PSMA compound, pharmaceutical composition containing same and application of PSMA compound

Abstract

The invention discloses a compound as shown in a formula I or pharmaceutically acceptable salt, ester or solvate thereof. The PSMA compound has higher tumor uptake and / or lower kidney uptake, the risk of renal injury can be greatly reduced while the drug targeting effect is improved, and the drug use requirements of patients can be better met. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of radiopharmaceuticals, and in particular relates to a compound capable of binding to prostate-specific membrane antigen (PSMA), a pharmaceutical composition containing the compound, and uses thereof. Background Art

[0002] Prostate cancer (PCa) is the second most common cancer in men, second only to lung cancer. The incidence of prostate cancer is 37.5 per 100,000 people in developed countries and 11.3 per 100,000 people in developing countries, while the mortality rate is 8.1 per 100,000 people in developed countries and 5.9 per 100,000 people in developing countries. Approximately 10 million men are currently diagnosed with prostate cancer. Prostate cancer causes more than 400,000 deaths worldwide each year, and by 2040, the mortality rate is expected to reach more than 800,000 per year.

[0003] PSMA (Prostate-Specific Membrane Antigen) is a type II transmembrane glycoprotein, also known as glutamate carboxypeptidase II and folate hydrolase 1, with folate hydrolase and N-acetyl-α-linked acid dipeptidase activity. The PSMA protein consists of 750 amino acids in three domains, of which the intracellular domain contains 19 amino acids, the transmembrane domain consists of 24 amino acids, and the extracellular domain contains 707 amino acids. The expression level of PSMA in normal prostate tissue and non-prostate tissue (such as liver, kidney, small intestine, etc.) is very low, but the expression in prostate cancer tissue is 100-1000 times higher than that in normal prostate tissue, and its expression level is highly correlated with the invasiveness of PCa, which is a specific molecular marker for prostate cancer. At the same time, the extracellular domain of PSMA is large and easy to design targeting molecules. Therefore, PSMA is a suitable therapeutic diagnostic target for imaging diagnosis and targeted radionuclide therapy of prostate cancer and its metastases.

[0004] The application of PSMA in diagnostic imaging mainly includes the manufacture and application of targeted imaging agents based on PSMA targets. Regarding the diagnostic technology of prostate cancer, including the application of imaging diagnostic methods such as SPECT (single photon emission computed tomography) and PET (positron emission tomography), by using radioactive isotope-labeled PSMA-targeted polypeptide substances. The early PSMA targeted imaging agent was ProstaScint (also known as 111In-capromab pentetide), which is a mouse monoclonal antibody (7E11) linked to 111-In and can be used for SPECT imaging. However, ProstaScint can only bind to the intracellular epitope of PSMA, and therefore cannot bind to living tumor cells, and its clinical performance is limited. 68Ga-PSMA-11 is a representative 68 Ga-labeled PSMA ligands are widely used as therapeutic diagnostic agents for PSMA targets. 18 F-labeled theranostic agents, such as 18 F-DCFBC, 18 F-DCFPyL and 18 FPSMA-1007, compared to the above 68 Ga-labeled diagnostic agents showed improved sensitivity and diagnostic accuracy in PSMA-based prostate cancer imaging applications.

[0005] Although a large number of imaging agents and inhibitors based on PSMA targets have been developed and applied, the diagnosis, management and / or treatment of prostate cancer are still full of challenges, such as reducing the impact of the drugs on the health of the kidneys or other organs of the patients while achieving efficient and accurate diagnosis or treatment. There is still a need to develop new diagnostic agents or imaging agents that can target PCa tumor cells in a highly selective manner and exhibit good pharmacokinetic properties and / or other effects to enable rapid and non-invasive tumor visualization and treatment to achieve early diagnosis and / or treatment of PCa. Summary of the invention

[0006] The purpose of the present invention is to provide a new class of PSMA compounds. Such PSMA compounds have higher tumor uptake and / or lower kidney uptake, which can greatly reduce the risk of kidney damage while improving the drug targeting effect, and are conducive to better meeting the drug needs of patients.

[0007] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, ester or solvate thereof,

[0008]

[0009] in,

[0010] Q is R0 is selected from carbonyl or methylene;

[0011] X b A chelating agent or X c Chelating agent or X d Chelating agent or X e Chelating agent or X f Chelating agent or X g Chelating agent or X aIt is a chelating agent;

[0012] R a1 , R b1 , R c1 , R d1 , R e1 , R f1 and R g1 Both R y1 ;

[0013] R a2 , R b2 , R c2 , R d2 , R e2 , R f2 and R g2 Both R y2 ;

[0014] R a3 , R b3 , R c3 , R d3 , R e3 , R f3 and R g3 Both R y3 ;

[0015] R y1 , R y2 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or -C(=S)R k ;

[0016] Or, R y2 With R y1 (or R y3 ) connected to form R 环A ;

[0017] R Y Selected from C1-C16 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl (including fused ring aryl, etc.) or 5-14-membered heteroaryl (including fused ring heteroaryl);

[0018] R 环A is a 3-12 membered heterocycloalkyl or a 5-14 membered heteroaryl;

[0019] R Y and R 环A Optionally substituted or unsubstituted with one or more substituents P1;

[0020] The substituent P1 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ;

[0021] R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2;

[0022] The substituent P2 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R X ;

[0023] R X is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R X Optionally substituted or unsubstituted with one or more substituents P3;

[0024] The substituent P3 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R V ;

[0025] R V is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R V Optionally substituted or unsubstituted with one or more substituents P4;

[0026] The substituent P4 is selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, oxo, thio, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl, sulfo-substituted C1-C6 alkyl, C1-C6 alkoxy, amino-substituted C1-C6 alkoxy, carboxyl-substituted C1-C6 alkoxy, sulfo-substituted C1-C6 alkoxy, C1-C6 alkylthioether, amino-substituted C1-C6 alkylthioether, carboxyl-substituted C1-C6 alkylthioether, sulfo-substituted C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl;

[0027] R k Selected from hydrogen, deuterium, tritium, halogen, -NR i R j, C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0028] R1, R2, R3, R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, nitro, cyano, halogen, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0029] R z Selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl;

[0030] a, b, c, d, e, f and g are each independently selected from an integer of 0-6 (e.g., 0, 1, 2, 3, 4, 5, 6);

[0031] L1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl is optionally substituted or unsubstituted by one or more substituents P1;

[0032] L2 is selected from -L3- or -NH-(CH2) t -L3- (for example, L2 includes but is not limited to the group L defined in claim 4 of international patent application WO2023030509A1);

[0033] For example, L2 includes but is not limited to the following groups:

[0034]

[0035] L3 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl is optionally substituted or unsubstituted by one or more substituents P1;

[0036] The heteroatoms of the 3-12-membered heterocycloalkyl or 5-14-membered heteroaryl are selected from one or more of N, O and S, and the number of heteroatoms of the 3-12-membered heterocycloalkyl or 5-14-membered heteroaryl is 1, 2 or 3;

[0037] m, n and t are each independently selected from integers of 0-6 (eg, 0, 1, 2, 3, 4, 5, 6).

[0038] In a preferred embodiment,

[0039] L1 is a 5-14 membered aryl or 5-14 membered heteroaryl group; the 5-14 membered aryl or 5-14 membered heteroaryl group is optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl.

[0040] In a preferred embodiment,

[0041] L1 is selected from phenyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, imidazolyl, furanyl, thiazolyl, thienyl, thiopyranyl, naphthyl, benzopyrrole (including: indole, isoindol) base, benzopyridine (including: quinoline, isoquinoline) base, benzoxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiopyranyl, purinyl, anthracenyl or phenanthryl;

[0042] Preferably, L1 is naphthyl, benzopyridyl or anthracenyl.

[0043] In a preferred embodiment,

[0044] L2 is -L3-; L3 is selected from 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; the 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl is optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl.

[0045] In a preferred embodiment,

[0046] L3 is selected from 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains 1-4 heteroatoms N;

[0047] Preferably,

[0048] L3 is R 环B -R 环C , R 环B and R 环C Share a carbon atom; R 环B is selected from 3-9 membered cycloalkyl or 3-9 membered heterocycloalkyl; R 环C is selected from 3-9 membered heterocycloalkyl; wherein the heteroatom of the 3-9 membered heterocycloalkyl is selected from one or more of N, O and S, and the number of heteroatoms of the 3-9 membered heterocycloalkyl is 1, 2 or 3; R 环C Contains 1-2 heteroatoms N;

[0049] R 环B and R 环C Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl;

[0050] More preferably,

[0051] R 环B is selected from cyclobutane, cyclopentane, cyclohexane or cycloheptane; R 环C is selected from pyrrolidinyl, piperidinyl, oxazolidinyl, oxazepanyl, thiazepanyl, azepanyl, oxazepanyl or thiazepanyl.

[0052] In a preferred embodiment,

[0053] L3 is selected from the following structures:

[0054] Z is O or S.

[0055] In a preferred embodiment,

[0056] L3 is selected from 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl contains 1-4 heteroatoms N;

[0057] Preferably,

[0058] L3 is R 环D -R 环E , R 环Dand R 环E Share two carbon atoms; R 环D is selected from 5-6 membered aryl or 5-6 membered heteroaryl, R 环E is selected from 3-9 membered heterocycloalkyl; wherein the heteroatoms of the 5-6 membered heteroaryl or 3-9 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms of the 3-9 membered heterocycloalkyl is 1, 2 or 3; R 环E Contains 1-2 heteroatoms N;

[0059] R 环D and R 环E Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl;

[0060] More preferably,

[0061] R 环D is selected from phenyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, imidazolyl, furanyl, thiazolyl, thienyl, thiopyranyl; R 环E is selected from pyrrolidinyl, piperidinyl, oxazolidinyl, oxazepanyl, thiazepanyl, azepanyl, oxazepanyl or thiazepanyl.

[0062] In a preferred embodiment,

[0063] L3 is selected from the following structures:

[0064] Z is O or S;

[0065] Preferably,

[0066] L3

[0067] In a preferred embodiment,

[0068] The chelating agent is selected from 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA: )、2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-pentanedioic acid (DOTAGA: ), N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 2-(4,7-bis(carboxymethyl)-1,4,7-triazolidine-1-yl)pentanedioic acid (NODAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9,3,1]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA: ),

[0069] Preferably, the chelating agent is DOTA or DOTAGA.

[0070] In a preferred embodiment,

[0071] m, n and t are each independently selected from 1 or 2; R1 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; R2 and R3 are each independently selected from hydroxyl or C1-C6 alkoxy.

[0072] In a preferred embodiment,

[0073] The R y1 or R y3 is S configuration or R configuration; and / or, the configuration of the compound represented by formula I is:

[0074]

[0075] In a preferred embodiment,

[0076] X b It is a chelating agent;

[0077] R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, cyano, amino, carboxyl, sulfonyl; R Yis selected from C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl;

[0078] R y2 is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, thiol, nitro or cyano; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring or a piperidine ring; said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl;

[0079] Preferably, the compound represented by formula I is:

[0080]

[0081] Among them, X b is a chelating agent; R a1 and R a3 are each independently selected from hydrogen, deuterium, tritium, R Y ; R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R a2 is selected from hydrogen, deuterium or tritium; or, R a2 With R a1 (or R a3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring; a is 0, 1 or 2.

[0082] In a preferred embodiment,

[0083] The compound represented by formula Ia is selected from:

[0084]

[0085]

[0086] In a preferred embodiment,

[0087] X b It is a chelating agent;

[0088] R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, cyano, amino, carboxyl or sulfonyl; R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl;

[0089] R y2 is a C1-C16 alkyl group which is optionally substituted or unsubstituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, amino, carboxyl, sulfo or R W ;

[0090] R W is selected from C1-C6 alkoxy or C1-C6 alkylthioether; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from -C(=O)R k 、-C(=O)OR k or R X ;

[0091] R X is selected from C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthioether; and R X Optionally substituted or unsubstituted by one or more substituents P3; the substituents P3 are selected from -C(=O)R k OR -C(=O)OR k ;

[0092] R k Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0093] Preferably, the compound represented by formula I is:

[0094]

[0095] Among them, X b is a chelating agent; R a1 and R a3 are each independently selected from hydrogen, deuterium, tritium or RY ;

[0096] R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R a2 is a C1-C14 alkyl group optionally substituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, carboxyl, sulfonyl or R W ;

[0097] R W is selected from C1-C6 alkoxy; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from -C(=O)OR k or R X ;

[0098] R X is selected from C1-C6 alkoxy or C1-C6 alkylthioether; and R X Optionally substituted or unsubstituted by one or more substituents P3; the substituents P3 are selected from -C(=O)OR k ; R k is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; a is 0, 1 or 2.

[0099] In a preferred embodiment,

[0100] The compound represented by formula Ib is selected from:

[0101]

[0102] In a preferred embodiment,

[0103] X b It is a chelating agent;

[0104] R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, amino, carboxyl or sulfo;

[0105] R Y Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl (including but not limited to oxadiazolidinyl), 5-14-membered aryl (including but not limited to phenyl) or 5-14-membered heteroaryl (including but not limited to imidazolyl, oxadiazolyl, benzopyrrolyl);

[0106] RY Optionally substituted or unsubstituted with one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ;

[0107] R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2; the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, amino, carboxyl, sulfo or R X ;

[0108] R X Selected from C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthioether;

[0109] R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0110] R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0111] Rz Selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl;

[0112] R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring or a piperidine ring; said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl;

[0113] Preferably, X b is a chelating agent; R y1 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; R y3 For R Y ; R Y is selected from C1-C6 alkyl; R Y Optionally substituted with one or more substituents P1; R y2 (R a2 ) is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring; a is 0, 1 or 2.

[0114] In a preferred embodiment, the compound represented by formula I is:

[0115]

[0116] Among them, X b It is a chelating agent;

[0117] R a1 Selected from hydrogen, deuterium, tritium or C1-C6 alkyl;

[0118] R a3 For R Y ; R Yis selected from C1-C6 alkyl; R Y Optionally substituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, -S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or R W ;

[0119] R W is selected from oxadiazolyl, phenyl or benzopyrrolyl; and R W Optionally substituted or unsubstituted with one or more substituents P2; wherein the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen or R X ;

[0120] R X is a C1-C6 alkyl group;

[0121] R k Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl;

[0122] R a2 is selected from hydrogen, deuterium or tritium; or, R a2 With R a1 (or R a3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring; a is 0, 1 or 2;

[0123] Preferably, the compound represented by formula Ic is selected from:

[0124]

[0125] In another preferred embodiment, the compound represented by formula I is:

[0126]

[0127] Among them, X b It is a chelating agent;

[0128] R a1 Selected from hydrogen, deuterium, tritium or C1-C6 alkyl;

[0129] R a3 For R Y ; R Y is selected from C1-C6 alkyl; R Y Optionally substituted by one or more substituents P1; said substituents P1 are selected from -C(=O)R k、-C(=O)OR k ; R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z OR -S(=O)(=O)OR z ; R z Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl;

[0130] R a2 is selected from hydrogen, deuterium, tritium or deuterated C1-C6 alkyl; or, R a2 With R a1 (or R a3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring; a is 0, 1 or 2;

[0131] Preferably, the compound represented by formula Id is selected from:

[0132]

[0133]

[0134] In a preferred embodiment,

[0135] X b for X c Chelating agent or X d Chelating agent or X e It is a chelating agent;

[0136] R a1 , R b1 , R c1 and R d1 Both R y1 ;

[0137] R a2 , R b2 , R c2 and R d2 Both R y2 ;

[0138] R a3, R b3 , R c3 and R d3 Both R y3 ;

[0139] R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, amino, carboxyl or sulfo; R Y Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl (including but not limited to oxadiazolidinyl), 5-14-membered aryl (including but not limited to phenyl) or 5-14-membered heteroaryl (including but not limited to imidazolyl, oxadiazolyl, benzopyrrolyl);

[0140] R Y Optionally substituted or unsubstituted with one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ;

[0141] R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2; wherein the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, amino, carboxyl, sulfo, R X ; R X Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether;

[0142] R k Selected from hydrogen, deuterium, tritium, -NR i R j, C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0143] R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl;

[0144] R z is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl;

[0145] R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring or a piperidine ring; said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl;

[0146] Preferably,

[0147] X b It is a chelating agent;

[0148] R y1 Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl;

[0149] R y3 is hydrogen, deuterium, tritium, carboxyl, sulfonyl or R Y ;

[0150] R Y is selected from C1-C6 alkyl; R Y Optionally substituted or unsubstituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thioxo, halogen, -C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or R W ;

[0151] R W is selected from C1-C6 alkoxy, C1-C6 alkylthioether, phenyl, benzopyrrolyl, imidazolyl, oxadiazolyl; R W Optionally substituted or unsubstituted with one or more substituents P2; wherein the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen or R X ; R X is a C1-C6 alkyl group;

[0152] R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z ; R z is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl;

[0153] R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A It is a tetrahydropyrrole ring;

[0154] a, b, c and d are each independently selected from 0, 1 or 2;.

[0155] In a preferred embodiment,

[0156] R a1 , R b1 , R c1 and R d1 Each is independently selected from hydrogen, deuterium, tritium or C1-C6 alkyl;

[0157] R a3、 R b3 , R c3 and R d3 are each independently selected from hydrogen, deuterium, tritium, carboxyl, sulfonyl or R Y ; R Y is a C1-C6 alkyl group; and R Y Optionally substituted or unsubstituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, carboxyl, sulfonyl or R W ; R W is selected from C1-C6 alkoxy, C1-C6 alkylthioether, phenyl, benzopyrrolyl or imidazolyl; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, halogen or C1-C6 alkyl;

[0158] R a2 , R b2 , R c2 and R d2 are each independently selected from hydrogen, deuterium, tritium or deuterated C1-C6 alkyl; or, R a2 With R a1 Connect to form R 环A , R b2 With R b1 Connect to form R 环A , R c2 With R c1 Connect to form R 环A , R d2 With R d1 Connect to form R 环A , the R 环A is a tetrahydropyrrole ring; a, b, c and d are each independently selected from 0, 1 or 2;

[0159] Preferably, the compound represented by formula I comprises:

[0160] ①

[0161] Among them, X c It is a chelating agent;

[0162] Further preferably, the compound represented by formula Ie is selected from:

[0163]

[0164]

[0165] Preferably, the compound represented by formula I is:

[0166] ②

[0167] Among them, X d It is a chelating agent;

[0168] Further preferably, the compound represented by the formula If is selected from:

[0169]

[0170] Preferably, the compound represented by formula I is:

[0171] ③

[0172] Among them, X e It is a chelating agent;

[0173] Further preferably, the compound represented by formula Ig is:

[0174]

[0175] The present invention also provides use of any of the above compounds or pharmaceutically acceptable salts, esters or solvates thereof in the preparation of radiolabeled complexes.

[0176] The present invention also provides a radiolabeled complex, which comprises: any one of the above compounds or a pharmaceutically acceptable salt, ester or solvate thereof, and a radionuclide;

[0177] Preferably, the radionuclide is selected from 94 Tc, 99m Tc, 90 In, 111 In, 67 Ga, 68 Ga, 86 Y. 90 Y. 177 Lu, 151 Tb, 186 Re, 188 Re, 64 Cu, 67 Cu, 55 Co. 57 Co. 43 Sc, 44 Sc, 47 Sc,225 Ac, 213 Bi, 212 Bi, 212 Pb, 227 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd, 166 Dy, 55 Fe, 18 F. 11 C. 89 Zr, 123 I. 124 I. 125 I. 131 I or 211 At;

[0178] More preferably, the radionuclide is 68 Ga or 177 Lu.

[0179] The present invention also provides a pharmaceutical composition, which comprises the radiolabeled complex described above, and one or more pharmaceutically acceptable excipients, diluents or carriers.

[0180] The present invention also provides the use of the aforementioned radiolabeled complex and / or the aforementioned pharmaceutical composition in the preparation of a drug for diagnosing and / or treating and / or preventing tumors; preferably, the tumor is cancer; more preferably, the cancer is prostate cancer.

[0181] The present invention also provides the use of the aforementioned radiolabeled complex and / or the aforementioned pharmaceutical composition in the preparation of a drug for imaging in a patient; or, the use of the aforementioned radiolabeled complex and / or the aforementioned pharmaceutical composition in the preparation of a contrast agent.

[0182] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0183] "Aryl" refers to an aromatic group having 5 to 20 carbon atoms, which is preferably a C5-C14 aromatic group (i.e., a 5-14 membered aromatic group), which is typically a 5- to 8-membered (e.g., 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, which may be a bridged ring or a spirocyclic ring, non-limiting examples of which include phenyl, naphthyl, or anthracenyl, etc.

[0184] "C1-C6 alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms, preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof.

[0185] "C1-C6 alkoxy" refers to RO, wherein R is C1-C6 alkyl and O is oxygen. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy. It is preferably C1-C4 alkoxy.

[0186] "Deuterated" means that some or all of the hydrogen atoms on the substituted group are replaced by deuterium atoms;

[0187] "Halo" means that some or all of the hydrogen atoms on the substituted group are replaced by halogens;

[0188] "halogen" means fluorine, chlorine, bromine or iodine;

[0189] “Heterocycloalkyl” refers to a saturated or unsaturated non-aromatic heterocyclic ring containing 2 to 50 carbon atoms (preferably 2 to 15 carbon atoms) and 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O or S, which can be a 3- to 10-membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic ring, a 4- to 12-membered (e.g. 4, 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring or a 10- to 15-membered (e.g. 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 4 (e.g. 1, 2, 3, 4) heteroatoms selected from N, O or S.

[0190] "Heterocycloalkyl" can be a bridged ring or a spirocycle. Non-limiting examples of "heterocycloalkyl" include oxirane, glycidyl, aziridine, oxetanyl, azetidinyl, thietanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, pyrrolidinyl, oxazolidinyl, oxazacyclohexane, thiazolinyl, azepanyl, oxetanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, piperidinyl, etc.

[0191] "Heteroaryl" refers to a 3- to 8-membered (e.g., 3, 4, 5, 6, 7, 8-membered) monocyclic ring, a 5- to 12-membered (e.g., 5, 6, 7, 8, 9, 10, 11, 12-membered) bicyclic ring, or a 10- to 15-membered (e.g., 10, 11, 12, 13, 14, 15-membered) tricyclic ring system, and contains 1 to 6 (e.g., 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably a 5- to 14-membered heteroatoms. Aryl; may be a bridged ring or a spiro ring, non-limiting examples include pyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, thiopyranyl, benzimidazolyl, benzoxazolyl, benzopyridine (including: indole, isoindole) base, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiopyranyl, pyrrolopyridinyl, purinyl.

[0192] "Solvate" means a compound or a pharmaceutically acceptable salt thereof, in which molecules of a suitable solvent are incorporated in the crystal lattice. The suitable solvent is physiologically tolerable at the dose administered. Examples of suitable solvents include ethanol, water, and the like. When water is the solvent, the molecule is referred to as a "hydrate."

[0193] "Ester" means that the free acid groups in the compounds of the present invention are esterified. Suitable esters include various alkyl esters, such as C1-C10 alkyl esters of saturated or unsaturated C1-C18 fatty acids.

[0194] In the chemical structures of the compounds described in the present invention, "bond" does not specify the configuration, i.e. It can be S configuration, R configuration, D configuration, L configuration, Z configuration or E configuration, or contain multiple (for example, two, three, four, etc.) configurations at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

[0195] Figure 1 This is a visualization image after administration of compound VWT011600. DETAILED DESCRIPTION

[0196] The present invention will be clearly and completely described below in conjunction with specific embodiments. Those skilled in the art will understand that the embodiments described below are only some embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of protection of the present invention.

[0197] In the present invention, if no specific conditions are specified, the experiments are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0198] Regarding the definitions of terms used in the present invention, unless otherwise stated, the initial definitions provided for the terms in this document apply to the terms throughout the text; for terms not specifically defined in this document, the meaning that a person skilled in the art can give them can be given based on the disclosure and / or context.

[0199] Example 1

[0200] Preparation of compound VWT011600

[0201] Step 1 (Preparation of VWT016100)

[0202] (1-1) Preparation of VWT016101

[0203]

[0204] CTC resin (2-chlorotrityl chloride bonded to polystyrene, 1.00 g, initial degree of substitution: 1.09 mmol / g) was swollen in DMF (N,N-dimethylformamide: 10 mL) for 30 minutes, and the CTC resin was washed twice with DMF (10 mL×2). The CTC resin was treated with a mixture of Fmoc-Lys(ivDde)-OH (940 mg, CAS No.: 204777-78-6; commercially available or synthesized by known methods; Fmoc refers to fluorenylmethyloxycarbonyl) and DIPEA (N,N-diisopropylethylamine: 426 mg) in DMF (4 mL) for 5 hours, and methanol (0.5 mL) was added to continue treating the resin for 1 hour. The CTC resin was then washed with DMF (10 mL) to obtain VWT016101.

[0205] (1-2) Preparation of VWT016102

[0206]

[0207] H-Glu(OtBu)-OtBu-HCl (5.00 g, CAS No.: 32677-01-3; commercially available product or synthesized by a known method; tBu refers to tert-butyl) was added to 200 mL of anhydrous acetonitrile (ACN) and stirred to dissolve. At room temperature, DSC (N,N'-succinimidyl carbonate: 4.32 g, CAS No.: 74124-79-1) was added and stirred continuously, and triethylamine (2.60 g) was slowly added dropwise. After reacting at room temperature overnight, the mixture was washed with 10% citric acid aqueous solution and saturated brine, separated, and the organic phase was concentrated and distilled to obtain 7.12 g of VWT016102.

[0208] (1-3) Preparation of VWT016103

[0209]

[0210] VWT016101 resin (0.34 mmol) was swelled in DMF (10 mL) for 30 minutes, washed twice with DMF (10 mL×2), treated with 20% piperidine / DMF (10 mL, volume ratio: piperidine / DMF=1 / 4) for 30 minutes, and washed with DMF (10 mL). Then, it was reacted with VWT016102 (3.49 g) in DMF (7 mL) under DIPEA alkaline conditions for 5 hours, and the resin was washed with DMF (10 mL) to obtain compound VWT016103.

[0211] (1-4) Preparation of VWT016100

[0212]

[0213] VWT016103 resin (0.34 mmol) was swelled in DMF (10 mL) for 30 minutes, treated with 8% hydrazine hydrate / DMF (10 mL, volume ratio: hydrazine hydrate-DMF = 8:92) for 30 minutes to remove the ivDde protecting group, washed with DMF (10 mL), and treated with a mixture of Fmoc-2-Nal-OH (765 mg, CAS No.: 112883-43-9; commercially available product or synthesized by a known method) and PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate: 918 mg, CAS No.: 128625-52-5), HOBT (1-hydroxybenzotriazole: 236 mg, CAS No.: 2592-95-2), and DIPEA (460 mg) in DMF (7 mL) for 4 hours, and washed with DMF (10 mL) to obtain compound VWT016100.

[0214] Step 2 (Preparation of VWT011602)

[0215] (2-1) Synthesis of Compound 2: (2-(tert-butyl)-6-ethyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate)

[0216]

[0217] Compound 1 (tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate: 1.0 g), DPPF (1,1'-bis(diphenylphosphino)ferrocene: 355 mg), and Pd(OAc)2 (palladium acetate: 71.9 mg) were added to a DMF-EtOH-DIPEA (30 mL, volume ratio: DMF-EtOH-DIPEA=8:2:1) solution, and the reaction solution was reacted at 100° C. for 16 hours under a CO (carbon monoxide) atmosphere; ethyl acetate (100 mL) was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate=3 / 1) to obtain compound 2 (600 mg, 2-(tert-butyl)-6-ethyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate, 61%) as a yellow solid.

[0218] (2-2) Synthesis of Compound 3: (1,2,3,4-Tetrahydroisoquinoline-6-carboxylic acid ethyl ester)

[0219]

[0220] Compound 2 (600 mg) was added to a 4.0 mol / L hydrochloric acid / ethyl acetate solution (20 mL, CAS: 7647-01-0), and the reaction solution was reacted at room temperature for 5 hours. The solid was collected and washed with ethyl acetate to obtain compound 3 (400 mg, 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester, 99%) as a white solid.

[0221] (2-3) Synthesis of Compound 5: (2-(((Benzyloxy)carbonyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester)

[0222]

[0223] Compound 4 (benzyloxycarbonyl-L-alanine: 243 mg), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate: 621 mg, CAS No.: 148893-10-1), compound 3 (335 mg), and DIPEA (422 mg) were added to DMF (30 mL) respectively. After the reaction solution was reacted at room temperature for 16 hours, ethyl acetate (100 mL) was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5 (440 mg, ethyl 2-(((benzyloxy)carbonyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate, 98%) as a colorless oil.

[0224] (2-4) Compound 6: (2-(((Benzyloxy)carbonyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid:

[0225]

[0226] 122.5 mg of lithium hydroxide (dissolved in 10 mL of water) was added to a solution of compound 5 (420 mg) in tetrahydrofuran (10 mL) and reacted at room temperature for 16 hours. The reaction solution was concentrated to remove tetrahydrofuran, and the pH value of the residue was adjusted to 7 with 1N hydrochloric acid. A large amount of solid appeared. The solid was collected and washed with water and then dried to obtain compound 6 (360 mg, 2-(((benzyloxy)carbonyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 90%) as a white solid.

[0227] (2-5) Synthesis of compound VWT011602

[0228]

[0229] Compound 6 (360 mg), compound 7 (N-(9-fluorenylmethoxycarbonyloxy)succinimide: 476 mg; can be represented by Fmoc-OSu) and Pd / C (40 mg) were added to tetrahydrofuran (10 mL), and the reaction solution was reacted at room temperature for 16 hours under a hydrogen atmosphere. The solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was prepared and purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to obtain compound VWT011602 (336.8 mg, 2-((((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid) as a white solid.

[0230] Step 3 (Preparation of VWT011603)

[0231]

[0232] VWT016100 resin (0.34 mmol) was swelled in DMF (3 mL) for 30 minutes, treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, the resin was washed with DMF (3 mL), and treated with a mixture of VWT011602 (191 mg) and PyAOP ((7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate: 217 mg, CAS No.: 156311-83-0), HOAT (1-hydroxy-7-azabenzotriazole: 55 mg, CAS No.: 39968-33-7), and DIPEA (112 mg) in DMF (3 mL) for 3 hours, and the resin was washed with DMF (3 mL) to obtain compound VWT011603.

[0233] Step 4 (Preparation of VWT011604)

[0234]

[0235] VWT016103 resin (0.34 mmol) was swelled in DMF (3 mL) for 30 minutes, then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (3 mL), and treated with a mixture of DOTA(tBu)3 (390 mg, CAS No.: 137076-54-1) and PyAOP (362 mg), HOAT (95 mg), and DIPEA (178 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (3 mL) to obtain compound VWT011604.

[0236] Step 5 (Preparation of VWT011600)

[0237]

[0238] VWT011604 was treated in 95% TFA / 5% H2O lysis solution (10 mL; TFA refers to trifluoroacetic acid) for 3 hours, methyl tert-butyl ether (MTBE) was added to induce crystallization, and VWT011600 was obtained as a white solid crude product after centrifugation and drying. The crude product was purified by preparative HPLC to obtain a crude product with a purity of 97.86% (e.g. Figure 1 The target product VWT011600 is shown in FIG. 5; LCMS: [M+H] + =1133.29.

[0239] Example 2

[0240] Preparation of compound VWT011400

[0241] Step 1 (Preparation of VWT016100)

[0242] VWT016100 was prepared in the same manner as in Example 1.

[0243] Step 2 (Preparation of compound 7-(((9H-fluoren-9-yl)methoxy)carbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid)

[0244]

[0245] The raw material 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid (0.5 g, CAS No.: 873924-12-0; commercially available product or synthesized by a known method) was added to TFA / DCM (10 mL, volume ratio: TFA / DCM=2 / 1; DCM refers to dichloromethane), stirred at room temperature for 4 hours, and concentrated to obtain a residue. The residue was slurried with methyl tert-butyl ether, crystallized, and centrifuged and dried to obtain the intermediate 7-azaspiro[3.5]nonane-2-carboxylic acid (0.49 g) as a white solid.

[0246] Then the intermediate 7-azaspiro [3.5] nonane-2-carboxylic acid (0.49 g) and Fmoc-OSu (0.92 g) were added to dichloromethane (50 mL) and stirred to dissolve, and then DIPEA (0.85 mL) was slowly added dropwise. After the addition, the mixture was reacted at room temperature for 16 hours. Purified water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the mixture was separated after sufficient stirring. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio EA: PE = 11: 1; EA refers to ethyl acetate; PE refers to petroleum ether) to obtain compound 7-(((9H-fluorene-9-yl) methoxy) carbonyl)-7-azaspiro [3.5] nonane-2-carboxylic acid (0.46 g) as a white solid.

[0247] Step 3 (Preparation of VWT0011402)

[0248]

[0249] VWT016100 resin (0.35 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes and then washed with DMF. 7-(((9H-fluorene-9-yl)methoxy)carbonyl)-7-azaspiro[3.5]nonane-2-carboxylic acid was coupled under the action of PyAOP / HOAt / DIPEA condensation system in the order in the sequence, and the reaction was carried out for 7 hours, and then the resin was washed with DMF to obtain compound VWT011401.

[0250] Compound VWT011401 was treated with 20% piperidine / DMF (3 mL) for 30 minutes, and then the resin was washed with DMF. Fmoc-alanine (Fmoc-Ala-OH) was coupled under the action of DIC / HOBT condensation system (DIC refers to N,N'-diisopropylcarbodiimide) for 5 hours, and then the resin was washed with DMF to obtain compound VWT011402.

[0251] Step 4 (Preparation of compound VWT011400)

[0252]

[0253] VWT011402 resin (0.35 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes, and then the resin was washed with DMF. The coupling compound DOTA(tBu)3 was reacted for 8 hours under the action of PyAOP / DIPEA condensation system, and then the resin was washed with DMF to obtain the fully protected peptide VWT011403.

[0254] VWT011403 was treated in 95% TFA / 5% H2O lysis solution (10 mL) for 5 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT011400, which was then purified by preparative HPLC to obtain 63.8 mg of the target product VWT011400 with a purity of 97.35%; LCMS: [M+H] + =1125.80.

[0255] Example 3

[0256] Preparation of compound VWT019300

[0257] Step 1 (Preparation of VWT019600)

[0258] (1-1) Synthesis of VWT016101

[0259] VWT016101 was prepared in the same manner as in Example 1.

[0260] (1-2) Synthesis of VWT019602

[0261]

[0262] (R)-2-Aminoadipic acid (13 g) was added to tert-butyl acetate (150 mL), stirred to dissolve, and 70% to 72% aqueous perchloric acid solution (12.20 g) was slowly added dropwise under ice-water bath conditions. After the addition was complete, the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated, ethyl acetate (400 mL) was added and stirred, the liquids were separated, the organic phase was washed with purified water and saturated brine, and the organic phase was concentrated by distillation to obtain 10.50 g of colorless oily (R)-2-aminoadipic acid di-tert-butyl ester.

[0263] Add (R)-di-tert-butyl 2-aminoadipate (10.5 g) to anhydrous acetonitrile (300 mL), stir to dissolve, add DSC (9.36 g) at room temperature, continue stirring, slowly add triethylamine (5.6 g) dropwise, react overnight at room temperature after the addition is complete, separate the layers, wash the organic phase with 10% citric acid aqueous solution and saturated brine, concentrate and distill the organic phase to obtain 17.09 g of compound VWT019602: (R)-di-tert-butyl 2-((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)amino)adipate.

[0264] (1-3) Preparation of VWT019603

[0265]

[0266] VWT016101 resin (3.24 mmol) was swelled in DMF (30 mL) for 30 minutes and washed with DMF (30 mL). The resin was treated with 20% piperidine / DMF (30 mL) for 30 minutes, washed with DMF (240 mL), reacted with VWT019602 (13.4 g) in DMF (25 mL) under DIPEA alkaline conditions for 4 hours, and washed with DMF (150 mL) to obtain compound VWT019603.

[0267] (1-4) Preparation of VWT019600

[0268]

[0269] VWT019603 resin (2.64 mmol) was swelled in DMF (30 mL) for 30 minutes, treated with 8% hydrazine hydrate / DMF (25 mL) for 30 minutes to remove the ivDde protecting group, washed with DMF (300 mL), and then treated with a mixture of Fmoc-Ala(9-Anth)-OH (Fmoc-L-9-anthralanine, 2.57 g, CAS No.: 268734-27-6; commercially available product or synthesized by known methods) and PyAOP (2.76 g), HOAT (0.54 g), and DIPEA (1.37 g) in 25 mL of DMF for 24 hours, and the resin was washed with DMF (150 mL) to obtain compound VWT019600.

[0270] Step 2 (Preparation of VWT019301)

[0271]

[0272] VWT019600 resin (0.25 mmol) was swelled in DMF (5 mL) for 30 minutes, treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (24 mL). It was treated with a mixture of VWT011602 (144 mg) and PyAOP (159 mg), HOAT (35 mg), and DIPEA (82 mg) in DMF (4 mL) for 4 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT019301.

[0273] Step 3 (Preparation of VWT019302)

[0274]

[0275] VWT019301 resin (0.25 mmol) was swelled in DMF (3 mL) for 30 minutes, then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (3 mL), treated with a mixture of DOTA(tBu)3 (285 mg) and PyAOP (260 mg), HOAT (65 mg), and DIPEA (130 mg) in DMF (4 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT019302.

[0276] Step 4 (Preparation of VWT019300)

[0277]

[0278] VWT019302 was treated in 95% TFA / 5% H2O lysis solution (5 mL) for 4 hours, methyl tert-butyl ether was added to induce crystallization, and centrifuged to dry to obtain 261 mg of crude white solid VWT019300, which was then purified by preparative HPLC to obtain 41.3 mg of the target product VWT019300 with a purity of 92.43%, LCMS: [M+H] + =1197.80.

[0279] Example 4

[0280] Preparation of compound VWT019000

[0281] Step 1 (Preparation of intermediate VWT019603)

[0282] VWT019603 was prepared in the same manner as in Example 3.

[0283] Step 2 (Preparation of compound VWT011601)

[0284] (2-1) Synthesis of Compound 2

[0285]

[0286] Sodium hydroxide (3.16 g, 79 mmol, 10.0 eq, dissolved in 20 mL of water) was added to a methanol (20 mL) solution of compound 1 (2.4 g, 7.9 mmol, 1.0 eq, CAS No.: 1443238-78-5) and reacted at room temperature for 5 hours. The reaction solution was concentrated to remove methanol, and then the pH of the residue was adjusted to 7 with 1N hydrochloric acid, and a large amount of solid appeared. It was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated to obtain compound 2: 2-(tert-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (1.77 g, yield 81%), which was a white solid.

[0287] (2-2) Synthesis of Compound 3

[0288]

[0289] Compound 2 (1.77 g, 6.4 mmol, 1.0 eq) and trifluoroacetic acid (5 mL) were added to dichloromethane (20 mL). After reacting at room temperature for 5 hours, the reaction solution was concentrated to obtain compound 3: 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (1.13 g, yield 100%), which was a colorless liquid.

[0290] (2-3) Synthesis of compound VWT011601

[0291]

[0292] Compound 3 (1.13 g, 6.4 mmol, 1.0 eq), compound 4 (3.24 g, 9.6 mmol, 1.5 eq) and triethylamine (6.46 g, 64 mmol, 10 eq) were added to tetrahydrofuran (50 mL) and reacted at room temperature for 5 hours. The reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 20:1) to obtain compound VWT011601: 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (1.79 g, yield 68%) as a white solid.

[0293] Step 3 (Preparation of compound VWT019003)

[0294]

[0295] The VWT019603 resin (0.6 mmol) was swelled in DMF (10 mL) for 30 minutes, then washed with DMF, treated with 8% hydrazine hydrate / DMF (5 mL) for 30 minutes to remove the ivDde protecting group, and then washed with DMF. The resin was coupled with Fmoc-2-Nal-OH, HATU, and DIPEA for 18 hours, and then washed with DMF to prepare the intermediate VWT019001.

[0296] VWT019001 resin (0.3 mmol) was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF. The resin was treated with VWT011601 (CAS No.: 2138226-21-6) and a mixture of PyAOP, HOAT, and DIPEA in DMF (5 mL) and reacted for 5 hours. The resin was washed with DMF to obtain compound VWT019002.

[0297] Compound VWT019002 was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and the resin was washed with DMF. The resin was treated with a mixture of Fmoc-Ala-OH and PyAOP, HOAT, and DIPEA in DMF (3 mL) and reacted for 2 hours. The resin was then washed with DMF to obtain compound VWT019003.

[0298] Step 4 (Preparation of compound VWT019000)

[0299]

[0300] The VWT019003 resin (0.3 mmol) was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF. The resin was treated with a mixture of DOTA(tBu)3 and PyAOP, HOAT, and DIPEA in DMF (3 mL) and reacted for 17 hours. The resin was then washed with DMF to obtain the fully protected peptide resin VWT019004.

[0301] VWT019004 was treated in 95% TFA / 5% H2O lysis solution (7 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 477 mg of a crude white solid of VWT019000. After purification by preparative HPLC, 45 mg of the target product VWT019000 with a purity of 94.8% was obtained; LCMS: [M+H] + =1147.70.

[0302] Example 5

[0303] Preparation of compound VWT021400

[0304] Step 1 (Preparation of VWT016100)

[0305] VWT016100 was prepared in the same manner as in Example 1.

[0306] Step 2 (Preparation of VWT021401)

[0307] (2-1) Synthesis of Compound 2: (5-Carboxyl-isoindoline)

[0308]

[0309] 2-(tert-Butoxycarbonyl)isoindoline-5-carboxylic acid (250 mg, CAS No.: 149353-71-9) was added to a trifluoroacetic acid / DCM (10 mL, volume ratio 2:1) solution, and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was distilled and concentrated to remove dichloromethane and most of the trifluoroacetic acid, and then methyl tert-butyl ether was crystallized and centrifuged to obtain 295 mg of an off-white solid crude product of 5-carboxyl-isoindoline.

[0310] (2-2) Synthesis of compound VWT021401

[0311]

[0312] Compound 5-carboxy-isoindoline (295 mg), compound N-(9-fluorenylmethoxycarbonyloxy)succinimide (596 mg, CAS No.: 82911-69-1) and DIPEA (470 mg) were added to DMF (4 mL), and the reaction solution was reacted at room temperature for 8 hours; the solid was filtered off, and the filtrate was concentrated under reduced pressure to obtain a residue; the residue was prepared and purified by prep-HPLC to obtain compound VWT024101 (150 mg, yield 80%; CAS No.: 149353-71-9) as a white solid.

[0313] (2-3) Preparation of compound VWT021402

[0314]

[0315] VWT016100 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL). The Fmoc protecting group was then removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). The mixture of VWT021401 (265 mg) and PyAOP (320 mg), HOAT (95 mg), and DIPEA (160 mg) in DMF (6 mL) was treated for 24 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT021402.

[0316] (2-4) Preparation of compound VWT021403

[0317]

[0318] VWT021402 resin (0.2 mmol) was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL), and treated with a mixture of Fmoc-Ala-OH (310 mg) and DIC (130 mg) and HOBT (155 mg) in DMF (3 mL) for 4 hours. The resin was washed with DMF (30 mL) to obtain compound VWT021403.

[0319] (2-5) Preparation of compound VWT021404

[0320]

[0321] VWT021403 resin (0.2 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was treated with a mixture of DOTA(tBu)3 (230 mg) and PyAOP (210 mg), HOAT (60 mg), and DIPEA (105 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT021404.

[0322] (2-6) Preparation of compound VWT021400

[0323]

[0324] VWT021404 was treated in 95% TFA / 5% H2O lysis solution (4.5 mL) for 3 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 157 mg of VWT021400 pale red solid crude product, which was then purified by preparative HPLC to obtain 37 mg of the target product VWT021400 with a purity of 96.81%; LCMS: [M+H] + =1119.90.

[0325] Example 6

[0326] Preparation of compound VWT021700

[0327] Step 1 (Synthesis of VWT016100)

[0328] VWT016100 was prepared in the same manner as in Example 1.

[0329] Step 2 (Preparation of VWT021702)

[0330] (2-1) Synthesis of Compound 2

[0331]

[0332] Acetyl chloride (3.2 g) and pyridine (50 mL) were added to a dichloromethane (50 mL) solution of compound 3-bromophenethylamine 1 (8.0 g) at 0°C, and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 2 (9.6 g, N-(3-bromophenethyl)acetamide, 99%) as a brown liquid.

[0333] (2-2) Synthesis of Compound 3

[0334]

[0335] Oxalyl chloride (55.4 g) was added to a dichloromethane (200 mL) solution of compound 2 (9.6 g) at 0°C, and the reaction solution was reacted at room temperature for 2 hours. After the reaction solution temperature was lowered to -78°C, ferric chloride (38.6 g) was added, and the reaction solution was heated to room temperature and continued to stir for 16 hours. The reaction solution was filtered, and the filtrate was concentrated and sulfuric acid / methanol solution (100 mL, volume ratio 1:10; sulfuric acid concentration was 98%) was added, and the reaction was continued for 16 hours after the temperature was raised to 80°C. After the reaction solution was concentrated, water (300 mL) was added, and the pH value was adjusted to 7 with ammonia water. The solid was filtered out, the filtrate was extracted with dichloromethane, and the organic phases were combined and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 50 / 1) to obtain compound 3 (378 mg, 6-bromo-1-methyl-3,4-dihydroisoquinoline, yield 4%) as a brown liquid.

[0336] (2-3) Synthesis of Compound 4

[0337]

[0338] Sodium borohydride (64 mg) was added to a methanol (10 mL) solution of compound 3 (378 mg) at 0°C, and the reaction solution was reacted at 0°C for 1 hour. The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 20 / 1) to obtain compound 4 (328 mg, 6-bromo-1-methyl-1,2,3,4-tetrahydroisoquinoline, 86%) as a colorless liquid.

[0339] (2-4) Synthesis of Compound 5

[0340]

[0341] Di-tert-butyl dicarbonate (475 mg) and triethylamine (293 mg) were added to a dichloromethane (10 mL) solution of compound 4 (328 mg) at room temperature, and the reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 4 / 1) to obtain compound 5 (380 mg, tert-butyl 6-bromo-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate, 80%) as a colorless liquid.

[0342] (2-5) Synthesis of Compound 6

[0343]

[0344] Compound 5 (280 mg), DPPF (95 mg), and Pd(OAc)2 (19 mg) were added to a DMF-EtOH-DIPEA solution (10 mL, volume ratio of DMF:EtOH:DIPEA=8:2:1), and the reaction solution was reacted at 100°C for 3 hours under a CO atmosphere, and ethyl acetate (100 mL) was added to the reaction solution. The mixed solution was then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate=2 / 1) to obtain compound 6 (155 mg, 2-(tert-butyl)6-ethyl 1-methyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxylate, 57%) as a colorless liquid.

[0345] (2-6) Synthesis of Compound 7

[0346]

[0347] 131 mg of sodium hydroxide (dissolved in 5 mL of water) was added to a solution of compound 6 (210 mg) in methanol (5 mL), and the reaction solution was reacted at room temperature for 5 hours. The pH value of the reaction solution was adjusted to 7 with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 7 (191 mg, 2-(tert-butoxycarbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 100%) as a white solid.

[0348] (2-7) Synthesis of Compound 8

[0349]

[0350] Compound 7 (191 mg) and trifluoroacetic acid (2 mL) were added to dichloromethane (5 mL) respectively. After the reaction solution was reacted at room temperature for 3 hours, the reaction solution was concentrated to obtain compound 8 (124 mg, 1-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 100%) as a colorless liquid.

[0351] (2-8) Synthesis of compound VWT021702

[0352]

[0353] Compound 8 (124 mg), N-(9-fluorenylmethoxycarbonyloxy)succinimide (328 mg) and triethylamine (196 g) were added to tetrahydrofuran (10 mL), and the reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 10 / 1) to obtain compound VWT021702 (178.2 mg, 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid, 66%) as a white solid.

[0354] Step 3 (Preparation of VWT021703)

[0355]

[0356] VWT016100 resin (0.15 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed twice with DMF (5 mL). Then, the Fmoc protecting group was removed by treatment with 2% DBu / 2% piperidine / DMF (5 mL; CAS number of DBu: 6674-22-2) for 30 minutes, and the resin was washed with DMF (40 mL). The mixture of VWT021702 (82 mg) and PyAOP (115 mg), HOAT (40 mg), and DIPEA (65 mg) in DMF (3 mL) was treated for 5 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT021703.

[0357] Step 4 (Preparation of VWT021704)

[0358]

[0359] VWT021703 resin (0.15 mmol) was swollen in DMF (5 mL) for 30 minutes and washed with DMF (5 mL). The resin was treated with 2% DBu / 2% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and the resin was washed with DMF (40 ml). The resin was treated with a mixture of Fmoc-Ala-OH (233 mg, CAS No.: 35661-39-3) and DIC (95 mg) and HOBT (115 mg) in DMF (3 mL) for 4 hours, and the resin was washed with DMF (18 ml) to obtain compound VWT021704.

[0360] Step 5 (Preparation of VWT021705)

[0361]

[0362] VWT021704 resin (0.15 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was treated with a mixture of DOTA(tBu)3 (250 mg) and PyAOP (230 mg), HOAT (60 mg), and DIPEA (115 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT021705.

[0363] Step 6 (Preparation of VWT021700)

[0364]

[0365] VWT021705 was treated in 95% TFA / 5% H2O lysis solution (4 mL) for 5 hours, and methyl tert-butyl ether was crystallized. After centrifugation and drying, 177 mg of crude white solid VWT021700 was obtained. After purification by preparative HPLC, 4 mg of the target product VWT021700 with a purity of 97.01% was obtained; LCMS: [M+H] + =1147.60.

[0366] Example 7

[0367] Preparation of compound VWT022100

[0368] Step 1 (Preparation of VWT016100)

[0369] VWT016100 was prepared in the same manner as in Example 1.

[0370] Step 2 (Preparation of VWT022102)

[0371] (2-1) Synthesis of Compound 3

[0372]

[0373] Compound 1 (5 g, CAS No.: 22717-56-2), compound 2 (3.48 g, N-Boc-ethanolamine, CAS No.: 26690-80-2) and triphenylphosphine (6.23 g) were added to tetrahydrofuran (50 mL), and DEAD (diethyl azodicarboxylate: 4.8 g) was added to the reaction solution. The reaction solution was reacted at room temperature for 16 hours and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 3 (8.12 g, methyl 4-bromo-2-(2-((tert-butoxycarbonyl)amino)ethoxy)benzoate) as a yellow oily liquid.

[0374] (2-2) Synthesis of Compound 4

[0375]

[0376] Compound 3 (8.12 g) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (9 mL) was added to the reaction solution, the reaction solution was reacted at room temperature for 16 hours, and concentrated to obtain a residue. Toluene was added to the residue, and after concentration under reduced pressure, it was dissolved in toluene, and then triethylamine (35 g) was added. The reaction solution was reacted at 100° C. for 16 hours, cooled to room temperature, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 2) to obtain compound 4 (4.2 g, 8-bromo-3,4-dihydrobenzo[F][1,4]oxazepine-5(2H)-one, 79.3%) as a white solid.

[0377] (2-3) Synthesis of Compound 5

[0378]

[0379] Compound 4 (4.2 g) was dissolved in tetrahydrofuran (30 mL). Under nitrogen protection, 1 mol / L borane tetrahydrofuran solution (104 mL) was slowly added to the reaction solution. The reaction solution was reacted at 65°C for 16 hours under a nitrogen environment. Methanol (20 mL) was added to the reaction solution, and then 2 mol / L hydrochloric acid (100 mL) was added. The reaction solution was reacted at 80°C for 1 hour. The reaction solution was concentrated, and water (100 mL) and ethyl acetate (100 mL) were added to the residue. The liquids were separated, and the pH value of the aqueous phase was adjusted to weak alkalinity with sodium hydroxide. The solution was extracted three times with ethyl acetate (3×100 mL). The organic phase was concentrated to obtain compound 5 (3.56 g, 8-bromo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine, 89.1%) as a colorless oily liquid.

[0380] (2-4) Synthesis of Compound 6

[0381]

[0382] Compound 5 (3.56 g) and di-tert-butyl dicarbonate (5.1 g) were dissolved in dichloromethane (200 mL), and DIPEA (4.02 g) was added to the reaction solution, and the reaction solution was reacted at room temperature for 16 hours. The residue was concentrated and purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 15 / 1) to obtain compound 6 (5.1 g, tert-butyl 8-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate, 98.1%) as a white solid.

[0383] (2-5) Synthesis of Compound 7

[0384]

[0385] Compound 6 (5.1 g) was dissolved in a solution of EtOH / DMF / DIPEA (200 mL, volume ratio: EtOH / DMF / DIPEA=2 / 8 / 1; EtOH refers to ethanol), DPPF (1.72 g) and palladium acetate (0.348 g) were added to the reaction solution, and the reaction solution was reacted at 100°C for 16 hours under a carbon monoxide environment, water (200 mL) was added to the reaction solution, and then extracted with ethyl acetate (3×200 mL); the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate=10 / 1) to obtain compound 7 (1.2 g, 4-(tert-butyl)-8-ethyl 2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate, 23.9%) as a green oily liquid.

[0386] (2-6) Synthesis of Compound 8

[0387]

[0388] Compound 7 (1.2 g) was dissolved in methanol (30 mL), and sodium hydroxide (1.48 g) was added and dissolved in water (20 mL). The reaction solution was reacted at room temperature for 16 hours, concentrated under reduced pressure, and the pH value was adjusted to acidic with 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to obtain compound 8 (1 g, 4-(tert-butoxycarbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylic acid, 91.9%) as a white solid.

[0389] (2-7) Synthesis of Compound 9

[0390]

[0391] Compound 8 (1 g) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added, the reaction solution was reacted at room temperature for 2 hours, and concentrated under reduced pressure to obtain compound 9 (0.6 g, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylic acid, 91.2%) as a white solid.

[0392] (2-8) Synthesis of compound VWT022102

[0393]

[0394] Compound 9 (0.6 g) and Fmoc-OSu (1.6 g) were dissolved in tetrahydrofuran (50 mL), and triethylamine (0.9 g) was added. The reaction solution was reacted at room temperature for 2 hours, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 20 / 1) to obtain a crude product. The crude product was slurried with dichloromethane, filtered, and dried to obtain compound VWT022102 (0.96 g, 4-(9-fluorenylmethoxycarbonyloxy)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylic acid, 74.4%) as a white solid.

[0395] Step 3 (Preparation of VWT022103)

[0396]

[0397] VWT016100 resin (0.12 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL). The mixture of VWT022102 (75 mg) and PyAOP (95 mg), HOAT (25 mg), and DIPEA (50 mg) in DMF (1.5 mL) was treated for 3.5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT022103.

[0398] Step 4 (Preparation of VWT022104)

[0399]

[0400] VWT022103 resin (0.12 mmol) was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL), and treated with a mixture of Fmoc-Ala-OH (190 mg) and DIC (80 mg) and HOBT (95 mg) in DMF (1.5 mL) for 3 hours. The resin was washed with DMF (18 ml) to obtain compound VWT022104.

[0401] Step 5 (Preparation of VWT022105)

[0402]

[0403] VWT022104 resin (0.12 mmol) was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL), and treated with a mixture of DOTA(tBu)3 (210 mg) and PyAOP (190 mg), HOAT (50 mg), and DIPEA (95 mg) in DMF (1.5 mL) for 5 hours. The resin was washed with DMF (18 mL) to obtain compound VWT022105.

[0404] Step 6 (Preparation of VWT022100)

[0405]

[0406] VWT022105 was treated in 95% TFA / 5% H2O lysis solution (5.0 mL) for 3 hours, and methyl tert-butyl ether was crystallized. After centrifugation and drying, 227 mg of crude white solid VWT022100 was obtained. After purification by preparative HPLC, 53 mg of the target product VWT022100 with a purity of 97.66% was obtained; LCMS: [M+H] + =1149.70.

[0407] Example 8

[0408] Preparation of compound VWT024000

[0409] Step 1 (Preparation of VWT016100)

[0410] VWT016100 was prepared in the same manner as in Example 1.

[0411] Step 2 (Preparation of VWT011601)

[0412] VWT011601 was prepared in the same manner as in Example 4.

[0413] Step 3 (Preparation of VWT024001)

[0414]

[0415] VWT016100 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL). A mixture of VWT011601 (100 mg) and PyAOP (125 mg), HOAT (35 mg), and DIPEA (70 mg) in DMF (3 mL) was treated for 3.5 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT024001.

[0416] Step 4 (Preparation of VWT024002)

[0417]

[0418] VWT024001 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL). A mixture of Fmoc-Glu (OtBu) -OH (425 mg, CAS No.: 71989-18-9) and DIC (130 mg), HOBT (155 mg) in DMF (3 mL) was treated for 2 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT024002.

[0419] Step 5 (Preparation of VWT024003)

[0420]

[0421] VWT024002 resin (0.2 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). A mixture of DOTA(tBu)3 (230 mg) and PyAOP (210 mg), HOAT (60 mg), and DIPEA (105 mg) in DMF (3 mL) was treated for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT024003.

[0422] Step 6 (Preparation of VWT024000)

[0423]

[0424] VWT024003 was treated in 95% TFA / 5% H2O lysis solution (6.5 mL) for 3 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 255 mg of a crude white solid of VWT024000. After purification by preparative HPLC, 110 mg of the target product VWT024000 with a purity of 92.65% was obtained; LCMS: [M+H] + =1191.90.

[0425] Example 9

[0426] Preparation of compound VWT024100

[0427] Step 1 (Preparation of VWT016100)

[0428] VWT016100 was prepared in the same manner as in Example 1.

[0429] Step 2 (Preparation of VWT024101)

[0430] VWT024101 (ie, VWT024001) was prepared in the same manner as in Example 8.

[0431] Step 3 (Preparation of VWT024102)

[0432]

[0433] VWT024101 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, and then washed with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). A mixture of Fmoc-L-Glu (OMe) -OH (380 mg, CAS No.: 145038-50-2) and DIC (130 mg), HOBT (155 mg) in DMF (3 mL) was treated for 2 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT024102.

[0434] Step 4 (Preparation of VWT024103)

[0435]

[0436] VWT024102 resin (0.2 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was treated with a mixture of DOTA(tBu)3 (230 mg) and PyAOP (210 mg), HOAT (60 mg), and DIPEA (105 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT024103.

[0437] Step 5 (Preparation of VWT024100)

[0438]

[0439] VWT024103 was treated in 95% TFA / 5% H2O lysis solution (5.5 mL) for 3 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 330 mg of crude white solid VWT024100, which was then purified by preparative HPLC to obtain 90 mg of the target product VWT024100 with a purity of 97.18%; LCMS: [M+H] + =1205.90.

[0440] Example 10

[0441] Preparation of compound VWT022600

[0442] Step 1 (Preparation of VWT024001)

[0443] VWT024001 was prepared in the same manner as in Example 8.

[0444] Step 2 (Preparation of VWT022600)

[0445]

[0446] VWT024001 resin (0.22 mmol) was coupled with (((9H-fluoren-9-yl)methoxy)carbonyl)(sulfo)-D-alanine (CAS No.: 751470-47-0) under the action of PyAOP / HOAT / DIPEA condensation system in the order in the sequence, and then the resin was washed with DMF, and the compound DOTA(tBu)3 was coupled under the action of PyAOP / HOAT / DIPEA condensation system, and the resin was washed with DMF to obtain the fully protected peptide VWT022603.

[0447] Then VWT022603 was treated in 95% TFA / 5% H2O lysis solution (4 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT022600, which was then purified by preparative HPLC to obtain 39.5 mg of the target product VWT022600 with a purity of 96.90%; LCMS: [M+H] + =1213.70.

[0448] Embodiment 11

[0449] Preparation of compound VWT023800

[0450] Step 1 (Preparation of VWT023803)

[0451] (1-1) Synthesis of VWT023801

[0452] VWT023801 (ie, VWT016101) was prepared in the same manner as in Example 1.

[0453] (1-2) Preparation of derivatives of dimethyl L-glutamate

[0454]

[0455] L-Glutamic acid dimethyl ester hydrochloride (1.06 g) was added to anhydrous acetonitrile (30 mL) and stirred to dissolve. DSC (1.30 g) was added at room temperature and stirred continuously. Triethylamine (1.0 g) was slowly added dropwise. After the addition was completed, the mixture was reacted at room temperature overnight. The organic phase was separated and washed with 10% citric acid aqueous solution and saturated brine, and then concentrated and distilled to obtain a derivative of L-glutamate dimethyl ester (1.95 g): (((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-L-glutamate-dimethyl ester.

[0456] (1-3) Preparation of VWT023803

[0457]

[0458] The VWT023801 resin (0.5 mmol) was treated with 20% piperidine / DMF (5 mL) for 30 minutes, and then washed with DMF (4 mL); the derivative of L-glutamic acid dimethyl ester ((((2,5-dioxopyrrolidin-1-yl)oxy)carbonyl)-L-glutamic acid-dimethyl ester: 1.85 g) was coupled in the DIPEA / DMF system in the order in the sequence and reacted in DMF (5 mL) for 2 hours, the resin was washed with DMF (30 mL), and then the resin was treated with 8% hydrazine hydrate / DMF solution for 0.5 hour to remove the ivDde protecting group, the resin was washed with DMF (60 mL), and Fmoc-2-Nal-OH was coupled under the action of PyBOP / HOBT / DIPEA condensation system for 3 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT023803.

[0459] Step 2 (Preparation of VWT011601)

[0460] VWT011601 was prepared in the same manner as in Example 8.

[0461] Step 3 (Preparation of VWT023800)

[0462]

[0463] The intermediate VWT023803 resin (0.25 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (24 mL); VWT011601 (CAS No.: 2138226-21-6) was coupled with the PyAOP / HOAT / DIPEA condensation system in the order of the sequence; the resin was then washed with DMF (24 ml), and then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and DMF (24 mL) was added to wash the resin, and Fmoc-alanine was coupled with the DIC / HOBT condensation system to obtain the compound VWT023805; then 24 mL The resin was washed with DMF, and then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group. DMF (24 mL) was added to wash the resin, and the compound DOTA(tBu)3 was coupled under the action of PyAOP / HOAT / DIPEA condensation system. After washing the resin with DMF (24 mL), the fully protected peptide VWT023806 was obtained.

[0464] Then VWT023806 was treated in 95% TFA / 5% H2O lysis solution (6.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT023800, which was then purified by preparative HPLC to obtain 41 mg of the target product VWT023800 with a purity of 94.60%; LCMS: [M+H] + =1161.70.

[0465] Example 12

[0466] Preparation of compound VWT023900

[0467] Step 1 (Preparation of VWT016100)

[0468] VWT016100 was prepared in the same manner as in Example 1.

[0469] Step 2 (Preparation of VWT023901)

[0470]

[0471] VWT016100 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, then washed with DMF (5 mL). The Fmoc protecting group was then removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). The reaction was then treated with a mixture of VWT011601 (100 mg) and PyAOP (125 mg), HOAT (35 mg) and DIPEA (70 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT023901.

[0472] Step 3 (Preparation of VWT023902)

[0473]

[0474] VWT023901 resin (0.2 mmol) was washed with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). A mixture of Fmoc-Glu(OtBu)-OH (425 mg), DIC (130 mg), and HOBT (155 mg) in DMF (3 mL) was treated for 2 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT023902.

[0475] Step 4 (Preparation of VWT023903)

[0476]

[0477] VWT023902 resin (0.2 mmol) was swollen in DMF (5 mL) for 30 minutes, and then washed with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). Then, a mixture of Fmoc-D-Glu(OtBu)-OH (425 mg, CAS No.: 104091-08-9) and DIC (130 mg), HOBT (155 mg) in DMF (3 mL) was treated for 3 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT023903.

[0478] Step 5 (Preparation of VWT023904)

[0479]

[0480] VWT023903 resin (0.2 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was treated with a mixture of DOTA(tBu)3 (230 mg) and DIC (55 mg) and HOBT (70 mg) in DMF (3 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT023904.

[0481] Step 6 (Preparation of VWT023900)

[0482]

[0483] VWT023904 was treated in 95% TFA / 5% H2O lysis solution (5.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 310 mg of crude white solid VWT023900, which was then purified by preparative HPLC to obtain 105 mg of the target product VWT023900 with a purity of 94.97%; LCMS: [M+H] + =1320.70.

[0484] Embodiment 13

[0485] Preparation of compound VWT023600

[0486] Step 1 (Preparation of VWT016103)

[0487] VWT016103 was prepared in the same manner as in Example 1.

[0488] Step 2 (Preparation of VWT022502)

[0489] (2-1) Synthesis of Compound 2

[0490]

[0491] Perchloric acid (1 mL, concentration of 70%) was added to a solution of compound 1 ((S)-2-amino-3-(naphthalene-2-yl)propionic acid: 2.0 g) in tert-butyl acetate (30 mL) at room temperature, and the reaction solution was reacted at room temperature for 16 hours. Ethyl acetate (200 mL) was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2 (tert-butyl (S)-2-amino-3-(naphthalene-2-yl)propanoate: 1.55 g) as a colorless liquid.

[0492] (2-2) Synthesis of Compound 3

[0493]

[0494] 2-Nitrobenzenesulfonyl chloride (1.06 g) and potassium carbonate (1.02 g) were added to a DMF (20 mL) solution of compound 2 (1.0 g) at room temperature, and the reaction solution was reacted at room temperature for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, and then the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3 ((S)-3-(naphthalene-2-yl)-2-((2-nitrophenyl)sulfonylamino)propionic acid tert-butyl ester: 1.28 g, 76%) as a white solid.

[0495] (2-3) Synthesis of Compound 4

[0496]

[0497] Deuterated iodomethane (813 mg) and potassium carbonate (775 mg) were added to a DMF (20 mL) solution of compound 3 (1.28 g) at room temperature, and the reaction solution was reacted at room temperature for 16 hours. Ethyl acetate (100 mL) was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 4 / 1) to obtain compound 4 ((S)-2-((N-(methyl-d3)-2-nitrophenyl)sulfonylamino)-3-(naphthalene-2-yl)propionic acid tert-butyl ester: 1.2 g) as a yellow liquid.

[0498] (2-4) Synthetic Compounds

[0499]

[0500] 2-Mercaptoethanol (396 mg) and DBu (772 mg) were added to a DMF (10 mL) solution of compound 4 (1.20 g) at room temperature, and the reaction solution was reacted at room temperature for 2 hours. The reaction solution was purified by C18 reverse phase silica gel column chromatography to obtain compound 5 ((S)-2-((methyl-d3)amino)-3-(naphthalen-2-yl)propionic acid tert-butyl ester: 620 mg) as a yellow liquid.

[0501] (2-5) Synthesis of Compound 6

[0502]

[0503] Trifluoroacetic acid (5 mL) was added to a dichloromethane (5 mL) solution of compound 5 (620 mg) at room temperature, and the reaction solution was reacted at room temperature for 5 hours. The reaction solution was concentrated to obtain compound 6 ((S)-2-((methyl-d3)amino)-3-(naphthalene-2-yl)propanoic acid: 500 mg) as a colorless liquid.

[0504] (2-6) Synthesis of compound VWT022502

[0505]

[0506] Fmoc-OSu (1.09 g) and triethylamine (651 mg) were added to a DMF (300 mL) solution of compound 6 (500 mg), and the reaction solution was reacted at room temperature for 72 hours. After the reaction solution was concentrated, ethyl acetate (200 mL) was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: dichloromethane / methanol=10 / 1) to obtain compound VWT022502: (S)-2-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl-d3)amino)-3-(naphthalene-2-yl)propionic acid (80.3 mg) as a white solid.

[0507] Step 3 (Preparation of VWT023601)

[0508]

[0509] VWT016103 resin (0.06 mmol) was swelled in DMF (5 mL) for 30 minutes, then treated with 8% hydrazine hydrate / DMF (5 mL) for 30 minutes to remove the ivDde protecting group, and then washed with DMF. VWT022502 (40 mg) was coupled with PyAOP / HOAT / DIPEA condensation system (solvent: DMF) for 4 hours, and the resin was washed with DMF to obtain compound VWT023601.

[0510] Step 4 (Preparation of VWT023602)

[0511]

[0512] VWT023601 resin (0.06 mmol) was swelled in DMF (5 mL) for 30 minutes, then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF. VWT011601 (30 mg) was then coupled with PyAOP / HOAT / DIPEA condensation system (solvent: DMF) for 6 hours, and the resin was washed with DMF to obtain compound VWT023602.

[0513] Step 5 (Preparation of VWT024302)

[0514] (5-1) Synthesis of Compound 3

[0515]

[0516] Compound 1 ((2S)-2-aminopropionic acid methyl ester: 1.00 g) and triethylamine (2.94 g) were added to 10 mL of dichloromethane, and 2-nitrobenzenesulfonyl chloride (2.15 g) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (volume ratio: PE / EA=5 / 1) to obtain compound 3 ((2S)-2-[(2-nitrobenzene)sulfonylamino]propionic acid methyl ester: 1.90 g) as a colorless liquid.

[0517] (5-2) Synthesis of Compound 4

[0518]

[0519] Compound 3 (1.90 g) was dissolved in N, N-dimethylformamide (10 mL), potassium carbonate (2.74 g) and deuterated iodomethane (1.91 g) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL × 3), and the organic phases were combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (volume ratio: PE / EA = 10:1) to obtain compound 4 ((2S)-2-[N-methyl(2-nitrobenzene)sulfonylamino]propionic acid methyl ester: 2.00 g) as a colorless liquid.

[0520] (5-3) Synthesis of Compound 6

[0521]

[0522] Compound 4 (2.00 g) was dissolved in N,N-dimethylformamide (20 mL), and 2-mercaptoethanol (2.56 g) and DBU (4.98 g) were added and reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 6 ((2S)-2-(methylamino)propionic acid methyl ester: 700 mg) as a yellow liquid. The crude product was directly used in the next step without purification.

[0523] (5-4) Synthesis of Compound 7

[0524]

[0525] Compound 6 (700 mg) was dissolved in 10 mL of methanol, and sodium hydroxide (1.16 g dissolved in 2 mL of water) was added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove methanol, and dilute hydrochloric acid was added to adjust the pH of the residue to neutral or weakly acidic, and the mixture was concentrated under reduced pressure to obtain a crude product of compound 7 ((2S)-2-(methylamino)propionic acid: 500 mg) as a light yellow solid. The crude product was directly used for the next step without purification.

[0526] (5-5) Synthesis of Compound VWT024302

[0527]

[0528] Compound 7 (500 mg) was added to 10 mL of tetrahydrofuran, and Fmoc-OSu (3.18 g) and triethylamine (1.43 g) were added, and the reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×3), and the organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (volume ratio: DCM / MeOH=10 / 1) to obtain compound VWT024302 ((2S)-2-({9-[(formyloxy)methyl]-9H-fluorene-4a-yl}(methyl)amino)propionic acid: 252.1 mg) as a yellow liquid.

[0529] Step 6 (Preparation of VWT023603)

[0530]

[0531] VWT023601 resin (0.06 mmol) was swelled in DMF (5 mL) for 30 minutes, and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF, and then VWT024302 (30 mg) was coupled with the PyAOP / HOAT / DIPEA condensation system for 6 hours. The resin was washed with DMF to obtain the intermediate VWT023603.

[0532] Step 7 (Preparation of VWT023600)

[0533]

[0534] VWT023603 resin (0.06 mmol) was swelled in DMF (5 mL) for 30 minutes, then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF. Then, DOTA(tBu)3 (70 mg) was used for coupling reaction under the action of PyAOP / HOAT / DIPEA condensation system (DMF as solvent) for 8 hours, and the resin was washed with DMF to obtain the fully protected peptide resin VWT023604 (173 mg).

[0535] VWT023604 was treated in 95% TFA / 5% H2O solution (9.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT023600. It was then purified by preparative HPLC to obtain 17 mg of the target product VWT023600 with a purity of 92.72%; LCMS: [M+H] + =1167.80.

[0536] Embodiment 14

[0537] Preparation of compound VWT026300

[0538] Step 1 (Preparation of VWT024001)

[0539] VWT024001 was prepared in the same manner as in Example 8.

[0540] Step 2 (Preparation of VWT026301)

[0541] (2-1) Synthesis of Compound 3

[0542]

[0543] Trifluoroacetic acid (10 mL) was added to a dichloromethane (10 mL) solution of compound 6 ((2S)-2-{[(tert-butoxy)carbonyl]amino}propionic acid benzyl ester: 5.0 g, CAS No.: 51814-54-1), and the reaction solution was reacted at room temperature for 2 hours; the reaction solution was concentrated to obtain compound 3: (2S)-2-aminopropionic acid benzyl ester, which was a colorless liquid.

[0544] (2-2) Synthesis of Compound 2

[0545]

[0546] TsCl (p-toluenesulfonyl chloride: 3.24 g) and triethylamine (3.3 g) were added to a dichloromethane (20 mL) solution of compound 1 (tert-butyl 3-[2-(2-hydroxyethoxy)ethoxy]propionate: 2.0 g, CAS No.: 133803-81-3), and the reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (volume ratio: PE / EA=10 / 1) to obtain compound 2: tert-butyl 3-[2-(2-{[(4-methylbenzene)sulfonyl]oxy}ethoxy)ethoxy]propionate, which was a light yellow solid.

[0547] (2-3) Synthesis of Compound 4

[0548]

[0549] Compound 3 (1.22 g) and anhydrous sodium carbonate (1.08 g) were added to a DMF (20 mL) solution of compound 2 (1.32 g), and the reaction solution was reacted at 60° C. for 16 hours. After the reaction was completed, ethyl acetate was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by silica gel column chromatography (volume ratio: dichloromethane / methanol=10 / 1) to obtain compound 4: (2S)-2-[(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethyl)amino]propionic acid benzyl ester, which was a colorless liquid.

[0550] (2-4) Synthesis of Compound 5

[0551]

[0552] 10% Pd / C (269 mg) was added to a methanol (10 mL) solution of compound 4 (1.0 g), and the reaction solution was reacted at room temperature for 16 hours under a hydrogen atmosphere. The solid was filtered and spin-dried to obtain compound 5: (2S)-2-[(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethyl)amino]propionic acid, which was a colorless liquid.

[0553] (2-5) Synthesis of Compound VWT026301

[0554]

[0555] Fmoc-OSu (1.53 g) and triethylamine (685 mg) were added to a tetrahydrofuran (5 mL) solution of compound 5 (690 mg), and the reaction solution was reacted at room temperature for 3 hours. After the reaction was completed, ethyl acetate was added to the reaction solution, and then the mixed solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue, which was purified by prep-HPLC (mobile phase: 0.1% formic acid aqueous solution-acetonitrile) to obtain compound VWT026301: (2S)-2-[(2-{2-[3-(tert-butoxy)-3-oxopropoxy]ethoxy}ethyl)({9-[(formyloxy)methyl]-9H-fluorene-4a-yl})amino]propionic acid, which was a brown liquid.

[0556] Step 3 (Preparation of VWT026302)

[0557]

[0558] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, a mixture of VWT026301 (50 mg) and PyAOP (46 mg), HOAT (15 mg), and DIPEA (25 mg) in DMF (1 mL) was treated for 5 hours, and the resin was washed with DMF (12 mL) to obtain compound VWT026302.

[0559] Step 4 (Preparation of VWT026300)

[0560]

[0561] The VWT026302 resin was treated with 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (16 mL). Then, the compound DOTA(tBu)3 (25 mg) was coupled under the action of the PyAOP / HOAT / DIPEA condensation system, and the resin was washed with DMF (4 mL) to obtain the fully protected peptide VWT026303.

[0562] Then VWT026303 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 5 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT026300, which was then purified by preparative HPLC to obtain 14 mg of the target product VWT026300 with a purity of 93.02%; LCMS: [M+H] + =1293.90.

[0563] Embodiment 15

[0564] Preparation of compound VWT031600

[0565] Step 1 (Preparation of VWT016100)

[0566] VWT016100 was prepared in the same manner as in Example 1.

[0567] Step 2 (Preparation of VWT031601)

[0568]

[0569] VWT016100 resin (0.1 mmol) was swollen in DMF (3 mL) for 30 minutes and then washed with DMF (3 mL). The swollen resin was then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). A mixture of VWT011601 (50 mg) and PyAOP (65 mg), HOAT (18 mg), and DIPEA (35 mg) in DMF (3 mL) was treated for 3.5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT031601.

[0570] Step 3 (Preparation of VWT031602)

[0571]

[0572] VWT031601 resin (0.1 mmol) was swollen in DMF (5 mL) for 30 minutes and then washed with DMF (5 mL). The Fmoc protecting group was then removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes and the resin was washed with DMF (40 mL). The mixture of Fmoc-D-Glu(OtBu)-OH (130 mg) and PyAOP (155 mg), HOAT (45 mg) and DIPEA (85 mg) in DMF (3 mL) was treated for 5 hours and the resin was washed with DMF (18 mL) to obtain compound VWT031602.

[0573] Step 4 (Preparation of VWT031603)

[0574]

[0575] VWT031602 resin (0.1 mmol) was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). A mixture of DOTA(tBu)3 (230 mg) and ethyl 2-oximecyanoacetate (50 mg) and DIC (42 mg) in DMF (3 mL) was treated for 5 hours, and the resin was washed with DMF (18 mL) to obtain compound VWT031603.

[0576] Step 5 (Preparation of VWT031600)

[0577]

[0578] VWT031603 was treated in 95% TFA / 5% H2O lysis solution (4.0 mL) for 4 hours, and methyl tert-butyl ether was crystallized. After centrifugation and drying, 152 mg of crude white solid VWT031600 was obtained. After purification by preparative HPLC, 47 mg of the target product VWT031600 with a purity of 97.93% was obtained; LCMS: [M+H] + =1191.80.

[0579] Example 16

[0580] Preparation of compound VWT032000

[0581] Step 1 (Preparation of VWT024001)

[0582] VWT024001 was prepared in the same manner as in Example 8.

[0583] Step 2 (Preparation of VWT032002)

[0584] (2-1) Synthesis of Compound 2

[0585]

[0586] Compound 1 ((2S,2'S)-4,4'-disulfanediylbis(2-aminobutyric acid): 1 g) was dissolved in acetic acid (30 mL), and hydrogen peroxide (30 mL) was added. The reaction solution was reacted at room temperature for 16 hours. The reaction solution was lyophilized to obtain compound 2: (S)-2-amino-4-sulfobutyric acid (0.56 g) as a white solid.

[0587] (2-2) Synthesis of VWT032002

[0588]

[0589] Compound 2 (0.56 g) was dissolved in dioxane (50 mL), and Fmoc-Cl (1.57 g) and sodium bicarbonate (1.3 g dissolved in 50 mL water) were added to the reaction solution, and the reaction solution was reacted at room temperature for 16 hours. Ethyl acetate was added to the reaction solution for separation, and the aqueous phase was retained. The aqueous phase was adjusted to pH 1 with 1N hydrochloric acid, and then lyophilized to obtain a residue, which was purified by C18 reverse phase silica gel column chromatography to obtain compound VWT032002: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-sulfobutyric acid (401.2 mg) as a white solid.

[0590] Step 3 (Preparation of VWT032003)

[0591]

[0592] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, a mixture of VWT032002 (75 mg) and PyAOP (94 mg), HOAT (25 mg), and DIPEA (50 mg) in DMF (1 mL) was treated for 5 hours, and the resin was washed with DMF (12 mL) to obtain compound VWT032003.

[0593] Step 4 (Preparation of VWT032000)

[0594]

[0595] The VWT032003 resin was treated with 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and the resin was washed with DMF (16 mL). Then, the compound DOTA(tBu)3 (74 mg) was coupled under the action of PyAOP (65 mg) / HOAT (20 mg) / DIPEA (35 mg) condensation system, and the resin was washed with DMF (4 mL) to obtain the fully protected peptide VWT032004.

[0596] Then VWT032004 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 5 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT032000, which was then purified by preparative HPLC to obtain 11.4 mg of the target product VWT032000 with a purity of 87.63%; LCMS: [M+H] + =1228.00.

[0597] Embodiment 17

[0598] Preparation of compound VWT032100

[0599] Step 1 (Preparation of VWT024001)

[0600] VWT024001 was prepared in the same manner as in Example 8.

[0601] Step 2 (Preparation of VWT032100)

[0602]

[0603] The VWT024001 resin (0.1 mmol) was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF; Fmoc-Pro-OH was coupled under the action of PyAOP / HOAT / DIPEA condensation system in the order in the sequence, and then the resin was washed with DMF to obtain the intermediate VWT032102; it was then treated with 20% piperidine / DMF (5 mL) for 30 minutes, and then washed with DMF; then the compound DOTA(tBu)3 was coupled under the action of PyAOP / HOAT / DIPEA condensation system, and the resin was washed with DMF to obtain the fully protected peptide resin VWT032103.

[0604] VWT032103 was treated in 95% TFA / 5% H2O solution (5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT032100, which was then purified by preparative HPLC to obtain 67 mg of the target product VWT032100 with a purity of 97.53%; LCMS: [M+H] + =1159.80.

[0605] Embodiment 18

[0606] Preparation of compound VWT032200

[0607] The difference from the preparation steps of VWT032100 in Example 17 is that Fmoc-D-Pro-OH is coupled.

[0608] Embodiment 19

[0609] Preparation of compound VWT032600

[0610] Step 1 (Preparation of VWT016100)

[0611] VWT016100 was prepared in the same manner as in Example 1.

[0612] Step 2 (Preparation of VWT032602)

[0613] (2-1) Synthesis of Compound 4

[0614] According to the same method as Example 1, compound 4 was prepared: 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid ethyl ester (1.34 g).

[0615] (2-2) Synthesis of Compound 2

[0616]

[0617] Isobutyl chloroformate (485.8 mg) was added to a solution of (S)-2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentanoic acid (Cbz-Glu(OtBu)-OH: 1.0 g) and triethylamine (449.9 mg) in tetrahydrofuran (20 mL) at 0°C, and the reaction solution was reacted at 0°C for 0.5 hour. Sodium borohydride (336.4 mg) was added to the reaction solution at 0°C and the reaction was continued for 0.5 hour. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2: (S)-tert-butyl 4-(((benzyloxy)carbonyl)amino)-5-hydroxypentanoate (529 mg), which was a colorless liquid.

[0618] (2-3) Synthesis of Compound 3

[0619]

[0620] Triphenylphosphine (1.29 g), iodine (1.25 g) and imidazole (556.8 mg) were added to dichloromethane (50 mL) at room temperature. After reacting at room temperature for half an hour, compound 2 (529 mg) was added to the reaction solution and the reaction was continued to stir for 3 hours. The reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 3: (S)-4-(((benzyloxy)carbonyl)amino)-5-iodopentanoic acid tert-butyl ester (540 mg), which was a colorless liquid.

[0621] (2-4) Synthesis of Compound 5

[0622]

[0623] Ethyl 1,2,3,4-tetrahydroisoquinoline-6-carboxylate (200 mg), compound 3 (506.6 mg) and potassium carbonate (249.3 mg) were added to dichloromethane (10 mL). After reacting at room temperature for 16 hours, the reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 5: (S)-2-(2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (190 mg), which was a colorless liquid.

[0624] (2-5) Synthesis of Compound 6

[0625]

[0626] Sodium hydroxide (74.4 mg dissolved in 5 mL of water) was added to a solution of compound 5 (190 mg) in methanol (5 mL), and the reaction was allowed to react at room temperature for 3 hours. The pH value of the reaction solution was adjusted to 7 with 1N hydrochloric acid, and then extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 6: (S)-2-(2-(((benzyloxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (140 mg) as a white solid.

[0627] (2-6) Synthesis of Compound 7

[0628]

[0629] Pd / C (20 mg) was added to a methanol (10 mL) solution of compound 6 (140 mg) and reacted at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated to obtain compound 7: (S)-2-(2-amino-5-(tert-butoxy)-5-oxopentyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (100 mg), which was a colorless liquid.

[0630] (2-7) Synthesis of Compound VWT032602

[0631]

[0632] Fmoc-OSu (111.4 mg) and sodium bicarbonate (72 mg dissolved in 5 mL of water) were added to a solution of compound 7 (100 mg) in tetrahydrofuran (5 mL) and reacted at room temperature for 5 hours. The reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: dichloromethane / methanol = 10 / 1) to obtain compound VWT032602: (S)-2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-5-(tert-butoxy)-5-oxopentyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (17.2 mg) as a white solid.

[0633] Step 3 (Preparation of VWT032603)

[0634]

[0635] The VWT016100 resin was swollen in DMF (1 mL) for 30 minutes, then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (1 mL) for 30 minutes, and then the resin was washed with DMF (8 mL). The mixture of VWT032602 (17.2 mg) and PyAOP (16 mg), HOAT (5 mg), and DIPEA (10 mg) in DMF (1 mL) was treated for 8 hours, and the resin was washed with DMF (6 mL) to obtain compound VWT032603.

[0636] Step 4 (Preparation of VWT032600)

[0637]

[0638] The VWT032603 resin was treated with 20% piperidine / DMF (1 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (8 mL). Then, the compound DOTA(tBu)3 (30 mg) was coupled under the action of PyAOP (27 mg) / HOAT (7 mg) / DIPEA (15 mg) condensation system, and the resin was washed with DMF (4 mL) to obtain the fully protected peptide VWT032604.

[0639] Then VWT032604 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 3 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT032600, which was then purified by preparative HPLC to obtain 36 mg of the target product VWT032600 with a purity of 94.46%; LCMS: [M+H] + =1178.0.

[0640] Embodiment 20

[0641] Preparation of compound VWT032800

[0642] Step 1 (Preparation of VWT024001)

[0643] VWT024001 was prepared in the same manner as in Example 8.

[0644] Step 2 (Preparation of VWT032802)

[0645]

[0646] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, the resin was treated with a mixture of Fmoc-α-Me-Glu(OtBu)-OH (33 mg, CAS No.: 1072845-48-7) and PyAOP (38 mg), HOAT (10 mg), and DIPEA (20 mg) in DMF (1 mL) for 8 hours, and the resin was washed with DMF (12 mL) to obtain the compound VWT032802.

[0647] Step 3 (Preparation of VWT032803)

[0648]

[0649] The VWT032802 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, a mixture of DOTA (tBu) 3 (105 mg) and PyAOP (95 mg), HOAT (26 mg), and DIPEA (50 mg) in DMF (1 mL) was treated for 5 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT032803.

[0650] Step 4 (Preparation of VWT032000)

[0651]

[0652] VWT032803 was treated in 95% TFA / 5% H2O lysis solution (2.2 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT032800, which was then purified by preparative HPLC to obtain 3.0 mg of the target product VWT032800 with a purity of 92.13%; LCMS: [M+H] + =1206.00.

[0653] Embodiment 21

[0654] Preparation of compound VWT032900

[0655] Step 1 (Preparation of VWT024001)

[0656] VWT024001 was prepared in the same manner as in Example 8.

[0657] Step 2 (Preparation of VWT032902)

[0658]

[0659] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, the mixture of Fmoc-Met(O2)-OH (51 mg) and PyAOP (62 mg), HOAT (18 mg), and DIPEA (40 mg) in DMF (1 mL) was treated for 8 hours, and the resin was washed with DMF (12 mL) to obtain the compound VWT032902.

[0660] Step 3 (Preparation of VWT032900)

[0661]

[0662] The VWT032902 resin was treated with 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (16 mL). Then, the compound DOTA(tBu)3 (170 mg) was coupled under the action of DIC (40 mg) / ethyl 2-oximecyanoacetate (50 mg) condensation system, and the resin was washed with DMF (4 mL) to obtain the fully protected peptide VWT032903.

[0663] Then VWT032903 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 3 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT032900, which was then purified by preparative HPLC to obtain 16.1 mg of the target product VWT032900 with a purity of 94.97%; LCMS: [M+H] + =1320.70.

[0664] Embodiment 22

[0665] Preparation of compound VWT033000

[0666] Step 1 (Preparation of VWT024001)

[0667] VWT024001 was prepared in the same manner as in Example 8.

[0668] Step 2 (Preparation of VWT024902)

[0669] (2-1) Synthesis of Compound 3

[0670]

[0671] Compound 1 ((S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid: 2 g) and HATU (2.76 g) were added to dichloromethane (100 mL), and then compound N-hydroxyacetamidine (0.49 g) and triethylamine (2 g) were added, and the reaction was carried out at room temperature for 16 hours. Dilute with sodium bicarbonate solution (100 mL), extract with dichloromethane (100 mL×3), combine the organic phases, and concentrate under reduced pressure to obtain a residue, which is then dissolved in tetrahydrofuran (50 mL). Cesium carbonate (6.44 g) is added to the reaction solution, and the mixture is reacted at 70°C for 16 hours, concentrated under reduced pressure, diluted with sodium bicarbonate solution (100 mL), extracted with ethyl acetate (100 mL×3), combine the organic phases, and concentrate under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (volume ratio: dichloromethane / methanol=10 / 1) to obtain compound 3: (S)-tert-butyl 2-((tert-butoxycarbonyl)amino)-4-(3-methyl-1,2,4-oxadiazol-5-yl)butanoate (2.1 g), a colorless liquid.

[0672] (2-2) Synthesis of Compound 4

[0673]

[0674] Compound 3 (2.1 g) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, the mixture was reacted at room temperature for 24 hours, and the mixture was concentrated under reduced pressure to obtain compound 4: (S)-2-amino-4-(3-methyl-1,2,4-oxadiazol-5-yl)butanoic acid (1.1 g) as a colorless liquid.

[0675] (2-3) Synthesis of Compound VWT024902

[0676]

[0677] Compound 4 (1.1 g) and Fmoc-OSu (3 g) were dissolved in tetrahydrofuran, triethylamine (2 g) was added, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by C18 reverse phase silica gel column chromatography to obtain compound VWT024902: (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3-methyl-1,2,4-oxadiazol-5-yl)butanoic acid (427 mg) as a white solid.

[0678] Step 3 (Preparation of VWT033002)

[0679]

[0680] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, a mixture of VWT024902 (50 mg) and PyAOP (62 mg), HOAT (17 mg), and DIPEA (37 mg) in DMF (1 mL) was treated for 8 hours, and the resin was washed with DMF (12 mL) to obtain the compound VWT033002.

[0681] Step 4 (Preparation of VWT033003)

[0682]

[0683] The VWT033002 resin was treated with 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (16 mL). It was then treated with a mixture of DOTA(tBu)3 (72 mg) and PyAOP (63 mg), HOAT (18 mg), and DIPEA (35 mg) in DMF (1 mL) for 8 hours. The resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT033003.

[0684] Step 4 (Preparation of VWT033000)

[0685]

[0686] VWT033003 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain crude VWT033000, which was then purified by preparative HPLC to obtain 5.7 mg of the target product VWT033000 with a purity of 90.73%; LCMS: [M+H] + =1230.10.

[0687] Embodiment 23

[0688] Preparation of compound VWT037100

[0689] Step 1 (Preparation of VWT024001)

[0690] VWT024001 was prepared in the same manner as in Example 8.

[0691] Step 2 (Preparation of VWT037102)

[0692]

[0693] The VWT024001 resin was washed twice with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 ml) for 30 minutes, and the resin was washed with DMF (40 ml). The mixture of Fmoc-Glu (OtBu) -OH (855 mg), DIC (260 mg), and ethyl 2-oximecyanoacetate (290 mg) in DMF (3 ml) was treated for 3 hours, and the resin was washed with DMF (30 ml) to obtain the compound VWT037101.

[0694] The VWT037101 resin was swelled in DMF (5 mL) for 30 minutes and then washed twice with DMF (5 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes and then the resin was washed with DMF (40 ml). The resin was treated with a mixture of Fmoc-D-Leu-OH (120 mg) and DIC (120 mg) and ethyl 2-oximecyanoacetate (150 mg) in DMF (3 mL) for 8 hours and the resin was washed with DMF (30 mL) to obtain VWT037102.

[0695] Step 3 (Preparation of VWT037100)

[0696]

[0697] The VWT037102 resin was swollen in DMF (2 mL) for 30 minutes, and then washed twice with DMF (2 mL). The Fmoc protecting group was then removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and the resin was washed with DMF (16 mL). The resin was then treated with a mixture of DOTA (tBu) 3 (170 mg) and PyAOP (155 mg), HOAT (43 mg), and DIPEA (50 mg) in DMF (1 mL) for 5 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT037103.

[0698] VWT037103 was then treated in 95% TFA / 5% H2O lysis solution (3 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 93 mg of a crude white solid of VWT037100, which was then purified by preparative HPLC to obtain 11.6 mg of the target product VWT037100 with a purity of 96.93%; LCMS: [M+H] + =1304.60.

[0699] Embodiment 24

[0700] Preparation of compound VWT038200

[0701] Step 1 (Preparation of VWT024001)

[0702] VWT024001 was prepared in the same manner as in Example 8.

[0703] Step 2 (Preparation of VWT038202)

[0704]

[0705] The VWT024001 resin was washed twice with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and then the resin was washed with DMF (40 mL). Then, the resin was treated with a mixture of Fmoc-Glu(OtBu)-OH (520 mg) and PyAOP (630 mg), HOAT (140 mg), and DIPEA (310 mg) in DMF (5 mL) for 3 hours, and the resin was washed with DMF (30 mL) to obtain the compound VWT038201.

[0706] VWT038201 was treated in 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of Fmoc-D-phenylalanine (150 mg), DIC (160 mg) and ethyl 2-oximecyanoacetate (170 mg) in DMF (5 mL) for 2 hours, and the resin was washed with DMF (30 mL) to obtain VWT038202.

[0707] Step 3 (Preparation of VWT038200)

[0708]

[0709] The VWT038202 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (3 mL) for 30 minutes, and then the resin was washed with DMF (24 mL). The mixture of DOTAGA-tetra-tert-butyl ester (65 mg) and PyAOP (50 mg), HOAT (15 mg), and DIPEA (30 mg) in DMF (1 mL) was treated for 3.5 hours, and the resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT038203.

[0710] Then, the VWT038203 resin was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 5 hours, and methyl tert-butyl ether was crystallized. After centrifugation and drying, 101 mg of a crude white solid product of VWT038200 was obtained. After purification by preparative HPLC, 11.2 mg of the target product VWT038200 with a purity of 88.84% was obtained; LCMS: [M+H] + =1410.60.

[0711] Embodiment 25

[0712] Preparation of compound VWT038600

[0713] Step 1 (Preparation of VWT024001)

[0714] VWT024001 was prepared in the same manner as in Example 8.

[0715] Step 2 (Preparation of VWT038602)

[0716]

[0717] The VWT024001 resin was washed twice with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and then the resin was washed with DMF (40 mL). Then, the resin was treated with a mixture of Fmoc-Glu(OtBu)-OH (520 mg) and PyAOP (630 mg), HOAT (140 mg), and DIPEA (310 mg) in DMF (5 mL) for 3 hours, and the resin was washed with DMF (30 mL) to obtain the compound VWT038601.

[0718] The VWT038601 resin was treated in 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 ml). It was then treated with a mixture of Fmoc-D-phenylalanine (150 mg), DIC (160 mg) and ethyl 2-oximecyanoacetate (170 mg) in DMF (5 mL) for 2 hours. The resin was washed with DMF (30 mL) to obtain the intermediate VWT038602.

[0719] Step 3 (Preparation of VWT038600)

[0720]

[0721] The VWT038602 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (2 mL), treated in 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 ml), treated with a mixture of Fmoc-D-Tyr(tBu)-OH (140 mg) and DIC (38 mg) and ethyl 2-oximecyanoacetate (45 mg) in DMF (3 mL) for 4 hours, and the resin was washed with DMF (18 mL) to obtain VWT038603.

[0722] VWT038603 was treated in 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was then treated with a mixture of DOTAGA-tetra-tert-butyl ester (65 mg) and PyAOP (50 mg), HOAT (15 mg), and DIPEA (25 mg) in DMF (1 mL) for 5 hours. The resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT038604.

[0723] VWT038604 was then treated in 95% TFA / 5% H2O lysis solution (2.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 100 mg of a white solid crude product of VWT038600, which was then purified by preparative HPLC to obtain 24.8 mg of the target product VWT038600 with a purity of 95.25%; LCMS: [M+H] + =1574.10.

[0724] Embodiment 26

[0725] Preparation of compound VWT038700

[0726] Step 1 (Preparation of VWT024001)

[0727] VWT024001 was prepared in the same manner as in Example 8.

[0728] Step 2 (Preparation of VWT038702)

[0729]

[0730] The VWT024001 resin was washed twice with DMF (5 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and then the resin was washed with DMF (40 mL). Then, the resin was treated with a mixture of Fmoc-Glu(OtBu)-OH (520 mg) and PyAOP (630 mg), HOAT (140 mg), and DIPEA (310 mg) in DMF (5 mL) for 3 hours, and the resin was washed with DMF (30 mL) to obtain the compound VWT038701.

[0731] The VWT038701 resin was treated in 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of Fmoc-D-phenylalanine (150 mg), DIC (160 mg) and ethyl 2-oximecyanoacetate (170 mg) in DMF (5 mL) for 2 hours, and the resin was washed with DMF (30 mL) to obtain VWT038702.

[0732] Step 3 (Preparation of VWT038700)

[0733]

[0734] The VWT038702 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (2 mL), and then treated in 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 ml), and treated with a mixture of Fmoc-D-Tyr(tBu)-OH (140 mg) and DIC (38 mg) and ethyl 2-oximecyanoacetate (43 mg) in DMF (3 ml) for 4 hours. The resin was washed with DMF (18 mL) to obtain VWT038703.

[0735] VWT038703 was treated in 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was then treated with a mixture of DOTA(tBu)3 (105 mg) and PyAOP (94 mg), HOAT (25 mg), and DIPEA (60 mg) in DMF (1 mL) for 5 hours. The resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT038704.

[0736] Then VWT038704 was treated in 95% TFA / 5% H2O lysis solution (2.5 mL) for 4.5 hours, methyl tert-butyl ether was crystallized, and centrifuged and dried to obtain 138 mg of crude white solid VWT038700, which was then purified by preparative HPLC to obtain 21 mg of the target product VWT038700 with a purity of 95.69%; LCMS: [M+H] + =1501.70.

[0737] Embodiment 27

[0738] Preparation of compound VWT039500

[0739] Step 1 (Preparation of VWT024001)

[0740] VWT024001 was prepared in the same manner as in Example 8.

[0741] Step 2 (Preparation of VWT039502)

[0742]

[0743] The VWT024001 resin was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (30 mL); Fmoc-alanine (300 mg) was coupled with the DIC (140 mg) / ethyl 2-oximecyanoacetate (150 mg) condensation system in the order of the sequence; the resin was then washed with DMF (30 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (30 mL), and then coupled with Fmoc-D-phenylalanine under the action of DIC (115 mg) / ethyl 2-oximecyanoacetate (130 mg) condensation system for 3 hours, and the resin was washed with DMF (30 mL) to obtain the intermediate resin VWT039502.

[0744] Step 3 (Preparation of VWT039500)

[0745]

[0746] The resin VWT039502 was treated in 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (18 mL). Fmoc-D-3-iodotyrosine (65 mg) was coupled with the PyAOP (65 mg) / HOAT (20 mg) / DIPEA (20 mg) condensation system in the order of the sequence, and the reaction was carried out for 8 hours, and the resin was washed with DMF (12 mL); then, the Fmoc protecting group was removed by treating in 20% piperidine / DMF (2 mL) for 30 minutes, and the resin was washed with DMF (18 mL). Then, a mixture of DOTA(tBu)3 (110 mg) and PyAOP (95 mg), HOAT (30 mg), and DIPEA (50 mg) in DMF (1 mL) was treated for 8 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT039504.

[0747] Then VWT039504 was treated in 95% TFA / 5% H2O lysis solution (3.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged and dried to obtain 160 mg of a crude white solid of VWT039500, which was then purified by preparative HPLC to obtain 7 mg of the target product VWT039500 with a purity of 96.07%; LCMS: [M+H] + =1569.60.

[0748] Embodiment 28

[0749] Preparation of compound VWT039600

[0750] Step 1 (Preparation of VWT024001)

[0751] VWT024001 was prepared in the same manner as in Example 8.

[0752] Step 2 (Preparation of VWT039602)

[0753]

[0754] The VWT024001 resin was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (30 mL); Fmoc-alanine (300 mg) was coupled in sequence according to the amino acid sequence in the sequence under the action of DIC (140 mg) / ethyl 2-oximecyanoacetate (150 mg) condensation system; the resin was then washed with DMF (30 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (30 mL), and coupled with Fmoc-D-phenylalanine under the action of DIC (115 mg) / ethyl 2-oximecyanoacetate (130 mg) condensation system for 3 hours, and the resin was washed with DMF (30 mL) to obtain VWT039602.

[0755] Step 3 (Preparation of VWT039600)

[0756]

[0757] The resin VWT039602 was treated in 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of DOTA(tBu)3 (105 mg) and PyAOP (95 mg), HOAT (30 mg), and DIPEA (45 mg) in DMF (1 mL) for 8 hours. The resin was washed with DMF (30 mL) to obtain the fully protected peptide resin VWT039603.

[0758] VWT039603 was then treated in 95% TFA / 5% H2O lysis solution (3.5 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged and dried to obtain 135 mg of a white solid crude product of VWT039600, which was then purified by preparative HPLC to obtain 6.6 mg of the target product VWT039600 with a purity of 92.13%.

[0759] Embodiment 29

[0760] Preparation of compound VWT039700

[0761] Step 1 (Preparation of VWT024001)

[0762] VWT024001 was prepared in the same manner as in Example 8.

[0763] Step 2 (Preparation of VWT039702)

[0764]

[0765] The VWT024001 resin was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fomc protecting group, and then washed with DMF (30 mL); Fmoc-alanine (300 mg) was coupled in sequence according to the amino acid sequence under the action of DIC (140 mg) / ethyl 2-oximecyanoacetate (150 mg) condensation system, and then the resin was washed with DMF (30 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fomc protecting group, and the resin was washed with DMF (30 mL), and Fmoc-D-phenylalanine was coupled under the action of DIC (115 mg) / ethyl 2-oximecyanoacetate (130 mg) condensation system for 3 hours, and the resin was washed with DMF (30 mL) to obtain VWT039702.

[0766] Step 3 (Preparation of VWT039700)

[0767]

[0768] The resin VWT039702 was treated in 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (18 mL). Fmoc-D-3-iodotyrosine (64 mg) was coupled in the order of amino acids in the sequence under the action of PyAOP (63 mg) / DIPEA (45 mg) condensation system and reacted for 8 hours. The resin was then washed with DMF (12 mL), treated in 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group, and the resin was washed with DMF (18 mL). Then, a mixture of DOTAGA-tetra-tert-butyl ester (65 mg) and PyAOP (50 mg), HOAT (15 mg), and DIPEA (25 mg) in DMF (1 mL) was treated for 8 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT039704.

[0769] VWT039704 was then treated in 95% TFA / 5% H2O lysis solution (3.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged and dried to obtain 149 mg of a white solid crude product of VWT039700, which was then purified by preparative HPLC to obtain 8.6 mg of the target product VWT039700 with a purity of 94.89%.

[0770] Embodiment 30

[0771] Preparation of compound VWT026000

[0772] Step 1 (Preparation of VWT024001)

[0773] VWT024001 was prepared in the same manner as in Example 8.

[0774] Step 2 (Preparation of VWT026001)

[0775] (2-1) Synthesis of Compound 3

[0776]

[0777] Compound 1 (tert-butyl 15-bromopentadecanoate: 1 g, 2.6 mmol, 1.0 eq) and compound 2 (L-alanine benzyl ester: 0.93 g, 5.2 mmol, 2.0 eq) were added to DMF (20 mL), and sodium carbonate (0.83 g, 7.8 mmol, 3.0 eq) was added, and the mixture was reacted at 50° C. for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate=5 / 1) to obtain compound 3 (tert-butyl (S)-15-((1-(benzyloxy)-1-oxopropane-2-yl)amino)pentadecanoate: 0.65 g, 54%), which was a colorless liquid.

[0778] (2-2) Synthesis of Compound 4

[0779]

[0780] Compound 3 (650 mg, 1.4 mmol, 1.0 eq) was dissolved in methanol (20 mL), palladium carbon catalyst (100 mg) was added, and hydrogen was passed through at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated to obtain compound 4 ((15-(tert-butoxy)-15-oxopentadecyl)-L-alanine: 450 mg, 85%) as a colorless liquid.

[0781] (2-3) Synthesis of Compound VWT026001

[0782]

[0783] Compound 4 (400 mg, 1.0 mmol, 1.0 eq) and Fmoc-OSu (524 mg, 1.6 mmol, 1.5 eq) were dissolved in tetrahydrofuran, triethylamine (314 mg, 3.1 mmol, 3.0 eq) was added, and the mixture was reacted at 24°C for 3 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was purified by C18 reverse phase silica gel column chromatography to obtain compound VWT026001 (N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-(15-(tert-butyloxy)-15-oxopentadecyl)-L-alanine: 146.3 mg, 23%) as a white solid.

[0784] Step 3 (Synthesis of VWT026002)

[0785]

[0786] The VWT024001 resin was swelled in DMF (2 mL) for 30 minutes, then washed with DMF (2 mL), and then treated with 20% piperidine / DMF (2 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (16 mL), and then treated with a mixture of VWT026001 (97 mg) and DIC (22 mg) and ethyl 2-oximecyanoacetate (25 mg) in DMF (0.5 mL) for 4 hours. The resin was washed with DMF (12 mL) to obtain compound VWT026002.

[0787] Step 4 (Synthesis of VWT026000)

[0788]

[0789] VWT026002 resin was coupled with compound DOTA(tBu)3(229mg) in DIC(50mg) / ethyl 2-oxime cyanoacetate(57mg) condensation system. After 7 hours of reaction, the resin was washed with DMF(12mL) to obtain VWT026003. VWT026003 was then treated in 95% TFA / 5% H2O lysis solution (3mL) for 6h, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT026000, which was then purified by preparative HPLC to obtain 10mg of the target product VWT026000 with a purity of 97.39%; LCMS: [M+H] + =1373.80.

[0790] Embodiment 31

[0791] Preparation of compound VWT035700

[0792] Step 1 (Preparation of VWT024001)

[0793] VWT024001 was prepared in the same manner as in Example 8.

[0794] Step 2 (Preparation of VWT035701)

[0795] (2-1) Synthesis of Compound 6

[0796]

[0797] Compound 11 (methyl carbamate: 3.0 g) and oxalyl chloride (7.6 g) were added to a chloroform (30 mL) solution at room temperature and reacted at 50° C. for 16 hours. The reaction solution was filtered and washed with dichloromethane, and the filtrate was concentrated to obtain compound 6 (methyl isocyanate: 2.0 g) as a white solid.

[0798] (2-2) Synthesis of Compound 2

[0799]

[0800] CDI (N,N'-carbonyldiimidazole: 1.78 g) was added to a dichloromethane (50 mL) solution of compound 1 ((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid: 2.89 g), and the mixture was reacted at room temperature for 1 hour, and then N,O-dimethylhydroxylamine (974 mg) was added and the mixture was continued to react at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, and then the mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 2 (tert-butyl N2-(tert-butoxycarbonyl)-N4-methoxy-N4-methyl-L-asparagine: 2.9 g), which was a colorless liquid.

[0801] (2-3) Synthesis of Compound 3

[0802]

[0803] DIBAL-H (diisobutylaluminum hydride: 11.4 mL) was added to a tetrahydrofuran (50 mL) solution of compound 2 (1.9 g) at -78°C, and the mixture was reacted at -78°C for 5 hours. The reaction solution was quenched with sodium bisulfate solution, extracted with ethyl acetate, and the combined organic phase was washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 3 (tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate: 1.5 g) as a colorless liquid.

[0804] (2-4) Synthesis of Compound 4

[0805]

[0806] Compound 3 (1.5 g), o-benzylhydroxylamine (676 mg) and acetic acid (0.1 mL) were added to methanol (20 mL) and reacted at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 10 / 1) to obtain compound 4 (tert-butyl (S, E)-4-((benzyloxy)imino)-2-((tert-butoxycarbonyl)amino)butanoate: 1.5 g), which was a colorless liquid.

[0807] (2-5) Synthesis of Compound 5

[0808]

[0809] Sodium cyanoborohydride (498 mg) was added to a solution of compound 4 (1.5 g) in acetic acid (20 mL) and reacted at room temperature for 5 hours. Water was added to the reaction solution, and the pH value of the reaction solution was adjusted to neutral with sodium hydroxide, and then extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 3 / 1) to obtain compound 5 ((S)-4-((benzyloxy)amino)-2-((tert-butoxycarbonyl)amino)butyric acid tert-butyl ester: 1.35 g) as a colorless liquid.

[0810] (2-6) Synthesis of Compound 7

[0811]

[0812] Compound 6 (531 mg) was added to a tetrahydrofuran (20 mL) solution of compound 5 (1.0 g) and reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by silica gel column chromatography (volume ratio: petroleum ether / ethyl acetate = 1 / 1) to obtain compound 7 ((S)-4-(1-(benzyloxy)-3-(methoxycarbonyl)ureido)-2-((tert-butoxycarbonyl)amino)butyric acid tert-butyl ester: 900 mg) as a colorless liquid.

[0813] (2-7) Synthesis of Compound 8

[0814]

[0815] Pd / C (100 mg) was added to a methanol (20 mL) solution of compound 7 (900 mg), and hydrogen was passed through the mixture at room temperature for 8 hours. The solid was filtered and the filtrate was concentrated to obtain compound 8 (tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(1-hydroxy-3-(methoxycarbonyl)ureido)butanoate: 688 mg) as a white solid.

[0816] (2-8) Synthesis of Compound 9

[0817]

[0818] Sodium hydroxide (1 mL) was added to a solution of compound 8 (680 mg) in dioxane (10 mL), and the mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to remove dioxane, and the pH value of the residue was adjusted to 5 with 1N hydrochloric acid, and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 9 ((S)-2-((tert-butoxycarbonyl)amino)-4-(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)butyric acid tert-butyl ester: 588 mg), which was a colorless liquid.

[0819] (2-9) Synthesis of Compound 10

[0820]

[0821] Trifluoroacetic acid (1 mL) was added to a solution of compound 9 (588 mg) in dichloromethane (5 mL) and reacted at room temperature for 5 hours. The reaction solution was concentrated to obtain compound 10 ((S)-2-amino-4-(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)butanoic acid: 332 mg) as a colorless liquid.

[0822] (2-10) Synthesis of Compound VWT035701

[0823]

[0824] Fmoc-OSu (826.9 mg) and triethylamine (826.8 mg) were added to a tetrahydrofuran (10 mL) solution of compound 10 (332 mg) and reacted at room temperature for 16 hours. The reaction solution was concentrated and purified using a C18 reverse phase column to obtain compound VWT035701 ((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(3,5-dioxo-1,2,4-oxadiazolidine-2-yl)butanoic acid: 263.8 mg) as a white solid.

[0825] Step 3 (Preparation of VWT035702)

[0826]

[0827] The VWT024001 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and the resin was washed with DMF (16 mL). VWT035701 (52 mg), DIC (16 mg), and ethyl 2-oximecyanoacetate (20 mg) were reacted in DMF (3 mL) for 8 hours, and the resin was washed with DMF (12 mL) to obtain compound VWT035702.

[0828] Step 4 (Preparation of compound VWT035700)

[0829]

[0830] VWT035702 resin was coupled with compound DOTA(tBu)3(229mg) in the condensation system of DIC(27mg) and ethyl 2-oxime cyanoacetate(35mg). After 3 hours of reaction, the resin was washed with DMF(12mL) to obtain fully protected peptide resin VWT035703. Then VWT035703 was treated in 95% TFA / 5% H2O lysis solution (2mL) for 6 hours, crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT035700, which was then purified by preparative HPLC to obtain 16mg of the target product VWT035700 with a purity of 93.87%; LCMS: [M+H] + =1247.60.

[0831] Embodiment 32

[0832] Preparation of compound VWT037200

[0833] Step 1 (Preparation of VWT024001)

[0834] VWT024001 was prepared in the same manner as in Example 8.

[0835] Step 2 (Preparation of VWT037202)

[0836]

[0837] The VWT024001 resin was washed with DMF (5 mL), then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL). Then, Fmoc-Glu(OtBu)-OH (855 mg) and DIC (260 mg) and ethyl 2-oximecyanoacetate (290 mg) were reacted in DMF (3 mL) for 3 hours, and the resin was washed with DMF (30 mL) to obtain compound VWT037201.

[0838] The VWT037201 resin was swollen in DMF (5 mL) for 30 minutes, and then washed with DMF (5 mL). The Fmoc protecting group was removed by treating with 20% piperidine / DMF (5 mL) for 30 minutes, and the resin was washed with DMF (40 mL). Then, Fmoc-D-Phe-OH (CAS No.: 86123-10-6; 120 mg) and DIC (125 mg), ethyl 2-oxime cyanoacetate (150 mg) were reacted in DMF (3 mL) for 6 hours, and the resin was washed with DMF (30 mL) to obtain VWT037202.

[0839] Step 3 (Preparation of compound VWT037200)

[0840]

[0841] The VWT037202 resin was swollen in DMF (2 mL) for 30 minutes, and then washed with DMF (2 mL). Then, the Fmoc protecting group was removed by treating with 20% piperidine / DMF (2 mL) for 30 minutes, and then the resin was washed with DMF (16 mL). Then, DOTA(tBu)3 (170 mg) and PyAOP (158 mg), HOAT (43 mg), and DIPEA (77 mg) were reacted in DMF (3 mL) for 6 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT037203. Then, VWT037203 was treated in 95% TFA / 5% H2O lysis solution (3 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 96 mg of crude VWT037200, which was then purified by preparative HPLC to obtain 30 mg of the target product VWT037200 with a purity of 96.37%; LCMS: [M+H] + =1338.70.

[0842] Embodiment 33

[0843] Preparation of compound VWT037400

[0844] Step 1 (Preparation of VWT024001)

[0845] VWT024001 was prepared in the same manner as in Example 8.

[0846] Step 2 (Preparation of VWT037402)

[0847]

[0848] The VWT024001 resin was washed with DMF (5 mL), then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL), and then treated with a mixture of Fmoc-Glu(OtBu)-OH (259 mg) and PyAOP (310 mg), HOAT (70 mg), and DIPEA (150 mg) in DMF (1 mL) for 3 hours. The resin was washed with DMF (12 mL) to obtain compound VWT037401.

[0849] The VWT037401 resin was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of Fmoc-D-Phe-OH (36 mg), DIC (38 mg) and ethyl 2-oximecyanoacetate (45 mg) in DMF (1.5 mL) for 2 hours, and the resin was washed with DMF (12 mL) to obtain VWT037402.

[0850] Step 3 (Preparation of VWT037404)

[0851]

[0852] The VWT037402 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (10 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL) and treated with a mixture of Fmoc-D-3-iodotyrosine (70 mg) and DIC (18 mg) and ethyl 2-oximecyanoacetate (20 mg) in DMF (3 mL) for 3 hours. The resin was washed with DMF (18 mL) to obtain VWT037403.

[0853] The resin VWT037403 was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). It was then treated with a mixture of N-(9-fluorenylmethoxycarbonyl)-D-glutamic acid-1-tert-butyl ester (Fmoc-Glu-OtBu, 256 mg) and PyAOP (315 mg), HOAT (70 mg), and DIPEA (160 mg) in DMF (3 mL) for 4 hours, and the resin was washed with DMF (18 mL) to obtain VWT037404.

[0854] Step 4 (Preparation of DOTA(tBu)3-NHS)

[0855]

[0856] 5.00 g of DOTA(tBu)3 was added to 500 mL of dichloromethane (DCM) and stirred to dissolve. 5.00 g of HOSU and 8.35 g of EDCI were added at room temperature and stirred continuously for 3 hours. After the reaction was complete, the product was washed three times with saturated brine. The organic phases were combined after separation and concentrated and distilled to obtain 7.14 g of DOTA(tBu)3-NHS.

[0857] Step 5 (Preparation of VWT037400)

[0858]

[0859] The resin VWT037404 was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL), and then treated with a mixture of DOTA (tBu) 3-NHS (80 mg) and DIPEA (35 mg) in DMF (1 mL) for 5 hours, and the resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT037405. Then VWT037405 was treated in 95% TFA / 5% H2O lysis solution (3 mL) for 4.5 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 122 mg of crude VWT037400, which was then purified by preparative HPLC to obtain 14.5 mg of the target product VWT037400 with a purity of 95.45%; LCMS: [M+H] + =1757.50.

[0860] Embodiment 34

[0861] Preparation of compound VWT038300

[0862] Step 1 (Preparation of VWT024001)

[0863] VWT024001 was prepared in the same manner as in Example 8.

[0864] Step 2 (Preparation of VWT038302)

[0865]

[0866] The VWT024001 resin was washed with DMF (5 mL), then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (40 mL), and then treated with a mixture of Fmoc-D-Pro-OH (140 mg) and PyAOP (230 mg), HOAT (65 mg), and DIPEA (115 mg) in DMF (1 mL) for 3 hours. The resin was washed with DMF (12 mL) to obtain compound VWT038301.

[0867] VWT038301 was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of Fmoc-D-Phe-OH (36 mg), DIC (38 mg) and ethyl 2-oximecyanoacetate (45 mg) in DMF (5 mL) for 3 hours, and the resin was washed with DMF (10 mL) to obtain VWT038302.

[0868] Step 3 (Preparation of VWT038300)

[0869]

[0870] The VWT038302 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (10 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL), and treated with a mixture of Fmoc-D-Tyr(tBu)-OH (136 mg) and DIC (40 mg) and ethyl 2-oximecyanate (50 mg) in DMF (3 mL) for 3 hours. The resin was washed with DMF (18 mL) to obtain VWT038303.

[0871] VWT038303 was treated in 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then treated with a mixture of DOTA(tBu)3 (110 mg) and PyAOP (94 mg), HOAT (25 mg), and DIPEA (60 mg) in DMF (1 mL) for 4 hours. The resin was washed with DMF (12 mL) to obtain the fully protected peptide resin VWT038304.

[0872] Then VWT038304 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 5 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 124 mg of crude VWT038300, which was then purified by preparative HPLC to obtain 5.43 mg of the target product VWT038300 with a purity of 99.46%; LCMS: [M+H] + =1469.70.

[0873] Embodiment 35

[0874] Preparation of compound VWT038400

[0875] Step 1 (Preparation of VWT038402)

[0876] VWT038402 is the same as VWT038302. VWT038402 was prepared according to the same method as Example 34.

[0877] Step 2 (Preparation of VWT038400)

[0878]

[0879] The VWT038402 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (10 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL), and treated with a mixture of DOTA(tBu)3 (105 mg) and DIC (26 mg) and ethyl 2-oximecyanoacetate (30 mg) in DMF (3 mL) for 3 hours. The resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT038403.

[0880] Then VWT038403 was treated in 95% TFA / 5% H2O lysis solution (2.5 mL) for 6 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 70 mg of crude VWT038400, which was then purified by preparative HPLC to obtain 0.5 mg of the target product VWT038400 with a purity of 95.23%; LCMS: [M+H] + =1306.60.

[0881] Embodiment 36

[0882] Preparation of compound VWT038500

[0883] Step 1 (Preparation of VWT038502)

[0884] VWT038502 is the same as VWT037202.

[0885] Step 2 (Preparation of VWT038500)

[0886]

[0887] The VWT038502 resin was swelled in DMF (5 mL) for 30 minutes, washed with DMF (2 mL), and then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (40 mL). Fmoc-D-3-iodotyrosine (65 mg) and DIC (16 mg) and ethyl 2-oximecyanoacetate (20 mg) were then reacted in DMF (3 mL) for 4 hours. The resin was washed with DMF (18 mL) to obtain VWT038503.

[0888] VWT038503 was treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL). Then, DOTAGA-tetra-tert-butyl ester (65 mg) and PyAOP (50 mg), HOAT (15 mg), and DIPEA (25 mg) were reacted in DMF (1 mL) for 5 hours, and the resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT038504.

[0889] Then VWT038504 was treated in 95% TFA / 5% H2O lysis solution (2.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 109 mg of crude VWT038500, which was then purified by preparative HPLC to obtain 14.5 mg of the target product VWT038500 with a purity of 94.91%; LCMS: [M+H] + =1699.50.

[0890] Embodiment 37

[0891] Preparation of compound VWT039800

[0892] Step 1 (Preparation of VWT039803)

[0893]

[0894] The VWT039802 resin was treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (40 mL). It was then reacted with Fmoc-D-Phe-OH (72 mg) and DIC (75 mg) and ethyl 2-oximecyanoacetate (88 mg) in DMF (1 mL) for 2 hours, and the resin was washed with DMF (12 mL) to obtain VWT039803.

[0895] Step 2 (Preparation of VWT039800)

[0896]

[0897] The VWT039803 resin was swelled in DMF (5 mL) for 30 minutes, then washed with DMF (2 mL), and then treated with 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (40 mL), and Fmoc-D-Tyr(tBu)-OH (140 mg) and DIC (40 mg) and ethyl 2-oximecyanate (45 mg) were reacted in DMF (3 mL) for 4 hours. The resin was washed with DMF (18 mL) to obtain VWT039804.

[0898] VWT039804 was treated in 20% piperidine / DMF (3 mL) for 30 minutes to remove the Fmoc protecting group, and then the resin was washed with DMF (24 mL), and then DOTA (tBu) 3 (105 mg) and DIC (25 mg) and ethyl 2-oxime cyanoacetate (30 mg) were reacted in DMF (3 mL) for 6 hours, and the resin was washed with DMF (18 mL) to obtain the fully protected peptide resin VWT039805. Then VWT039805 was treated in 95% TFA / 5% H2O lysis solution (2 mL) for 6 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 107 mg of crude VWT039800, which was then purified by preparative HPLC to obtain 49.2 mg of the target product VWT039800 with a purity of 95.97%; LCMS: [M+H] + =1631.70.

[0899] Embodiment 38

[0900] Preparation of compound VWT043300

[0901] Step 1 (Preparation of VWT043304)

[0902]

[0903] VWT043302 was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (30 mL) and coupled with a second Fmoc-alanine (310 mg) under the action of a DIC (125 mg) / ethyl 2-oximecyanoacetate (145 mg) condensation system; the resin was then washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (30 mL), and coupled with DOTA(tBu)3 (290 mg) under the action of a DIC (64 mg) / ethyl 2-oximecyanoacetate (145 mg) condensation system for 5 hours. The resin was washed with DMF (30 mL) to obtain the fully protected resin VWT043304.

[0904] Step 2 (Preparation of VWT043300)

[0905]

[0906] VWT043304 was treated in 95% TFA / 5% H2O lysis solution (3 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to obtain 117 mg of crude VWT043300, which was then purified by preparative HPLC to obtain 23.7 mg of the target product VWT043300 with a purity of 97.14%; LCMS: [M+H]+ =1204.50.

[0907] Embodiment 39

[0908] Preparation of compound VWT043400

[0909] Step 1 (Preparation of VWT043404)

[0910]

[0911] The VWT043403 resin was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (30 mL), and coupled with the third Fmoc-alanine (310 mg) under the action of DIC (125 mg) / ethyl 2-oximecyanoacetate (145 mg) condensation system. The reaction was carried out for 3 hours, and the resin was washed with DMF (30 mL) to obtain VWT043404.

[0912] Step 2 (Preparation of VWT043400)

[0913]

[0914] The VWT043404 resin was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with 30 mL DMF. DOTA(tBu)3 (290 mg) was coupled with DIC (64 mg) / ethyl 2-oxime cyanoacetate (145 mg) condensation system for 5 hours, and the resin was washed with DMF (30 mL) to obtain the fully protected resin VWT043405. VWT043405 was treated in 95% TFA / 5% H2O lysis solution (2.5 mL) for 4 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 121 mg of crude VWT043400, which was then purified by preparative HPLC to obtain 13 mg of the target product VWT043400 with a purity of 95.83%; LCMS: [M+H] + =1275.60.

[0915] Embodiment 40

[0916] Preparation of compound VWT043500

[0917] Step 1 (Preparation of VWT043504)

[0918]

[0919] The VWT043502 resin was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (30 mL) and coupled with Fmoc-L-Phe-OH (388 mg) under the action of DIC (125 mg) / ethyl 2-cyanoacetate (145 mg) condensation system to obtain VWT043503.

[0920] The VWT043503 resin was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group. The resin was washed with DMF (30 mL), and coupled with Fmoc-alanine (315 mg) under the action of DIC (125 mg) / ethyl 2-oximecyanoacetate (145 mg) condensation system for 3 hours. The resin was washed with DMF (30 mL) to obtain VWT043504.

[0921] Step 2 (Preparation of VWT043500)

[0922]

[0923] The VWT043504 resin was washed with DMF (18 mL), and then treated with 20% piperidine / DMF (5 mL) for 30 minutes to remove the Fmoc protecting group, and then washed with DMF (30 mL). DOTA (tBu) 3 (290 mg) was coupled with DIC (64 mg) / ethyl 2-oxime cyanoacetate (145 mg) condensation system for 5 hours, and the resin was washed with DMF (30 mL) to obtain the fully protected resin VWT043505. VWT043505 was treated in 95% TFA / 5% H2O lysis solution (3 mL) for 3 hours, crystallized with methyl tert-butyl ether, and centrifuged to dry to obtain 127 mg of crude VWT043500, which was then purified by preparative HPLC to obtain 19.3 mg of the target product VWT043500 with a purity of 98.41%; LCMS: [M+H] + =1351.60.

[0924] Embodiment 41

[0925] Preparation of compound VWT043600

[0926] It should be noted that the difference between compounds VWT043600 and VWT043500 is only the different configuration of phenylalanine.

[0927]

[0928] According to the method similar to VWT043500 (the difference is that the coupling raw material is Fmoc-D-Phe-OH), 21.2 mg of the target product VWT043600 with a purity of 94.33% was prepared; LCMS: [M+H] + =1351.70.

[0929] Experimental Example 1: Biodistribution Study

[0930] 1. Materials and Methods

[0931] 1.1 Test instruments and reagents

[0932] Radioactivity meter (CRC-55tR, Capintec, USA); constant temperature mixer (TS100, Thermo); electronic balance (ME104E, Mettler-Toledo Instruments (Shanghai) Co., Ltd.); electronic balance (BT457A10, Shenzhen Botu Electronic Technology Co., Ltd.); small animal SPECT-CT imaging system (U-SPECT+ / CT, MI Labs); sodium acetate (250 g / bottle, SIGMA); 177 LuCl3 (100 mCi, China Tongfu Pharmaceutical Co., Ltd.); normal saline (250 mL / bag, Sichuan Kelun Pharmaceutical Co., Ltd.).

[0933] 1.2 Tumor mouse model

[0934] The mice were LnCap mice, obtained from Shanghai Model Organisms Science Co., Ltd., 6-8 weeks old, female. The mouse strain was M-NSG nude mice. 7 (10 to the power of 7) LnCaP cells (0.1 mL (PBS:Matrigel = 1:1)) were subcutaneously inoculated into the right dorsal flank of each mouse. When the average tumor volume reached 200-400 mm 3 The specific breeding conditions of the above mice are shown in Table 1.

[0935] Table 1. Environmental conditions of the experimental animal breeding room

[0936]

[0937]

[0938] 2. Biodistribution research experiments

[0939] 2.1. Preparation of test injection solution,

[0940] The properties of the tested compounds are shown in Table 2.

[0941] Table 2. Test compounds

[0942] Serial number Compound Shape and physical and chemical properties Molecular weight Storage conditions 1 VWT019000 solid 1146.7 -20℃ 2 VWT019300 solid 1196.8 -20℃ 3 VWT011600 solid 1133.2 -20℃ 4 VWT022600 solid 1212.7 -20℃ 5 VWT024000 solid 1190.9 -20℃ 6 VWT024100 solid 1204.9 -20℃ 7 VWT021400 solid 1118.9 -20℃ 8 VWT023800 solid 1160.7 -20℃ 9 VWT023900 solid 1319.7 -20℃ 10 VWT022100 solid 1148.8 -20℃ 11 VWT001500 solid 1041.9 -20℃

[0943] Among them, VWT001500 is a known compound (i.e., PSMA-617), and its structural formula is as follows:

[0944]

[0945] Prepare a precursor solution with a concentration of 1 μmol / mL (1 nM) using physiological saline and the test compounds shown in Table 2. The initial volume is 200 μL. Take 100 μL of the precursor solution and dilute it in 900 μL of acetic acid solution (pH = 4.5, 0.4 mol / L). Take 10 μL or 20 μL of the diluted solution and add 177 LuCl3 solution, and add 40 μL of acetic acid solution (pH=4.5, 0.4 mol / L). The above solution was heated at 95°C for 30 min. After the reaction was completed, the final solution was cooled to room temperature.

[0946] After preparation, the radioactive compound was identified for purity using chromatography paper (Xinhua No. 1 paper), and the developing solvent used in the identification was 1% EDTA.

[0947] 2.2 Drug administration and testing

[0948] The drug solution prepared above was injected into LnCap tumor-bearing mice: the drug concentration (dose) was 1 nmol / 200 μCi / 0.2 mL; tail vein injection (consistent with the intended clinical administration); single administration; and biodistribution study was performed.

[0949] SPECT / CT scans were performed using a small animal SPECT-CT imaging system (U-SPECT+ / CT, MI Labs), with data acquisition using static SPECT for 10 min followed by a low-resolution whole-body CT scan.

[0950] Mice were killed by cervical dislocation 4h and 24h after administration. Animal weight, injection dose, injection time, residual dose were recorded, and the injection dose measurement time and residual dose measurement time were recorded respectively. Tissue samples were collected by dissection to obtain heart, liver, spleen, lung, kidney and tumor. First, the net weight of the tissue was weighed, and then the radioactivity of the tissue was counted to determine the distribution of radioisotope labels in different tissues and organs of the mouse. In addition, the test sample was diluted 100 times, and 0.1mL was taken in a counting tube as a standard 1%ID (i.e., one percent of the dose), and the radioactivity counts of the 1%ID standard and the biological samples taken were measured on a γ-counter to determine the biodistribution of the drug in mice.

[0951] 3. Results Analysis

[0952] 3.1 Labeling efficiency

[0953] The labeling efficiency of each tested compound was greater than 95%, indicating that the compound did not need to be purified.

[0954] 3.2 Biological distribution

[0955] The tissue distribution of each drug is observed by SPECT / CT, and the tissue distribution is visualized and quantified. The data of biological tissue distribution is expressed as the percentage of radioactive count per gram of tissue or organ to the total dose (radioactive count) (%ID / g).

[0956] Visualization of compound VWT011600 after administration, such as Figure 1 The results of the quantitative processing are shown in Table 3, where T / K refers to the ratio of tumor uptake to kidney uptake.

[0957] Table 3. Biodistribution of drugs in prostate tumor-bearing mice

[0958] ID% / g(4h) Heart liver spleen lung kidney tumor T / K VWT019000 0.06 0.10 0.10 0.08 1.27 4.78 3.76 VWT019300 0.14 0.19 0.14 0.26 3.28 1.03 0.32 VWT011600 0.15 0.17 0.28 0.06 1.34 6.68 4.98 VWT022600 0.12 0.11 0.19 0.17 1.86 / / VWT024000 0.04 0.03 0.65 0.04 1.35 16.88 12.51 VWT024100 0.04 0.07 0.35 0.16 1.02 5.83 5.69 VWT021400 0.04 0.05 0.17 0.05 0.62 5.40 8.75 VWT023800 0.05 0.13 0.05 0.24 0.48 0.26 0.55 VWT023900 0.09 0.04 1.30 0.05 2.37 18.09 7.62 VWT022100 0.11 0.08 0.59 0.15 1.23 10.40 8.44 ID% / g(24h) Heart liver spleen lung kidney tumor T / K VWT019000 0.02 0.06 0.05 0.03 0.62 2.94 4.71 VWT019300 0.06 0.10 0.09 0.05 0.64 0.65 1.02 VWT011600 0.01 0.02 0.08 0.01 0.23 6.98 30.64 VWT022600 0.04 0.05 0.05 0.04 0.38 8.88 23.07 VWT024000 0.01 0.02 0.05 0.01 0.11 13.56 124.39 VWT024100 0.01 0.03 0.06 0.01 0.17 6.54 37.90 VWT021400 0.02 0.04 0.08 0.02 0.58 11.68 19.97 VWT023800 0.02 0.03 0.04 0.02 0.07 0.07 1.09 VWT023900 0.03 0.04 0.14 0.02 0.32 12.32 39.09 VWT022100 0.02 0.01 0.05 0.02 0.45 6.47 14.23 VWT001500 0.00 0.02 0.04 0.00 0.15 5.98 38.63

[0959] The results show:

[0960] Compared with the existing VWT001500 (known compound PSMA-617, marketed drug), the PSMA compound provided in the present application has higher tumor uptake and / or lower kidney uptake; wherein, higher tumor uptake means better targeting effect, and lower kidney uptake means lower nephrotoxicity of the drug; T / K (ratio of tumor uptake to kidney uptake) is an important indicator for screening drugs and / or clinical drug selection, and generally the larger the T / K value, the better.

[0961] The PSMA compound provided in the present application can greatly reduce the risk of renal injury while improving the drug targeting effect, which is conducive to better meeting the medication needs of patients. It has broad clinical promotion prospects and higher application value, especially can be applied to targeted treatment and imaging technology of prostate cancer.

[0962] Of course, the present invention may have many other embodiments. Without violating the spirit and essence of the present invention, those skilled in the art may make various corresponding changes and / or deformations based on the present invention. These corresponding changes and / or deformations should all fall within the scope of protection of the claims attached to the present invention.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt, ester or solvate thereof, in, Q is R0 is selected from carbonyl or methylene; X b A chelating agent or X c Chelating agent or X d Chelating agent or X e Chelating agent or X f Chelating agent or X g Chelating agent or X a It is a chelating agent; R a1 , R b1 , R c1 , R d1 , R e1 , R f1 and R g1 Both R y1 ; R a2 , R b2 , R c2 , R d2 , R e2 , R f2 and R g2 Both R y2 ; R a3 , R b3 , R c3 , R d3 , R e3 , R f3 and R g3 Both R y3 ; R y1 , R y2 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or -C(=S)R k ; Or, R y2 With R y1 (or R y3 ) connected to form R 环A ; R Y is selected from C1-C16 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl (including condensed ring aryl, etc.) or 5-14-membered heteroaryl (including condensed ring heteroaryl); R 环A is a 3-12 membered heterocycloalkyl or a 5-14 membered heteroaryl; R Y and R 环A Optionally substituted or unsubstituted with one or more substituents P1; The substituent P1 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ; where R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2; The substituent P2 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R X ; where R X is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R X Optionally substituted or unsubstituted with one or more substituents P3; The substituent P3 is selected from deuterium, tritium, hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R V ; where R V is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R V Optionally substituted or unsubstituted with one or more substituents P4; The substituent P4 is selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, oxo, thio, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl, sulfo-substituted C1-C6 alkyl, C1-C6 alkoxy, amino-substituted C1-C6 alkoxy, carboxyl-substituted C1-C6 alkoxy, sulfo-substituted C1-C6 alkoxy, C1-C6 alkylthioether, amino-substituted C1-C6 alkylthioether, carboxyl-substituted C1-C6 alkylthioether, sulfo-substituted C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl, or 5-14-membered heteroaryl; R k Selected from hydrogen, deuterium, tritium, halogen, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R1, R2, R3, R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, nitro, cyano, halogen, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R z Selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl; a, b, c, d, e, f, g are each independently selected from an integer of 0-6; L1 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl is optionally substituted or unsubstituted by one or more substituents P1; L2 is selected from -L3- or -NH-(CH2) t -L3-; L3 is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl; wherein the 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl, 5-14 membered heteroaryl is optionally substituted by one or more substituents P1 or unsubstituted; The heteroatoms of the 3-12-membered heterocycloalkyl group and the 5-14-membered heteroaryl group are selected from one or more of N, O and S, and the number of heteroatoms of the 3-12-membered heterocycloalkyl group and the 5-14-membered heteroaryl group is 1, 2 or 3; m, n, and t are each independently selected from integers of 0-6.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L1 is a 5-14 membered aryl or 5-14 membered heteroaryl group; wherein the 5-14 membered aryl or 5-14 membered heteroaryl group is optionally substituted by one or more substituents P 1a Substituted or unsubstituted; and the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L1 is selected from phenyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, imidazolyl, furanyl, thiazolyl, thienyl, thiopyranyl, naphthyl, benzopyrrole (including: indole, isoindol) base, benzopyridine (including: quinoline, isoquinoline) base, benzoxazolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzothiopyranyl, purinyl, anthracenyl or phenanthryl; Preferably, L1 is naphthyl, benzopyridyl or anthracenyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L2 is -L3-; and L3 is selected from 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; wherein the 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl is optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L3 is selected from 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl contains 1-4 heteroatoms N; Preferably, L3 is R 环B -R 环C , R 环B and R 环C Share a carbon atom; R 环B is selected from 3-9 membered cycloalkyl or 3-9 membered heterocycloalkyl; R 环C is selected from 3-9 membered heterocycloalkyl; wherein the heteroatom of the 3-9 membered heterocycloalkyl is selected from one or more of N, O and S, and the number of heteroatoms of the 3-9 membered heterocycloalkyl is 1, 2 or 3; preferably, R 环C Contains 1-2 heteroatoms N; R 环B and / or R 环C Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl; More preferably, R 环B is selected from cyclobutane, cyclopentane, cyclohexane or cycloheptane; and R 环C is selected from pyrrolidinyl, piperidinyl, oxazolidinyl, oxazepanyl, thiazepanyl, azepanyl, oxazepanyl or thiazepanyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L3 is selected from the following structures: and Z is O or S.

7. The compound according to claim 4 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L3 is selected from 5-14 membered heteroaryl, wherein the 5-14 membered heteroaryl contains 1-4 heteroatoms N; Preferably, L3 is R 环D -R 环E , R 环D and R 环E Share two carbon atoms; R 环D is selected from 5-6 membered aryl or 5-6 membered heteroaryl, R 环E is selected from 3-9 membered heterocycloalkyl; wherein the heteroatoms of the 5-6 membered heteroaryl and 3-9 membered heterocycloalkyl are selected from one or more of N, O and S, and the number of heteroatoms of the 3-9 membered heterocycloalkyl is 1, 2 or 3; R 环E Contains 1-2 heteroatoms N; R 环D and / or R 环E Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl; More preferably, R 环D is selected from phenyl, pyrimidinyl, pyridinyl, pyrrolyl, oxazolyl, imidazolyl, furanyl, thiazolyl, thienyl or thiopyranyl; and R 环E is selected from the group consisting of pyrrolidinyl, piperidinyl, oxazolidinyl, oxazepanyl, thiazepanyl, azepanyl, azepanyl, oxazepanyl or thiazepanyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: L3 is selected from the following structures: and Z is O or S; Preferably, L3 9. The compound according to claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The chelating agent is selected from 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA: )、2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-pentanedioic acid (DOTAGA: ), N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 2-(4,7-bis(carboxymethyl)-1,4,7-triazolidine-1-yl)pentanedioic acid (NODAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9,3,1]pentadecan-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA: ), Preferably, the chelating agent is DOTA or DOTAGA.

10. The compound according to claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: m, n and t are each independently selected from 1 or 2; R1 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; R2 and R3 are each independently selected from hydroxyl or C1-C6 alkoxy.

11. The compound according to claim 1 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The R y1 or R y3 is S configuration or R configuration; and / or, the configuration of the compound represented by formula I is:

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: X b It is a chelating agent; R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, cyano, amino, carboxyl or sulfonyl; wherein R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; R y2 is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, thiol, nitro or cyano; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring or a piperidine ring; said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl; Preferably, the compound represented by formula I is: Among them, X b is a chelating agent; R a1 and R a3 are each independently selected from hydrogen, deuterium, tritium or R Y ; R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; and R a2 is selected from hydrogen, deuterium or tritium; or, R a2 With R a1 (or R a3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring; and a is 0, 1 or 2.

13. The compound according to claim 12 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The compound represented by formula Ia is selected from:

14. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: X b It is a chelating agent; R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, cyano, amino, carboxyl or sulfonyl; R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 5-14 membered aryl or 5-14 membered heteroaryl; R y2 is a C1-C16 alkyl group which is optionally substituted or unsubstituted by one or more substituents P1; wherein the substituents P1 are selected from deuterium, tritium, amino, carboxyl, sulfo or R W ; where R W is selected from C1-C6 alkoxy or C1-C6 alkylthioether; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from -C(=O)R k 、-C(=O)OR k or R X ; where R X is selected from C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthioether; and R X Optionally substituted or unsubstituted by one or more substituents P3; the substituents P3 are selected from -C(=O)R k OR -C(=O)OR k ; where R k Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; Preferably, the compound represented by formula I is: Among them, X b is a chelating agent; R a1 and R a3 are each independently selected from hydrogen, deuterium, tritium or R Y ; R Y is selected from C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R a2 is a C1-C14 alkyl group optionally substituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, carboxyl, sulfonyl or R W ; where R W is selected from C1-C6 alkoxy; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from -C(=O)OR k or R X ; where R X is selected from C1-C6 alkoxy or C1-C6 alkylthioether; and R X Optionally substituted or unsubstituted by one or more substituents P3; the substituents P3 are selected from -C(=O)OR k ; where R k is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritated C1-C6 alkyl; and a is 0, 1 or 2.

15. The compound according to claim 14 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The compound represented by formula Ib is selected from:

16. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: X b It is a chelating agent; R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, amino, carboxyl or sulfo; wherein R Y Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl (including but not limited to oxadiazolidinyl), 5-14-membered aryl (including but not limited to phenyl) or 5-14-membered heteroaryl (including but not limited to imidazolyl, oxadiazolyl, benzopyrrolyl); R Y Optionally substituted or unsubstituted with one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ; R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2; the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, amino, carboxyl, sulfo or R X ; where R X Selected from C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylthioether; R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R z Selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl; R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A is a tetrahydropyrrole ring or a piperidine ring; and said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl; Preferably, X b is a chelating agent; R y1 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; R y3 For R Y ; where R Y is selected from C1-C6 alkyl; and R Y Optionally substituted with one or more substituents P1; R y2 (R a2 ) is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , where R 环A is a tetrahydropyrrole ring; and a is 0, 1 or 2.

17. The compound according to claim 16 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The compound shown in formula I is: Among them, X b It is a chelating agent; R a1 Selected from hydrogen, deuterium, tritium or C1-C6 alkyl; R a3 For R Y ; where R Y is selected from C1-C6 alkyl; and R Y Optionally substituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, -S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or R W ; where R W is selected from oxadiazolyl, phenyl, benzopyrrolyl; and R W Optionally substituted or unsubstituted with one or more substituents P2; wherein the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen or R X ; where R X is a C1-C6 alkyl group; R k Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; R a2 is selected from hydrogen, deuterium, tritium; or, R a2 With R a1 (or R a3 ) connected to form R 环A , where R 环A is a tetrahydropyrrole ring; and a is 0, 1 or 2; Preferably, the compound represented by formula Ic is selected from:

18. The compound according to claim 16 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: The compound shown in formula I is: in, X b It is a chelating agent; R a1 Selected from hydrogen, deuterium, tritium or C1-C6 alkyl; R a3 For R Y ; where R Y is selected from C1-C6 alkyl; and R Y Optionally substituted by one or more substituents P1; said substituents P1 are selected from -C(=O)R k 、-C(=O)OR k ; R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z OR -S(=O)(=O)OR z ; where R z Selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; R a2 is selected from hydrogen, deuterium, tritium or deuterated C1-C6 alkyl; or, R a2 With R a1 (or R a3 ) connected to form R 环A , where R 环A is a tetrahydropyrrole ring; and a is 0, 1 or 2; Preferably, the compound represented by formula Id is selected from:

19. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: X b for X c Chelating agent or X d Chelating agent or X e It is a chelating agent; R a1 , R b1 , R c1 and R d1 Both R y1 ; R a2 , R b2 , R c2 and R d2 Both R y2 ; R a3 , R b3 , R c3 and R d3 Both R y3 ; R y1 and R y3 are each independently selected from hydrogen, deuterium, tritium, R Y , hydroxyl, thiol, nitro, cyano, oxo, thio, halogen, amino, carboxyl or sulfo; wherein R Y Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl (including but not limited to oxadiazolidinyl), 5-14-membered aryl (including but not limited to phenyl) or 5-14-membered heteroaryl (including but not limited to imidazolyl, oxadiazolyl, benzopyrrolyl); R Y Optionally substituted or unsubstituted with one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, -NR i R j 、-C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k 、-C(=S)R k or R W ; R W is selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-12-membered cycloalkyl, 3-12-membered heterocycloalkyl, 5-14-membered aryl or 5-14-membered heteroaryl; and R W Optionally substituted or unsubstituted with one or more substituents P2; the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, amino, carboxyl, sulfo or R X ; where R X Selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether; R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z 、-S(=O)(=O)OR z , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, deuterated C1-C6 alkyl, tritiated C1-C6 alkyl, halogenated C1-C6 alkyl, amino-substituted C1-C6 alkyl, carboxyl-substituted C1-C6 alkyl or sulfo-substituted C1-C6 alkyl; R z Selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, tritium substituted C1-C6 alkyl or halogenated C1-C6 alkyl; R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , where R 环A is a tetrahydropyrrole ring or a piperidine ring; and said R 环A Optionally substituted by one or more substituents P 1a Substituted or unsubstituted; the substituent P 1a Selected from deuterium, tritium, halogen, hydroxyl, thiol, nitro, cyano, amino, carboxyl, sulfo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthioether, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl or tritium-substituted C1-C6 alkyl; Preferably, X b It is a chelating agent; R y1 Selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; R y3 is hydrogen, deuterium, tritium, carboxyl, sulfonyl or R Y ; R Y is selected from C1-C6 alkyl; and R Y Optionally substituted or unsubstituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen, -C(=O)R k 、-C(=O)OR k 、-S(=O)R k 、-S(=O)OR k 、-S(=O)(=O)R k 、-S(=O)(=O)OR k or R W ; where R W is selected from C1-C6 alkoxy, C1-C6 alkylthioether, phenyl, benzopyrrolyl, imidazolyl or oxadiazolyl; and R W Optionally substituted or unsubstituted with one or more substituents P2; wherein the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, cyano, oxo, thio, halogen or R X ; where R X is a C1-C6 alkyl group; R k Selected from hydrogen, deuterium, tritium, -NR i R j , C1-C6 alkyl, deuterated C1-C6 alkyl or tritiated C1-C6 alkyl; R i and R j are each independently selected from hydrogen, deuterium, tritium, hydroxyl, thiol, cyano, -S(=O)R z 、-S(=O)OR z 、-S(=O)(=O)R z OR -S(=O)(=O)OR z ; where R z is selected from hydrogen, deuterium, tritium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl or tritium substituted C1-C6 alkyl; R y2 is selected from hydrogen, deuterium, tritium, C1-C6 alkyl or deuterated C1-C6 alkyl; or, R y2 With R y1 (or R y3 ) connected to form R 环A , the R 环A It is a tetrahydropyrrole ring; a, b, c and d are each independently selected from 0, 1 or 2.

20. The compound according to claim 19 or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that: R a1 , R b1 , R c1 and R d1 Each is independently selected from hydrogen, deuterium, tritium or C1-C6 alkyl; R a3、 R b3 , R c3 and R d3 are each independently selected from hydrogen, deuterium, tritium, carboxyl, sulfonyl or R Y ; where R Y is a C1-C6 alkyl group; and R Y Optionally substituted or unsubstituted by one or more substituents P1; the substituents P1 are selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, carboxyl, sulfonyl or R W ; where R W is selected from C1-C6 alkoxy, C1-C6 alkylthioether, phenyl, benzopyrrolyl or imidazolyl; and R W Optionally substituted or unsubstituted by one or more substituents P2; the substituents P2 are selected from deuterium, tritium, hydroxyl, thiol, halogen or C1-C6 alkyl; R a2 , R b2 , R c2 and R d2 are each independently selected from hydrogen, deuterium, tritium or deuterated C1-C6 alkyl; or, R a2 With R a1 Connect to form R 环A , R b2 With R b1 Connect to form R 环A , R c2 With R c1 Connect to form R 环A , and R d2 With R d1 Connect to form R 环A , the R 环A is a tetrahydropyrrole ring; and a, b, c and d are each independently selected from 0, 1 or 2; Preferably, the compound represented by formula I is: ① Among them, X c It is a chelating agent; Further preferably, the compound represented by formula Ie is selected from: Preferably, the compound represented by formula I is: ② Among them, X d It is a chelating agent; Further preferably, the compound represented by formula If is selected from: Preferably, the compound represented by formula I is: ③ Among them, X e It is a chelating agent; Further preferably, the compound represented by formula Ig is selected from:

21. Use of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a radiolabeled complex.

22. A radiolabeled complex comprising: A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, ester or solvate thereof, and a radionuclide; Preferably, the radionuclide is selected from 94 Tc, 99m Tc, 90 In, 111 In, 67 Ga, 68 Ga, 86 Y. 90 Y. 177 Lu, 151 Tb, 186 Re, 188 Re, 64 Cu, 67 Cu, 55 Co. 57 Co. 43 Sc, 44 Sc, 47 Sc, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 227 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd, 166 Dy, 55 Fe, 18 F. 11 C. 89 Zr, 123 I. 124 I. 125 I. 131 I or 211 At; More preferably, the radionuclide is 68 Ga or 177 Lu.

23. A pharmaceutical composition comprising the radiolabeled complex of claim 22, and one or more pharmaceutically acceptable excipients, diluents or carriers.

24. Use of the radiolabeled complex of claim 22 and / or the pharmaceutical composition of claim 23 in the preparation of a medicament for diagnosing and / or treating and / or preventing tumors; preferably, the tumor is cancer; more preferably, the cancer is prostate cancer.

25. Use of the radiolabeled complex of claim 22 and / or the pharmaceutical composition of claim 23 in the preparation of a medicament for imaging in a patient; or use of the radiolabeled complex of claim 22 and / or the pharmaceutical composition of claim 23 in the preparation of a contrast agent.

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