA-SM1 was added to a 250mL three-necked flask, 50mL of dichloromethane was added to dissolve, and 1548mg of DIPEA was added. 297mg of triphosgene was added under ice bath. The mixture was warmed to room temperature and stirred overnight. LC-MS showed that the starting material disappeared. The product was washed three times with 50mL of saturated ammonium chloride, three times with 50mL of saturated sodium bicarbonate, and once with 50mL of saturated brine. The organic phase was retained, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography with a gradient elution of PE:EA = 8:1-5:1 to obtain 1.14g of a white solid with a yield of 75%. MS (ESI + ):567.3298,m / zFound:567.3282,Calculated:567.3258[M+Na] + . 1 H NMR(500MHz,Chloroform-d)δ5.18(d,J=8.0Hz,2H),4.35(td,J=8.0,4.9Hz,2H),2.40–2.25( m,4H),2.11–2.05(m,2H),1.86(dddd,J=14.1,9.5,8.1,6.0Hz,2H),1.45(d,J=15.8Hz,27H).

[0088] Synthesis of DUPA

[0089] 544 mg of tBuDUPA was added to a 100 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of trifluoroacetic acid. The reaction was stirred at room temperature and monitored by LC-MS until the starting material disappeared. 50 mL of ether was added, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed twice with 50 mL of ether. Drying gave 210 mg of a white solid. Yield: 66%. MS (ESI + ): m / z found: 321.0945, calculated: 321.0934 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.41(s,4H),6.34(d,J=8.4Hz,2H),4.09(td,J=8.2,4.7Hz,2H),2. 23(qd,J=16.9,16.5,7.6Hz,4H), 1.92(dq,J=13.8,6.5Hz,2H), 1.71(dq,J=14.9,7.8Hz,2H).

[0090] Synthesis of ALPL-A

[0091] 3.4 g ALPL-SM1 was added to a 100 mL three-necked flask, 30 mL DMA was added to dissolve, 5.6 g HBTU and 4.4 mL DIPEA were added and stirred at room temperature for 30 minutes, 2.6 g N-Boc-piperazine was added, and the reaction was allowed to proceed for 2 h at room temperature. The raw material disappeared after monitoring by TLC, and the reaction was stopped. The reaction solution was slowly added dropwise to 300 mL water and stirred vigorously. A large amount of white solid precipitated and was filtered off. The mixture was washed three times with 100 mL water and three times with 50 mL methyl tert-ether, and the filter cake was vacuum dried. The filter cake was dissolved in 30 mL anhydrous ethanol, refluxed for 1 h, cooled naturally to room temperature for crystallization, filtered off, and washed with 15 mL anhydrous ethanol. The filter cake was vacuum dried to obtain 4.5 g of white solid with a yield of 80.5%. MS (ESI + ):489.1925, m / z found: 489.1912, calculated: 489.1914 [M+Na] + . 1 H NMR (500MHz, DMSO-d6) δ12.62(s,1H),8.27(dd,J=7.8,1.4Hz,1H),7.97(d,J=8.0Hz,1H ),7.90(td,J=8.1,7.7,1.5Hz,1H),7.84(td,J=7.5,1.2Hz,1H),7.45(ddd,J=8.2,5.2, 2.3Hz,1H),7.36(dd,J=6.6,2.3Hz,1H),7.24(t,J=9.0Hz,1H),4.34(s,2H),3.59(s,2H),3.39(s,2H),3.24(s,2H),1.41(s,9H).

[0092] Synthesis of ALPL-B

[0093] 4 g of ALPL-A was added to a 100 mL three-necked flask, dissolved in 10 mL of ethanol, and then added with 10 mL of concentrated hydrochloric acid. The reaction was stirred at room temperature for 1 h. 20 mL of water was added and washed three times with 50 mL of dichloromethane. The pH was adjusted to 9-10 with concentrated aqueous ammonia under ice bath, and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 2.98 g of foamy solid, with a yield of 95.1%. MS (ESI + ): m / z found: 367.1554, calculated: 367.1565 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.27(dd,J=8.0,1.6Hz,1H),7.97(dt,J=7.9,1. 6Hz,1H),7.89(td,J=7.6,1.6Hz,1H),7.86–7.81(m,1H),7.44(ddt,J=9.1,6.5,3.2Hz ,1H),7.34(ddd,J=29.5,6.5,2.3Hz,1H),7.23(td,J=9.0,4.0Hz,1H),4.34(s,2H),3. 64(d,J=29.4Hz,2H),3.19(dt,J=40.5,5.0Hz,2H),2.89(s,2H),2.75(t,J=5.0Hz,2H).

[0094] Synthesis of ALPL

[0095] 915 mg of ALPL-B was added to a 25 mL three-necked flask and dissolved in 10 mL of DCM. The mixture was placed in an ice bath, and 387 mg of cyclopropanecarbonyl chloride was added. The temperature was slowly raised to room temperature. The reaction was completed in about 1 hour. The product was washed three times with 10 mL of saturated sodium bicarbonate and three times with 10 mL of saturated brine. The product was dried over anhydrous sodium sulfate and concentrated by column chromatography to obtain 976 mg of a white solid with a yield of 75%. MS (ESI + ): m / z found: 435.1809, calculated: 435.1827 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(dd,J=7.9,1.5Hz,1H),8.00–7.95(m ,1H),7.93–7.87(m,1H),7.84(td,J=7.5,1.2Hz,1H),7.45(ddd,J=8.3,5.2,2.2H z,1H),7.39(s,1H),7.25(t,J=9.0Hz,1H),4.34(s,2H),3.82–3.57(m,4H),3.51 –3.37(m,2H),3.20(d,J=33.9Hz,2H),1.95(d,J=48.4Hz,1H),0.79–0.70(m,4H).

[0096] Synthesis of 1-1

[0097] 732 mg of ALPL-B was added to a 100 mL three-necked flask, dissolved in 10 mL of dichloromethane, and then 228 mg of glutaric anhydride and 200 mg of triethylamine were added. The mixture was stirred at room temperature. After about 2 hours, the starting material disappeared and the reaction was stopped. The organic phase was washed three times with 10 mL of 0.1 mM hydrochloric acid. The retained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain 825 mg of a white solid (yield 85%). MS (ESI + ): m / z found: 950.5021, calculated: 950.5034 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ12.24(s,1H),11.69(s,1H),8.46(t,J=7.8Hz,1H), 7.92(d,J=4.1Hz,1H),7.88–7.73(m,2H),7.38–7.27(m,2H),7.08(dt,J=14.8,8.7 Hz,1H),4.31(d,J=8.7Hz,2H),3.76(d,J=33.3Hz,2H),3.58(dt,J=10.5,5.8Hz,2 H),3.56–3.43(m,2H),3.28(s,2H),2.45(q,J=7.2,5.3Hz,4H),1.99–1.95(m,2H).

[0098] Synthesis of 1-2

[0099] 480 mg of compound 1-1 was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. 494 mg of HBTU and 322 mg of DIPEA were added, and the mixture was stirred at room temperature for approximately 10 minutes. Then, 487 mg of PSMA-C was added. The reaction was stirred at room temperature for approximately 1 hour until completion. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to obtain 578 mg of a white foamy solid (yield 59%). MS (ESI + ): m / z found: 950.5021, calculated: 950.5034 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ11.20(d,J=55.5Hz,1H),8.48(dt,J =7.4,1.9Hz,1H),7.78(ddd,J=9.6,7.6,4.7Hz,2H),7.76–7.67(m,1H),7.37–7.31(m,2H),7.04(td,J=9.1,1.9Hz,1H),6 .61(dt,J=11.5,5.7Hz,1H),6.00(dd,J=19.5,8.3Hz,1H),5.80(dd,J=21.5,8.1Hz,1H),4.34(dt,J=8.6,3.9Hz,2H),4.30 (s,2H),3.62(s,1H),3.52–3.48(m,1H),3.38–3.33(m,1H),3.31–3.26(m,1H),3.12–3.02(m,1H),2.47(t,J=7.2Hz,1H), 2.43–2.20(m,6H),2.06(qd,J=7.8,7.3,5.1Hz,1H),1.96(dq,J=21.2,7.0Hz,2H),1.47–1.40(m,27H),1.32–1.24(m,2H).

[0100] Synthesis of compound CQ-01

[0101] 468 mg of 1-2 was added to a 100 mL three-necked flask, dissolved in 1 mL of dichloromethane, and stirred overnight at room temperature. The reaction was monitored by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. Drying gave 325 mg of a white solid with a yield of 85%. Melting point: 194.5-194.9°C. MS (ESI + ): m / z found: 782.3149, calculated: 782.3161 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=7.9Hz,1H),7.90(d,J=7.0Hz,1H),7.83(q,J= 6.9,6.0Hz,2H),7.45(dq,J=8.6,2.7Hz,1H),7.41–7.36(m,1H),7.24(td,J=9.0,3.3Hz,1H),6.33(dd,J=16.9,8.2Hz ,2H),4.34(s,2H),4.12–4.04(m,2H),3.68–3.50(m,8H),3.19(m,2H),3.01(q,J=6.7Hz,2H),2.58(t,J=7.0Hz,1H),2 .34–2.29(m,2H),2.29–2.19(m,2H),1.98–1.70(m,2H),1.68–1.49(m,2H),1.42–1.37(m,2H),1.28(m,J=7.9Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.64,170.70,164.54,159.89,157.7 8,155.87,145.35,135.29,134.00,132.05(d,J=25Hz),129.55,129.41,128.35,126.55 ,125.92,123.99,116.48,116.31,65.38,52.73,52.12,47.01,46.73,45.27,44.85,42.03,41.73,41.17,38.84,36.90,32.22,30.80,30.35,29.25,28.31,27.97,23.06,15.62.

[0102] Example 2

[0103] Referring to Example 1, PSMA-SM1 was replaced with 3-hydroxypropionic acid methyl ester hydrochloride, and PSMA-SM2 was replaced with ALPL-B.

[0104] Synthesis of 2-1

[0105] 200 mg of triphosgene was added to a 25 mL three-necked flask, 10 mL of anhydrous DCM was added to dissolve, and the mixture was stirred in an ice bath. 208 mg of methyl 3-hydroxypropionate was added to the three-necked flask, 506 mg of DIPEA was added, and the reaction was stirred for 1 hour. 734 mg of ALPL-B was added, and the mixture was heated to room temperature and stirred overnight. TLC showed that the starting material disappeared. The mixture was washed 3 times with 10 mL of 1 mM hydrochloric acid and 3 times with saturated brine. The organic phase was retained and concentrated by column chromatography to obtain 745 mg of a white solid with a yield of 76%. MS (ESI + ): m / z found: 497.1819, calculated: 497.1831 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.29–8.24(m,1H),7.96(d,J=8.0Hz,1H),7.8 6(dddd,J=28.7,8.3,7.3,1.3Hz,2H),7.44(dddd,J=8.5,5.1,2.3Hz,1H),7.36(dd,J =6.5,2.3Hz,1H),7.23(dd,J=9.4,8.6Hz,1H),4.33(s,2H),4.22(t,J=6.2Hz,2H),3 .62(s,3H),3.41(t,J=5.3Hz,2H),3.34(s,7H),3.16(s,2H),2.67(t,J=6.1Hz,2H).

[0106] Synthesis of 2-2

[0107] 497 mg of compound 2-2 was added to a 100 mL three-necked flask, dissolved in 1.5 mL of tetrahydrofuran, and then 0.5 mL of water and 80 mg of hydrated lithium hydroxide. After 1 h of reaction, the pH was adjusted to 3-4, and a large amount of solid precipitated. After filtration and drying, the mixture was dissolved in 10 mL of dichloromethane, 494 mg of HBTU and 322 mg of DIPEA were added. The mixture was stirred at room temperature for approximately 10 min, and 487 mg of PSMA-C was added. The reaction was stirred at room temperature for approximately 1 h, and the mixture was allowed to react. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to obtain 484 mg of a white foamy solid (yield 51%). MS (ESI + ): m / z found: 952.4826, calculated: 952.4832 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.54(s,1H),8.43–8.37(m,1H),7.75–7.67(m,2H),7.67–7.61(m,1H),7.30–7.23(m,2H), 6.97(q,J=8.2Hz,1H),5.85(dd,J=16.5,8.3Hz,1H),4.27(ddd,J=18.2,8.7,4.8Hz,2H),4.22(s,2H),3.68(ddt,J=7.7,6. 1,2.2Hz,2H),3.59(dq,J=13.3,6.5Hz,2H),3.38(dt,J=19.4,6.2Hz,2H),3.24(d,J=30.6Hz,2H),2.93(d,J=12.3Hz,2H) ,2.34(d,J=16.0Hz,2H),2.28–2.19(m,2H),2.06–1.78(m,2H),1.77–1.62(m,2H),1.48–1.42(m,6H),1.40–1.34(m,27H).

[0108] Synthesis of CQ-02

[0109] 468 mg of compound 2-2 was added to a 100 mL three-necked flask, 1 mL of dichloromethane was added to dissolve, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 325 mg of white solid was obtained by drying, with a yield of 85%. Melting point: 192.4–192.8°C. MS (ESI + ): m / z found: 784.2956, calculated: 784.2948 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),12.46(s,3H),8.26(d,J=7.9Hz,1H),7.95(t,J=8.8Hz,2H),7.89(t,J=7.6Hz,1H),7.84 (t,J=7.4Hz,1H),7.44(ddd,J=8.2,5.1,2.4Hz,1H),7.35(dd,J=6.4,2.3Hz,1H),7.23(t,J=8.9Hz,1H),6.32(s,2H),4.33(s, 2H),4.18(t,J=6.4Hz,2H),4.07(d,J=30.1Hz,2H),3.67–3.54(m,2H),3.40(s,2H),3.27–3.22(m,2H),3.16(s,2H),3.08–2.9 5(m,2H),2.39(d,J=6.4Hz,2H),2.24(s,2H),2.04–1.86(m,2H),1.67(d,J=46.4Hz,2H),1.48(d,J=16.2Hz,2H),1.38(s,2H). 13 C NMR(126MHz,DMSO-d6)δ169.63,164.52,159.89,157.78,156.65,153.97,153.30,145.37,135.10,134.00,132.08,1 29.54(d,J=20Hz),128.33,126.55,125.95,123.91,116.49,62.28,41.54,38.82,36.89,35.59,31.88,29.28,23.06.

[0110] Example 3

[0111] Synthesis of 3-1

[0112] Add 420 mg of 3,3'-dithiodipropionic acid to a 100 mL three-necked flask and dissolve in 20 mL of dichloromethane. Add 988 mg of HBTU and 644 mg of DIPEA. Stir at room temperature for approximately 10 minutes, then add 732 mg of ALPL-B. Stir at room temperature for approximately 1 hour until the reaction is complete. Wash with 30 mL of saturated ammonium chloride. Concentrate to dryness and feed directly to the following step without purification. MS (ESI + ): m / z found: 559.1495, calculated: 559.1480 [M+H] + .

[0113] Synthesis of compound 3-2

[0114] 294 mg of compound 3-1 was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. 247 mg of HBTU and 166 mg of DIPEA were added, and the mixture was stirred at room temperature for approximately 10 minutes. Then, 244 mg of PSMA-C was added. The reaction was stirred at room temperature for approximately 1 hour until complete. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to obtain 298 mg of a white foamy solid (59% yield). MS (ESI + ): m / z found: 1028.4645, calculated: 1028.4632 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.44(d,J=86.8Hz,1H),8.44–8.38(m,1H),7.74–7.71(m,1H),7.71–7.69(m,1H),7.69–7.61(m,1H),7.26(dq,J =8.3,3.0,2.3Hz,2H),7.06(dd,J=8.6,1.8Hz,1H),6.98(td,J=8.9,4.4 Hz,1H),6.81–6.60(m,1H),6.41–6.26(m,1H),5.76–5.58(m,2H),4.32– 4.24(m,2H),4.22(d,J=1.9Hz,2H),3.50(m,4H),3.35(d,J=6.4Hz,2H) ,3.24(s,2H),3.07–2.94(m,2H),2.93–2.87(m,2H),2.79–2.64(m,2H), 2.60–2.47(m,2H),2.25(ddd,J=17.1,9.8,6.9Hz,2H),2.08–1.88(m,2H ),1.76(dt,J=14.3,8.5Hz,2H),1.53–1.40(m,4H),1.40–1.34(m,27H).

[0115] Synthesis of compound CQ-03

[0116] 257 mg of 1-2 was added to a 100 mL three-necked flask, 1 mL of dichloromethane was added to dissolve, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 325 mg of white solid was obtained by drying, with a yield of 85%. Melting point: 188.9–189.4°C. MS (ESI + ): m / z found: 890.2741, calculated: 890.2754 [M+H] + .1 H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.27(d,J=7.9Hz,1H),7.97(dd,J=8.2,3.3Hz,1H),7.93–7.89(m,1H),7.84(td, J=7.6,3.6Hz,1H),7.48–7.33(m,2H),7.24(t,J=9.0Hz,1H),7.08(d,J=8.7Hz,2H),6.83(d,J=8.8Hz,2H),6.29(dd,J= 16.7,8.4Hz,1H),4.34(s,2H),4.16–3.98(m,2H),3.99–3.85(m,2H),3.65–3.55(m,2H),3.53(s,2H),3.21(s,2H),3.1 6(s,2H),3.02(s,2H),2.92–2.86(m,2H),2.69(t,J=7.2Hz,2H),2.45(q,J=6.8Hz,2H),2.34–2.05(m,2H),1.54(m,4H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.66,174.20,170.27,169.50,159.87,158.95,15 8.64,157.76,145.32,135.30,133.97,132.03(d,J=26.3Hz),129.55,129.44,128.36 ,126.55,125.92,116.48,116.31,65.39,52.71,52.10,47.03,46.69,45.28,42.02,41.75,38.89,36.90,35.45,34.30,32.77,32.23,30.35,29.23,27.98,23.09,15.63.

[0117] Example 4

[0118] In Reference Example 1, glutaric anhydride was replaced by succinic anhydride.

[0119] Synthesis of intermediate 4-1

[0120] 732 mg of ALPL-B was added to a 100 mL three-necked flask, dissolved in 10 mL of dichloromethane, and then 200 mg of succinic anhydride and 200 mg of triethylamine were added. The mixture was stirred at room temperature. After about 2 hours, the starting material disappeared and the reaction was stopped. The organic phase was washed three times with 10 mL of 0.1 mM hydrochloric acid. The retained organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to obtain 830 mg of a white solid (yield 89%). MS (ESI+ ) 467.1742: m / z found: 467.1751, calculated: 467.1731 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ12.61(s,1H),12.07(s,1H),8.30–8.24(m,1H),7.97(d,J=8.0Hz, 1H),7.90(q,J=6.4Hz,1H),7.84(t,J=7.5Hz,1H),7.45(ddt,J=8.3,5.3,2.5Hz,1H),7. 38(ddd,J=8.6,6.4,2.3Hz,1H),7.24(td,J=9.0,3.7Hz,1H),5.76(s,1H),4.34(s,2H), 3.68–3.50(m,4H),3.38(s,2H),3.15(s,2H),2.58(t,J=6.6Hz,2H),2.46–2.42(m,2H).

[0121] Synthesis of intermediate 4-2

[0122] 466 mg of 4-1 was added to a 100 mL three-necked flask and dissolved in 10 mL of dichloromethane. 494 mg of HBTU and 322 mg of DIPEA were added, and the mixture was stirred at room temperature for approximately 10 minutes. Then, 487 mg of PSMA-C was added. The reaction was stirred at room temperature for approximately 1 hour until complete. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to obtain 560 mg of a white foamy solid (60% yield). MS (ESI) + ): m / z found: 936.4860, calculated: 936.4883 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.74(s,1H),8.40(dt,J=7.9,2.9Hz,1H),7.76–7.62 (m,3H),7.30–7.23(m,2H),6.97(q,J=8.2Hz,1H),5.87(dd,J=42.6,10.1Hz,2H),4. 30–4.23(m,2H),4.22(s,2H),3.78–3.47(m,4H),3.29(d,J=73.1Hz,4H),2.59(d,J= 15.4Hz,2H),2.29–2.19(m,2H),1.53–1.44(m,2H),1.39–1.32(m,27H),1.18(s,2H).

[0123] Synthesis of compound CQ-04

[0124] 468 mg of 4-2 was added to a 100 mL three-necked flask, dissolved in 1 mL of dichloromethane, and stirred overnight at room temperature. The reaction was monitored by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The filter cake was filtered and washed three times with 30 mL of ether. 325 mg of white solid was obtained by drying, with a yield of 85%. Melting point: 213.6–214.4°C. MS (ESI + ): m / z found: 768.3021, calculated: 768.3005 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=7.9Hz,1H),7.90(d,J=7.0Hz,1H),7.83(q,J= 6.9,6.0Hz,2H),7.45(dq,J=8.6,2.7Hz,1H),7.41–7.36(m,1H),7.24(td,J=9.0,3.3Hz,1H),6.33(dd,J=16.9,8.2Hz ,2H),4.34(s,2H),4.12–4.04(m,2H),3.68–3.50(m,8H),3.19(m,2H),3.01(q,J=6.7Hz,2H),2.58(t,J=7.0Hz,1H),2 .34–2.29(m,2H),2.29–2.19(m,2H),1.98–1.70(m,2H),1.68–1.49(m,2H),1.42–1.37(m,2H),1.28(m,J=7.9Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.64,170.70,164.54,159.89,157.7 8,155.87,145.35,135.29,134.00,132.05(d,J=25Hz),129.55,129.41,128.35,126.55 ,125.92,123.99,116.48,116.31,65.38,52.73,52.12,47.01,46.73,45.27,44.85,42.03,41.73,41.17,38.84,36.90,32.22,30.80,30.35,29.25,28.31,27.97,23.06,15.62.

[0125] Example 5

[0126] Synthesis of 5-1

[0127] 298 mg of ALPL-SM1 was added to a 50 mL three-necked flask and dissolved in 5 mL of dichloromethane. 494 mg of HBTU and 322 mg of DIPEA were added, and the mixture was stirred at room temperature for approximately 10 minutes. Then, 487 mg of PSMA-C was added. The reaction was stirred at room temperature for approximately 1 hour until complete. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to obtain 578 mg of a white foamy solid (yield 59%). MS (ESI) + ): m / z found: 782.3152, calculated: 782.3161 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.34(s,1H),8.48–8.43(m,1H),8.06 (dd,J=7.3,2.5Hz,1H),7.80–7.70(m,3H),7.33(ddd,J=7.7,4.8,2.5Hz,1H),7.03(dd,J=1 1.5,8.5Hz,1H),6.80(dt,J=11.8,5.6Hz,1H),5.33(t,J=8.4Hz,2H),4.34(ddt,J=8.4,7.1 ,3.4Hz,2H),4.31(s,2H),3.44(q,J=6.7Hz,2H),2.32(qdd,J=16.3,9.4,6.1Hz,2H),2.13– 1.84(m,2H),1.84–1.66(m,2H),1.64–1.55(m,2H),1.46–1.41(m,27H),1.37–1.21(m,2H).

[0128] Synthesis of CQ-05

[0129] Add 384 mg of compound 5-1 to a 50 mL three-necked flask, add 1 mL of dichloromethane to dissolve, add 1 mL of TFA, stir at room temperature for 2 h, monitor the reaction completion by LC-MS, and stop the reaction. Add the reaction solution dropwise to 30 mL of ether, and a large amount of white solid precipitates. Filter and wash the filter cake three times with 30 mL of ether. Dry to obtain 240 mg of white solid, with a yield of 80%. Melting point: 205.5–206.3°C. MS (ESI + ): m / z found: 600.2091, calculated: 600.2100 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),12.42(s,3H),8.36–8.24(m,2H),7.97(d,J=8.0Hz,1H),7.90(t,J=7. 6Hz, 1H), 7.83 (t, J=7.5Hz, 1H), 7.56 (dd, J=6.8, 2.4Hz, 1H), 7.43 (ddd, J=7.8, 4.8, 2.4Hz, 1H), 7.19 (dd, J=1 0.2, 8.4Hz, 1H), 6.33 (dd, J=12.2, 8.2Hz, 2H), 4.33 (s, 2H), 4.08 (dtd, J=22.2, 8.1, 5.1Hz, 2H), 3.20 (q, J=6. 8Hz,2H),2.32–2.17(m,2H),1.97–1.69(m,2H),1.69–1.53(m,2H),1.52–1.43(m,2H),1.33(q,J=7.7Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ175.03,174.66,174.21,163.89,159.87,159.24,157.77,157.28,145.45,134.77,134.02,132.75,132.05 (d, J=25Hz ),130.49,130.47,129.53,128.34,126.53,126.02,124.70,124.58,11 6.68,116.50,52.74,52.09,36.91,32.22,30.34,29.12,27.98,23.08.

[0130] Example 6

[0131] Synthesis of compound 6-1

[0132] 732 mg of ALPL-B was added to a 50 mL three-necked flask and dissolved in 10 mL of tetrahydrofuran. 402 mg of p-nitrophenyl chloroformate and 260 mg of DIPEA were added. LC-MS monitoring revealed the disappearance of the starting material and the reaction was stopped. The mixture was concentrated to a small volume, 20 mL of water was added, and the mixture was extracted three times with 20 mL of dichloromethane. The combined dichloromethane was dried over anhydrous sodium sulfate, and concentrated by column chromatography to yield 796 mg of a white foamy solid (yield 75%). MS (ESI + ): m / z found: 532.1621, calculated: 532.1627 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ11.30(s,1H),8.52–8.46(m,1H),8.25(t,J=9.7Hz,2H),7.82–7.75(m,2H),7.74(s,1H),7.40–7.35( m,2H),7.35–7.28(m,2H),7.27(s,1H),7.07(t,J=8.9Hz,1H),5.30(s,1H),4.32(s,2H),3.94–3.67(m,4H),3.49(d,J=72.6Hz,4H).

[0133] Synthesis of compound 6-2

[0134] 531 mg of 6-1 was added to a 50 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 130 mg of DIPEA and 487 mg of PSMA-C were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 650 mg of a white foamy solid with a yield of 74%. MS (ESI + ): m / z found: 880.4604, calculated: 880.4615 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.92(s,1H),8.50–8.45(m,1H),7.83 –7.70(m,3H),7.32(ddd,J=11.3,6.9,2.3Hz,2H),7.04(t,J=8.7Hz,1H),5.70(dd,J=35.4,8 .0Hz,2H),4.30(d,J=1.8Hz,2H),4.26(dt,J=8.1,4.1Hz,2H),3.76(t,J=5.3Hz,2H),3.47(s ,2H),3.33(s,2H),3.27(s,2H),3.19(d,J=6.1Hz,2H),2.34–2.21(m,2H),1.82–1.69(m,2H) ,1.65–1.50(m,2H),1.49(d,J=6.3Hz,2H),1.46–1.40(m,27H),1.34(td,J=7.1,1.0Hz,2H).

[0135] Synthesis of compound CQ-06

[0136] Add 220 mg of compound 6-2 to a 50 mL three-necked flask, add 1 mL of dichloromethane to dissolve, add 1 mL of TFA, stir at room temperature for 2 h, monitor the reaction completion by LC-MS, and stop the reaction. Add the reaction solution dropwise to 30 mL of ether, and a large amount of white solid precipitates. Filter with suction, and wash the filter cake three times with 30 mL of ether. Dry to obtain 134 mg of white solid, with a yield of 75%. Melting point: 248.8–249.8°C. MS (ESI + ): m / z found: 712.2729, calculated: 712.2737 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.60(s,1H),12.44(s,3H),8.27(dd,J=7.8,1.4Hz,1H),8.00–7.95(m,1H),7.90(ddd,J=8.1,7.2,1.5Hz,1H),7.84(td,J= 7.5,1.2Hz,1H),7.43(ddd,J=8.5,5.1,2.3Hz,1H),7.37(dd,J=6.5,2.3Hz ,1H),7.23(t,J=9.0Hz,1H),6.57(t,J=5.5Hz,1H),6.31(dd,J=12.7,8.2H z,2H),4.33(s,2H),4.08(dtd,J=25.8,8.1,5.1Hz,2H),3.58(t,J=5.3Hz, 2H),3.35(t,J=5.4Hz,2H),3.22(dd,J=6.8,3.6Hz,2H),3.14(t,J=5.0Hz, 2H),3.00(q,J=6.4Hz,2H),2.37–2.15(m,2H),1.98–1.69(m,2H),1.69–1. 45(m,2H),1.40(ddd,J=13.6,7.9,4.8Hz,2H),1.27(p,J=8.8,8.2Hz,2H). 13C NMR(126MHz,DMSO-d6)δ175.04,174.65,174.19,164.44,159.86,157.79,157.75, 157.70,155.84,145.35,135.26,133.96,132.05(d,J=23.8Hz),129.55,129.40,1 29.37,128.36,126.55,125.93,124.24,124.09,116.47,116.30,65.38,52.76,52.10,46.85,43.98,43.65,41.78,36.89,32.33,30.35,29.93,27.99,23.07,15.63.

[0137] Example 7

[0138] Synthesis of compound 7-1

[0139] 600 mg of triphosgene was added to a 100 mL three-necked flask and dissolved in 10 mL of dichloromethane. 280 mg of methyl 3-aminopropionate hydrochloride and 260 mg of DIPEA were dissolved in 20 mL of dichloromethane and then added dropwise to the 100 mL three-necked flask. The mixture was stirred in an ice bath for 2.5 hours. 734 mg of ALPL-B was added and stirred at room temperature overnight. The mixture was washed three times with 50 mL of 0.1 M hydrochloric acid and three times with 50 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 643 mg of a white solid with a yield of 65%. MS (ESI + ): m / z found: 496.1986, calculated: 496.1991 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.27(dd,J=7.9,1.4Hz,1H),7.98(d,J=8.0Hz,1H),7.9 0(td,J=7.6,1.5Hz,1H),7.84(td,J=7.6,1.2Hz,1H),7.44(ddd,J=8.1,5.0,2.3Hz,1H),7.37 (dd,J=6.6,2.4Hz,1H),7.23(t,J=9.0Hz,1H),6.71(t,J=5.4Hz,1H),4.33(s,2H),3.5 9(s,3H),3.57(s,2H),3.30–3.18(m,4H),3.14(t,J=5.2Hz,2H),2.46(t,J=7.0Hz,2H).

[0140] Synthesis of compound 7-2

[0141] 594 mg of 7-1 was added to a 50 mL three-necked flask, followed by 3 mL of THF, 1 mL of water, and 80 mg of LiOH·H2O. The mixture was stirred at room temperature overnight. The solution was concentrated to a small volume and the pH was adjusted to 3 with 0.1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 482 mg of a white solid (83% yield). MS (ESI + ): m / z found: 482.1825, calculated: 482.1834 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),12.18(s,1H),8.27(dd,J=7.8,1.4Hz,1H),7 .97(d,J=7.9Hz,1H),7.90(td,J=8.0,7.6,1.5Hz,1H),7.86–7.81(m,1H),7.43(ddd ,J=8.1,5.1,2.4Hz,1H),7.37(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.67(t ,J=5.4Hz,1H),4.33(s,2H),3.57(s,2H),3.35–3.03(m,8H),2.38(t,J=7.1Hz,2H).

[0142] Synthesis of compound 7-3

[0143] Add 385 mg of 7-2 to a 50 mL three-necked flask, dissolve in 10 mL of dichloromethane, add 103 mg of DIPEA, and add 390 mg of PSMA-C. Stir the reaction at room temperature. Monitor the disappearance of the starting material by LC-MS and stop the reaction. Concentrate to a small volume, add 20 mL of water, and extract three times with 20 mL of dichloromethane. Combine the dichloromethane, dry over anhydrous sodium sulfate, and concentrate by column chromatography to obtain 456 mg of a white foamy solid with a yield of 60%. Melting point: 200.4–201.4°C. MS (ESI + ): m / z found: 951.4575, calculated: 951.4586 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.38(s,1H),8.49–8.44(m,1H),7.78(ddd,J=6.9,4.3,1.9Hz,2H),7.72(dd,J=6.6,2.5Hz,1H),7.35– 7.31(m,1H),7.30–7.28(m,1H),7.04(t,J=8.8Hz,1H),6.45(s,1H),5.78(s,1H),5.74(s,1H),5.68(d,J=8.0Hz,1H),4.32–4.29(m,1H ),4.28(s,2H),3.76(s,2H),3.71(s,1H),3.47(s,2H),3.41(dd,J=13.5,6.5Hz,2H),3.29(s,2H),3.26(s,2H),3.06(dd,J=13.2,6.2H z,2H),2.55–2.42(m,2H),2.38–2.29(m,2H),2.12–2.00(m,2H),1.85(dd,J=14.5,6.5Hz,2H),1.56–1.34(m,27H),1.34–1.28(m,4H).

[0144] Synthesis of compound CQ-07

[0145] Compound 7 (200 mg) was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and then 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The filter cake was washed three times with 30 mL of ether. Drying gave 125 mg of a white solid with a yield of 76%. MS (ESI + ): m / z found: 783.3115, calculated: 783.3108 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.60(s,1H),11.93(s,3H),8.27(dd,J=7.8,1.4Hz,1H),7.97(d,J=8.0Hz,1H),7.90(td,J=7.7,1.5Hz,1H),7.83(dd,J =9.7,5.3Hz,2H),7.43(ddd,J=8.1,5.1,2.3Hz,1H),7.36(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.64(t,J=5.5Hz,1H),6.32(dd,J=17.6 ,8.2Hz,2H),4.33(s,2H),4.07(dtd,J=27.8,8.2,5.1Hz,2H),3.57(d,J=6.9Hz,2H),3.34(t,J=5.3Hz,2H),3.24–3.18(m,4H),3.13(dd,J=6.9, 3.6Hz,2H),3.00(q,J=6.6Hz,2H),2.32–2.17(m,4H),1.98–1.67(m,2H) ,1.68–1.44(m,2H),1.38(dq,J=8.9,6.2Hz,2H),1.26(p,J=7.4Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.67,174.20,170.90,164.45,159.86,157.77,157 .66,145.36,135.30,133.98,132.06(d,J=23.5Hz),129.57,129.40,128.36,126.56, 125.95,124.22,52.71,52.10,46.79,43.98,43.60,41.73,38.75,37.51,36.89,36.61,32.24,30.35,29.30,27.97,23.09.

[0146] Example 8

[0147] In Reference Example 7, 3-aminopropionic acid methyl ester hydrochloride was replaced by 3-aminobutyric acid methyl ester hydrochloride.

[0148] Synthesis of compound 8-1

[0149] 600 mg of triphosgene was added to a 100 mL three-necked flask and dissolved in 10 mL of dichloromethane. 308 mg of methyl 3-aminobutyrate hydrochloride and 260 mg of DIPEA were dissolved in 20 mL of dichloromethane and then added dropwise to the 100 mL three-necked flask. The mixture was stirred in an ice bath for 2.5 hours. 734 mg of ALPL-B was added and stirred at room temperature overnight. The mixture was washed three times with 50 mL of 0.1 M hydrochloric acid and three times with 50 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 661 mg of a white solid with a yield of 65%. MS (ESI + ): m / z found: 510.2155, calculated: 510.2147 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.25(s,1H),8.50–8.43(m,1H),7.82–7.74(m,2H ),7.74–7.69(m,1H),7.32(dd,J=7.7,5.3Hz,2H),7.04(ddd,J=9.1,7.8,1.2Hz,1 H),4.28(s,2H),3.78(s,2H),3.68(s,3H),3.44(t,J=5.4Hz,2H),3.36(d,J=5.1H z,2H),3.29(td,J=6.6,5.2Hz,4H),2.41(t,J=6.8Hz,2H),1.86(p,J=6.7Hz,2H).

[0150] Synthesis of compound 8-2

[0151] 594 mg of 7-1 was added to a 50 mL three-necked flask, followed by 3 mL of THF, 1 mL of water, and 80 mg of LiOH·H2O. The mixture was stirred overnight at room temperature. The solution was concentrated to a small volume and the pH was adjusted to 3 with 0.1 M hydrochloric acid. A large amount of solid precipitated, which was filtered and dried to obtain 505 mg of a white solid (83% yield). MS (ESI + ): m / z found: 496.1985, calculated: 496.1991 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),12.06(s,1H),8.26(dd,J=7.9,1.4Hz,1H),7.98(d,J=8.0Hz ,1H),7.90(td,J=8.2,7.7,1.5Hz,1H),7.84(td,J=7.6,1.2Hz,1H),7.43(ddd,J=8.1,5.2,2.4Hz,1 H),7.37(dd,J=6.5,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.61(t,J=5.5Hz,1H),4.33(s,2H),3.63–3 .51(m,2H),3.32–3.09(m,4H),3.03(q,J=6.5Hz,2H),2.21(t,J=7.4Hz,2H),1.63(p,J=7.2Hz,2H).

[0152] Synthesis of compound 8-3

[0153] 385 mg of 7-2 was added to a 50 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 103 mg of DIPEA and 390 mg of PSMA-C were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 472 mg of a white foamy solid with a yield of 60%. MS (ESI + ): m / z found: 965.5137, calculated: 965.5143 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.82(s,1H),8.49–8.45(m,1H),7.80–7.73(m,3H),7.35–7.30(m,2H),7.04(t ,J=8.7Hz,1H),6.65(t,J=5.4Hz,1H),5.97(d,J=8.3Hz,1H),5.88(t,J=4.8Hz,1H),5.82(d,J=8.2Hz,1H),4. 32(dt,J=8.5,6.8Hz,2H),4.29(s,2H),3.79–3.74(m,2H),3.48(t,J=5.5Hz,2H),3.42–3.15(m,8H),2.31(dt ,J=14.9,6.3Hz,4H),1.95–1.84(m,2H),1.60–1.46(m,4H),1.47–1.41(m,27H),1.35(dd,J=16.0,8.2Hz,2H).

[0154] Synthesis of compound CQ-08

[0155] 180 mg of compound 7 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 131 mg of white solid was obtained by drying, with a yield of 76%. Melting point: 202.2–202.7°C. MS (ESI + ): m / z found: 797.3259, calculated: 797.3265 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.59(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.89(t,J=7.5Hz,1H),7.83(t,J=7.5Hz,1H),7.77(t,J=5. 7Hz,1H),7.43(ddd,J=8.0,5.0,2.2Hz,1H),7.36(dd,J=6.4,2.3Hz,1H),7.23(t,J=9.0Hz,1H),6.58(t,J=5.5Hz,1H),6.30(dd,J=18.7,8.2Hz, 2H),4.33(s,2H),4.07(dtd,J=27.2,8.2,5.1Hz,2H),3.61–3.55(m,2H ),3.23–3.20(m,2H),3.13(t,J=5.1Hz,2H),3.00(q,J=6.5Hz,4H),2.51 (s,13H),2.30–2.18(m,2H),2.03(q,J=6.9,6.4Hz,2H),2.02–1.83(m,2 H),1.80–1.43(m,6H),1.41–1.33(m,2H),1.26(dd,J=15.6,6.5Hz,4H). 13C NMR (126MHz, DMSO-d6) δ175.00,174.64,174.19,172.24,164.46,159.86,157.79,157. 76,155.85,145.35,135.30,135.27,133.96,132.04(d,J=25Hz),129.55,129.40,128. 37,126.55,125.93,124.24,124.09,116.47,116.30,65.38,52.72,52.12,46.83,43.99,43.63,41.77,38.78,36.90,33.46,32.27,30.36,29.32,27.99,26.45,23.08,15.63.

[0156] Example 9

[0157] In reference example 3, 3,3'-dithiodipropionic acid was replaced with suberic acid.

[0158] Synthesis of compound 9-1

[0159] 348 mg of suberic acid was added to a 100 mL three-necked flask and dissolved in 20 mL of dichloromethane. 988 mg of HBTU and 644 mg of DIPEA were added, and the mixture was stirred at room temperature for approximately 10 minutes. 732 mg of ALPL-B was then added. The reaction was stirred at room temperature for approximately 1 hour until complete. The mixture was washed with 30 mL of saturated ammonium chloride. The mixture was eluted by column chromatography using a gradient of DCM:MeOH = 50:1 to 30:1, and concentrated to dryness to afford 626 mg of a white foamy solid. Yield: 60%. MS (ESI) + ): m / z found: 523.2345, calculated: 523.2351 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ12.23(s,1H),8.47(d,J=8.0Hz,1H),7.95–7.92 (m,2H),7.85(ddd,J=8.2,5.2,3.0Hz,1H),7.78(d,J=6.3Hz,1H),7.08(dt,J=1 8.0,8.7Hz,2H),4.32(s,2H),3.75(d,J=28.5Hz,4H),3.58–3.50(m,4H),3.43 (d,J=5.5Hz,2H),2.37–2.35(m,4H),1.66(d,J=8.0Hz,2H),1.41–1.37(m,4H).

[0160] Synthesis of compound 9-2

[0161] 417 mg of 9-1 was added to a 50 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 103 mg of DIPEA and 390 mg of PSMA-C were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 395 mg of a white foamy solid with a yield of 50%. MS (ESI + ): m / z found: 992.5521, calculated: 992.5503 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0H z,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.80–7.74(m,2H),7.44(s, 1H),7.41–7.33(m,1H),7.24(t,J=8.9 Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2 Hz,1H),3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2 Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12.3,10.8,5.4 Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8 Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5 Hz,2H).

[0162] Synthesis of compound CQ-09

[0163] 175 mg of compound 9-2 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 127 mg of white solid was obtained by drying, with a yield of 76%. Melting point: 200.5–201.1°C. MS (ESI + ): m / z found: 824.3612, calculated: 824.3625 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ12.61(s,1H),12.28(s,3H),8.27(d,J=7.8 Hz,1H),7.97(d,J=8.0 Hz,1H),7.90(t,J=7.7 Hz,1H),7.84(t,J=7.5 Hz,1H),7.75(t,J=4.6 Hz,1H),7.45(dd,J=7.9,4.4 Hz,1H),7.40–7.34(m,1H),7.28–7.20(m,1H),6.32(dd,J=17.1,8.2 Hz,2H),4.34(s,2H),4.14–3.98(m,2H),3.60(d,J=30.1 Hz,2H),3.51(t,J=5.2 Hz,2H),3.37(ddd,J=11.0,7.6,4.5 Hz,2H),3.16(dt,J=20.7,5.2 Hz,2H),2.99(q,J=6.2 Hz,2H),2.30(dt,J=24.2,7.1 Hz,2H),2.26–2.19(m,2H),2.03(td,J=7.3,3.6 Hz,2H),1.97–1.67(m,2H),1.66–1.49(m,2H),1.46(t,J=7.4 Hz,4H),1.38(dd,J=11.8,5.1 Hz, 2H), 1.25 (t, J = 9.6 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ175.02,174.66,174.20,172.38,171.37,159.86,157.75,145.32,135.30,133.97,132.26,132.04(d,J=26.3 Hz),129.55,129.43,128.36,126.55,125.93,52.71,52.10,45.41,44.98,42.13,41.74,41.0 1,38.72,36.89,35.85,32.69,32.25,30.34,29.33,29.02,28.99,27.98,25.69,25.05,23.09.

[0164] Example 10

[0165] Synthesis of compound 10-1

[0166] 732 mg of ALPL-B was added to a 100 mL three-necked flask, 20 mL of acetonitrile was added to dissolve, 306 mg of 3-bromopropionic acid and 276 mg of potassium carbonate were added, and the mixture was stirred at room temperature for about 10 minutes. The reaction was stirred at room temperature for about 1 hour until completion. 20 mL of 0.1 M sodium hydroxide solution was added, and the mixture was washed three times with 30 mL of ethyl acetate. The aqueous phase was retained. 0.1 M hydrochloric acid was added to adjust the pH to 3-4. A large amount of solid precipitated, which was filtered and dried to obtain 613 mg of a white foamy solid. Yield: 75%. MS (ESI + ): m / z found: 439.1789, calculated: 439.1776 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ12.76(s,1H),8.26(dd,J=7.9,1.4 Hz,1H),7.98(d,J=8.0 Hz,1H),7.90(td,J=7.7,1.5 Hz,1H),7.83(t,J=7.5 Hz,1H),7.42 (ddd,J=8.0,5.0,2.3Hz,1H),7.32(dd,J=6.4,2.3Hz,1H),7.21(t,J=9.0Hz,1H),4.33(s,2H),3.57(s,2H) ,3.11(t,J=5.1Hz,2H),2.49–2.43(m,2H),2.35(t,J=5.3Hz,2H),2.22(s,2H),1.97(dd,J=8.6,6.8Hz,2H).

[0167] Synthesis of compound 10-2

[0168] Refer to Example 1 except that 1-1 is replaced by 10-1.

[0169] 439 mg of 10-1 was added to a 50 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 322 mg of DIPEA and 488 mg of PSMA-C were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 362 mg of a white foamy solid with a yield of 45%. MS (ESI + ): m / z found: 908.4941, calculated: 908.4928 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.74(s,1H),7.79–7.76(m,2H),7.72(s,1H),7.5 8(s,1H),7.35(s,1H),7.21(d,J=5.9Hz,1H),7.06(t,J=8.8Hz,1H),5.68(s,2H) ,4.30(s,3H),3.82(s,4H),2.71(d,J=6.8Hz,2H),2.60(s,4H),2.42–2.27(m,6H ),1.66–1.55(m,2H),1.51(q,J=7.2Hz,2H),1.46(d,J=1.9Hz,18H),1.42(s,9H).

[0170] Synthesis of compound CQ-10

[0171] 250 mg of compound 10-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The filter cake was washed three times with 30 mL of ether. 132 mg of white solid was obtained by drying, with a yield of 65%. Melting point: >250°C. MS (ESI + ): m / z found: 740.3039, calculated: 740.3050 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.63(s,3H),9.85(s,1H),8.27(d,J=7.7Hz,1H),8.16(t,J=5.6Hz,1H),7.96(d,J=8.0Hz,1H), 7.90(t,J=7.5Hz,1H),7.84(t,J=7.5Hz,1H),7.50(ddd,J=8.1,5.1,2.3Hz,1H),7.39(dd,J=6.5,2.3Hz,1H),7.27(t,J=9 .1Hz,1H),6.34(dd,J=16.0,8.3Hz,2H),4.34(s,2H),4.07(dtd,J=25.5,8.2,5.1Hz,2H),3.44–3.27(m,8H),3.06(q,J=6 .7Hz,4H),2.57(t,J=7.1Hz,2H),2.35–2.17(m,2H),1.82(m,2H),1.58(m,2H),1.46–1.36(m,2H),1.29(p,J=7.8Hz,2H). 13C NMR (126MHz, DMSO-d6) δ175.03,174.67,174.21,168.98,164.39,159.91,157.76,155.96,145.27,134.03,132.10(d,J=23.8Hz),129 .55,128.36,126.57,125.94,123.14,122.95,116.46,65.39,52.67,52.10,38.72,36.93,32.26,30.34,29.05,27.96,23.12,15.64.

[0172] Example 11

[0173] Synthesis of compound 11-1

[0174] 522 mg of 9-1 was added to a 50 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 300 mg of DIPEA was added, and 154 mg of methyl 4-aminobutyrate hydrochloride was added. The reaction was stirred at room temperature. The starting material disappeared after monitoring by LC-MS, and the reaction was stopped. Concentrate to a small volume, add 20 mL of water, and extract three times with 20 mL of dichloromethane. Combine the dichloromethane, dry over anhydrous sodium sulfate, and concentrate by column chromatography to obtain 434 mg of white foamy solid. Add 3 mL of THF, 1 mL of water, and 80 mg of LiOH·H2O, and stir at room temperature overnight. Concentrate to a small volume, adjust the pH to 3 with 0.1 M hydrochloric acid, and a large amount of solid precipitates. After filtration and drying, 316 mg of white solid was obtained, with a yield of 56%. It was directly used for the next step without further purification. MS (ESI + ): m / z found: 608.2886, calculated: 608.2879 [M+H] + .

[0175] Synthesis of compound 11-2

[0176] 303 mg of 11-1 was added to a 50 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 160 mg of DIPEA and 244 mg of PSMA-C were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 350 mg of a white foamy solid with a yield of 65%. MS (ESI + ): m / z found: 1077.6021, calculated: 1077.6031 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.8 0–7.74(m,2H),7.44(s,1H),7.41–7.33(m,1H),7.24(t,J=8.9Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2Hz,1H) ,3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12 .3,10.8,5.4Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5Hz,2H).

[0177] Synthesis of compound CQ-11

[0178] 300 mg of compound 11-3 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The filter cake was washed three times with 30 mL of ether. 180 mg of white solid was obtained by drying, with a yield of 71%. Melting point: >250°C. MS (ESI + ): m / z found: 909.4145, calculated: 909.4153 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.61(s,1H),8.26(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.8Hz,1H),7.86–7.81(m,1H),7.8 0–7.74(m,2H),7.44(s,1H),7.41–7.33(m,1H),7.24(t,J=8.9Hz,1H),6.33–6.24(m,2H),4.33(s,2H),4.03(td,J=8.6,5.2Hz,1H) ,3.97–3.93(m,1H),3.57(s,2H),3.51(s,2H),3.16(d,J=21.2Hz,2H),2.99(s,4H),2.32–2.17(m,6H),2.02(s,4H),1.86(td,J=12 .3,10.8,5.4Hz,2H),1.59(d,J=8.6Hz,2H),1.48(dd,J=15.5,7.8Hz,8H),1.40–1.37(m,27H),1.30(s,2H),1.12(d,J=6.5Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ175.01, 174.66, 174.20, 172.50, 172.01, 159.87, 157.75, 145.33, 133.98, 132.05 (d, J = 25Hz), 129.55, 129.43, 128. 42,126.55,125.94,52.71,52.10,45.40,38.78,38.62,36.89,35.87, 33.38,32.68,32.25,30.35,29.32,29.00,25.96,25.68,25.05,23.09.

[0179] Synthesis of PSMA-D

[0180] 2.440 g of PSMA-C was added to 20 mL of dioxane, followed by 600 mg of succinic anhydride. The mixture was stirred at 80°C overnight. The mixture was concentrated to a small volume, dissolved in 50 mL of DCM, and washed three times with 50 mL of saturated ammonium chloride solution. The mixture was concentrated to dryness to obtain 2.377 g of a colorless oil. No further purification was required, with a yield of 81%. MS (ESI + ): m / z found: 588.3520, calculated: 588.3491 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.76(s,-1H),6.60(s,1H),5.89(d,J=8.5Hz,1H),5 .64(s,1H),4.37(tt,J=8.6,4.1Hz,1H),4.28–4.13(m,1H),3.45–3.11(m,2H),2.7 9–2.65(m,2H),2.62–2.41(m,2H),2.33(pt,J=10.2,4.7Hz,2H),1.94–1.67(m,2H) ,1.67–1.50(m,2H),1.46(d,J=6.5Hz,27H),1.42–1.35(m,2H),1.35–1.26(m,2H).

[0181] Example 12

[0182] Synthesis of 12-1

[0183] 434 mg of N-Boc-L-valine was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed 3 times with 20 mL of saturated ammonium chloride, 3 times with 20 mL of saturated brine, and the mixture was separated. The DCM phase was retained, dried over anhydrous sodium sulfate, and concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed 3 times with 10 mL of DCM, the DCM was discarded, and the aqueous phase was retained. In an ice bath, the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted 3 times with 20 mL of DCM. The mixture was concentrated to dryness to obtain 604 mg of a white foamy solid with a yield of 65%. MS (ESI + ): m / z found: 466.2261, calculated: 466.2249 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.49(s,1H),8.50–8.43(m,1H),7.77(dd,J=6.5,2.7Hz,2H),7.72(s,1H),7.38–7.29(m,2H),7.09–6 .98(m,1H),4.29(s,2H),3.73(d,J=63.3Hz,4H),3.57(s,1H),3.54–3.42(m,2H),3.31(s,2H),1.87–1.78(m,1H),1.01–0.81(m,6H).

[0184] Synthesis of 12-2

[0185] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 465 mg of 12-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 403 mg of a white foamy solid with a yield of 39%. MS (ESI + ): m / z found: 1035.5557, calculated: 1035.5561 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.96(s,1H),8.41(dt,J=9.2,2.4Hz,1H),7.77–7.61(m,3H),7.43(d,J=8.3Hz,1H),7.30–7.22(m,2H),6.96(q,J=8.9Hz, 1H),6.81–6.71(m,1H),6.27(d,J=9.1Hz,1H),6.17–5.90(m,1H),4.81–4.5 3(m,1H),4.42–4.30(m,2H),4.22(s,2H),3.93(d,J=43.0Hz,2H),3.79(t,J= 14.5Hz,2H),3.62–3.42(m,2H),3.42–3.25(m,2H),3.14(d,J=40.8Hz,2H), 3.05(d,J=6.4Hz,1H),2.66–2.43(m,2H),2.43–2.33(m,2H),2.30–2.18(m,2 H),2.03–1.91(m,2H),1.76–1.63(m,2H),1.46(t,J=10.6Hz,2H),1.40–1.30 (m,27H),1.23(dd,J=21.8,13.4Hz,2H),0.88(ddd,J=15.2,7.6,5.2Hz,6H).

[0186] Synthesis of CQ12

[0187] 310 mg of compound 12-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 166 mg of white solid was obtained by drying, with a yield of 64%. Melting point: 227.7–228.0°C. MS (ESI+ ): m / z found: 867.3698, calculated: 867.3683 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.60(s,1H),8.27(d,J=7.9Hz,1H),8.07(d,J=8.5Hz,1H),7.97(dd,J=7.8,3.0Hz,1H),7.90(t,J=6.8Hz,1H),7.84(t, J=7.5Hz,1H),7.80–7.75(m,1H),7.44(td,J=5.9,2.9Hz,1H),7.38(dd,J=6.5,2.3Hz,1H),7.24(d,J=8.8Hz,1H),6.32(d,J=8.0Hz,2H),4.55(t, J=8.3Hz,1H),4.33(d,J=2.3Hz,2H),4.08–4.02(m,2H),3.65–3.60(m,4H),3.52–3.49(m,4H),3.17(dd,J=6.1,3.2Hz,2H),2.34(dd,J=12.0,4. 9Hz,2H),2.29–2.23(m,4H),1.97–1.88(m,2H),1.75–1.63(m,2H),1.38 –1.34(m,2H),1.26(d,J=7.9Hz,2H),0.84(d,J=5.2Hz,6H),0.81(m,1H). 13 C NMR(126MHz,DMSO-d6)δ175.07,174.69,174.35,171.89,171.54,164.51,159.88,158.93, 157.75,156.81,145.34,133.99,132.05(d,J=25Hz),129.55,128.35,126.55,125.92,116. 50,91.14,70.38,66.19,66.02,65.64,63.26,63.19,53.71,52.81,52.31,47.27,42.59,41.15,38.83,36.91,32.26,31.27,30.98,30.75,30.41,29.26,28.31,23.08,19.86,18.52.

[0188] Example 13

[0189] Refer to Example 12, except that N-Boc-L-valine was replaced with N-Boc-D-valine.

[0190] Synthesis of 13-1

[0191] 434 mg of N-Boc-D-valine was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride three times, and with 20 mL of saturated brine three times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed with 10 mL of DCM three times, the DCM was discarded, and the aqueous phase was retained. The mixture was placed in an ice bath, and the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted with 20 mL of DCM three times. The mixture was concentrated to dryness to obtain 596 mg of a white foamy solid with a yield of 64%. MS (ESI + ): m / z found: 466.2261, calculated: 466.2249 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ11.26(s,1H),8.51–8.43(m,1H),7.82–7.70(m,3H),7.34(t,J=6.4Hz,2H),7.04(q,J=8.2,7.5H z,1H),4.62(s,1H),4.30(s,2H),3.87–3.34(m,8H),3.31(s,1H),1.87–1.85(m,2H),1.28(p,J=5.7Hz,1H),1.00–0.90(m,6H).

[0192] Synthesis of 13-2

[0193] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 465 mg of 13-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 415 mg of a white foamy solid with a yield of 40%. MS (ESI + ): m / z found: 1035.5557, calculated: 1035.5561 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ12.25(s,1H),8.42(d,J=7.8Hz,1H),7.98(d,J=2.5Hz,2H),7.88(dd,J=8.1,2.9Hz,1H),7.47–7.4 0(m,2H),7.10(dt,J=9.3,4.8Hz,2H),6.76(d,J=23.8Hz,1H),5.97–5.77(m,2H),4.91–4.57(m,1H),4.36(s,2H),4.31(dt,J=8.6 ,4.3Hz,2H),3.69(dd,J=103.6,67.7Hz,8H),3.30(d,J=29.5Hz,2H),2.65–2.39(m,4H),2.33–2.25(m,2H),2.11(s,2H),2.05–2 .00(m,2H),1.75(d,J=40.5Hz,2H),1.55(s,1H),1.42(dd,J=12.3,8.5Hz,27H),1.30–1.24(m,2H),0.92(dd,J=19.3,6.6Hz,6H).

[0194] Synthesis of CQ13

[0195] 300 mg of compound 13-2 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 140 mg of white solid was obtained by drying, with a yield of 56%. Melting point: 217.5–218.1°C. MS (ESI + ): m / z found: 867.3698, calculated: 867.3683 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ14.43(s,1H),12.60(s,1H),11.06(s,2H),8.27(dd,J=7.8,1.4H z,1H),8.07(d,J=8.6Hz,1H),7.97(dd,J=8.2,2.6Hz,1H),7.90(q,J=6.8Hz,1H),7.84(t ,J=7.5Hz,1H),7.78(dd,J=14.3,8.6Hz,1H),7.44(ddt,J=7.9,5.1,2.4Hz,1H),7.38(dd ,J=6.4,2.3Hz,1H),7.23(t,J=8.9Hz,1H),6.32(dd,J=16.8,8.3Hz,2H),4.46(d,J=9.6H z,1H),4.33(s,2H),4.07–4.00(m,2H),3.68(d,J=8.3Hz,4H),3.58(s,2H),3.48(s,4H), 3.19–3.15(m,2H),3.02–3.00(m,2H),2.96(dd,J=14.5,7.3Hz,2H),2.34(ddd,J=33.2,1 7.3,7.7Hz,4H),2.25(dt,J=15.3,7.5Hz,4H),2.04–1.84(m,2H),1.84–1.71(m,2H),1.6 5–1.48(m,2H),1.35(s,2H),1.27(t,J=7.6Hz,2H),0.89–0.85(m,1H),0.85–0.80(m,6H). 13 C NMR (126MHz, DMSO-d6) δ175.10,174.68,174.41,171.87,171.51,159.86,157.71,145.32,136.29,133.99,132.43(d,J=21.3Hz),132.04,129. 56,128.37,126.55,125.93,65.38,53.70,52.82,52.41,42.60,41.15, 38.83,36.92,32.28,30.41,29.28,28.56,23.10,19.87,18.53,15.63.

[0196] Example 14

[0197] Refer to Example 12, except that N-Boc-L-valine was replaced with N-Boc-L-Ala.

[0198] Synthesis of 14-1

[0199] 378mg N-Boc-L-Ala was added to a 100mL three-necked flask, 20mL DCM was added to dissolve, 988mg HBTU was added, 1mL DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL saturated ammonium chloride 3 times, and 20mL saturated brine was washed 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL anhydrous ethanol was added to dissolve, 1mL concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL water was added to the system. The mixture was washed 3 times with 10mL DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20mL DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 460mg of a white foamy solid with a yield of 53%. MS (ESI + ): m / z found: 438.1921, calculated: 438.1936 [M+H] + . 1 H NMR (500MHz, Chloroform-d) δ11.34(s,1H),8.50–8.45(m,1H),7.77(dt,J=5.9,2.3Hz,2H),7.72(t,J=6.3Hz,1H),7.34(t,J=6. 5Hz,2H),7.04(t,J=8.6Hz,1H),4.30(s,2H),3.94–3.66(m,4H),3.63(s,1H),3.58–3.27(m,4H),1.85(s,2H),1.31–1.22(m,3H).

[0200] Synthesis of 14-2

[0201] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 437 mg of 14-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 400 mg of a white foamy solid with a yield of 40%. MS (ESI + ): m / z found: 1007.5233, calculated: 1007.5248 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.64(s,1H),8.39(d,J=7.6Hz,1H),7.74(dd,J=17.9,8.9Hz,1H),7.70–7.61(m,2H),7.28(h,J=7.6,6.0Hz,3H ),6.96(t,J=8.8Hz,1H),6.87(s,1H),6.17(t,J=10.3Hz,1H),6.10–5.99(m,1H),4.92(dt,J=29.2,7.2Hz,1H),4.32–4.29(m,2H),4.21(s,2H ),3.86(s,2H),3.71–3.54(m,2H),3.50–3.31(m,2H),3.27(d,J=37.0Hz,2H),3.11(d,J=68.2Hz,2H),2.58(t,J=12.2Hz,2H),2.47–2.38(m,4 H),2.24(dt,J=9.5,6.8Hz,4H),1.99–1.73(m,2H),1.38(d,J=1.9Hz,9H),1.35–1.30(m,18H),1.25(d,J=6.9Hz,3H),1.20(d,J=11.7Hz,2H).

[0202] Synthesis of CQ14

[0203] 300 mg of compound 14-2 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 133 mg of white solid was obtained by drying, with a yield of 56%. Melting point: 224.6–224.8°C. MS (ESI + ): m / z found: 839.3385, calculated: 839.3370 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.60 (s, 1H), 8.27 (dd, J=7.8, 1.4Hz, 1H), 8.16 (d, J= 7.7Hz,1H),7.97(d,J=8.2Hz,1H),7.90(t,J=7.6Hz,1H),7.87–7.81(m,1H),7 .77(dt,J=19.5,5.6Hz,1H),7.44(ddd,J=8.1,5.0,2.3Hz,1H),7.38(dd,J=6. 4,2.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=21.4,8.2Hz,2H),4.71(d,J=2 3.1Hz,1H),4.34(s,2H),4.10(td,J=8.0,5.0Hz,1H),4.06–4.02(m,1H),3.82 –3.49(m,4H),3.45(s,2H),3.18(d,J=16.9Hz,2H),2.97(dq,J=31.2,6.5Hz,2 H),2.30(dt,J=18.9,6.4Hz,4H),2.26–2.17(m,2H),1.96–1.66(m,2H),1.57( dq,J=57.6,7.2Hz,2H),1.36(p,J=7.6Hz,2H),1.26(q,J=8.4,7.7Hz,2H),1.14 (d, J = 6.1 Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,171.49,171.26,171.10,164.52,159.87,157.77,145.32,135.30,133.98,132.05(d,J =25Hz),129.46,128.36,126.55,125.92,116.48,52.74,52.12,44.64,38.78,36.91,32.24,31.00,30.36,29.27,27.98,23.06,18.16.

[0204] Example 15

[0205] Refer to Example 12, except that Boc-L-valine was replaced with N,N-Me-Boc-L-glycine.

[0206] Synthesis of 15-1

[0207] 378 mg of N, N-Me-Boc-L-glycine was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride three times, and with 20 mL of saturated brine three times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed with 10 mL of DCM three times, the DCM was discarded, and the aqueous phase was retained. In an ice bath, the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted with 20 mL of DCM three times. The mixture was concentrated to dryness to obtain 448 mg of a white foamy solid with a yield of 51%. MS (ESI + ): m / z found: 438.1921, calculated: 438.1936 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.95(s,1H),8.49–8.43(m,1H),7.81–7.69(m,3H),7.33(d,J=6.8Hz,2H),7.05(t,J=9.0Hz, 1H),4.29(s,2H),3.66(d,J=71.0Hz,4H),3.59(s,1H),3.53(s,2H),3.52–3.18(m,4H),2.62(d,J=16.8Hz,2H),2.50(s,3H).

[0208] Synthesis of 15-2

[0209] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 437 mg of 15-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 390 mg of a white foamy solid with a yield of 39%. MS (ESI + ): m / z found: 1007.5233, calculated: 1007.5248 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.41(s,1H),8.46(d,J=7.6Hz,1H),7.79–7.71(m,3H),7.36(d,J=6.1Hz,1H),7.29(s ,1H),7.01(d,J=13.1Hz,1H),6.79(s,1H),6.00–5.78(m,2H),4.36(d,J=37.4Hz,2H),4.27(s,2H),3.73(s,2H),3.59 –3.37(m,4H),3.38–3.18(m,4H),3.14(d,J=4.3Hz,3H),3.01(d,J=31.4Hz,2H),2.89(s,2H),2.67–2.56(m,2H),2.39 –2.29(m,2H),2.27(s,2H),2.11–1.87(m,2H),1.75(s,2H),1.59(s,9H),1.45(d,J=15.9Hz,18H),1.26–1.24(m,2H).

[0210] Synthesis of CQ15

[0211] 300 mg of compound 15-2 was added to a 50 mL three-necked flask, 1 mL of dichloromethane was added to dissolve it, 1 mL of TFA was added, and the mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 133 mg of white solid was obtained by drying, with a yield of 56%. Melting point: 249.9–250.9°C. MS (ESI + ): m / z found: 839.3385, calculated: 839.3370 [M+H] + . 1HNMR(500MHz,DMSO-d6)δ14.03(s,1H),12.60(d,J=3.0Hz,1H),12.41(s,2H),8.27(d,J =7.8Hz,1H),7.97(d,J=8.1Hz,1H),7.90(q,J=7.7,6.6Hz,1H),7.84(t,J=7.6Hz,1H),7.79(t,J=5.6Hz,1H),7.52–7.41(m, 1H),7.41–7.35(m,1H),7.25(dt,J=11.9,7.1Hz,1H),6.31(dd,J=18.0,8.2Hz,2H),4.34(s,2H),4.24–4.10(m,2H),4.06(dd d,J=21.4,8.5,4.9Hz,2H),3.76–3.57(m,4H),3.51(s,3H),3.38–3.31(m,2H),3.24–3.14(m,2H),3.06–2.98(m,2H),2.96(s ,2H),2.66–2.52(m,2H),2.29–2.24(m,2H),1.97–1.68(m,2H),1.68–1.44(m,2H),1.44–1.32(m,2H),1.28(q,J=7.6Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,172.89,172.32,171.73,171.62,159.87,157.77,145.32,133.99,132.06(d,J=26.3Hz ),120.56,129.43,128.37,126.56,125.93,65.38,52.73,52.12,38.84,36.91,36.45,35.13,32.24,30.36,29.28,27.98,23.08,15.63

[0212] Example 16

[0213] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-1-aminocyclopropylcarboxylic acid.

[0214] Synthesis of 16-1

[0215] 402mg of Boc-1-aminocyclopropylcarboxylic acid was added to a 100mL three-necked flask, 20mL of DCM was added to dissolve, 988mg of HBTU was added, 1mL of DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg of ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL of saturated ammonium chloride 3 times, and 20mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL of anhydrous ethanol was added to dissolve, 1mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL of water was added to the system. The mixture was washed 3 times with 10mL of DCM, the DCM was discarded, and the aqueous phase was retained. The mixture was placed in an ice bath, and the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted 3 times with 20mL of DCM. The mixture was concentrated to dryness to obtain 475mg of a white foamy solid with a yield of 53%. MS (ESI + ): m / z found: 450.1921, calculated: 450.1931 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ11.22(s,1H),8.51–8.44(m,1H),7.82–7.74(m,2H),7.74–7.70(m,1H),7.34(tt,J=8.4,2. 4Hz,2H),7.05(t,J=8.7Hz,1H),4.30(s,2H),4.05–3.70(m,4H),3.69–3.28(m,4H),1.08–1.02(m,2H),0.84–0.78(m,2H).

[0216] Synthesis of 16-2

[0217] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 450 mg of 16-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 230 mg of a white foamy solid with a yield of 23%. MS (ESI + ): m / z found: 1019.5232, calculated: 1019.5248 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ11.29(s,1H),8.47(dd,J=8.1,1.6Hz,1H),7.98(s,1H),7.85–7.70(m,3H),7.34(dd,J=7.6,5.2Hz,2H),7. 04(t,J=8.9Hz,1H),6.78(s,1H),6.06(d,J=39.7Hz,2H),4.40–4.30(m,2H),4.29(d,J=4.6Hz,2H),3.73(d,J=24.1Hz,4H),3.27(d,J=24 .5Hz,2H),3.24–2.97(m,2H),2.57(d,J=15.6Hz,2H),2.46(d,J=12.4Hz,2H),2.33(ddd,J=8.9,6.7,1.9Hz,2H),2.16–1.88(m,2H),1.86 –1.72(m,2H),1.61–1.48(m,2H),1.45(s,9H),1.43(d,J=2.7Hz,18H),1.39–1.32(m,2H),1.28(d,J=21.0Hz,4H),1.04(d,J=19.5Hz,2H)

[0218] Synthesis of CQ16

[0219] Add 200 mg of compound 16-2 to a 50 mL three-necked flask, add 1 mL of dichloromethane to dissolve, add 1 mL of TFA, stir at room temperature for 2 h, monitor the reaction completion by LC-MS, and stop the reaction. Add the reaction solution dropwise to 30 mL of ether, and a large amount of white solid precipitates. Filter and wash the filter cake three times with 30 mL of ether. Dry to obtain 95 mg of white solid, with a yield of 57%. Melting point: 247.7–248.6°C. MS (ESI + ): m / z found: 851.3389, calculated: 851.3370 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.59(s,1H),12.42(s,3H),8.44(s,1H),8.27(dt,J=7.8,2.0Hz,1H),7.96(t,J=8.5Hz,1H),7.90(td,J=7.6,1.6Hz,1H), 7.84(t,J=7.5Hz,1H),7.79(q,J=5.4Hz,1H),7.43(dt,J=5.1,2.6Hz,1H) ,7.38(td,J=6.3,2.3Hz,1H),7.25(dt,J=15.3,9.0Hz,1H),6.33(d,J=8.2 Hz,1H),6.28(dd,J=8.2,4.1Hz,1H),4.34(d,J=3.8Hz,2H),4.12–4.01(m ,2H),3.58(t,J=10.0Hz,4H),3.42(t,J=10.0Hz,4H),3.14(d,J=5.4Hz,2H ),2.97(q,J=6.4Hz,2H),2.31–2.19(m,6H),1.92–1.66(m,2H),1.66–1.5 7(m,2H),1.41–1.33(m,2H),1.26(q,J=7.3Hz,2H),1.14(q,J=4.6Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,172.51,171.40,169.53,164.51,159.87,157.76,145.33,133.97,132.06(d,J=26.5Hz),12 9.56,129.42,128.36,126.56,125.92,124.12,52.73,52.12,41.82,3 8.83,36.91,34.95,32.24,30.90,30.36,29.29,27.98,23.10,13.54.

[0220] Example 17

[0221] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-glycine.

[0222] Synthesis of 17-1

[0223] 350mg of Boc-glycine was added to a 100mL three-necked flask, 20mL of DCM was added to dissolve, 988mg of HBTU was added, 1mL of DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg of ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL of saturated ammonium chloride 3 times, and 20mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL of anhydrous ethanol was added to dissolve, 1mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL of water was added to the system. The mixture was washed 3 times with 10mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 458mg of a white foamy solid with a yield of 54%. MS (ESI + ): m / z found: 424.1766, calculated: 424.1779 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.69(s,1H),8.50–8.43(m,1H),7.77(dd,J=6.5,2.8Hz,2H),7.72(s,1H),7.3 4(s,2H),7.06(d,J=8.9Hz,1H),4.29(s,2H),3.77(s,2H),3.67–3.46(m,4H),3.46–3.25(m,4H),2.81(s,2H)

[0224] Synthesis of 17-2

[0225] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 423 mg of 17-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 215 mg of a white foamy solid with a yield of 22%. MS (ESI + ): m / z found: 993.5083, calculated: 993.5092 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ8.49–8.45(m,1H),7.82–7.76 (m,2H),7.72(dt,J=8.6,3.7Hz,1H),7.36–7.31(m,2H),7.14–6.98(m,2H),6.71(d,J=49.9Hz,1H ),6.15(d,J=8.8Hz,2H),4.35(dt,J=18.7,9.9Hz,2H),4.29(d,J=4.0Hz,2H),4.17–4.07(m,1H),3 .82(s,2H),3.70–3.18(m,8H),3.08–2.77(m,2H),2.77–2.56(m,2H),2.54–2.38(m,2H),2.31(dtt ,J=10.0,7.7,4.3Hz,2H),1.80–1.62(m,2H),1.61–1.53(m,2H),1.51–1.36(m,27H),1.26(s,2H).

[0226] Synthesis of CQ17

[0227] 195 mg of compound 17-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The filter cake was washed three times with 30 mL of ether. Drying gave 99 mg of a white solid with a yield of 55%. Melting point: >250°C. MS (ESI + ): m / z found: 825.3201, calculated: 825.3214 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ13.04(s,1H),12.59(s,1H),12.43(s,2H),8.27(d ,J=7.7Hz,1H),7.99–7.94(m,2H),7.90(q,J=7.2,6.8Hz,1H),7.84(t,J=7 .5Hz,1H),7.79(q,J=5.2Hz,1H),7.44(ddd,J=8.1,5.1,2.3Hz,1H),7.38( t,J=6.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=18.6,8.3Hz,2H),4.33( s,2H),4.07(dtd,J=26.8,8.2,5.1Hz,2H),3.94(dd,J=29.3,5.4Hz,2H),3 .62(d,J=24.0Hz,4H),3.50(t,J=5.0Hz,4H),3.19(d,J=24.4Hz,2H),3.04– 2.94(m,2H),2.38(t,J=7.4Hz,2H),2.29(t,J=8.0Hz,2H),1.97–1.69(m,2 H),1.69–1.45(m,2H),1.37(q,J=15.2,11.7Hz,2H),1.27(p,J=7.6Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,172.11,171.51,167.79 ,159.87,157.76,154.52,145.32,135.90,135.26,133.98,132.05(d,J=2 5Hz),129.68,129.56,128.37,126.55,125.93,65.38,52.73,52.12,40.9 3,38.82,36.90,32.24,31.26,31.16,30.36,29.28,27.97,23.06,15.63.

[0228] Example 18

[0229] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-L-serine.

[0230] Synthesis of 18-1

[0231] 410 mg of Boc-L-serine was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride 3 times, and 20 mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed 3 times with 10 mL of DCM, the DCM was discarded, and the aqueous phase was retained. The mixture was placed in an ice bath, and the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted 3 times with 20 mL of DCM. The mixture was concentrated to dryness to obtain 493 mg of a white foamy solid with a yield of 54%. MS (ESI + ): m / z found: 454.1898, calculated: 454.1885 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.94(s,1H),8.47(dd,J=7.1,2.2Hz,1H),7.84–7.75(m,2H),7.73(d,J=8.1Hz,1H),7.34(dd,J=8.1,5.0Hz,2H),7. 06(t,J=8.7Hz,1H),4.30(s,2H),4.00–3.84(m,1H),3.87–3.67(m,4H),3 .65(d,J=4.9Hz,1H),3.64–3.44(m,4H),3.33(s,2H),2.15–1.93(m,2H).

[0232] Synthesis of 18-2

[0233] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 453 mg of 18-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 229 mg of a white foamy solid with a yield of 22%. MS (ESI + ): m / z found: 1023.5182, calculated: 1023.5197 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.86(d,J=74.8Hz,1H),8.47(dd,J=7.5,1.8Hz,1H),7.76(dq,J=19.9,8.4Hz,3H),7.34(s ,3H),7.03(d,J=8.6Hz,1H),6.76(d,J=6.4Hz,1H),6.22(t,J=7.3Hz,1H),6.11(d,J=8.3Hz,1H),5.25–5.05(m,1H),4.33( d,J=7.7Hz,2H),4.29(s,2H),4.12(s,1H),3.74(s,8H),3.38(s,2H),3.31(s,1H),3.00(s,1H),2.80–2.64(m,2H),2.52– 2.38(m,2H),2.31(h,J=8.3,7.8Hz,2H),2.05(t,J=7.0Hz,2H),1.92–1.74(m,2H),1.47–1.37(m,27H),1.29–1.22(m,2H).

[0234] Synthesis of CQ18

[0235] Compound 18-2 (200 mg) was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and then 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS and the reaction was stopped. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 105 mg of white solid was obtained by drying, with a yield of 62%. Melting point: 239.9–240.5°C. MS (ESI + ): m / z found: 855.3331, calculated: 855.3319 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.60(s,1H),12.10(s,1H),8.27(dd,J=8.0,1.4Hz,1H),8.06(d,J=8.1Hz,1H),7.97(d,J=8.1Hz,1H),7.90(t,J=7.6H z,1H),7.87–7.81(m,1H),7.80(s,1H),7.44(ddd,J=8.2,5.1,2.3Hz,1H),7.39(dd,J=6.7,2.4Hz,1H),7.24(t,J=9.0Hz,1H),6.32(dd,J=20.6 ,8.1Hz,2H),4.78(dd,J=37.5,7.3Hz,2H),4.34(s,2H),4.08(dd,J=28.7,6.5Hz,3H),3.65–3.54(m,4H),3.54–3.39(m,4H),3.19(d,J=18.5Hz ,2H),3.05–2.88(m,2H),2.35(q,J=8.0Hz,2H),2.29–2.25(m,2H),1.9 9–1.68(m,2H),1.58(d,J=60.8Hz,2H),1.36(s,2H),1.31–1.20(m,2H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,171.70,171.52,169.56,164. 53,159.87,157.77,145.33,135.30,133.97,132.05(d,J=25Hz),129.55,129.4 5,128.36,126.55,125.92,116.48,116.31,65.38,62.13,52.73,52.12,50.80,47.21,42.17,38.81,36.92,32.24,30.97,30.36,29.27,27.97,23.08,15.62.

[0236] Example 19

[0237] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-L-methionine.

[0238] Synthesis of 19-1

[0239] 500 mg of Boc-L-methionine was added to a 100 mL three-necked flask and dissolved in 20 mL of DCM. 988 mg of HBTU and 1 mL of DIEPA were added and stirred at room temperature for 5 minutes. 732 mg of ALPL-B was added and stirred at room temperature for 2 hours. The mixture was washed three times with 20 mL of saturated ammonium chloride and three times with 20 mL of saturated brine. The mixture was separated, and the DCM phase was retained. It was dried over anhydrous sodium sulfate and concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve the mixture, and 1 mL of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for approximately 1 hour. 10 mL of water was added to the mixture. The mixture was washed three times with 10 mL of DCM, and the DCM phase was discarded, retaining the aqueous phase. The mixture was placed in an ice bath. The pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted three times with 20 mL of DCM. The mixture was concentrated to dryness to yield 515 mg of a white foamy solid (52% yield). MS (ESI+): m / z found: 498.1956, calculated: 498.1970 [M+H] + . 1 H NMR (500MHz, Chloroform-d) δ11.34(s,1H),8.50–8.45(m,1H),7.77(dt,J=5.9,2.3Hz,2H),7.72(t,J=6.3Hz,1H),7.34(t,J=6. 5Hz,2H),7.04(t,J=8.6Hz,1H),4.30(s,2H),3.94–3.66(m,4H),3.63(s,1H),3.58–3.27(m,4H),1.85(s,2H),1.31–1.22(m,3H).

[0240] Synthesis of 19-2

[0241] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 498 mg of 19-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 210 mg of a white foamy solid with a yield of 20%. MS (ESI + ): m / z found: 1067.5298, calculated: 1067.5282 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.70(s,1H),8.50–8.44(m,1H),7.85–7.76(m,2H),7.76–7.66(m,1H),7.57–7.39(m,1H),7.34(ddt,J=10.7,4.8,2.8Hz, 2H),7.04(q,J=8.8Hz,1H),6.81(d,J=23.7Hz,1H),6.21(d,J=8.5Hz,1H),6 .12–5.96(m,1H),5.12(dq,J=36.6,8.0,7.5Hz,1H),4.38(d,J=31.0Hz,2H), 4.29(s,2H),4.07–3.68(m,4H),3.67–3.44(m,2H),3.40–3.24(m,4H),2.61 (dd,J=19.5,7.2Hz,2H),2.54–2.43(m,4H),2.31(qd,J=10.6,9.3,5.5Hz,2H ),2.08(d,J=16.3Hz,4H),1.95(dd,J=14.6,7.8Hz,2H),1.90(s,3H),1.85– 1.71(m,2H),1.47(s,9H),1.41(dd,J=11.1,4.2Hz,18H),1.31–1.24(m,2H).

[0242] Synthesis of CQ19

[0243] 190 mg of compound 19-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 100 mg of white solid was obtained by drying, with a yield of 62%. Melting point: 246.0–246.8°C. MS (ESI + ): m / z found: 899.3421, calculated: 899.3404 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.59(s,1H),12.57–11.93(m,3H),8.27(d,J=7.8Hz,1H),8.21 (d,J=8.3Hz,1H),7.96(dd,J=8.2,4.4Hz,1H),7.90(t,J=7.6Hz,1H),7.84(t,J=7.5Hz,1 H),7.77(dt,J=20.4,5.5Hz,1H),7.44(ddd,J=8.1,5.1,2.3Hz,1H),7.38(t,J=5.0Hz,1H ),7.24(t,J=9.0Hz,1H),6.31(dd,J=19.9,8.2Hz,2H),4.88–4.72(m,1H),4.34(s,2H),4 .07(dtd,J=28.4,8.1,5.1Hz,2H),3.78–3.48(m,4H),3.44(dd,J=28.2,8.2Hz,4H),3.2 0(s,2H),2.97(dq,J=31.0,7.0,6.4Hz,2H),2.46–2.39(m,2H),2.34(p,J=6.3,5.3Hz,2H ),2.31–2.21(m,4H),2.03(d,J=13.9Hz,3H),1.97–1.82(m,2H),1.72(ddd,J=14.2,8.9, 5.9Hz, 2H), 1.66–1.46 (m, 2H), 1.36 (dt, J=16.6, 7.0Hz, 2H), 1.26 (q, J=8.5, 7.5Hz, 2H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.65,174.20,171.74,171.44,165.00,1 59.86,157.76,145.32,135.31,133.97,132.05(d,J=26.3Hz),130.34,130. 21,129.55,128.37,126.56,125.92,116.50,116.33,52.74,52.13,47.86,41.66,38.79,36.94,32.26,31.95,30.38,30.00,29.29,28.01,23.09,15.11

[0244] Example 20

[0245] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-L-leucine.

[0246] Synthesis of 20-1

[0247] 460 mg of Boc-L-leucine was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride 3 times, and 20 mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed 3 times with 10 mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20 mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 515 mg of a white foamy solid with a yield of 52%. MS (ESI + ): m / z found: 480.2421, calculated: 480.2405 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.65(s,1H),8.43–8.38(m,1H),7.70(dd,J=6. 4,2.9Hz,2H),7.64(s,1H),7.32–7.23(m,2H),7.20(s,1H),6.98(t,J=8.8Hz, 1H),4.22(s,2H),3.53(d,J=54.1Hz,4H),3.26(d,J=23.8Hz,4H),1.52(s,2H) ,1.31(d,J=11.2Hz,1H),1.23(d,J=11.6Hz,1H),0.87(dt,J=25.3,7.9Hz,6H).

[0248] Synthesis of 20-2

[0249] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 479 mg of 20-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 210 mg of a white foamy solid with a yield of 20%. MS (ESI + ): m / z found: 1049.5728, calculated: 1049.5718 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.32(s,1H),8.49(d,J=7.2Hz,1H),7.85–7.78(m,2H),7.77–7.68(m,1H),7.44(s,1H),7.36(d,J=19.1H z,2H),7.06(t,J=8.6Hz,1H),6.86(s,1H),6.38–6.09(m,2H),4.95(d,J=38.6Hz,1H),4.45(d,J=51.0Hz,2H),4.30(s,2H),4.08(t,J=6 .7Hz,2H),3.92(dd,J=32.8,13.7Hz,2H),3.47(d,J=36.5Hz,4H),3.32(d,J=40.4Hz,4H),2.72–2.42(m,4H),2.38–2.29(m,2H),1.87–1 .76(m,2H),1.62(d,J=7.7Hz,2H),1.49–1.38(m,27H),1.30(d,J=3.6Hz,2H),1.25–1.16(m,2H),1.16–1.11(m,1H),0.98–0.91(m,6H).

[0250] Synthesis of CQ20

[0251] 190 mg of compound 20-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 95 mg of white solid was obtained by drying, with a yield of 59%. Melting point: 235.5–235.9°C. MS (ESI + ): m / z found: 881.3852, calculated: 881.3840 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.59(s,1H),12.42(s,3H),8.27(d,J=7.8Hz,1H),8.13(t,J=7.4Hz,1H),7.97(d,J=8.1Hz,1H),7.90(t,J=7. 6Hz,1H),7.83(t,J=7.5Hz,1H),7.77(dt,J=19.3,5.7Hz,1H),7.44(ddd,J=8.1,5.1,2.2Hz,1H),7.38(d,J=6.3Hz,1H),7.24(t,J=9.0 Hz,1H),6.31(dd,J=19.7,8.2Hz,2H),4.71(d,J=33.9Hz,1H),4.33(s,2H),4.07(dtd,J=28.4,8.1, 5.0Hz,2H),3.87–3.53(m,4H),3.52–3.26(m,4H),3.23–3.11(m,2H),3.03–2.89(m,2H),2.33(dt,J= 14.0,8.2Hz,2H),2.27(t,J=9.4Hz,2H),2.24–2.19(m,1H),1.97–1.68(m,2H),1.68–1.52(m,2H),1 .51–1.39(m,2H),1.35(dd,J=13.1,7.2Hz,2H),1.26(q,J=7.9Hz,2H),0.85(dt,J=16.7,6.3Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.56,171.45,170.94,159.8 6,157.75,145.31,135.30,133.96,132.68,132.45,132.04(d,J=28.8Hz),129. 56,128.37,126.55,125.94,116.49,116.32,52.73,52.11,46.93,41.08,38.83,36.93,32.26,31.01,30.36,29.28,27.99,24.61,23.52,23.08,22.25,22.14.

[0252] Example 21

[0253] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-L-isoleucine.

[0254] Synthesis of 21-1

[0255] 460mg of Boc-L-isoleucine was added to a 100mL three-necked flask, 20mL of DCM was added to dissolve, 988mg of HBTU was added, 1mL of DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg of ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL of saturated ammonium chloride 3 times, and 20mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL of anhydrous ethanol was added to dissolve, 1mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL of water was added to the system. The mixture was washed 3 times with 10mL of DCM, the DCM was discarded, and the aqueous phase was retained. The mixture was placed in an ice bath, and the pH was adjusted to 10-11 with saturated sodium carbonate solution, and the mixture was extracted 3 times with 20mL of DCM. The mixture was concentrated to dryness to obtain 501mg of a white foamy solid with a yield of 51%. MS (ESI + ): m / z found: 480.2417, calculated: 480.2405 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.34(s,1H),8.49–8.44(m,1H),7.77(dd,J=6.7, 2.6Hz,2H),7.72(s,1H),7.33(d,J=6.4Hz,2H),7.05(d,J=6.8Hz,1H),4.28(s,2H ),3.80(s,2H),3.62(d,J=34.8Hz,4H),3.53(s,2H),3.31(s,2H),1.53(s,2H),1. 14(s,1H),1.03–0.92(m,3H),0.92(d,J=1.6Hz,1H),0.90(dd,J=7.8,3.3Hz,3H).

[0256] Synthesis of 21-2

[0257] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 479 mg of 21-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 206 mg of a white foamy solid with a yield of 20%. MS (ESI + ): m / z found: 1049.5732, calculated: 1049.5718 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ8.43–8.36(m,1H),7.84–7.55(m,3H),7.28(dd,J=6.3,2.3Hz,2H),7.03 –6.89(m,1H),6.75(s,1H),6.37–6.01(m,2H),4.44–4.30(m,2H),4.22(s,2H),3.98(s,2H),3.64(s,1H ),3.55(d,J=45.2Hz,2H),3.34(d,J=11.5Hz,2H),3.24(s,2H),2.96(s,2H),2.62–2.31(m,4H),2.29–2 .19(m,2H),2.02–1.95(m,1H),1.74–1.68(m,2H),1.41–1.29(m,27H),1.19(s,6H),0.86–0.75(m,6H).

[0258] Synthesis of CQ21

[0259] 190 mg of compound 21-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. Drying gave 97 mg of a white solid with a yield of 59%. Melting point: 238.8–239.6°C. MS (ESI + ): m / z found: 881.3829, calculated: 881.3840 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ14.82 (s, 1H), 12.60 (s, 1H), 12.42 (s, 2H), 8.27 (d, J = 7. 8Hz,1H),8.09(d,J=8.7Hz,1H),7.97(dd,J=8.3,4.5Hz,1H),7.84(tt,J=32.2,11 .3Hz,3H),7.44(t,J=6.6Hz,1H),7.39(d,J=6.4Hz,1H),7.24(t,J=9.0Hz,1H),6 .32(dd,J=19.3,8.2Hz,2H),4.54(dt,J=39.8,8.6Hz,1H),4.34(s,2H),4.17–3.9 9(m,2H),3.77–3.54(m,4H),3.52–3.46(m,2H),3.17(dt,J=11.7,6.4Hz,2H),2. 98(dq,J=14.1,6.8Hz,2H),2.44–2.31(m,2H),2.25(dtd,J=22.5,16.3,14.0,5.9 Hz,4H),1.98–1.73(m,2H),1.73–1.58(m,2H),1.56–1.41(m,2H),1.36(qd,J=12 .6,7.6,6.8Hz,2H),1.27(p,J=7.7Hz,2H),1.11–1.00(m,1H),0.87–0.75(m,6H). 13 C NMR(126MHz,DMSO-d6)δ175.02,174.66,174.20,171.81,171.50,170.55,159.87, 157.77,145.32,135.28,133.97,132.19,132.04(d,J=25Hz),129.56,128.36,126 .55,125.92,116.46,116.31,52.74,52.58,52.13,47.30,42.08,38.82,36.92,36.54,32.25,31.28,30.97,30.38,29.27,28.01,24.46,23.08,16.00,11.46,11.42.

[0260] Example 22

[0261] In Reference Example 12, N-Boc-L-valine was replaced with Boc-L-phenylalanine.

[0262] Synthesis of 22-1

[0263] 530 mg of Boc-L-phenylalanine was added to a 100 mL three-necked flask, 5 mL of DMA was added to dissolve it, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 minutes. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 hours to complete the reaction. The mixture was poured into saturated ammonium chloride and extracted with 30 mL of DCM. The DCM was retained, and the mixture was dried over anhydrous sodium sulfate. Column chromatography was performed to obtain 1042 mg of a white solid (85% yield). MS (ESI + ): m / z found: 614.2791, calculated: 614.2773 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ9.89(d,J=13.5Hz,1H),8.46(s,1H),7.77(s,2H),7.70(d,J=7.2Hz,1H),7.28(s,5H),7.19(dd,J=14.5,7.2Hz ,3H),7.02(d,J=8.4Hz,1H),5.36(d,J=8.8Hz,1H),4.26(s,2H),3.51– 3.24(m,4H),3.18–3.02(m,4H),2.99–2.90(m,2H),1.44–1.41(m,9H).

[0264] Synthesis of 22-2

[0265] 990 mg of 22-1 was dissolved in 2 mL of anhydrous ethanol, and 1 mL of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for about 1 hour, and 10 mL of water was added to the system. The mixture was washed three times with 10 mL of DCM, and the DCM was discarded, retaining the aqueous phase. The mixture was placed in an ice bath, and the pH was adjusted to 10-11 with saturated sodium carbonate solution. The mixture was extracted three times with 20 mL of DCM, dried over anhydrous sodium sulfate, and concentrated to dryness. 10 mL of DCM was added, 160 mg of succinic anhydride was added, and 419 mg of DIPEA was added. The mixture was stirred at room temperature overnight and reacted. Concentration column chromatography gave 640 mg of a white solid with a yield of 64%. MS (ESI + ): m / z found: 614.2421, calculated: 614.2409 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ12.34(s,1H),11.36(s,1H),8.46(d,J=8.0Hz,1H),8.23(d,J=8.4Hz,1H),7.90(s,1H),7.85(s,2H),7 .34–7.28(m,2H),7.26–7.16(m,5H),7.09–7.01(m,1H),5.21(d,J=68.0Hz,1H),4.27(d,J=23.0Hz,2H),3.57(d,J=43.6Hz,4H),3.44 –3.13(m,4H),3.13–3.07(m,2H),2.73–2.52(m,4H).

[0266] Synthesis of 22-3

[0267] 614 mg of 22-2 was added to a 100 mL three-necked flask, dissolved in 10 mL of dichloromethane, and 322 mg of DIPEA and 488 mg of PSMA-B were added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The product was concentrated to a small volume, 20 mL of water was added, and the product was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 310 mg of a white foamy solid with a yield of 29%. MS (ESI + ): m / z found: 1083.5545, calculated: 1083.5561 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.16(s,1H),8.50–8.44(m,1H),7.78(dt,J=10.6,4.4Hz,2H),7.71(dd,J=16.1,8.4Hz,1H),7.49(d,J=19.5Hz ,1H),7.34–7.27(m,4H),7.24(d,J=8.5Hz,2H),7.22–7.19(m,1H),7.01(t,J=8.7Hz,1H),6.83(s,1H),6.35(d,J=9.1Hz,1H),6.13–6.00(m,1 H),5.17–5.05(m,1H),4.43(d,J=38.1Hz,2H),4.27(s,2H),3.61(t,J=58.0Hz,4H),3.28(d,J=42.2Hz,2H),3.20–3.04(m,4H),2.70–2.46(m, 4H),2.34(ddd,J=14.7,10.1,5.5Hz,2H),1.84(dt,J=10.6,5.6Hz,2H),1.63(s,6H),1.48(s,9H),1.43–1.38(m,18H),1.27(d,J=14.4Hz,2H).

[0268] Synthesis of CQ22

[0269] Compound 22-2 (250 mg) was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and then 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LC-MS and the reaction was stopped. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 130 mg of white solid was obtained by drying, with a yield of 62%. Melting point: 231.7–232.7°C. MS (ESI + ): m / z found: 915.3699, calculated: 915.3683 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ13.91(s,1H),12.60(s,1H),11.08(s,2H),8.33(d,J =8.1Hz,1H),8.27(dd,J=7.8,1.4Hz,1H),8.01–7.93(m,1H),7.89(td,J=7.7, 1.5Hz,1H),7.83(td,J=7.3,2.7Hz,1H),7.76(dt,J=18.6,5.6Hz,1H),7.43( ddd,J=8.1,5.1,2.3Hz,1H),7.34(dt,J=7.1,3.5Hz,1H),7.29–7.20(m,5H),7 .20–7.16(m,1H),6.31(dd,J=20.9,8.1Hz,2H),4.88(dq,J=42.2,7.7Hz,1H) ,4.33(s,2H),4.07(dd,J=29.6,6.7Hz,2H),3.50(s,4H),3.30–3.06(m,2H),3 .08–2.85(m,4H),2.91–2.67(m,2H),2.36–2.15(m,6H),2.00–1.67(m,2H),1 .57(ddt,J=64.2,13.8,6.5Hz,2H),1.41–1.31(m,2H),1.27(p,J=7.8Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.45,170.14,159.86,15 8.92,158.62,157.76,145.31,138.94,135.29,133.97,132.04(d,J=27.5Hz ),129.88,129.56,128.59,128.37,126.89,126.55,125.92,65.38,52.73,52.12,50.08,38.83,36.91,32.25,30.96,30.36,29.27,27.99,23.08,15.63.

[0270] Example 23

[0271] In Reference Example 12, N-Boc-L-valine was replaced with Boc-D-phenylglycine.

[0272] Synthesis of 23-1

[0273] 502mg of Boc-D-phenylglycine was added to a 100mL three-necked flask, 20mL of DCM was added to dissolve, 988mg of HBTU was added, 1mL of DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg of ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL of saturated ammonium chloride 3 times, and 20mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL of anhydrous ethanol was added to dissolve, 1mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL of water was added to the system. The mixture was washed 3 times with 10mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 558mg of a white foamy solid with a yield of 56%. MS (ESI + ): m / z found: 500.2081; calculated: 500.2092 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.10(s,1H),8.47–8.42(m,1H),7.77(dd,J=6.1,3.2Hz,2H),7.72–7.67(m,1H),7.38–7.36(m,2H),7 .35–7.28(m,5H),7.06–6.98(m,1H),4.80(d,J=23.4Hz,1H),4.25(d,J=11.1Hz,2H),3.71(d,J=1.3Hz,2H),3.35(d,J=50.7Hz,8H).

[0274] Synthesis of 23-2

[0275] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 499 mg of 23-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 290 mg of a white foamy solid with a yield of 29%. MS (ESI + ): m / z found: 1069.5419, calculated: 1069.5405 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ10.36(s,1H),8.48–8.43(m,1H),7.76(hept,J=4.8Hz,2H),7.71–7.63(m,1H) ,7.59–7.43(m,2H),7.37(d,J=7.4Hz,1H),7.34(d,J=6.5Hz,3H),7.30(s,2H),6.98(s,1H),6.76(d,J=47.2H z,1H),6.36–6.10(m,1H),6.07–5.79(m,2H),4.39(s,2H),4.26(s,2H),3.84–3.17(m,8H),2.60–2.18(m,4H ),2.09(s,2H),1.55(d,J=26.9Hz,2H),1.50–1.35(m,27H),1.33(s,2H),1.28(d,J=5.4Hz,2H),1.26(s,2H).

[0276] Synthesis of CQ23

[0277] 220 mg of compound 23-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 130 mg of white solid was obtained by drying, with a yield of 62%. Melting point: 216.9–217.5°C. MS (ESI + ): m / z found: 901.3541, calculated: 901.3527 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ12.59(s,1H),12.42(s,3H),8.51(d,J=7.6Hz,1H),8.30–8.24(m,1H),7.95(t,J=6.3Hz,1H),7.92–7.81(m,2H),7.77 (dt,J=10.6,5.6Hz,1H),7.40(d,J=19.6Hz,2H),7.38–7.27(m,5H),7.21(td,J=9.0,4.9Hz,1H),6.31(dd,J=19.3,8.2Hz,2H),5.86(dd,J=40. 5,7.7Hz,1H),4.31(d,J=3.1Hz,2H),4.08(dtd,J=27.3,8.2,5.1Hz,2H),3.58(d,J=44.7Hz,4H),3.42(s,4H),3.22–3.09(m,2H),2.98(dd,J= 11.6, 6.0Hz, 2H), 2.40 (q, J = 6.9Hz, 2H), 2.31–2.20 (m, 4H), 1.64 (td, J = 14.4, 13.7, 7.6Hz, 2H), 1.36 (h, J = 6.4, 4.3Hz, 2H), 1.31–1.21 (m, 2H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,171.50,159.86,157.76,145.30,138.04,135.25,133.95,132.04(d,J=18.8Hz),129.5 5,129.07,128.36,126.54,125.90,123.96,123.81,53.51,52.73,52.12,38.83,36.89,32.25,31.16,30.94,30.37,29.27,27.98,23.08

[0278] Example 24

[0279] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-4-aminovaline.

[0280] Synthesis of 24-1

[0281] 406 mg of Boc-4-aminobutyric acid was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride 3 times, and 20 mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed 3 times with 10 mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20 mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 507 mg of a white foamy solid with a yield of 56%. MS (ESI + ): m / z found: 452.2079; calculated: 452.2092 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ13.26(s,1H),8.48(d,J=6.8Hz,1H),7.79(d,J=7.9Hz,2H),7.73(s,1H),7.35(t,J=7.1Hz,2H),7.10 –7.05(m,1H),4.30(s,2H),3.65–3.17(m,8H),2.81(t,J=6.8Hz,2H),2.51–2.40(m,2H),2.20–1.95(m,2H),1.83(d,J=9.9Hz,2H).

[0282] Synthesis of 24-2

[0283] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 451 mg of 24-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 290 mg of a white foamy solid with a yield of 28%. MS (ESI + ): m / z found: 1021.5418, calculated: 1021.5405 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ11.25(s,1H),10.46(s,1H),8.46(t,J=6.3Hz,1H),7.84–7.67(m,3H),7.31(d,J=25.2Hz,2H), 7.08–7.01(m,1H),6.80(d,J=20.8Hz,1H),6.10(dd,J=13.8,8.2Hz,1H),5.93(t,J=9.2Hz,1H),4.31(s,1H),4.28(s,2H),3. 76(d,J=24.1Hz,2H),3.70(s,1H),3.56(d,J=6.1Hz,2H),2.99(d,J=34.5Hz,8H),2.66(d,J=11.3Hz,1H),2.63–2.54(m,1H), 2.43(d,J=8.1Hz,2H), 2.32(d,J=7.9Hz,2H), 1.84(dq,J=14.2,6.8Hz,4H), 1.44(d,J=12.9Hz,27H), 1.27(d,J=15.6Hz,6H).

[0284] Synthesis of CQ24

[0285] Compound 24-2 (250 mg) was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and then 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 130 mg of white solid was obtained by drying, with a yield of 62%. Melting point: 200.4–200.8°C. MS (ESI + ): m / z found: 853.3508, calculated: 853.3527 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ14.41(s,1H),12.60(s,1H),10.94(s,2H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0Hz,1H),7.90(t,J=7.6Hz, 1H),7.85(d,J=7.6Hz,1H),7.82–7.74(m,2H),7.48–7.42(m,1H),7.37(d,J=6.3Hz,1H),7.24(t,J=9.0Hz,1H),6.31(dd,J=22.9,8 .1Hz,2H),4.33(s,2H),4.07(d,J=16.7Hz,2H),3.65–3.50(m,4H),3.39–3.34(m,2H),3.21–3.12(m,2H),3.06–2.94(m,4H),2.38– 2.29(m,2H),2.28(d,J=6.4Hz,4H),2.26–2.21(m,2H),1.93–1.67(m,2H),1.62(d,J=7.2Hz,2H),1.61–1.44(m,2H),1.40–1.32(m, 2H),1.26(dt,J=12.6,6.7Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ175.01,174.65,174.19,171.81,171.63,171.05,159.87,157.77,145.33,133.98,132.05(d,J=23.5Hz ),129.55,129.41,128.37,126.56,125.92,52.73,52.12,38.56,36.90,32.23,31.33,30.36,30.06,29.26,27.98,25.25,23.06

[0286] Example 25

[0287] Refer to Example 12, except that N-Boc-L-valine was replaced with Boc-L-citrulline.

[0288] Synthesis of 25-1

[0289] 550mg of Boc-L-citrulline was added to a 100mL three-necked flask, 20mL of DCM was added to dissolve, 988mg of HBTU was added, 1mL of DIEPA was added, and the mixture was stirred at room temperature for 5min. 732mg of ALPL-B was added, and the mixture was stirred at room temperature for 2h. The mixture was washed with 20mL of saturated ammonium chloride 3 times, and 20mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2mL of anhydrous ethanol was added to dissolve, 1mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1h to complete the reaction. 10mL of water was added to the system. The mixture was washed 3 times with 10mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 548mg of a white foamy solid with a yield of 52%. MS (ESI + ) m / z found: 524.2416, calculated: 524.2431 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.63(s,1H),8.52(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0 Hz,1H),7.90(t,J=7.5Hz,1H),7.84(t,J=7.5Hz,1H),7.44(ddd,J=8.4,5.2,2.4Hz,1H),7 .37(d,J=6.2Hz,1H),7.24(t,J=9.0Hz,1H),6.39–5.78(m,2H),5.39(s,2H),4.33(s,2H) ,3.60(d,J=37.4Hz,8H),3.16(s,1H),2.99–2.90(m,2H),1.49–1.38(m,2H),1.27(m,2H).

[0290] Synthesis of 25-2

[0291] 587 mg of PSMA-D was added to a 100 mL three-necked flask, 10 mL of dichloromethane was added to dissolve, 322 mg of DIPEA was added, and 523 mg of 25-1 was added. The reaction was stirred at room temperature. After monitoring the disappearance of the starting material by LC-MS, the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the solution was extracted three times with 20 mL of dichloromethane. The dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography to obtain 299 mg of a white foamy solid with a yield of 27%. MS (ESI + ): m / z found: 1093.5713, calculated: 1093.5728 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ11.69(s,1H),8.47(d,J=7.7Hz,1H),7.86(d,J=4.1Hz,1H),7.83–7.62(m,2H),7.42–7.28( m,3H),7.07(dd,J=13.6,8.7Hz,1H),6.98–6.77(m,1H),6.48–6.18(m,2H),6.12(s,1H),5.94–5.65(m,2H),5.19(s,2H), 5.05–4.84(m,2H),4.43–4.34(m,1H),4.28(s,2H),3.72(q,J=7.0Hz,8H),3.49(s,2H),3.32(d,J=28.4Hz,2H),3.02(s,2 H),2.83–2.65(m,2H),2.53–2.38(m,2H),2.33(d,J=7.7Hz,2H),1.99(s,2H),1.51–1.39(m,27H),1.28(d,J=9.9Hz,6H).

[0292] Synthesis of CQ25

[0293] Compound 25-2 (250 mg) was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and then 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 130 mg of white solid was obtained by drying, with a yield of 62%. Melting point: >250°C. MS (ESI + ): m / z found: 925.3838, calculated: 925.3850 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ12.60(d,J=3.1Hz,1H),12.42(s,3H),8.27(d,J=7.8Hz,1H),8.14 (d,J=8.2Hz,1H),7.97(d,J=8.3Hz,1H),7.90(q,J=7.0Hz,1H),7.84(t,J=7.6Hz, 1H),7.78(dt,J=19.1,5.4Hz,1H),7.44(ddd,J=8.1,5.2,2.3Hz,1H),7.38(dd,J= 6.5,2.3Hz,1H),7.24(t,J=9.0Hz,1H),6.36–6.27(m,2H),5.92(q,J=5.4Hz,1H),5 .39(d,J=8.9Hz,2H),4.75–4.56(m,1H),4.34(s,2H),4.12–4.01(m,2H),3.60(s, 2H),3.48(s,2H),3.42(d,J=18.4Hz,2H),3.18(d,J=19.8Hz,2H),2.99(p,J=7.3Hz ,2H),2.96–2.89(m,2H),2.37–2.30(m,2H),2.30–2.22(m,4H),1.93–1.69(m,2H) ,1.63(s,2H),1.53–1.42(m,2H),1.35(q,J=11.6,10.7Hz,4H),1.28–1.21(m,2H). 13 C NMR (126MHz, DMSO-d6) δ175.02,174.67,174.20,171.63,171.49,164.52,159.88,159.25,157.77,145.33,134.01,132.06(d, J=25Hz),129.56,128.36,126.55,125.92,65.38,52.74,52.12,48.36,36.91,32.25,30.36,29.27,27.98,26.66,23.07,15.63

[0294] Example 26

[0295] In Reference Example 12, N-Boc-L-valine was replaced with Boc-L-proline.

[0296] Synthesis of 26-1

[0297] 406 mg of Boc-L-proline was added to a 100 mL three-necked flask, 20 mL of DCM was added to dissolve, 988 mg of HBTU was added, 1 mL of DIEPA was added, and the mixture was stirred at room temperature for 5 min. 732 mg of ALPL-B was added, and the mixture was stirred at room temperature for 2 h. The mixture was washed with 20 mL of saturated ammonium chloride 3 times, and 20 mL of saturated brine 3 times. The mixture was separated, the DCM phase was retained, anhydrous sodium sulfate was added to dryness, and the mixture was concentrated to dryness. 2 mL of anhydrous ethanol was added to dissolve, 1 mL of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for about 1 h. 10 mL of water was added to the system. The mixture was washed 3 times with 10 mL of DCM, the DCM was discarded, and the aqueous phase was retained. Ice bath, saturated sodium carbonate solution was adjusted to pH 10-11, and 20 mL of DCM was extracted 3 times. The mixture was concentrated to dryness to obtain 488 mg of a white foamy solid with a yield of 53%. MS (ESI + ): m / z found: 464.2078; calculated: 464.2092 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ10.30(s,1H),8.47(d,J=7.3Hz,1H),7.77(dd,J=9.3,5.9Hz,3H),7.33(s,2H),7.0 5(t,J=8.7Hz,1H),4.28(s,2H),4.00(s,1H),3.75(t,J=7.3Hz,2H),3.68–3.06(m,8H),2.92(m,1H),2.06(s,4H).

[0298] Synthesis of 26-2

[0299] 587 mg of PSMA-D was added to a 100 mL three-necked flask and dissolved in 10 mL of dichloromethane. 322 mg of DIPEA and 463 mg of 26-1 were added. The reaction was stirred at room temperature. LC-MS monitoring revealed the disappearance of the starting material, and the reaction was stopped. The solution was concentrated to a small volume, 20 mL of water was added, and the mixture was extracted three times with 20 mL of dichloromethane. The combined dichloromethane solution was dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 265 mg of a white foamy solid (27% yield). MS (ESI+): m / z found: 1033.5423, calculated: 1033.5405 [M+H]+. 1H NMR(500MHz,Chloroform-d)δ10.55(s,1H),8.49–8.43(m,1H),7.76(ddt,J=13.7,11.7,7.5Hz,3H),7. 40–7.35(m,1H),7.29(dd,J=5.8,3.3Hz,1H),7.08–6.95(m,2H),6.50–6.30(m,1H),6.12(d,J=9.3Hz,1H ),5.10(s,1H),4.51–4.38(m,1H),4.30(q,J=4.9Hz,1H),4.27(s,2H),3.90(d,J=14.8Hz,2H),3.66(q, J=7.3,6.1Hz,2H),3.57(s,2H),3.46–3.33(m,2H),3.24(d,J=9.9Hz,2H),3.04–2.86(m,2H),2.76–2.49 (m,2H),2.40–2.17(m,4H),2.02(s,4H),1.85(s,4H),1.77(s,4H),1.52–1.28(m,27H).

[0300] Synthesis of CQ26

[0301] 230 mg of compound 26-2 was added to a 50 mL three-necked flask, dissolved in 1 mL of dichloromethane, and 1 mL of TFA was added. The mixture was stirred at room temperature for 2 h. The reaction was stopped after monitoring by LC-MS. The reaction solution was added dropwise to 30 mL of ether, and a large amount of white solid precipitated. The mixture was filtered and the filter cake was washed three times with 30 mL of ether. 80 mg of white solid was obtained by drying, with a yield of 42%. Melting point: 238.0–238.3°C. MS (ESI + ): m / z found: 865.3509, calculated: 865.3527 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),8.27(d,J=7.8Hz,1H),7.97(d,J=8.0H z,1H),7.90(q,J=7.0Hz,1H),7.81(dt,J=21.0,6.6Hz,2H),7.48–7.36(m,2H) ,7.24(t,J=9.0Hz,1H),6.32(dd,J=16.2,8.3Hz,2H),4.34(s,2H),4.12–4.04 (m,2H),3.70–3.59(m,2H),3.53(dd,J=17.5,8.8Hz,4H),3.37(dt,J=6.8,3.4 Hz,2H),3.26–3.15(m,2H),3.00(p,J=8.7,7.7Hz,2H),2.57(dd,J=16.5,8.2H z,1H),2.40(ddt,J=30.1,14.4,7.7Hz,2H),2.32–2.25(m,2H),2.25–2.16(m, 2H),2.18–1.93(m,2H),1.90(q,J=7.7Hz,2H),1.77–1.69(m,2H),1.57(ddt,J =64.1,15.3,6.7Hz,2H),1.37(dq,J=13.9,6.3Hz,2H),1.27(t,J=7.7Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ175.01,174.65,174.19,171.63,169.95,159.87,1 58.94,158.64,157.77,145.34,135.30,133.99,132.05(d,J=25Hz),129.5 6,129.45,128.36,126.55,125.91,116.49,56.37,52.74,52.12,47.09,46 .82,38.83,36.91,32.22,30.56,30.35,29.79,29.26,27.98,24.68,23.04.

[0302] In order to thoroughly and comprehensively study the targeted therapeutic effect and safety of this series of conjugates and to clarify whether they can be used as an effective targeted therapeutic strategy for PSMA-positive prostate cancer, the present invention will conduct research from the following aspects.

[0303] Example 27

[0304] First, through in vitro cell experiments, it was preliminarily verified that the conjugate can specifically kill PSMA-positive prostate tumor cells without obvious effects on negative cells, especially with sufficient safety for normal cells.

[0305] Take LNCaP, C4-2B, 22RV1, PC3 and RWPE-1 cell lines in the logarithmic growth phase and plant them in 96-well plates with 100 μL per well. After 24 hours of culture, treat the cells with different concentration gradients of the above compounds with DMSO as the control, and use Olaparib as the positive control. After incubation for 72 hours, add 20 μL of 5 mg / mL MTT solution to each well, incubate in the incubator for 4 hours, discard the supernatant, add 150 μL DMSO to each well, shake for 10 minutes to dissolve completely, set the zero hole, and read the absorbance at 570 nm with a microplate reader. Calculate IC 50 、CC 50 The experiments were repeated three times independently, and the results are expressed as the mean ± standard deviation of three experiments.

[0306] Table 1 Inhibitory effect of conjugates on proliferation of LNCaP, C4-2B, 22RV1, PC3 and RWPE-1

[0307] The results, as shown in Table 1, show that the PARP inhibitor olaparib alone has a strong toxic effect, with significant killing effects on the above five cell types, and no significant difference in killing effects on PSMA-positive and negative cells. The cell-killing effects of the compounds provided by the present invention are dependent on PSMA expression. They have significantly stronger killing effects on PSMA-positive LNCaP, C4-2B, and 22RV1 cell lines than on PSMA-negative PC3 and RWPE-1 cell lines, and have no significant toxicity to normal prostate epithelial cells, thus extending the drug's safety window.

[0308] DUPA is a known, highly effective PSMA inhibitor. In our experiments, we co-incubated DUPA with the conjugates of the present invention, such as CQ-04 and CQ-16, on PSMA-positive cells. We found that DUPA competitively inhibited the anti-tumor effects of the conjugates on PSMA-positive cells, further demonstrating that the conjugates of the present invention are dependent on PSMA expression and have good selectivity for PSMA-positive cells, as shown in Figure 1.

[0309] Example 28

[0310] The antitumor activity of the conjugate CQ-04 of the present invention was evaluated in nude mice transplanted with human prostate cancer cell 22RV1.

[0311] 1. Experimental animals, reagents, and instruments

[0312] SPF-grade BALB / c nude mice (4 weeks old), male, weighing 21±1g, were supplied by Zhejiang Provincial Experimental Animal Center, with animal qualification certificate number (SYXK(Zhe)2019-0011). The animals were housed in the animal room of the SPF-grade animal center. The animal cages, drinking water, feed, and bedding were sterilized by high-pressure steam. The animals were given free access to food and water to ensure nutrition. The experimental temperature was kept constant at about 20°C and the relative humidity was about 50%. The light cycle was 12 hours day and night. All operations in the experiment were carried out in a sterile environment. The experiment began after one week of adaptive feeding.

[0313] 2. Experimental Methods

[0314] 2.1 Establishment of 22RV1-bearing prostate cancer xenograft model

[0315] Human prostate cancer 22RV1 cells in logarithmic growth phase (density of about 80%–90%) were selected and resuspended in PBS to adjust the cell concentration to 10 8 100 / mL, add an equal volume of concentrated Matrigel to suspend, and under sterile conditions, inoculate 22RV1 cells subcutaneously in the right forelimb of nude mice using a 1mL syringe, with an inoculation volume of 0.1mL / mouse (approximately 5 million cells). Three days after inoculation, small protrusions with hard texture appeared at the inoculation site, which gradually increased in size. Body weight and tumor volume were measured every two days. When the tumor volume reached 100-200mm 3 , and the state is relatively stable, the model is successfully made.

[0316] 2.2 Animal grouping and drug administration

[0317] The successfully inoculated model nude mice were randomly divided into 5 groups, with 6 mice in each group, namely (I) normal saline group, (II) olaparib group (80 mg / kg / day, po), (III) CQ-04 group (140 mg / kg / day, po), (IV) CQ-04 group (140 mg / kg / day, iv), and (V) CQ-04 group (280 mg / kg / day, po), and the drugs were administered for a total of 14 days.

[0318] 2.3 Pharmacodynamic Evaluation of Conjugate CQ-04

[0319] General observation of nude mice: Observe the effects of the drugs on the nude mice's fur, mental state, diet and water intake every day. Measure and record the changes in the nude mice's body weight every two days using an electronic balance.

[0320] Observation of tumor changes: After tumor nodules are formed, the longest diameter (a) and the maximum transverse diameter (b) of the tumor are measured with a vernier caliper 2-3 times a week, the tumor volume is calculated, and a tumor growth curve is drawn.

[0321] Tumor volume V (mm3 )=a×b 2 / 2

[0322] Calculation of tumor inhibition rate: After the end of treatment, the nude mice were killed by cervical dislocation, the tumors were completely removed and the tumor weight was weighed using an analytical balance.

[0323] Tumor inhibition rate (IR): IR (%) = (1-average tumor weight of the treatment group / average tumor weight of the control group) × 100%

[0324] Treatment of experimental animals after treatment

[0325] After the last dose (day 14), the nude mice were fasted for 8 hours and then transferred to the dissection room. Before being sacrificed by cervical dislocation, the eyes were removed and blood was collected. The blood was divided into two parts: one with anticoagulant and the other without anticoagulant. After blood collection, the nude mice were sacrificed by cervical dislocation and the tumors were removed by dissection. The tumor tissue in each group was weighed, recorded, and photographed using an analytical balance.

[0326] 2.4 Blood biochemistry and routine blood tests of mice

[0327] The unanticoagulated blood samples were placed at room temperature for 1 hour and then centrifuged. Serum was collected for blood biochemical analysis and determination of creatinine (CRE) index. Routine blood tests were performed to determine lymphocyte count, white blood cell count, neutrophil count, platelet count, hemoglobin count, and mean corpuscular volume (MCV).

[0328] 3. Experimental Results

[0329] Thirty nude mice with successfully established models were randomly divided into five groups of six mice each and treated with different drugs. From the start of modeling to the end of the experiment, no nude mice died. As shown in Figure 3, there was no significant difference in body weight between the groups. Figure 4 shows that tumor volume in the model group increased significantly over time, while tumor volume in the treatment group and the positive control group was significantly suppressed. At the treatment endpoint, 14 days after administration, tumor volume and weight in the three CQ-04 treatment groups and the positive control group were significantly lower than those in the model group (p < 0.05). Tumor weights in the positive group receiving olaparib (80 mg / kg, po), the equimolar oral CQ-04 group (140 mg / kg, po), the equimolar intravenous CQ-04 group (140 mg / kg, iv), and the high-dose oral CQ-04 group (280 mg / kg, po) were all significantly lower than those in the model group (p < 0.05). The anti-tumor effect of CQ-04 at an equimolar dose and the same administration method was superior to that of Olaparib, and no significant decrease in lymphocytes was observed, while lymphocytes decreased in the Olaparib group (Figure 2), indicating that CQ-04 has better efficacy and safety (Table 2).

[0330] Table 2

[0331] Example 29

[0332] The antitumor activity of the conjugate CQ-16 of the present invention was evaluated in nude mice transplanted with human prostate cancer cell 22RV1.

[0333] The experimental operation is the same as Example 28.

[0334] 3. Experimental Results

[0335] We established the following groups: (I) saline vehicle, (II) olaparib (100 mg / kg / day, po), (III) low-dose CQ-06 (25 mg / kg / day, po), (IV) intermediate-dose CQ-16 (50 mg / kg / day, po), and (V) high-dose CQ-16 (100 mg / kg / day, po). A 22rv1 nude mouse tumor-bearing model was established using the aforementioned experimental methods. At the endpoint, blood was collected from the nude mice's orbits after enflurane anesthesia and anticoagulated with potassium EDTA, and routine blood tests were performed.

[0336] As shown in Figure 5C, there were no significant differences in the body weights of mice in each group. Figures 5A, 5B, and 5D show that tumor volume in the model group increased significantly over time, while tumor volume in the treatment group and the positive control group was significantly suppressed. At the treatment endpoint of 24 days after administration, tumor volume and weight in the three CQ-16 groups and the positive control group were significantly lower than those in the model group, with significant differences (p < 0.05). Tumor weights in the positive group (100 mg / kg, daily, po) and the high, medium, and low dose CQ-16 groups were significantly lower than those in the model group, with significant differences (p < 0.05). The antitumor efficacy of CQ-16 (50 mg / kg, daily, po) was comparable to that of olaparib (100 mg / kg, daily, po), further demonstrating that CQ-16 has superior antitumor efficacy to olaparib. In routine blood tests at the treatment endpoint (Figure 5E), CQ-16 at 25, 50, and 100 mg / kg doses showed no hematologic toxicity compared to the control group, whereas the 100 mg / kg olaparib group showed significant decreases in lymphocytes, granulocytes, erythrocytes, and hemoglobin. These results suggest that CQ-16 is safer and more effective than olaparib.

[0337] Example 30

[0338] Subacute toxicity and hematological toxicity evaluation of the conjugates CQ-04 and CQ-16 of the present invention in normal ICR mice.

[0339] We selected normal ICR mice as the evaluation model for 30-day subacute toxicity.

[0340] Animals were randomly divided into five groups: a control group (vehicle), an olaparib group (100 mg / kg, 0.23 mmol / kg), a CQ-04 group (175 mg / kg, 0.23 mmol / kg), a CQ-16 group (195 mg / kg, 0.23 mmol / kg), and a CQ-16 group (390 mg / kg, 0.46 mmol / kg). Mice were administered daily by oral gavage for 30 days. Body weight and mortality were observed and recorded daily for 30 days. All animals were deprived of food and water 12 hours beforehand. All animals were weighed and then sacrificed by cervical dislocation under enflurane anesthesia, with anticoagulated whole blood collected from the ophthalmic vein via orbital excision. The condition of major organs was observed.

[0341] After one month of treatment with olaparib, mice achieved a weight reduction of approximately 8% compared to the control group. There were no significant differences in weight between the conjugate and the control group. Complete blood counts at the end of treatment showed that compared to the control group, 100 mg / kg of olaparib caused a 15.73% decrease in white blood cell (RBC) count, an 11.69% decrease in hemoglobin (HGB), and a 12.82% decrease in hematocrit (HCT). White blood cell (WBC) count, neutrophil (NEU) count, and lymphocyte (Lym) count decreased by 28.12%, 10.40%, and 32.71%, respectively. There were no significant differences in hematological parameters between the conjugate and control groups, indicating a safer treatment.

[0342] In summary, it can be seen that the targeted therapy strategy of the present invention for the conjugate of Olaparib and PSMA-targeted PARP inhibitor can indeed improve the efficiency of drug delivery and killing in tumor tissue, and can specifically and efficiently kill PSMA-positive prostate tumor cells, while having sufficiently low toxicity to PSMA-negative normal cells, reducing toxic side effects, thereby achieving precise and efficient attack on prostate tumors while controlling and reducing drug toxic and side effects.

[0343] It will be apparent to those skilled in the art that the apparatus and method of the present invention are not limited to the details of the exemplary embodiments described above, and that the technical solutions of the present invention can be implemented in other specific forms without departing from the purpose or essential features of the present invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the present invention is defined by the appended claims rather than the foregoing description.

Claims

1. A PSMA-PARPi conjugate targeting PSMA or a pharmaceutically acceptable salt thereof, characterized in that: The general formula of the conjugate is shown below: in: Linkers include diacids, alkyl chains, disulfides, amides, carbamates, heterocyclyl alkyls, alkoxycarbonyls, alkylaminos, natural or unnatural amino acids of different lengths, specifically, general formula I and general formula II, X=CH2、NH、O, Y=carbonyl, CH2, n=an integer from 0 to 10; R1=H, alkyl, heteroalkyl, or aromatic group with 1 to 10 carbon atoms, R2=H, alkyl with 1 to 5 carbon atoms, * is R configuration or S configuration.

2. The PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The alkyl group in R1 in the general formula II is selected from methyl, isopropyl, cyclopropyl or isobutyl, the heteroalkyl group is selected from hydroxymethyl, and the aromatic group is selected from phenyl.

3. The PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The alkyl group in R2 in the general formula II is selected from methyl group.

4. The PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: Selected from any of the following compounds: CQ-01: (((S)-1-carboxy-5-(5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5-oxopentanamido)pentyl)carbamoyl)-L-glutamic acid, CQ-02: (11S, 15S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,5,13-trioxo-2-oxa-6,12,14-triazaheptadecan-11,5,17-tricarboxylic acid, CQ-03: (14S, 18S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,8,16-trioxo-4,5-dithio-9,15,17-triazaeicosane-14,18,20-tricarboxylic acid, CQ-04: (((S)-1-carboxy-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid, CQ-05: (((S)-1-carboxy-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzamido)pentyl)carbamoyl)-L-glutamic acid, CQ-06: (((S)-1-carboxy-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carboxamido)pentyl)carbamoyl)-L-glutamic acid, CQ-07: (11S, 15S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,5,13-trioxy-2,6,12,14-tetraazaheptadecan-11,5,17-tricarboxylic acid, CQ-08: (12S, 16S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,6,14-trioxo-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid, CQ-09: (((S)-1-carboxy-5-(8-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-8-oxooctylamido)pentyl)carbamoyl)-L-glutamic acid, CQ-10: (((S)-1-carboxy-5-(3-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)propionamido)pentyl)carbamoyl)-L-glutamic acid, CQ-11: (3S,7S)-25-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5,13,18,25-tetraoxo-4,6,12,17-tetraazapentacosane-1,3,7-tricarboxylic acid, CQ-12: (3S, 7S, 18S)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid, CQ-13: (3S,7S,18R)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid acid, CQ-14: (2S, 13S, 17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-methyl-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid, CQ-15: (13S, 17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-3-methyl-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid, CQ-16: (((S)-1-carboxy-5-(4-(1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)cyclopropyl)amino)-4-oxobutyramido)pentyl)carbamoyl)-L-glutamic acid, CQ-17: (((S)-1-carboxy-5-(4-(2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethyl)amino)-4-oxobutyramido)pentyl)carbamoyl)-L-glutamic acid, CQ-18: (2S, 13S, 17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-2-(hydroxymethyl)-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid, CQ-19: (5S, 16S, 20S)-5-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-7,10,18-trioxo-2-thio-6,11,17,19-tetraazadocosapentaenoic acid-16,22-tricarboxylic acid, CQ-20: (3S, 7S, 18S)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-20-methyl-5,13,16-trioxo-4,6,12,17-tetraazaphthalic acid-1,3,7-tricarboxylic acid, CQ-21: (3S, 7S, 18S, 19R)-18-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-19-methyl-5,13,16-trioxo-4,6,12,17-tetraazacyclohexane-1,3,7-tricarboxylic acid, CQ-22: (2S, 13S, 17S)-2-benzyl-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,4,7,15-tetraoxo-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid, CQ-23: (2R, 13S, 17S)-1-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-1,4,7,15-tetraoxo-2-phenyl-3,8,14,16-tetraazaundecane-13,17,19-tricarboxylic acid, CQ-24: (3S,7S)-21-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazin-1-yl)-5,13,6,21-tetraoxo-4,6,12,17-tetraazaeicosane-1,3,7-tricarboxylic acid, CQ-25: (6S, 17S, 21S)-1-amino-6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalic acid-1-yl)methyl)benzoyl)piperazine-1-carbonyl)-1,8,11,19-tetraoxo-2,7,12,18,20-pentaazatriazine-17,23-tricarboxylic acid, CQ-26: (((S)-1-carboxy-5-(4-(S)-2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazine-1-carbonyl)pyrrolidin-1-yl)-4-oxobutanamido)pentyl)carbamoyl)-L-glutamic acid.

5. The PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: n is an integer from 1 to 5.

6. A method for preparing a PSMA-PARPi conjugate targeted by PSMA or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: Step 1: Compound a and compound b are used as raw materials to obtain compound c through condensation reaction. Step 2: After deprotection of c, compound I is obtained. Step 3: Compound d and e are used as raw materials, and after condensation reaction, Boc removal is performed to obtain compound f. Step 4: Compound b reacts with succinic anhydride to obtain compound g. Step 5: Compound f and compound g are used as raw materials to obtain compound h through condensation reaction. Step 6: h is deprotected to obtain compound II, X=CH2, NH, O; Y = carbonyl, CH2; n=an integer from 0 to 10; R1=H, alkyl, heteroalkyl or aromatic group with 1-10 carbon atoms; R2=H, alkyl with 1-5 carbon atoms; * is R configuration or S configuration.

7. The preparation method according to claim 6, characterized in that: The alkyl group in R1 is selected from methyl, isopropyl, cyclopropyl or isobutyl, the heteroalkyl group is selected from hydroxymethyl, and the aromatic group is selected from phenyl.

8. The preparation method according to claim 6, characterized in that: The alkyl group in R2 is selected from methyl group.

9. The preparation method according to claim 6, characterized in that: n is an integer from 1 to 5.

10. Use of the PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of an anti-prostate tumor drug.

11. The use according to claim 10, characterized in that: The prostate tumor includes primary prostate tumor and metastatic prostate tumor.

12. The use according to claim 10, characterized in that: The prostate tumors include hormone-sensitive prostate tumors and hormone-resistant prostate tumors.

13. The use according to claim 12, characterized in that: The hormone-resistant prostate tumor includes castration-resistant prostate cancer (CRPC); preferably, the castration-resistant prostate cancer (CRPC) includes metastatic castration-resistant prostate cancer (mCRPC).

14. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (i) the PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5; and (ii) a pharmaceutically acceptable carrier, diluent or excipient.

15. A method for preventing and / or treating prostate tumors, characterized in that: The method comprises the step of administering to a subject in need thereof the PSMA-targeted PSMA-PARPi conjugate or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 14.

Images