Inhibitors of prostate specific membrane antigen and pharmaceutical uses thereof

Abstract

The present invention relates to an inhibitor of prostate specific membrane antigen and its pharmaceutical use. Specifically, the present invention relates to a compound represented by formula (IV) or a pharma- ceutical acceptable salt thereof, which belongs to the field of radiopharmaceuticals. TIFF2024532475000134.tif6867

Description

[Technical field]

[0001] The present disclosure is in the field of radiopharmaceuticals, and specifically relates to inhibitors of prostate specific membrane antigen (PSMA) and their pharmaceutical uses. [Background technology]

[0002] Prostate cancer (PCa) is currently the second most common cancer in men, second only to lung cancer in incidence and mortality, with nearly 1.6 million new cases per year worldwide. In 2018, there were 366,000 prostate cancer-related deaths, but in many developed countries, prostate cancer mortality rates are declining, mainly due to widespread use of prostate-specific antigen (PSA) blood testing. PSA is considered to revolutionize PCa screening, as it is an effective detection indicator of disease recurrence after initial treatment (e.g., radical prostatectomy (RP) or localized radiotherapy (RT)). Such a disease state, defined as biochemical recurrence (BCR), is characterized by an increase in PSA levels after initial treatment for PCa.

[0003] In recent decades, new diagnostic / prognostic tools, especially imaging tests, have been introduced in clinical practice to better assist the care of patients with prostate cancer and overcome some limitations of PSA level detection. Current clinical imaging methods include transrectal ultrasound (TRUS) for biopsy guidance and placement of brachytherapy particles, magnetic resonance imaging (MRI) and computed tomography (CT) for staging prostate cancer and detection of metastatic spread, and bone imaging for bone metastasis evaluation. These traditional imaging techniques have low sensitivity and specificity in detecting early / microrecurrence or metastasis, such as lymph node and sclerotic bone metastasis. In recent years, the use of radioactive imaging methods and radioactive drugs has played an important role in the care of genitourinary system diseases, especially PCa.

[0004] New detection methods are useful for staging and classification of the disease and are undoubtedly of great importance for monitoring recurrence and evaluating efficacy. With the continuous scientific discoveries and technological improvements, researchers have investigated new biochemical pathways and cellular structures that can be targeted for the treatment of the disease. Among them, prostate-specific membrane antigen (PMSA) is gaining importance as a specific target for the action of drugs, especially radioactive drugs.

[0005] PSMA, also called folate hydrolase I (FOLH1) or glutamate carboxypeptidase II (GCPII), is a 750 amino acid type II transmembrane glycoprotein expressed in healthy human tissues such as lacrimal and salivary glands, epididymis, ovary, normal human prostate epithelium, central nervous system (CNS), and astrocytes and Schwann cells in the small intestinal jejunal brush border. PSMA has two main enzymatic activities: hydrolytic cleavage of γ-biglutamic acid from poly-γ-glutamylfolate and proteolysis of the neuropeptide N-acetyl-L-aspartic-L-glutamic acid (NAAG). In addition to its enzymatic function, PSMA is also upregulated (1000-fold higher than physiological levels) and strongly expressed in prostate cancer cells, especially in castration-resistant and metastatic prostate cancer, and in lymph node, bone, rectal, and lung metastatic tumor tissues. The expression level of PSMA is significantly increased in the neovascularization of tumor tissue, and the expression level is significantly related to the degree of tumor differentiation, metastasis tendency, and sensitivity to hormone therapy.Research has confirmed that PSMA is highly expressed in almost all prostate cancer tissues, which makes PSMA capable of targeting the metastatic lesions of prostate cancer with high sensitivity and high specificity, and is an ideal biomarker and can be used for radionuclide targeted therapy of advanced cancer.In recent decades, the development of new radiopharmaceuticals that target PSMA mainly has two different directions:

[0006] Initially, research focused mainly on the macromolecular protein structure of PSMA, providing specific monoclonal antibodies against PSMA epitopes. The first PSMA-targeted radioactive tracer used in clinical practice was111 In]capromab pendetide, trademarked as ProstaScint TM It was approved by the FDA in 1997 as a PSMA developer. Capromab (7E11-C5) is a monoclonal antibody developed from the membranes of human prostate cancer cells LNCaP and labeled with indium-111 using diethylenetriaminepentaacetic acid (DTPA) as a chelator. Other second-generation monoclonal antibodies and antibody derivatives targeting PSMA are currently in development, of which J591 is the most widely studied to date. Such non-immunized monoclonal antibodies have high affinity for live cells expressing PSMA outside the cell membrane, overcoming the main limitations of capromab, such as the ability to effectively target PSMA only through the destruction of the cell membrane and the long retention of radioactivity in non-target organs. J591 is coupled to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to target PSMA. 111 In, 99m Tc, 89 Zr, 90 Y, 177 Lu and 225 They have been successfully labeled with radioactive metal elements such as Ac and applied to clinical practice. However, antibodies have significant limitations as a clinically routine molecular imaging tool, as they require a relatively long in vivo metabolism time (usually 3-7 days) to reduce the background of blood circulation so that a sufficient signal-to-noise ratio can be achieved, and their size also limits their tumor penetration.

[0007] Following the analysis of the crystal structure of PSMA, various PSMA inhibitors that are low molecular weight and have the potential to be used as radiopharmaceuticals have been synthesized and evaluated, based on the enzyme activity of PSMA. Compared to antibodies, low molecular weight ligands are easier to prepare on a large scale and have good pharmacokinetic properties (e.g., bioavailability, biological half-life, etc.). Among them, the glutamic acid-phosphamide series [ka] , glutamic acid-ureido derivatives [ka] are two widely studied chemical entities whose corresponding PSMA inhibitors are being investigated for nuclear medicine applications. Of these compounds, ureido derivative inhibitors are currently the most commonly used PSMA targeting molecules. In 2021, the FDA approved [ 18 The company approved [F]DCFPyL, which has a short blood retention time, high binding affinity to PSMA, and high tumor uptake. 18 [F]PSMA-1007 has good binding and internalization properties in vitro and high specific uptake in vivo. Furthermore, compared to other known PSMA ligands, PSMA-1007 has a unique biological distribution and is almost entirely excreted via the hepatobiliary route. This means that it is advantageous for identifying lymph node metastases of recurrent PCa from urinary radioactivity or local recurrence from the bladder. As a PSMA-specific tracer labeled with Ga-68, [ 68 Ga]PSMA-11([ 68 Ga]Glu-Urea-Lys(Ahx)-HBED-CC) is the most widely used and structurally consists of a urea-based pharmacophore and a 68 Ga]HBED-CC complex and can directly interact with PSMA hydrophobic binding pocket S1. 68[Ga]PSMA-11 is rapidly cleared from blood and non-target organs, has low accumulation in the liver, and has high specific uptake in PSMA-high expressing organs and tumors. In addition, Benesova et al. reported the synthesis and preclinical evaluation of a ligand for PSMA-617. PSMA-617 is a clinically integrated ligand in which the chelator DOTA is coupled to the pharmacophore Glu-Urea-Lys via a naphthalene-containing linker. Lu-177-labeled PSMA-617 has high binding affinity and internalization properties, high tumor uptake at late time points, low splenic accumulation, and high clearance efficiency from the kidney.

[0008] At present, the development of a large number of PSMA inhibitors has been reported in the literature, but prostate cancer patients still have a high need for better PSMA targeting drugs. Therefore, developing a PSMA inhibitor that is stable in vivo and has higher affinity and specificity has important scientific research value and prospects for wide application. Summary of the Invention

[0009] The present disclosure provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof: [ka] Among them, Q is selected from H or a protecting group, preferably H; R1 and R2 are each independently H or C 1-4 alkyl group, each of which is preferably H; 1-4 The alkyl group is optionally unsubstituted or substituted with one or more substituents P, Q, R1, and R2 may be the same or different each time they occur; R4 is H, C 1-6 an alkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; 1-6 the alkyl group, the 6- to 10-membered aryl group or the 5- to 12-membered heteroaryl group is optionally unsubstituted or substituted with one or more substituents P; Y1 is S or O, preferably O; A is selected from -NR4(CO)-, -NR4(SO2)-, -NR4(CH2) or is absent; The above E is a 3- to 12-membered cycloalkyl group or [ka] or absent, [ka] is a heterocyclyl group or a heteroaryl group containing one or more N atoms, in which the above 3- to 12-membered cycloalkyl group, heterocyclyl group, and heteroaryl group are optionally substituted or unsubstituted with one or more substituents P; When A is selected from -NR4(CO)- or is absent, E is not cyclohexane; W is selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group; 3-12 the cycloalkyl group, the 3- to 12-membered heterocycloalkyl group, the 6- to 10-membered aryl group, the 5- to 12-membered heteroaryl group are optionally substituted or unsubstituted by one or more substituents P; The above-mentioned substituent P is a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, -NR i R j , oxo, thio, -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, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring aryl group, and a 5- to 12-membered fused heteroaryl group; R i , R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; R k are independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a hydroxy group, -NR i R j wherein the alkyl group, alkoxy group, and haloalkyl group are optionally selected from the group consisting of C1-C6 alkyl groups, halogens, hydroxy groups, mercapto groups, -NR i R j , oxo, thio, a carboxy group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; a, b, e, g, and h each independently represent an integer from 0 to 6; When neither A nor E is present, W is not a naphthyl group; R3 is selected from H or a chelating agent.

[0010] In some embodiments, A is -NH(CO)- and E is [ka] Selected from the above [ka] is a heterocyclyl group containing one or more N atoms, and the heterocyclyl group is preferably a 3- to 12-membered heterocyclyl group, more preferably a 3- to 8-membered monoheterocyclyl group, and most preferably [ka] It is.

[0011] In some embodiments, A is -NH(CO)- and E is [ka] Selected from the above [ka] is a fused heterocyclyl group having 5 to 12 members, the heterocyclyl group containing one or more N atoms, preferably [ka] It is.

[0012] In some embodiments, A is -NH(CO)- and E is [ka] Selected from the above [ka] is a fused heteroaryl group having 5 to 12 members and containing one or more N atoms, preferably [ka] It is.

[0013] In some embodiments, A is -NH(CO)-, E is selected from a 3- to 12-membered cycloalkyl group and is not cyclohexane, and the 3- to 12-membered cycloalkyl group is a 5- to 12-membered fused cycloalkyl group, preferably [ka] It is.

[0014] In some embodiments, A is -NH(CO)-, e is 1, and E is selected from a 3- to 12-membered cycloalkyl group, and the 3- to 12-membered cycloalkyl group is a spirocycloalkyl group.

[0015] In some embodiments, A is -NH(CO)-, e is 1, and E is selected from a 3- to 12-membered cycloalkyl group, which is a 5- to 12-membered monospirocycloalkyl group.

[0016] In some embodiments, A is -NH(CO)-, e is 1, and E is selected from a 3- to 12-membered cycloalkyl group, and the 3- to 12-membered cycloalkyl group is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered monospirocycloalkyl group.

[0017] In some embodiments, A is -NH(CO)-, e is 1, and E is selected from a 3- to 12-membered cycloalkyl group, [ka] Selected from.

[0018] In some embodiments, A is -NH(CO)-, e is 1, and E is selected from a 3- to 12-membered cycloalkyl group, [ka] It is.

[0019] In some embodiments, A is -NH(CO)-, E is selected from a 3- to 12-membered cycloalkyl group, and the 3- to 12-membered cycloalkyl group is a bridged cycloalkyl group.

[0020] In some embodiments, A is -NH(CO)- and E is [ka] is selected from 3- to 12-membered cycloalkyl groups selected from

[0021] In some embodiments, A is -NH(CO)- and E is [ka] In some embodiments, A is -NH(CO)- and E is absent.

[0022] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein a is 1 and W is selected from a phenyl group or a naphthyl group.

[0023] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, wherein a is 1 and W is a naphthyl group.

[0024] In some embodiments, the disclosure provides a compound of Formula (I), or a pharma- ceutically acceptable salt thereof, wherein Q is selected from H or a protecting group.

[0025] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein Q is H.

[0026] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein each R2 is independently H.

[0027] In some embodiments, the present disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein each R1 is independently H.

[0028] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein h is selected from 1 or 2.

[0029] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein h is 1.

[0030] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein g is selected from 3 or 4.

[0031] In some embodiments, the present disclosure provides a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, wherein g is 3.

[0032] In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, wherein a is 1, W is a naphthyl group, and Q, R2, and R1 are each independently H.

[0033] In some embodiments, the compound of formula (I) is a compound represented by formula (I-1) or a pharma- ceutically acceptable salt thereof: [ka] Among them, Q is selected from H or a protecting group, preferably H, and each occurrence may be the same or different; E is a 3- to 12-membered cycloalkyl group; [ka] or absent, [ka] is a heterocyclyl group containing one N atom, wherein the above 3- to 12-membered cycloalkyl group, the heterocyclyl group containing one N atom is optionally substituted with one or more substituents P or is not substituted, and the 3- to 12-membered cycloalkyl group is not cyclohexane, the above 3- to 12-membered cycloalkyl group is preferably a fused cycloalkyl group, and the above heterocyclyl group containing one N atom is preferably a 6-membered ring; W is selected from 6- to 10-membered aryl groups, which are optionally unsubstituted or substituted with one or more substituents P; The substituent P is selected from a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, and a mercapto group; R3 is selected from H or a chelating agent.

[0034] In some embodiments, in the compound represented by formula (I-1) above or a pharma- ceutically acceptable salt thereof, W above is a phenyl group or a naphthyl group.

[0035] In some embodiments, in the compound of formula (I) or a pharma- ceutically acceptable salt thereof, A is -NH(SO2)- and E is C. 3-12 A cycloalkyl group is preferably a 3- to 8-membered cycloalkyl group, more preferably cyclohexane, and most preferably [ka] It is.

[0036] In some embodiments, in the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, A is -N(CH2)-, and E is selected from a 3- to 12-membered cycloalkyl group, preferably a 3- to 12-membered cycloalkyl group, more preferably cyclohexane, and most preferably [ka] It is.

[0037] In some embodiments, the compound represented by formula (I) is a compound represented by formula (I-2) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H, and each occurrence may be the same or different; A is selected from -NH(SO2)- or -N(CH2)-; E is selected from 3- to 12-membered cycloalkyl groups or is absent, said 3- to 12-membered cycloalkyl groups being optionally substituted or unsubstituted with one or more substituents P; W is selected from 6- to 10-membered aryl groups, which are optionally unsubstituted or substituted with one or more substituents P; The substituent P is selected from a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, and a mercapto group; R3 is selected from H or a chelating agent.

[0038] In some embodiments, in the compound represented by formula (I-2) above or a pharma- ceutically acceptable salt thereof, W above is a naphthyl group.

[0039] In some embodiments, in the compound of formula (I) or a pharma- ceutically acceptable salt thereof, A is absent and E is [ka] Selected from the above [ka] is a 5-12 membered fused heterocyclyl group containing one or more N atoms, preferably [ka] It is.

[0040] In some embodiments, in the compound of formula (I) or a pharma- ceutically acceptable salt thereof, A is absent and E is [ka] Selected from the above [ka] is a 5-12 membered heteroaryl group containing one or more N atoms, preferably [ka] It is.

[0041] In some embodiments, the compound represented by formula (I) is a compound represented by formula (I-3) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H, and each occurrence may be the same or different; E is [ka] Selected from the above [ka] is a 5- to 12-membered fused heterocyclyl group or a 5- to 12-membered heteroaryl group containing one or more N atoms, the 5- to 12-membered fused heterocyclyl group or the 5- to 12-membered heteroaryl group containing one or more N atoms being optionally substituted or unsubstituted with one or more substituents P; W is selected from 6- to 10-membered aryl groups, which are optionally unsubstituted or substituted with one or more substituents P; The substituent P is selected from a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, and a carbonyl group; e is selected from 0 or 1; R3 is selected from H or a chelating agent.

[0042] In some embodiments, in the compound represented by the above formula (I-3) or a pharma- ceutically acceptable salt thereof, the above E is a 5-12 membered heteroaryl group containing one or more N atoms and is unsubstituted, preferably [ka] or [ka] It is.

[0043] In some embodiments, in the compound represented by the above formula (I-3) or a pharma- ceutically acceptable salt thereof, the above E is a 5-12 membered fused heterocyclyl group containing one or more N atoms, and the above 5-12 membered fused heterocyclyl group containing one N atom is substituted with a carbonyl group, preferably [ka] It is.

[0044] In some embodiments, in the compound represented by formula (I-3) above or a pharma- ceutically acceptable salt thereof, W above is a phenyl group or a naphthyl group.

[0045] In some embodiments, in the compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, neither A nor E is present.

[0046] In some embodiments, the compound represented by formula (I) above is a compound represented by formula (I-4) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H, and each occurrence may be the same or different; W is selected from a 6- to 10-membered aryl group and a 5- to 12-membered heteroaryl group, the 6- to 10-membered aryl group and the 5- to 12-membered heteroaryl group being optionally substituted or unsubstituted with one or more substituents P; The substituent P is selected from a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, and a mercapto group; R3 is selected from H or a chelating agent.

[0047] In some embodiments, in the compound represented by the above formula (I-4) or a pharma- ceutical acceptable salt thereof, the above W is selected from 6- to 10-membered aryl groups, preferably a phenyl group, a naphthyl group, a biphenyl group, a phenylhydroxy group, and more preferably a phenyl group. [ka] It is.

[0048] In some embodiments, in the compound represented by the above formula (I-4) or a pharma- ceutical acceptable salt thereof, the above W is selected from 5- to 12-membered heteroaryl groups, preferably 5- to 6-membered heteroaryl groups or fused heteroaryl groups, more preferably indole, pyridine, imidazole, quinoline, and most preferably [ka] It is.

[0049] The present disclosure further provides a compound of formula (II) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H; R1 and R2 are independently H, substituted or unsubstituted C1-4 alkyl groups, preferably all of which are H; Q, R1, and R2 may be the same or different each time they occur; F is -N(CH2) n -or-(CH2) m OG(CH2) n -Selected from Y1, Y2 are independently selected from S or O, preferably O; g, h, n, and m are each independently selected from integers of 0 to 6; G is selected from a 3- to 12-membered cycloalkyl group, a 3- to 12-membered heterocycloalkyl group, a 6- to 10-membered aryl group, and a 5- to 12-membered heteroaryl group, and the 3- to 12-membered cycloalkyl group, the 3- to 12-membered heterocycloalkyl group, the 6- to 10-membered aryl group, and the 5- to 12-membered heteroaryl group are optionally substituted or unsubstituted by one or more substituents P; The above-mentioned substituent P is a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, -NR i R j , oxo, thio, -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 , a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring aryl group, and a 5- to 12-membered fused heteroaryl group; R i , R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; R k are independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a hydroxy group, -NR i R jwherein the alkyl group, alkoxy group, and haloalkyl group are optionally selected from the group consisting of C1-C6 alkyl groups, halogens, hydroxy groups, mercapto groups, -NR i R j , oxo, thio, a carboxy group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; R3 is selected from H or a chelating agent.

[0050] In some embodiments, in the compound of formula (II) or a pharma- ceutically acceptable salt thereof, F is -N(CH2). n -Selected from.

[0051] In some embodiments, in the compound of formula (II) or a pharma- ceutically acceptable salt thereof, F is -(CH2) m OG(CH2) n -, and the above G is selected from 6- to 10-membered aryl groups, and is preferably a phenyl group.

[0052] In some embodiments, the above formula (II) is a compound represented by formula (II-1) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H, and each occurrence may be the same or different; F is -N(CH2) n -or-(CH2) m OG(CH2) n -Selected from The above G is selected from 6- to 10-membered aryl groups, n and m are each independently selected from integers of 0 to 6; R3 is selected from H or a chelating agent.

[0053] In some embodiments, in the compound represented by formula (II-1) above, G is a phenyl group.

[0054] The present disclosure further provides a compound of formula (III) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H; R1 and R2 are independently H, substituted or unsubstituted C 1-4 alkyl groups, preferably all of which are H; Q, R1, and R2 may be the same or different each time they occur; g, h, and j are each independently selected from integers of 0 to 6; i is an integer selected from 1 to 3; J is a linking group selected from the group consisting of a C1-C6 alkylene group, a C3-C6 cycloalkylene group, an arylene group, and a heteroarylene group, wherein the C1-C6 alkylene group, the C3-C6 cycloalkylene group, the arylene group, and the heteroarylene group are optionally substituted or unsubstituted with one or more substituents P; The above-mentioned substituent P is a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, -NR i R j , oxo, thio, -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, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring aryl group, and a 5- to 12-membered fused heteroaryl group; R i , R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; R k are independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a hydroxy group, -NR i R j wherein the alkyl group, alkoxy group, and haloalkyl group are optionally selected from the group consisting of C1-C6 alkyl groups, halogens, hydroxy groups, mercapto groups, -NR i R j , oxo, thio, a carboxy group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; K is selected from the group consisting of -NR5-(C=O)-, -NR5-(C=S)-, -(C=O)-NR5-, and -(C=S)-NR5-; R5 is selected from H or a C1-C4 alkyl group; R3 is selected from H or a chelating agent.

[0055] In some embodiments, in the compound represented by formula (III) or a pharma- ceutically acceptable salt thereof, i is selected from 2, K is selected from -NH-(C=O)-, and J is selected from an arylene group or a heteroarylene group, preferably a pyridine or phenyl group, more preferably [ka] It is.

[0056] In some embodiments, the compound represented by formula (III) is a compound represented by formula (III-1) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group, preferably H; J is a linking group selected from the group consisting of arylene and heteroarylene groups, the arylene and heteroarylene groups being optionally unsubstituted or substituted with one or more substituents P; The substituent P is selected from a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, an oxo group, and a thio group; wherein Q and J may be the same or different each time they appear; j is selected from integers from 0 to 6; R3 is selected from H or a chelating agent.

[0057] In some embodiments, in the compound of formula (III) or a pharma- ceutically acceptable salt thereof, J is selected from pyridine or phenyl, preferably [ka] where J is different each time it appears and j is chosen from 1.

[0058] The present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof: [ka] , Among them, Q is selected from H or a protecting group; R1 and R2 are each independently H or C 1-4 alkyl group, 1-4 The alkyl group is optionally unsubstituted or substituted with one or more substituents P, Q, R1, and R2 may be the same or different each time they occur; Y1 is S or O; T is selected from -NR4(CO)-, -NR4(SO2)-, -NR4(CH2)-; R4 is H, C 1-6 an alkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; 1-6 the alkyl group, the 6- to 10-membered aryl group or the 5- to 12-membered heteroaryl group is optionally unsubstituted or substituted with one or more substituents P; Ring A is selected from 3- to 12-membered nitrogen-containing heterocyclyl groups, which are optionally substituted or unsubstituted with one or more substituents P; W is selected from a 6- to 10-membered aryl group and a 5- to 12-membered heteroaryl group, the 10- to 12-membered aryl group and the 5- to 12-membered heteroaryl group being optionally substituted or unsubstituted with one or more substituents P; The above-mentioned substituent P is a C1-C6 alkyl group, a halogen, a deuterium atom, a hydroxyl group, a mercapto group, -NR i R j , oxo, thio, -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 , a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring aryl group, and a 5- to 12-membered fused heteroaryl group; R i , R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; R kare independently a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a hydroxy group, -NR i R j wherein the alkyl group, alkoxy group, and haloalkyl group are optionally selected from the group consisting of C1-C6 alkyl groups, halogens, hydroxy groups, mercapto groups, -NR i R j , oxo, thio, a carboxy group, a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; y, z, g, and h each independently represent an integer of 0 to 6; R3 is selected from H or a chelating agent.

[0059] In some embodiments, in the compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, Q is a protecting group, and a hydroxy protecting group can be specifically selected. The hydroxy protecting group generally includes all groups that can be used as a protecting group for a hydroxy group, and examples thereof include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-366, 2007, John Wiley & Sons, Inc. Specific examples include C 1-6 Alkyl group, C 2-6 Chain alkenyl group, aryl group C 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, acyl group, C 1-6 Alkoxycarbonyl group, C 1-6 Examples of such groups include alkylsulfonyl groups, arylsulfonyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups, or silyl groups.

[0060] In some embodiments, the present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is a 5-12 membered nitrogen-containing spiroheterocyclyl group.

[0061] In some embodiments, the present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is selected from 5-12 membered nitrogen-containing monospiroheterocyclyl groups.

[0062] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is selected from 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, and 6-membered / 6-membered nitrogen-containing monospiroheterocyclyl groups.

[0063] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is [ka] Selected from.

[0064] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is [ka] Selected from.

[0065] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein T is -NH(CO)- and ring A is [ka] It is.

[0066] In some embodiments, the present disclosure provides a compound represented by formula (IV), or a pharma- ceutically acceptable salt thereof, wherein W is selected from a 6- to 10-membered aryl group.

[0067] In some embodiments, the present disclosure provides a compound of Formula (IV), or a pharma- ceutically acceptable salt thereof, wherein W is a naphthyl group.

[0068] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein Y1 is O.

[0069] In some embodiments, the present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, wherein R1 and R2 are each independently H.

[0070] In some embodiments, the present disclosure provides a compound of Formula (IV), or a pharma- ceutically acceptable salt thereof, wherein Q is selected from H or a protecting group.

[0071] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein Q is H.

[0072] In some embodiments, the present disclosure provides a compound represented by formula (IV), or a pharma- ceutically acceptable salt thereof, wherein y and h are each independently selected from 0, 1, or 2.

[0073] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein y is 1.

[0074] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein h is 1.

[0075] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein g is selected from 3 or 4.

[0076] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein g is 3.

[0077] In some embodiments, the present disclosure provides a compound represented by formula (IV), or a pharma- ceutically acceptable salt thereof, wherein z is selected from 0 or 1.

[0078] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, wherein z is 0.

[0079] In some embodiments, the chelating agent is [ka] Selected from.

[0080] In some embodiments, the chelating agent is [ka] It is.

[0081] In some embodiments, the chelating agent is [ka] It is.

[0082] In some embodiments, the compound is selected from Table 1 below.

[0083] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] In some embodiments, the chelating agents described in the present disclosure comprise a radionuclide.

[0084] In some embodiments, the radionuclide is 18 F, 11 C. 68 Ga, 124 I, 89 Zr, 64 Cu, 86 Y, 99m Tc, 111 In, 123 I, 90 Y, 125 I, 131 I, 177 Lu, 211 At, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb or 67 At least one selected from Ga.

[0085] In some embodiments, the radionuclide is 68 It's Ga.

[0086] In some embodiments, the radionuclide is 177 This is Lu.

[0087] In some embodiments, the disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, which is [ka] It is.

[0088] In an alternative embodiment, the present application provides a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, which is [ka] It is.

[0089] In some embodiments, the present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, [ka] It is.

[0090] In some embodiments, the present disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, [ka] It is.

[0091] In some embodiments, the disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, which is [ka] wherein the chelating agent comprises a radionuclide, the radionuclide being 68 It's Ga.

[0092] In some embodiments, the disclosure provides a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, which is [ka] wherein the chelating agent comprises a radionuclide, the radionuclide being 177 This is Lu.

[0093] The present disclosure further provides a method for preparing a compound represented by formula (IV) or a pharma- ceutically acceptable salt thereof, the compound represented by formula (IV) being a compound represented by formula v or a pharma- ceutically acceptable salt thereof, comprising the steps of removing tert-butyl from a compound represented by formula v-5: [ka] Further includes:

[0094] In an alternative embodiment, the method for preparing a compound of formula (IV) or a pharma- ceutically acceptable salt thereof comprises the steps of: subjecting a compound of formula v-3 to a condensation reaction with a compound of formula v-4 to obtain a compound of formula v-5; [ka] Further includes:

[0095] The method for preparing a compound of formula (IV) or a pharma- ceutically acceptable salt thereof comprises the step of preparing a compound of formula (IV) or a pharma- ceutically acceptable salt thereof and further comprises the step of complexing a radionuclide with a chelating agent in the compound of formula (IV) or a pharma- ceutically acceptable salt thereof.

[0096] In an alternative embodiment, the present disclosure provides a method for preparing a compound of formula (IV) or a pharma- ceutically acceptable salt thereof, comprising: The compound represented by the above formula (IV) or a pharma- ceutically acceptable salt thereof is [ka] and By normal division [ka] The method includes obtaining a single isomer from

[0097] In some embodiments, the compounds may be labeled with a radionuclide as described above.

[0098] The present disclosure further provides isotopic variations of the above compounds, preferably deuterated compounds.

[0099] The present disclosure further provides a pharmaceutical composition comprising at least one of the above compounds or a medicamentable salt thereof and a pharma- ceutically acceptable vector, diluent or excipient.

[0100] In one embodiment, the unit dose of the pharmaceutical composition is 0.001 to 1000 mg.

[0101] In some embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of the compound, based on the total weight of the composition. In some embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of the compound. In some embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the compound. In some embodiments, the pharmaceutical composition comprises 1% to 99% of the compound. In some embodiments, the pharmaceutical composition comprises 2% to 98% of the compound.

[0102] In one embodiment, based on the total weight of the composition, the pharmaceutical composition comprises 0.01% to 99.99% of a pharma- ceutically acceptable vector, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 0.1% to 99.9% of a pharma- ceutically acceptable vector, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 0.5% to 99.5% of a pharma- ceutically acceptable vector, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 1% to 99% of a pharma- ceutically acceptable vector, diluent, or excipient. In one embodiment, the pharmaceutical composition comprises 2% to 98% of a pharma- ceutically acceptable vector, diluent, or excipient.

[0103] The disclosure further provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, and an isotopic variant thereof, in the preparation of a composition for imaging in a patient.

[0104] The present disclosure further provides the use of the above compounds or pharma- ceutically acceptable salts and isotopic variants thereof in the preparation of a medicament for diagnosing and / or treating and / or preventing a PSMA-mediated disease or condition.

[0105] The present disclosure further provides the use of the above compounds or their pharma- ceutically acceptable salts and isotopic variants thereof in the preparation for diagnosing and / or treating and / or preventing tumors and cancers, wherein the tumors and cancers are preferably prostate cancer and / or metastases thereof. Explanation of terms

[0106] Unless specifically stated to the contrary, terms used in the specification and claims have the following meanings.

[0107] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 6-methylhexyl, 7-methylhexyl, 8-methylhexyl, 9-methylhexyl, 10-methylhexyl, 11-methylhexyl, 12-methylhexyl, 13-methylhexyl, 14-methylhexyl, 15-methylhexyl, 16-methylhexyl, 17-methylhexyl, 18-methylhexyl, 19-methylhexyl, 20-methylhexyl, 21-methylhexyl, 22-methylhexyl, 23-methylhexyl, 24-methylhexyl, 25-methylhexyl, 26-methylhexyl, 27-methylhexyl, 28-methylhexyl, 29-methylhexyl, 30-methylhexyl, 31-methylhexyl, 32-methylhexyl, 33-methylhexyl, 34-methylhexyl, 35-methylhexyl, 36-methylhexyl, 37-methylhexyl, 38-methylhexyl, 39-methylhexyl, 40-methylhexyl, 41-methylhexyl, 42-methylhexyl, 43-methylhex Examples of such groups include 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.More preferably, it is an alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available attachment point, and said substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or carboxylate groups.

[0108] The term "alkylene group" refers to a saturated linear or branched aliphatic hydrocarbon group having two residues derived by removing two hydrogen atoms from the same carbon atom or from two different carbon atoms of a parent alkane, and is a linear or branched alkylene group containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. Alkylene groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment.

[0109] The term "alkenylene group" includes a straight-chain alkenyl group having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, and having at least one double bond at any position, such as a vinylidene group, an allylene, a propenylene group, a butenylene group, a phenylene group, a butadienylene group, a pentenylene group, a pentadienyl group, a hexenylene group, and a hexadienylene group.

[0110] The term "alkynylene group" includes straight-chain alkynylene groups having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, and having at least one triple bond at any position, such as, for example, an ethynylene group, a propynylene group, a butynylene group, a pentynylene group, and a hexynylene group.

[0111] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Carbocycle" refers to a ring system in a cycloalkyl group.

[0112] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, in which the monocyclic rings share one carbon atom (called a spiro atom), and may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into monospirocycloalkyl groups, bisspirocycloalkyl groups, and polyspirocycloalkyl groups, and are preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, they are 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. "Spirocarbocycle" refers to a ring system in a spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups are: [ka] Includes.

[0113] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, in which one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that it comprises, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. "Fused carbocyclic ring" refers to a ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups are: [ka] Includes.

[0114] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group having 5 to 20 members, in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings that it comprises, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and is preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups are: [ka]

[0115] The cycloalkyl ring may be fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, in which the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or carboxylic acid ester groups.

[0116] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more of the ring atoms is nitrogen, oxygen or S(O). m (wherein m is an integer of 0 to 2), but does not include the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, and preferably piperidinyl and pyrrolidinyl. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups. "Heterocycle" refers to the ring system in the heterocyclyl group.

[0117] The term "spiroheterocyclyl group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which the monocyclic rings share one atom (called a spiro atom) in which one or more of the ring atoms is nitrogen, oxygen, or S(O). m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are divided into monospiroheterocyclyl groups, bisspiroheterocyclyl groups, and polyspiroheterocyclyl groups, and are preferably monospiroheterocyclyl groups and bisspiroheterocyclyl groups. More preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered monospiroheterocyclyl groups. "Spiroheterocycle" refers to a ring system in a spiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] Includes.

[0118] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and in which one or more of the ring atoms is nitrogen, oxygen, or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings constituting the heterocyclyl group, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl groups. "Fused heterocycle" refers to a ring system in a fused heterocyclyl group. Non-limiting examples of fused heterocyclyl groups are: [ka] Includes.

[0119] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, any two of which share two non-directly linked atoms, and which may contain one or more double bonds, but none of which has a completely conjugated pi-electron system, and in which one or more ring atoms is not nitrogen, oxygen, or S(O) m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of constituting rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclyl groups are: [ka] Includes.

[0120] The heterocyclyl ring may be fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, where the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which are: [ka] etc.

[0121] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxy groups, or carboxylic acid ester groups.

[0122] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6-14 members, such as phenyl and naphthyl groups. The aryl ring may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, in which the ring connected to the parent structure is an aryl ring. An "aromatic ring" refers to a ring system in an aryl group. Non-limiting examples of aryl groups are: [ka] Including, The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxy group, or a carboxylate group, and is preferably a phenyl group.

[0123] The term "fused ring aryl group" may be an unsaturated fused ring structure having aromaticity, which contains 8 to 14 ring atoms and is formed by linking two or more ring structures by sharing two adjacent atoms, and preferably has 8 to 12 ring atoms. For example, it includes fully unsaturated fused ring aryl groups such as naphthalene and phenanthrene, and further includes partially saturated fused ring aryl groups such as benzo 3-8 membered saturated monocyclic cycloalkyl group and benzo 3-8 membered partially saturated monocyclic cycloalkyl group. "Fused aromatic ring" refers to a ring system in the fused ring aryl group. Specific examples of fused ring aryl groups are, for example, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc.

[0124] The term "heteroaryl group" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5-12 membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl, more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, of which the ring connected to the parent structure is a heteroaryl ring. "Heteroaromatic ring" refers to a ring system in a heteroaryl group. Non-limiting examples of heteroaryl groups are: [ka] Includes.

[0125] A heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a carboxy group, or a carboxylic acid ester group.

[0126] The term "fused heteroaryl group" refers to an unsaturated fused ring structure having aromaticity, which contains 5 to 14 ring atoms (including at least one heteroatom) and is formed by linking two or more ring structures by sharing two adjacent atoms, and at the same time, contains a carbon atom, a nitrogen atom and a sulfur atom which can be substituted by oxo, and is preferably a "5- to 12-membered fused heteroaryl group", a "7- to 12-membered fused heteroaryl group", a "9- to 12-membered fused heteroaryl group", etc., and examples thereof include benzofuranyl. groups, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazinyl, phenothiazinyl, etc. "Fused heteroaromatic ring" refers to a ring system in a fused heteroaryl group.

[0127] The fused heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxy groups, or carboxylate groups.

[0128] The above cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups have one residue derived by removing one hydrogen atom from a parent ring atom, or two residues derived by removing two hydrogen atoms from the same parent ring atom or two different parent ring atoms, i.e., a "divalent cycloalkyl group", a "divalent heterocyclyl group", an "arylene group", or a "heteroarylene group".

[0129] The term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylic acid ester groups.

[0130] The term "alkylthio group" refers to -S-(alkyl group) and -S-(unsubstituted cycloalkyl group), where alkyl group is defined above. Non-limiting examples of alkylthio groups include methylthio group, ethylthio group, propylthio group, butylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, and cyclohexylthio group. An alkylthio group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, and heterocycloalkylthio groups.

[0131] The term "hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group, where alkyl is defined above.

[0132] The term "haloalkyl group" refers to an alkyl group substituted with a halogen, wherein alkyl group is defined above.

[0133] The term "deuterated alkyl group" refers to an alkyl group substituted with a deuterium atom, wherein alkyl group is defined above.

[0134] The term "hydroxy" refers to an -OH group.

[0135] The term "oxo" refers to a =O group, e.g., a carbon atom and an oxygen atom are linked by a double bond where a ketone or aldehyde group is formed.

[0136] The term "thio" refers to the group =S. For example, a carbon atom and a sulfur atom are joined by a double bond to form thiocarbonyl -C(S)-.

[0137] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0138] The term "amino group" refers to -NH2.

[0139] The term "cyano" refers to -CN.

[0140] The term "nitro group" refers to --NO.sub.2.

[0141] The term "carboxy" refers to -C(O)OH.

[0142] The term "aldehyde group" refers to --CHO.

[0143] The term "carboxylic acid ester group" refers to a -C(O)O(alkyl group) or a -C(O)O(cycloalkyl group), where alkyl and cycloalkyl groups are defined above.

[0144] The term "acyl halide" refers to a compound that contains the group -C(O)-halogen.

[0145] The term "sulfonyl group" refers to -S(O)(O)-.

[0146] The term "sulfinyl group" refers to -S(O)-.

[0147] An "isostere" of a chemical group is another chemical group that exhibits the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because tetrazole mimics the properties of carboxylic acid, even though the two have significantly different molecular formulas. Tetrazole is one of many possible isostere substitutions of carboxylic acid. Other contemplated carboxylic acid isosteres include -SO3H, -SO2HNR, -PO2(R)2, -PO3(R)2, -CONHNHSO2R, -COHNSOR, and -CONRCN, where R is selected from, for example, hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups as defined herein. Additionally, carboxylic acid isosteres may include 5-7 membered carbocyclic or heterocyclic rings, where the heterocyclic rings include any combination of CH2, O, S, or N in any chemically stable oxidation state, where any one atom of the ring structure is optionally substituted at one or more positions. Predictably, when a chemical substituent is added to a carboxy isostere, the compound is expected to retain the properties of the carboxy isostere. Predictably, when the carboxy isostere is optionally substituted with one or more moieties selected from R as defined above, the degree of substitution and the position of substitution are selected so as not to remove the carboxylic acid isostere properties of the compound. Similarly, it is also expected that if one or more R substituents impair the carboxylic acid isostere properties of the compound, the position of such substituents in the carbocyclic or heterocyclic carboxylic acid isostere will not be substitutions located at one or more atoms that complete or complete the carboxylic acid isostere properties of the compound.

[0148] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the phrase includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may or may not be present, and the description includes cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0149] "Substituted" refers to one or more hydrogen atoms in a group, preferably 5 or less, more preferably 1 to 3 hydrogen atoms, being substituted with a corresponding number of substituents independently of each other. Of course, the substituents are located only at their chemically possible sites, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0150] In the chemical structures of the compounds described in this disclosure, [ka] The bond is unspecified, i.e. [ka] The bond [ka] or [ka] In the chemical structure of the compound described in the present disclosure, [ka] The bond "Z" is not specified, i.e., it may be in the Z or E configuration, or it may include the two configurations simultaneously.

[0151] For convenience, all of the above structural formulas are depicted in certain isomeric forms; however, the present disclosure includes all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.

[0152] Tautomers are structural isomers of organic compounds that are easily interconverted by a chemical reaction called tautomerization. Such reactions always involve the migration of a hydrogen atom or a proton in the form of a single bond accompanied by the exchange of an adjacent double bond. Some common tautomeric pairs are keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0153] [ka] Also, when the chelate ring (DOTA-like ring) is complexed with a metal ion, it can form two conformations in solution, namely antisquare prism (SAP) and twisted antisquare prism (TSAP), so that tautomers can be formed by rotating the pendant arm of the chelate ring or by inverting the ring, and furthermore, inversion of the side chain attached to the chelate ring can also lead to the formation of tautomers, as specifically explained in journals (Dalton Trans.2018,47(31):10360; Dalton Trans.2016, 45(11),4673; Nature Communication 2018,9:857; Bioconjugate Chem.2015,26(2),338.).

[0154] [ka] .

[0155] All of the compounds in this disclosure can be depicted in Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of a compound does not exclude any tautomeric forms.

[0156] All of the compounds in this disclosure can be depicted in Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of a compound does not exclude any tautomeric forms.

[0157] Any isotopically labeled derivatives of the compounds described in this disclosure or their medicamentable salts, or isomers thereof, are also covered by this disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc., each of which is an isotopically labeled atom. 2 H(D), 3 H, 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, etc. Unless otherwise specified, when a position is specifically designated as deuterium (D), it is to be understood that the position is deuterium having an abundance at least 3000 times greater than the natural abundance of deuterium, which is 0.015%, (i.e., at least 45% deuterium is incorporated).

[0158] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert biological activity. [Brief description of the drawings]

[0159] [Figure 1]Comparison of PSMA-617, compound v and x enzyme activity experiments. [Diagram 2] 2h biological distribution of 68Ga-v and 68Ga-x in LnCaP tumor-bearing mice. [Diagram 3] 1 shows blood metabolic curves of 68Ga-PSMA-617 and 68Ga-v (Example 9) in normal mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0160] The present disclosure will be described in more detail below in conjunction with examples, but the examples of the present disclosure are merely for the purpose of illustrating the technical solutions of the present disclosure, and the spirit and scope of the present disclosure are not limited thereto. Unless otherwise specified, all raw materials used in the present disclosure are generally commercially available. EXAMPLES

[0161] NMR shift () is 10 -6 The unit of the NMR spectrum is shown in ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0162] For MS measurements, a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer was used.

[0163] For HPLC measurements, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200 LC high performance liquid chromatograph (Ultimate XB-C18 3.0×150 mm column or Xtimate C18 2.1×30 mm column) were used.

[0164] For chiral HPLC analysis and measurements, Chiralpak IC-3 100×4.6mm ID, 3μm, Chiralpak AD-3 150×4.6mm ID, 3μm, Chiralpak AD-3 50×4.6mm ID, 3μm, Chiralpak AS-3 150×4.6mm ID, 3μm, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3μm, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5μm, Chiralcel OJ-3 150×4.6mm A column with ID of 3 μm was used, and Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates were used as silica gel plates for thin layer chromatography. The specifications for the silica gel plates used in thin layer chromatography (TLC) were 0.15-0.2 mm, and the specifications for separation and purification of products by thin layer chromatography were 0.4-0.5 mm.

[0165] For column chromatography, Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel was generally used as the vector.

[0166] The chiral preparative columns used were DAICEL CHIRALPAK IC (250×30 mm, 10 μm) or Phenomenex-Amylose-1 (250×30 mm, 5 μm).

[0167] CombiFlash high-speed preparative chromatography was performed using Combiflash Rf150 (TELEDYNE ISCO).

[0168] Kinase mean inhibition rate and IC 50 The values ​​were measured using a plate reader NovoStar (BMG, Germany).

[0169] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0170] In the examples, unless otherwise stated, all reactions can be carried out in an argon or nitrogen atmosphere.

[0171] An argon or nitrogen atmosphere refers to an argon or nitrogen balloon of approximately 1 L volume connected to the reaction flask.

[0172] Hydrogen atmosphere refers to a hydrogen balloon of approximately 1 L volume connected to the reaction flask.

[0173] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0174] The hydrogenation reaction was generally carried out by repeating the process of evacuating and refilling with hydrogen three times.

[0175] A CEM Discover-S 908860 microwave reactor was used for microwave reactions.

[0176] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0177] In the examples, unless otherwise specified, the reaction temperature was room temperature, 20 to 30°C.

[0178] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The developing solvents used in the reaction, the eluent system of column chromatography for purifying the compounds, and the developing solvent system of thin layer chromatography included A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol, and the volume ratio of the solvents was adjusted according to the polarity of the compounds, and may be adjusted by adding a small amount of basic or acidic reagent such as triethylamine and acetic acid.

[0179] The abbreviations used in the following experiments have the following meanings:

[0180] EtOAc (EA): ethyl acetate, DCM: dichloromethane, THF: tetrahydrofuran, DIPEA: N,N-diisopropylethylamine, PPTS: p-toluenesulfonic acid pyridinium salt, Boc: tert-butoxycarbonyl group, MeOH: methanol, HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DIEA: N,N-diisopropylethylamine. Example 1

[0181] [ka] (((S)-5-((S)-2-(4-(aminomethyl)piperidine-1-carboxamido)-3-(2-naphthyl)propionylamino)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka] Step 1 (Preparation of Resin Compound S-4) [ka] The desired raw materials and resins were taken out and placed in a desiccator to equilibrate to room temperature. 25 g of Wang Resin (sub=0.38 mmol / g, 8.75 mmol) (Wang Resin, purchased from Xi'an Lanxiao Technology Co., Ltd.) was weighed into a 500 mL single-neck flask, 250 mL of DMF was added, and the flask was shaken for 30 min in a shaker. Fmoc-Lys(Alloc)-OH (19.8 g, 43.75 mmol) (N-[(9H-fluorene-9-methoxy)carbonyl]-N'-[(2-propenyloxy)carbonyl]-L-lysine, purchased from Jilin Chemical Co., Ltd.), DIC (5.5 g, 43.75 mmol), HOBt (13.0 g, 43.75 mmol) (1-hydroxybenzotriazole, purchased from Meryer), DMAP (0.11 g, 0.875 mmol) (4-dimethylaminopyridine, purchased from Energy) were added and reacted at room temperature for 23 h in a shaker. The resin was transferred to a solid-phase reaction column and the reaction solution was removed. The resin was washed three times with 300 mL each of DMF. The resin was blocked with 150 mL of pyridine:acetic anhydride = 1:1 (V:V). The resin was blocked for 8 h and the peptide resin was shrunk and dried with methanol to give the product S-1 (8.75 mmol).

[0182] At room temperature, product S-1 (7 mmol) was swollen with 150 mL of DMF, and then 200 mL of 20% DBLK (20% piperidine / DMF solution, purchased from Energy) was added and deprotected for 10 minutes. After drying by suction, 200 mL of 20% DBLK was added and deprotected for 10 minutes. The blue color of the resin was detected by Kaiser test, dried by suction, and the resin was washed with DMF until neutral to obtain product S-2.

[0183] At room temperature, product S-2 (7 mmol) was added to the glutamyl isocyanate reaction solution, and the mixture was allowed to react for 18 h with a constant temperature shaker while slowly stirring. The resin was detected as colorless by Kaiser test. The resin was transferred to a solid-phase reaction column, and the reaction solution was sucked dry. The resin was washed three times with 300 mL each of DMF to obtain product S-3.

[0184] At room temperature, product S-3 (7 mmol) was placed in a reaction column, phenylsilane (4.6 g, 42 mmol), tetrakistriphenylphosphine palladium (0.81 g, 0.7 mmol) were dissolved in 180 mL of DCM, the solution was placed in a reaction column, nitrogen gas was blown in for 0.5 h to react, the solvent was sucked dry, and the above steps were repeated twice, and the resin was detected as blue-black by Kaiser test. After the reaction was completed, the solvent was sucked dry, washed with DMF three times, sucked dry, and then shrunk with methanol three times. After vacuum drying at 30 ° C for 2 h, product S-4 (22.2 g, 7 mmol) was obtained and prepared for use.

[0185] Step 2 Resin compound S-4 (4.0 g, 1.28 mmol) was swollen in dichloromethane (purchased from Sinopharm Group Chemical Reagents Co., Ltd.) at room temperature for 0.5 h, sucked dry, washed with DMF three times, sucked dry and prepared for use.

[0186] Fmoc-2-NAL-OH (1.68 g, 3.84 mmol) (Fmoc-3-(2-naphthyl)-L-alanine, purchased from Meryer), HOBt (0.52 g, 3.84 mmol) (1-hydroxybenzotriazole, purchased from Meryer), HATU (1.46 g, 3.84 mmol) 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, purchased from Macklin), DIEA (1.01 g, 7.68 mmol) (N,N-diisopropylethylamine, purchased from Energy) were weighed and dissolved in DMF (25 mL) (N,N-dimethylformamide, purchased from Energy), and then added to the solid-phase reaction column containing compound S-4 and reacted for 2 h. The resin was detected as colorless by Kaiser test. The reaction solution was sucked dry, and the resin was washed three times with DMF to obtain the title product a-1.

[0187] Step 3 At room temperature, 40 mL of 20% DBLK (20% piperidine / DMF solution, purchased from Energy) was added to the solid-phase reaction column containing a-1 and deprotected for 10 minutes. After drying by suction, 40 mL of 20% DBLK was added and deprotected for 10 minutes. The resin was detected to be blue by Kaiser test, dried by suction, and washed with DMF until the resin was neutral to obtain the product compound a-2.

[0188] Step 4 At room temperature, compound a-2 (1.0 mmol) and triphosgene (0.2 g, 0.68 mmol) were added to 6 mL of DCM solution, the temperature was lowered to 0°C, DIEA (0.65 g, 5 mmol) was added dropwise, and after the addition, the mixture was kept warm for 2 hours and reacted. The resin was detected as colorless by Kaiser test, 4-Boc-aminomethylpiperidine was added, the mixture was heated to room temperature and reacted for 3 hours, the reaction solution was sucked dry, the resin was washed with DMF (N,N-dimethylformamide) three times, and then shrunk with methanol three times. The mixture was vacuum dried at 30°C for 2 hours to obtain the product compound a-3, which was ready for use.

[0189] Step 5 At room temperature, 40 mL of a dissolving solution (dissolving solution TFA (trifluoroacetic acid): HO: Tis (triisopropylsilane, purchased from Macklin) = 95: 2.5: 2.5) was prepared, and the peptide resin compound 4 was added with stirring and reacted for 2 h. Then, it was filtered by suction to remove the resin, and the filtrate was concentrated by rotary evaporation, and the concentrated solution was put into 100 mL of isopropyl ether, filtered by suction, and dried under reduced pressure to obtain 0.40 g of crude peptide, with a yield of 60.9%. It was purified by high-performance preparative liquid chromatography to obtain the title product, compound a (105 mg, yield: 26.2%). MS m / z (ESI): 657.3 [M+1] + 1H NMR (400 MHz, Deuterium Oxide) δ 7.82 (t, J = 9.1 Hz, 3H), 7.64 (s, 1H), 7.46 (s, 2H), 7.37 (d, J = 8.4 Hz, 1H), 4.51 (t, J = 8.1 Hz, 1H), 4.14 (s, 1H), 3.85 (dd, J = 30.1, 11.1 Hz, 2H), 3.71 (d, J = 13.8 Hz, 1H), 3.22 (dd, J = 13.6, 7.5 Hz, 1H), 3.14 - 3.01 (m, 1H), 2.97 - 2.83 (m, 1H), 2.67 (dt, J = 33.6, 12.7 Hz, 2H), 2.40 (dt, J = 15.4, 6.9 Hz,4H), 2.12 - 1.97 (m, 1H), 1.84 (dd, J = 14.3, 7.5 Hz, 1H), 1.68 (s, 1H), 1.49 (d, J = 19.0 Hz, 4H), 1.36 (s, 1H), 1.13 (d, J = 7.4 Hz, 2H), 0.93 (s, 2H), 0.66 (d, J = 12.2 Hz, 1H), 0.54 (s, 1H). Example 2

[0190] [ka] (((S)-5-((S)-2-((((1R,4S)-4-(aminomethyl)cyclohexyl)methyl)amino)-3-(2-naphthyl)propionamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0191] Step 1 At room temperature, trans-4-(Boc-aminomethyl)cyclohexanemethanol compound e-1 (3 g, 12 mmol) was dissolved in 60 mL of DCM, cooled to -60 °C, and DMP / DCM solution (7.95 g, 18 mmol, DCM 60 mL) was added. After the addition, the mixture was allowed to naturally warm to room temperature and stirred for 4 h to react. The completion of the reaction was monitored by TLC. The reaction solution was washed with 100 mL of aqueous solutions of Na2CO3 and Na2S2O3, and 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system of n-heptane / ethyl acetate = 10:1 to 4:1 to obtain compound e-2 (1.8 g, yield: 59.7%). MS m / z (ESI): 242.3 [M+1] +

[0192] Step 2 At room temperature, compound e-3 (1.56 g, 6.8 mmol) and compound e-2 (1.48 g, 6.1 mmol) were dissolved in 40 mL of DCM / THF (V1:V2=1:1) solution and stirred for 2 h to react. Sodium cyanoborohydride (0.5 g, 7.9 mmol) and glacial acetic acid (0.3 mL) were slowly added and stirred for 3 h to react. The reaction solution was washed with water, extracted with DCM (40 mL x 3), the organic phase was combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography eluted with the eluent system n-heptane / ethyl = 10:1 to 4:1 to obtain compound e-4 (1.54 g, yield: 55.6%). MS m / z (ESI): 455.3 [M+1] +

[0193] Step 3 At room temperature, compound e-4 (1.5 g, 3.3 mmol) was dissolved in 12 mL of THF and 5 mL of water, lithium hydroxide (0.24 g, 9.9 mmol) was added, and the mixture was allowed to react at room temperature overnight after addition. 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL x 2), the aqueous phases were combined, cooled to 0 ° C in an ice bath, adjusted to pH = 3-4 with 0.5 N citric acid, precipitated solids, replenished with 100 mL of H2O and 50 mL of DCM, reacted by stirring for 0.5 h, remeasured if the pH did not change, filtered, and the filter cake was dried under vacuum (40 ° C, 4 h) to a constant weight to obtain the product compound e-5 (1.1 g, yield: 75.9%). MS m / z (ESI): 441.3 [M+1] +

[0194] Step 4 At room temperature, compound e-5 (0.13 g, 0.3 mmol), HATU (0.16 g, 0.42 mmol), DIEA (0.18 g, 1.41 mmol), and DCM (1 mL) were added to a reaction flask, stirred to clear, and compound e-6 was added and reacted by stirring overnight. The reaction solution was washed with water and extracted with EA (30 mL x 3), the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with the eluent system n-heptane / ethyl acetate = EA (0% to 90%) to obtain the product compound e-7 (0.13 g, yield: 59.4%). MS m / z (ESI): 784.4 [M+1] +

[0195] Step 5 At room temperature, compound e-7 (0.13 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate, and 2 M HCL / EA solution (2 mL, 4 mmol) was added with stirring and reacted with stirring for 2 h. Completion of the reaction was monitored by TLC. The reaction solution was concentrated to constant weight under reduced pressure to obtain the product compound e-8 (0.11 g, yield: 92%). MS m / z (ESI): 684.3 [M+1] +

[0196] Step 6 At room temperature, compound e-8 (0.11 g, 0.16 mmol) was dissolved in 2 mL of THF and 1 mL of water, lithium hydroxide (29 mg, 1.2 mmol) was added, and the mixture was allowed to react overnight at room temperature after addition. TFA was added to the reaction solution to adjust the pH to 2-3, and the mixture was stirred for 0.5 h. The pH was measured again to ensure that it did not change, and the product was purified by high-performance preparative liquid chromatography to obtain the title product compound e (80 mg, yield: 78.4%). MS m / z (ESI): 640.3 [M-1] - 1H NMR (400 MHz, Deuterium Oxide) δ 7.94 (t, J = 6.7 Hz, 3H), 7.91 - 7.80 (m, 1H), 7.54 (p, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.1 Hz, 1H), 4.18 (dt, J = 9.1, 5.6 Hz, 2H), 4.05 (d, J = 7.6 Hz, 2H), 3.69 (dd, J = 13.3, 4.9 Hz, 2H), 3.53 (t, J = 12.3 Hz, 2H), 2.94 - 2.70 (m, 3H), 2.42 (s, 1H), 2.08 (s, 2H), 1.80 (s, 1H), 1.68 (s, 2H), 1.58 (s, 2H), 1.39 (d, J = 9.7 Hz, 2H), 1.27 (s, 3H), 1.02 (q, J = 10.5, 9.9 Hz, 3H), 0.63 (s, 2H), 0.46 (s, 2H). Example 3

[0197] [ka] (((S)-5-((S)-2-(4-(aminomethyl)-1-pyrazolyl)-3-phenylpropionamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0198] Step 1 At room temperature, Boc-L-tyrosine methyl ester compound g-1 (0.5 g, 2.78 mmol) was dissolved in 120 mL of DCM, pyridine (1.2 mL, 14.61 mmol) was added, the temperature was lowered to 0 ° C, trifluoromethanesulfonic anhydride (2.4 mL, 14.10 mmol) was added, and after the addition was completed, the temperature was naturally raised to room temperature and the reaction was stirred for 3 h. The completion of the reaction was monitored by TLC. The reaction solution was washed in sequence with 100 mL of saturated sodium bicarbonate solution, 100 mL of 1N HCl, and 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain compound g-2 (0.84 g, yield: 99.0%).

[0199] Step 2 At room temperature, 4-(Boc-aminomethyl)pyrazole (0.61 g, 3.01 mmol) was dissolved in 25 mL of DCM, DIEA (0.49 g, 3.72 mmol) was added, and the mixture was stirred for 1 h to react. Compound 2 (0.84 g, 2.69 mmol) / DCM solution was added dropwise, and the mixture was stirred overnight to react. The reaction solution was washed with 30 mL of saturated sodium bicarbonate solution and 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system of n-heptane / ethyl = 10:1 to 3:1 to obtain compound g-3 (0.51 g, yield: 48.4%). MS m / z (ESI): 360.2 [M+1] +

[0200] Step 3 At room temperature, compound g-3 (0.51 g, 1.4 mmol) was dissolved in 1.5 mL of THF and 1 mL of water, lithium hydroxide was added, and the mixture was allowed to react overnight at room temperature after addition. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 2), the aqueous phases were combined, cooled to 0 ° C. in an ice bath, adjusted to pH = 3-4 with 0.5 N citric acid, and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product compound g-4 (0.39 g, yield: 80.0%). MS m / z (ESI): 344.5 [M-1] -

[0201] Step 4 At room temperature, the resin compound S-4 (1.1 g, 0.38 mmol) prepared in Example 1 was swollen in DCM for 0.5 h, sucked dry, and washed with DMF three times for use. Compound g-4 (0.36 g, 1.04 mmol), HATU (0.4 g, 1.04 mmol), HOBt (0.14 g, 1.04 mmol), DIEA (0.27 g, 2.08 mmol), and DMF (10 mL) were placed in a reaction flask and shaken until clear. The resin that had been previously swollen was placed in the reaction flask and shaken overnight to react, and the resin was detected as colorless by Kaiser test. The reaction solution was sucked dry, and the resin was washed three times with DMF, then shrunk with methanol and dried in preparation for use. The product compound g-5 was obtained.

[0202] Step 5 At room temperature, 10 mL of a dissolving solution (dissolving solution TFA:H2O:Tis = 95:2.5:2.5) was prepared, and the peptide resin compound g-5 was added while stirring and reacted for 2 h. Then, it was filtered by suction to remove the resin, and the filtrate was concentrated by rotary evaporation, and the concentrated solution was put into 40 mL of isopropyl ether to precipitate a solid, and the solid was obtained by suction filtration and dried under reduced pressure to obtain 0.15 g of crude peptide, with a yield of 72.1%. It was purified by high-performance preparative liquid chromatography to obtain the title product, compound g (26 mg, yield: 17.3%). MS m / z (ESI): 547.8 [M+1] + 1H NMR (400 MHz, Deuterium Oxide) δ 7.77 (s, 1H), 7.54 (s, 1H), 7.26 - 7.13 (m, 3H), 7.13 - 7.06 (m, 2H), 5.07 (t, J = 8.2 Hz, 1H), 4.17 - 4.08 (m, 1H), 3.95 (s, 3H), 3.32 (d, J = 8.2 Hz, 2H), 3.06 (dt, J = 12.8, 6.2 Hz, 1H), 2.92 (dt, J = 13.4, 6.5 Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.04 (dq, J = 13.1, 7.2 Hz, 1H), 1.83 (dq, J = 14.9, 7.3 Hz, 1H), 1.59 (s, 1H), 1.47 (dd, J = 9.4, 4.7 Hz, 1H), 1.25 - 1.17 (m, 2H), 0.98 (d, J = 6.7Hz, 2H). Example 4

[0203] [ka] (((S)-5-((S)-2-amino-3-(4-pyridine)propionylamino)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0204] Step 1 Resin compound S-4 (1.7 g, 0.65 mmol) was swollen in DCM for 0.5 h at room temperature, sucked dry and washed three times with DMF before use. Boc-3-(4-pyridine)-L-alanine (0.54 g, 2.01 mmol), HATU (0.76 g, 2.01 mmol), HOBt (0.27 g, 2.01 mmol), DIEA (0.52 g, 4.02 mmol), and DMF (15 mL) were added to a reaction flask and shaken until clear. The pre-swollen resin was added to the reaction flask and shaken for 2 h to react, and the resin was detected as colorless by Kaiser test. The reaction solution was sucked dry, and the resin was washed three times with DMF, then shrunk with methanol and dried for use. The title product, compound j-1, was obtained.

[0205] Step 2 At room temperature, 20 mL of a dissolving solution (dissolving solution TFA:H2O:Tis = 95:2.5:2.5) was prepared, and the peptide resin compound 2 was added with stirring and reacted for 2 h. Then, it was filtered by suction to remove the resin, and the filtrate was concentrated by rotary evaporation, and the concentrated solution was added to 50 mL of isopropyl ether to precipitate a solid, and the solid was obtained by suction filtration and dried under reduced pressure to obtain 0.20 g of crude peptide, with a yield of 66.7%. It was purified by high-performance preparative liquid chromatography to obtain the title product, compound j (75 mg, yield: 37.5%). MS m / z (ESI): 468.8 [M+1] + 1H NMR (400 MHz, Deuterium Oxide) δ 8.73 - 8.66 (m, 2H), 7.90 (d, J = 6.3 Hz, 2H), 4.17 (ddd, J = 23.5, 9.1, 5.6 Hz, 2H), 4.00 (dd, J = 8.9, 5.0 Hz, 1H), 3.50 - 3.30 (m, 2H), 3.08 (dt, J = 13.6, 6.8 Hz, 1H), 2.95 (dt, J = 13.5, 6.8 Hz, 1H), 2.40 (t, J = 7.3 Hz, 2H), 2.07 (dq, J = 13.2, 7.2 Hz, 1H), 1.85 (ddd, J = 16.1, 14.1, 7.1 Hz, 1H), 1.59 (dtd, J = 55.3, 14.5, 14.1, 7.9 Hz, 2H), 1.25 (s, 2H), 1.08 (d, J = 9.0 Hz, 2H). Example 5

[0206] [ka] (((S)-5-(2-(4-((S)-2-(2-aminoacetamido)-2-carboxyethyl)phenoxy)acetamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0207] Step 1 At room temperature, Fmoc-L-tyrosine tert-butyl (5.0 g, 10.9 mmol) was dissolved in 50 mL of DMF, potassium carbonate (1.81 g, 13.1 mmol) was added, and the mixture was stirred at room temperature for 12 h to react. Boc-glycine (2.29 g, 13.1 mmol) and HATU (4.98 g, 13.1 mmol) were added, the mixture was cooled to 0 °C in an ice bath, DIEA was added dropwise, and the mixture was stirred at room temperature for 2 h to react. 100mL of water was added to the reaction solution, extracted with ethyl acetate (100mL x 2), the organic phases were combined, washed with saturated sodium bicarbonate solution (100mL), saturated ammonium chloride solution (100mL x 2), saturated sodium chloride solution (100mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography eluted with an eluent system of PE / EA = 100:1 to 50:50 to obtain the product compound O-1 (3.8g, yield: 70%). MS m / z (ESI): 395.4 [M+1] +

[0208] Step 2 At room temperature, compound O-1 (3.8 g, 9.7 mmol) was dissolved in 40 mL of DMF, potassium carbonate (1.81 g, 13.1 mmol) and methyl bromoacetate (2.22 g, 14.5 mmol) were added, and the mixture was heated to 80 ° C. and stirred for 5 to 10 h to react. 100 mL of water was added to the reaction solution, extracted with ethyl acetate (100 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product compound O-2 (4.2 g, yield: 110%). MS m / z (ESI): 467.4 [M+1] +

[0209] Step 3 At room temperature, compound O-2 (4.2 g, 9.0 mmol) was dissolved in 50 mL of THF and 50 mL of water, cooled to 0 ° C. in an ice bath, and an aqueous solution of lithium hydroxide was slowly added. After addition, the mixture was reacted at room temperature for 2 h. Ethyl acetate was added to the reaction solution for extraction (100 mL x 2), the aqueous phase was combined, cooled to 0 ° C. in an ice bath, adjusted to pH = 3-4 with 0.5 N dilute hydrochloric acid, extracted with ethyl acetate (100 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography using an eluent system of DCM / MeOH = 100: 1-20: 1 to obtain the product compound O-3 (3.5 g, yield: 80%). MS m / z (ESI): 451.4 [M-1] -

[0210] Step 4 At room temperature, compound O-3 (500 mg, 1.1 mmol) was dissolved in 30 mL of DCM, HATU was added, the temperature was lowered to 0 ° C. in an ice bath, DIEA was added dropwise, and the mixture was stirred at room temperature for 0.5 h to react. The temperature was lowered to 0 ° C. in an ice bath, compound O-4 was added, and the mixture was stirred at room temperature for 2 to 5 h to react. 100 mL of water was added to the reaction solution, extracted with DCM (100 mL x 2), the organic phase was combined, washed with saturated sodium bicarbonate solution (100 mL) and saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using an eluent system of DCM / MeOH = 100: 1 to 20: 1 to obtain the product compound O-5 (970 mg, yield: 80%). MS m / z (ESI): 796.5 [M+1] +

[0211] Step 5 At room temperature, compound O-5 (970 mg, 1.22 mmol) was dissolved in 5 mL of ethyl acetate, and 2N hydrogen chloride ethyl acetate solution (15 mL) was added and reacted with stirring for 1 to 2 h. The reaction solution was concentrated under reduced pressure to obtain the product compound O-6 (1.2 g, yield: 110%). MS m / z (ESI): 696.5 [M+1]+

[0212] Step 6 At room temperature, compound O-6 (200 mg, 0.29 mmol) was dissolved in 10 mL of THF and 10 mL of water, cooled to 0 ° C. in an ice bath, lithium hydroxide (41.76 mg, 1.74 mmol) was slowly added, and after addition, the mixture was reacted at room temperature for 12 h. Ethyl acetate was added to the reaction solution to extract (20 mL × 2), the aqueous phase was combined, cooled to 0 ° C. in an ice bath, adjusted to pH = 2-3 with 1N dilute hydrochloric acid, and purified by high-performance preparative liquid chromatography to obtain the title product, compound O (20 mg, yield: 20%). MS m / z (ESI): 598.3 [M+1] + 1H NMR (400 MHz, D2O) δ 7.15 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.52 (s, 2H), 4.44 (dd, J = 8.9, 5.1 Hz, 1H), 4.09 (dd, J = 8.6, 5.0 Hz, 1H), 3.99 (dd, J = 8.2, 4.9 Hz, 1H), 3.73-3.58 (m, 3H), 3.18 (t, J = 6.6 Hz, 2H), 3.10-3.04 (m, 1H), 2.84 (dd, J = 14.6, 9.1 Hz, 1H), 2.37 (t, J = 7.3 Hz, 2H), 2.07-2.00 (m, 1H), 1.88-1.79 (m, 1H), 1.67 (s, 1H), 1.55 (d, J = 7.5 Hz, 1H), 1.46-1.39 (m, 2H), 1.20 (d, J = 15.5 Hz, 3H). Example 6

[0213] [ka] (((S)-5-(6-(4-(aminomethyl)benzamido)picolinamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0214] Step 1 At room temperature, compound q-1 (3 g, 11.94 mmol) was dissolved in 60 mL of dichloromethane, EDCI (5.49 g, 28.66 mmol) (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, purchased from Macklin), DMAP (4.37 g, 35.82 mmol) were added, and the mixture was stirred for 20 min under a N2 atmosphere. Compound q-2 (2.17 g, 14.33 mmol) was added, and the mixture was allowed to react with stirring at room temperature for 16 to 18 h. The reaction solution was added with 60 mL of water, extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with an eluent system (PE / EA = 100% ~ 50%) to obtain the product compound q-3 (2.0 g, yield: 43.5%). MS m / z (ESI): 386.2 [M+1] +

[0215] Step 2 At room temperature, compound q-3 (1 g, 2.59 mmol) was dissolved in 6 mL of tetrahydrofuran, and 4 mL of aqueous solution of LiOH (187 mg, 7.77 mmol) was added, and the mixture was stirred at room temperature for 16 to 18 h to react. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The aqueous phase was adjusted to pH = 3 to 4 with 0.5 mol / L citric acid, and then extracted with ethyl acetate (50 mL x 4). The organic phases were combined, dried with saturated sodium chloride solution (50 mL) and anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product compound q-4 (0.6 g, yield: 62.5%). MS m / z (ESI): 372.2 [M+1] +

[0216] Step 3 Resin compound S-4 (2.11 g, 0.68 mmol) was swollen in DMF (20 mL) for 30 min at room temperature. Compound q-4 (760 mg, 2.05 mmol), HATU (779 mg, 2.05 mmol), HOBt (277 mg, 2.05 mmol), DIEA (529 mg, 4.09 mmol) were dissolved in DMF (15 mL) and added to the swollen resin, and reacted at room temperature for 2.5 h. A small amount of resin was taken, filtered by suction, washed with DMF (2 mL x 3), and then colored with ninhydrin to become colorless. The reacted resin was filtered by suction and washed with DMF (50 mL x 3), DCM (50 mL x 3), and isopropyl ether (50 mL x 3) to obtain the wet product resin compound q-5.

[0217] Step 4 At room temperature, the resin compound q-5 obtained in the previous step was added to TFA:Tis:HO = 95:2.5:2.5 (20 mL) and reacted at room temperature for 2 h. The resin was then suction filtered, and the filtrate was concentrated under reduced pressure with TFA (5 mL × 3) until no clear fraction remained. The obtained oily liquid was dropped into isopropyl ether (20 mL), filtered, and the filter cake was separated and purified to obtain a total of 20 mg of compound q. MS m / z (ESI): 573.2 [M+1] + . 1H NMR (400 MHz,D2O): δ 8.04 (d, 1H), 7.86 (dd, 3H), 7.65 (d, 1H), 7.49 (d, 2H), 4.18 (s, 2H), 4.18 (s, 2H), 4.12-4.06 (m, 2H), 3.29 (s, 1H), 3.36-3.20 (m, 2H), 2.32 (t, 2H), 2.03-1.94 (m, 1H), 1.87-1.72 (m, 2H), 1.70-1.47 (m, 3H), 1.37 (d, 2H). Example 7

[0218] [ka] (((S)-5-((S)-2-(3-(aminomethyl)bicyclo[1.1.1]pentane-1-carboxamido)-3-(naphthalen-2-yl)propionylamino)-1-carboxypentyl)carbamoyl)-L-glutamic acid [ka]

[0219] Step 1 At room temperature, r-1 (106 mg, 0.44 mmol), HATU (166 mg, 0.44 mmol), DIEA (113 mg, 0.88 mmol), and DCM (10 mL) were added to a reaction flask and stirred to clear, and r-2 (200 mg, 0.29 mmol) was added and reacted with stirring overnight. Completion of the reaction was monitored by TLC, and the reaction solution was washed with water and extracted with DCM (30 mL × 3), the organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with the eluent system dichloromethane / methanol = methanol (0% to 7%) to give r-3 (200 mg, yield: 75.4%). MS m / z (ESI): 908.9 [M+1] +

[0220] Step 2 At room temperature, r-3 (200 mg, 0.42 mmol) was dissolved in TFA (5 mL), and after addition, the mixture was reacted overnight at 33° C. The reaction solution was evaporated to dryness and purified by high-performance preparative liquid chromatography to obtain the title product r (71.5 mg, yield: 50.7%). MS m / z (ESI): 640.4 [M-1] - Example 8

[0221] [ka] (((1S)-1-Carboxy-5-((2S)-3-(naphthalen-2-yl)-2-(6-azaspiro[2.5]octane-1-carboxamido)propionylamino)pentyl)carbamoyl)-L-glutamic acid [ka]

[0222] Step 1 NE-benzyloxycarbonyl-L-lysine tert-butyl hydrochloride (10g, 0.03mol) and DIEA (3.84g, 0.03mol) were dissolved in 120mL of DCM, cooled to -10℃ to 0℃, stirred for 0.5h, triphosgene (4.4g, 0.015mol) was added, and after addition, DIEA (19.2g, 0.149mol) was added dropwise at -10℃ to 0℃, and after completion of addition, the mixture was allowed to react for 3h while keeping the temperature constant, and L-glutamic acid di-tert-butyl hydrochloride (10g, 0.039mol) was added, and the mixture was allowed to naturally warm to room temperature and stirred overnight. Completion of the reaction was monitored by TLC. The reaction solution was washed successively with 100 mL of saturated NaHCO3 solution and 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography eluted with an eluent system of n-heptane / ethyl = 10:1 to 1:1, and the solvent was evaporated to dryness to obtain oily substance t-3 (9.8 g, yield: 53.2%). MS m / z (ESI): 622.3 [M+1] +

[0223] Step 2 At room temperature, t-3 (9.8 g, 15.8 mmol) was dissolved in 100 mL of methanol solution, stirred until clear, and Pd / C (4.9 g, water content 58%) was added. The reaction flask was purged with nitrogen gas three times and with hydrogen gas three times, and the reaction was stirred at room temperature for 5 h and monitored for completion by TLC. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain t-4 (6.2 g, yield: 80.7%). MS m / z (ESI): 488.3 [M+1] +

[0224] Step 3 At room temperature, Fmoc-3-(2-naphthyl)-L-alanine (2.3 g, 5.3 mmol), HATU (2.0 g, 5.3 mmol), DIEA (2.1 g, 16.4 mmol), and DCM (20 mL) were added to a reaction flask and stirred to clear, and t-4 (2 g, 4.1 mmol) was added and reacted with stirring overnight. Completion of the reaction was monitored by TLC, and the reaction solution was washed with water and extracted with EA (30 mL x 3), and the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with the eluent system dichloromethane / methanol = methanol (0%-10%) to give t-5 (2.8 g, yield: 76%). MS m / z (ESI): 907.5 [M+1] +

[0225] Step 4 At room temperature, t-5 (2.8 g, 3 mmol) and DCM (20 mL) were added to a reaction flask, stirred to clear, diethylamine was added, and the mixture was reacted by stirring overnight. The reaction mixture was washed with water, extracted with EA (30 mL x 3), the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with the eluent system n-heptane / ethyl acetate = EA (0% to 100%) to give the title product t-6 (1.4 g, yield: 66.7%). MS m / z (ESI): 685.4 [M+1] +

[0226] Step 5 At room temperature, 6-Boc-6-azaspiro[2.5]octane-1-carboxylic acid (145 mg, 0.57 mmol), HATU (216 mg, 0.57 mmol), DIEA (226 mg, 1.75 mmol), and DCM (4 mL) were added to a reaction flask and stirred to clear, and t-6 (300 mg, 0.44 mmol) was added and reacted with stirring overnight. Completion of the reaction was monitored by TLC, and the reaction solution was washed with water and extracted with EA (30 mL × 3), and the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with the eluent system dichloromethane / methanol = methanol (0%-10%) to give the title product t-8 (300 mg, yield: 74.2%). MS m / z (ESI): 922.8 [M+1] +

[0227] Step 6 At room temperature, t-8 (300 mg, 325 mmol) was dissolved in 2 mL of DCM, and TFA (3 mL) was added. After the addition was completed, the mixture was reacted overnight at 30° C. The reaction solution was evaporated to dryness and purified by high-performance preparative liquid chromatography to obtain the title product t (70 mg, yield: 32.8%). MS m / z (ESI): 654.3 [M-1] -

[0228] Example 9 [ka] (((S)-1-Carboxy-5-((S)-3-(2-naphthyl)-2-((6S,9r)-4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-formamido)propionamido)pentyl)carbamoyl)-L-glutamic acid [ka]

[0229] Step 1 At room temperature, DOTA (1636 mg, 2.86 mmol), HATU (1087 mg, 2.86 mmol), DIEA (N,N-diisopropylethylamine, 851 mg, 6.6 mmol), and DCM (10 mL) were added to a reaction flask and stirred to clear, and v-1 (500 mg, 2.20 mmol) was added and reacted with stirring overnight. Completion of the reaction was monitored by TLC, and the reaction was washed with water and extracted with EA (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with the eluent system dichloromethane / methanol to give the title product v-2 (1290 mg, yield: 75.1%). MS m / z (ESI): 782.5 [M+1] +

[0230] Step 2 At room temperature, v-2 (800 mg, 1.01 mmol) was dissolved in 12 mL of THF and 10 mL of water, and lithium hydroxide (73 mg, 3.2 mmol) was added. After addition, the mixture was allowed to react at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 2-3, and the mixture was stirred for 0.5 h. When the pH did not change, the reaction solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain the title product v-3 (675 mg, yield: 87.5%). MS m / z (ESI): 754.4 [M+1] +

[0231] Step 3 At room temperature, v-3 (600 mg, 0.80 mmol), HATU (303 mg, 0.80 mmol), DIEA (316 mg, 2.45 mmol), DCM (8 mL) were added to a reaction flask and stirred to clear, and v-4 (420 mg, 0.61 mmol, see t-6 in Example 8 for preparation method) was added and stirred to react. Completion of the reaction was monitored by TLC, and the reaction solution was washed with water and extracted with EA (30 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with the eluent system dichloromethane / methanol to give v-5 (638 mg, yield: 73.3%). MS m / z (ESI): 1421 [M+1] +

[0232] Step 4 At room temperature, v-5 (500 mg, 0.35 mmol) was dissolved in 4 mL of DCM, and TFA (5 mL) was added. After the addition was completed, the mixture was reacted overnight at 30° C. The reaction solution was evaporated to dryness and purified by high-performance preparative liquid chromatography to give the title product v (27 mg, yield: 7.1%). MS m / z (ESI): 1084.5 [M-1] - 1H NMR (400 MHz, Deuterium Oxide) δ 7.84(t, 3H), 7.65(s, 1H), 7.47-7.49 (m, 2H), 7.38 (d, 1H), 4.55 (t, 1H), 4.18-4.19 (m, 1H), 3.10-3.87 (m, 33H), 2.42(t, 2H),1.91 (dt, 1H), 1.89 (m, 1H), 1.87 (m, 3H), 0.84-1.42 (m, 14H). Example 10

[0233] [ka] (((S)-1-Carboxy-5-((S)-3-(2-naphthyl)-2-(4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl)-1-acetyl)methyl)piperidine-1-formamido)propionamido)pentyl)carbamoyl)-L-glutamic acid [ka]

[0234] Step 1 At room temperature, w-2 (3 g, 11.3 mmol) and DIEA (1.45 g, 11.3 mmol) were dissolved in 120 mL of DCM, the temperature was lowered to -10 ° C to 0 ° C, and stirring was continued for 0.5 h. Triphosgene (1.7 g, 5.7 mmol) was added, and after the addition was completed, DIEA (7.3 g, 56.6 mmol) was added dropwise at -10 ° C to 0 ° C, and after the dropwise addition was completed, the mixture was kept warm for 3 h to react, and w-1 (3.2 g, 14.7 mmol) was added, and the mixture was allowed to naturally warm to room temperature and stirred overnight to react. Completion of the reaction was monitored by TLC. The reaction solution was washed successively with 100 mL of saturated NaHCO3 solution and 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography eluted with an eluent system of n-heptane / ethyl = 10:1 to 1:1, and the solvent was evaporated to dryness to obtain a white solid w-3 (4.0 g, yield: 75.5%). MS m / z (ESI): 470.6 [M+1] +

[0235] Step 2 At room temperature, w-3 (4.0 g, 8.5 mmol) was dissolved in 20 mL of THF and 10 mL of water, lithium hydroxide (0.62 g, 25.6 mmol) was added, and after addition, the mixture was reacted at room temperature overnight. 10 mL of water was added to the reaction solution, extracted with ethyl acetate (10 mL x 2), the aqueous phases were combined, cooled to 0 ° C in an ice bath, adjusted to pH 3-4 with 0.5 N citric acid, solids were precipitated, and the mixture was reacted by stirring for 0.5 h. The pH was remeasured if it did not change, filtered, and the filter cake was dried under vacuum to a constant weight (40 ° C, 4 h) to obtain the title product w-4 (3.4 g, yield: 87.6%). MS m / z (ESI): 456.6 [M+1] +

[0236] Step 3 At room temperature, w-4 (1.0 g, 2.2 mmol), HATU (1.02 g, 2.7 mmol), DIEA (1.39 g, 10.8 mmol), and DCM (20 mL) were added to a reaction flask and stirred to clear, and w-5 (0.66 g, 1.8 mmol) was added and reacted with stirring overnight. The reaction solution was washed with water and extracted with DCM (40 mL x 3), the organic phases were combined, washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with the eluent system dichloromethane / methanol = methanol (0% to 10%) to give the title product w-6 (0.86 g, yield: 59.4%). MS m / z (ESI): 799.4 [M+1] +

[0237] Step 4 At room temperature, w-6 (0.86 g, 1.1 mmol) was dissolved in 2 mL of ethyl acetate, and 4 M HCl / EA solution (8 mL, 32 mmol) was added with stirring and reacted with stirring for 2 h. Completion of the reaction was monitored by TLC. The reaction was concentrated to constant weight under reduced pressure to give the title product w-7 (0.82 g, yield: 95.3%). MS m / z (ESI): 699.3 [M+1] +

[0238] Step 5 At room temperature, DOTA-tris(t-Bu ester) (209 mg, 0.36 mmol), HATU (137 mg, 0.36 mmol), DIEA (464 mg, 3.6 mmol), and DCM (3 mL) were placed in a reaction flask, stirred until clear, and w-7 (170 mg, 0.24 mmol) was added. The mixture was stirred overnight to react, leaving the raw material and DOTA-tris(t-Bu ester) (139 mg, 0.24 mmol) and HATU (91 mg, 0.24 mmol) were added and the reaction was continued for 2 h. After the reaction was completed, the reaction solution was washed with water and extracted with DCM (20 mL × 3). The organic phases were combined, washed with 20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluted with the eluent system dichloromethane / methanol=methanol (0% to 20%) to obtain w-8 (110 mg, yield: 36.6%). MS m / z (ESI): 1253.4 [M+1] +

[0239] Step 6 At room temperature, w-8 (110 mg) was dissolved in 2 mL of THF and 1 mL of water, and lithium hydroxide was added. After the addition was completed, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was evaporated to dryness under reduced pressure to obtain w-9. Step 7 At room temperature, w-9 and TFA (2 mL) were added to a reaction flask, stirred until clear, and reacted at room temperature for 2 h after addition. After the reaction was completed, the mixture was evaporated to dryness under reduced pressure and purified by high-performance preparative liquid chromatography to obtain the title product w (13 mg). MS m / z (ESI): 1043.6 [M+1] + Example 11

[0240] [ka] (((S)-1-Carboxy-5-((S)-3-(2-naphthyl)-2-((6R,9s)-4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecyl)acetyl)-1-oxa-4-azaspiro[5.5]undecane-9-formamido)propionamido)pentyl)carbamoyl)-L-glutamic acid Compound x was prepared according to the same method as in Example 9.

[0241] Example 12. Compound 177 Preparation of Lu-v Total reaction volume 400 μL, 15 nmol of compound v, 15 mCi 177 Lu, and 321 μL of acetic acid-sodium acetate buffer (0.1 M, pH 4.5) was added to a 1.5 mL centrifuge tube, followed by 15 μL of compound v solution to obtain 7 μL of nuclide. 177 LuCl3 (activity: 15.23 mCi) was taken and placed in a thermostatic mixer and shaken. The reaction temperature was 95°C, the reaction time was 15 min, the activity was 15.15 mCi, and the HPLC result was >99%.

[0242] Example 13. Compound 68 Preparation of Ga-v Weigh out 13.5 mg of compound v, dissolve it in ultrapure water and make the volume to 25 mL, weigh out 136 mg of sodium acetate trihydrate and dissolve it in 1 mL of ultrapure water, and pipette 20 μL of the solution obtained in step 1 into a reaction vial, and then add 4.5 mL of 68 GaCl3 hydrochloric acid eluent, 0.5mL of buffer solution from step 2 was added, gently shaken, and reacted at 95℃ for 10min, then cooled to room temperature and sent for detection and use. Test Example 1. PSMA Inhibitory Activity Test

[0243] 1. Experimental materials and equipment 1. Multi-function plate reader (SPARK, TECAN) 2. rhPSMA (R&D, 4234-ZN) 3.N-Acetyl-Asp-Glu (Sigma, A5930) 4. OPA (Sigma, P0657)

[0244] II. Experimental Procedure PSMA inhibitors can bind to the PSMA enzyme and prevent the degradation of the substrate N-Acetyl-Asp-Glu by the PSMA enzyme. This experiment evaluated the binding ability of PSMA inhibitors to the PSMA enzyme by detecting the change in UV absorption according to the degree of degradation of the substrate, and also measured the IC 50 The activity of the compounds was evaluated according to the magnitude of the . 0.4μg / mL rhPSMA solution and 40μM substrate N-Acetyl-Asp-Glu were prepared using Buffer 1 (50mM HEPES, 0.1M NaCl, pH7.5). rhPSMA and the test small molecule were mixed in a 96-well plate, and the content of rhPSMA was maintained at 50ng / well, and the final concentrations of the small molecule were 1μM, 100nM, 33.3nM, 11.1nM, 3.7nM, 1.2nM, 0.41nM, 0.137nM, 0.045nM, and 0nM by gradient dilution. PSMA-617 was used as a positive control. 40μL / well of rhPSMA-small molecule was taken and mixed evenly with 40μL / well of 40μM substrate N-Acetyl-Asp-Glu, and incubated at 37℃ in the dark for 1h. The reaction was quenched by heating at 70℃ for 5min and cooled to room temperature. 15mM OPA solution was prepared using buffer 2 (0.2M NaOH, 0.1% beta-Mercaptoethanol). 80μL / well of OPA solution was added to the reaction system, mixed evenly, and incubated at room temperature for 10min. 100μL / well of the mixture was taken and placed in a 96-well Flat Black, the excitation wavelength was set to 330nm, the emission wavelength was set to 465nm, the signal intensity was read, and the IC was calculated by the dose-response curve. 50 asked for.

[0245] 3. Experimental Data The ability of the compounds of the present disclosure to bind to the GCPII enzyme can be measured by the above test, and the measured IC 50 The values ​​are shown in Table 1.

[0246] [Table 2-1] [Table 2-2] [Table 2-3] Test Example 2. Affinity measurement by enzyme activity method

[0247] 0.4μg / mL rhPSMA solution and 40μM substrate N-Acetyl-Asp-Glu were prepared using Buffer 1 (50mM HEPES, 0.1M NaCl, pH7.5). rhPSMA and the test small molecule were mixed in a 96-well plate, and the content of rhPSMA was maintained at 50ng / well, and the final concentrations of the small molecule were 1μM, 100nM, 33.3nM, 11.1nM, 3.7nM, 1.2nM, 0.41nM, 0.137nM, 0.045nM, and 0nM by gradient dilution. PSMA-617 was used as a positive control. 40μL / well of rhPSMA-small molecule was taken and mixed evenly with 40μL / well of 40μM substrate N-Acetyl-Asp-Glu, and incubated at 37℃ in the dark for 1h. The reaction was quenched by heating at 70℃ for 5min and cooled to room temperature. 15mM OPA solution was prepared using buffer 2 (0.2M NaOH, 0.1% beta-Mercaptoethanol). 80μL / well of OPA solution was added to the reaction system, mixed evenly, and incubated at room temperature for 10min. 100μL / well of the mixture was taken and placed in a 96-well Flat Black, the excitation wavelength was set to 330nm, the emission wavelength was set to 465nm, the signal intensity was read, and the IC was calculated by the dose-response curve. 50 asked for.

[0248] [Table 3-1] [Table 3-2]

[0249] The specific structure is shown in Figure 1. By comparing compound v in Example 9 and compound x in Example 11 through enzyme activity experiments, it can be confirmed that compound v has better affinity. Test Example 3. Biological distribution of compounds in tumor-bearing mice

[0250] A single intravenous injection into the tail vein of mice 68 The in vivo distribution of Ga-labeled compounds v (Example 9) and x (Example 11) in positive LnCaP tumor-bearing animals was observed.

[0251] The test time was 2 h, and a total of three animals were killed by decapitation, and tissue samples including blood, heart, lung, liver, spleen, kidney, stomach, intestine, bone, flesh, brain, salivary gland, large intestine, pancreas, and tumor were collected. The net weight of the tissue was first weighed, and then the tissues taken were counted by gamma counter. The distribution of the labeled compound in different tissues and organs of the mice was measured. At the same time, the test sample was accurately diluted 100 times, and 0.1 mL was taken and placed in a counting tube to be used as the standard 1% ID (i.e., 1 / 100 of the dose), and the radioactivity count of the 1% ID standard and the biological sample was measured simultaneously by gamma counter. The biological distribution data was expressed as the percentage of radioactivity count per gram of tissue or organ (%ID / g) relative to the total dose (radioactivity count).

[0252] The specific results are shown in Figure 2. 68 Ga-v (Example 9) had the highest uptake in the LnCap tumor at about 10 Id% / g, followed by the kidney, liver, lung, and spleen. The uptake in the other tissues was very low. 68 It was demonstrated that Ga-v (Example 9) had a relatively good targeting effect on LnCap tumors. 68 Ga-v (Example 9) showed high tumor uptake 68 It is superior to Ga-x (Example 11). Test Example 4. Pharmacokinetics and Toxicity

[0253] 4.1 68 Blood half-life of Ga-v (Example 9) A single intravenous injection into the tail vein of mice 68 A blood pharmacokinetic study was carried out for Ga-v (Example 9) and PSMA-617.

[0254] Each mouse was administered 50μCi / 100μL, and blood was collected from the orbit at 0.083, 0.25, 0.5, 1, 2, and 4h after administration. Four animals were collected at each time point into pre-weighed sample tubes, and the weights of the blood samples were weighed and recorded, and radioactivity counting was performed using a γ-counter. At the same time, the test sample was accurately diluted 100 times, and 0.1mL was taken and placed in a counting tube to set the standard of 1%ID (i.e., 1 / 100 of the dose), and the radioactivity counts of the 1%ID standard and the biological samples were simultaneously measured using a γ-counter. The blood data were expressed as the percentage of radioactivity counts per gram of blood (%ID / g) relative to the total dose (radioactivity count). Pharmacokinetic parameters were calculated based on the blood drug concentration data. The results of uptake in the blood of normal mice are shown in Table 3 below (n=4).

[0255] [Table 4-1] [Table 4-2]

[0256] The calculated pharmacokinetic parameters are shown in Table 4 (0-4h) below.

[0257] [Table 5]

[0258] According to the results of the above experiment, 68 Ga-v (Example 9), 68When Ga-PSMA-617 was administered into the blood of normal mice, the radioactive material was rapidly distributed, with the blood content being only 1.25 (0.22%) and 2.27 (0.44%) ID / g 0.25 h after injection, respectively, and was rapidly eliminated, with a blood half-life of only 0.13 h (7.8 min) and 0.22 h (13.2 min).

[0259] 68 Ga-v (Example 9) has a half-life of 0.13h (7.8min) in the blood in mice and a half-life of 0.758h in the clearance phase. The time until the metabolism is completed is generally estimated based on five half-lives, and it should be almost metabolized 3.9h after administration. In addition, from the imaging data, there was almost no signal in normal organs after 4h. The effective half-life was calculated to be Te=0.45h, which is estimated to be 2.27h based on the five effective half-lives.

[0260] 4.2 Radiation absorbed dose Bio-D biodistribution data were used to calculate drug metabolism AUCs and imported into OLINDA software to generate whole-organ radiation absorbed doses.

[0261] [Table 6-1] [Table 6-2]

[0262] As can be seen from the above table, 68 Ga-v (Example 9) 68 Compared to Ga-PSMA-617, it has a lower radiation absorbed dose by one time and has better safety. 177 Lu-v (Example 9) has a radiation absorbed dose of 177 lower than Lu-PSMA-617.

Claims

1. A compound of formula (IV) or a pharmaceutically acceptable salt thereof, 【Chemical 1】 Among them, Q is selected from H or a protecting group, preferably H; R １ , R ２ are each independently H or C １－４ alkyl groups, preferably H; １－４ The alkyl group is optionally substituted or unsubstituted with one or more substituents P, Q, R １ , R ２ may be the same or different on each occurrence, Y １ is S or O, preferably O, T is -NR ４ (CO)-, -NR ４ (SO ２ ) -, -NR ４ (CH ２ ) - selected from R ４ is H, C １－６ an alkyl group, a 6- to 10-membered aryl group, or a 5- to 12-membered heteroaryl group; １－６ the alkyl group, the 6- to 10-membered aryl group or the 5- to 12-membered heteroaryl group is optionally unsubstituted or substituted with one or more substituents P; Ring A is selected from 3- to 12-membered nitrogen-containing heterocyclyl groups, which are optionally substituted or unsubstituted with one or more substituents P; W is selected from a 6- to 10-membered aryl group, a 5- to 12-membered heteroaryl group, which is optionally substituted or unsubstituted with one or more substituents P; The substituent P is C １ -C ６ Alkyl group, halogen, deuterium, hydroxy group, mercapto group, -NR ｉ R ｊ , oxo, thio, -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 , nitro group, cyano group, C １ -C ６ Alkoxy group, C １ -C ６ Alkyl thioether group, C ２ -C ６ Alkenyl group, C ２ -C ６ selected from an alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused ring aryl group, and a 5- to 12-membered fused ring heteroaryl group; R ｉ , R ｊ are each independently a hydrogen atom, a hydroxy group, or C １ -C ６ Alkyl group, C １ -C ６ alkoxy groups, R ｋ are independently a hydrogen atom, C １ -C ６ Alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, hydroxy group, —NR ｉ R ｊ wherein the alkyl group, alkoxy group, and haloalkyl group are optionally selected from C １ -C ６ Alkyl group, halogen, hydroxy group, mercapto group, -NR ｉ R ｊ , oxo, thio, carboxy group, nitro group, cyano group, C １ -C ６ Alkoxy group, C １ -C ６ Alkyl thioether group, C ２ -C ６ Alkenyl group, C ２ -C ６ substituted by one or more substituents selected from an alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; y, z, g, and h each independently represent an integer from 0 to 6; R ３ is selected from H or a chelating agent, The compound or a pharmaceutically acceptable salt thereof.

2. T is —NH(CO)—, and ring A is a 5- to 12-membered nitrogen-containing spiroheterocyclyl group, preferably a 5- to 12-membered nitrogen-containing monospiroheterocyclyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, or 6-membered / 6-membered nitrogen-containing monospiroheterocyclyl group, and most preferably 【Chemistry 2】 and particularly preferably 【Chemistry 3】 That is, A compound of formula (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. W is selected from 6- to 10-membered aryl groups, preferably naphthyl groups; 3. A compound of formula (IV) according to claim 2 or a pharmaceutically acceptable salt thereof.

4. Y １ is O, A compound of formula (IV) according to claim 3 or a pharmaceutically acceptable salt thereof.

5. R １ and R ２ are each independently H; The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Q is selected from H or a protecting group, preferably H; The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

7. Y and h are each independently selected from 0, 1 or 2, preferably 1; The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

8. g is selected from 3 or 4, preferably 3; The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

9. z is selected from 0 or 1, preferably 0; The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

10. The chelating agent is 【Chemistry 4】 Preferably, 【Chemistry 5】 That is, The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

11. the below described: 【Chemistry 6】 【Chemistry 7】 or a pharmaceutically acceptable salt thereof, wherein R ３ is H or 【Chemistry 8】 Selected from The compound represented by (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

12. the below described: 【Chemistry 9】 and preferably 【Chemistry 10】 and most preferably 【Chemistry 11】 or a pharmaceutically acceptable salt thereof; A compound of formula (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

13. the chelating agent comprises a radionuclide; 2. The compound of formula (IV) according to claim 1 or a pharmaceutically acceptable salt thereof.

14. The radionuclide is １８ F. １１ C. ６８ Ga, １２４ I, ８９ Zr, ６４ Cu, ８６ Y. ９９ｍ Tc, １１１ In, １２３ I, ９０ Y. １２５ I, １３１ I, １７７ Lu, ２１１ At, １５３ Sm, １８６ Re, １８８ Re, ６７ Cu, ２１２ Pb, ２２５ Ac, ２１３ Bi, ２１２ Bi, ２１２ Pb or ６７ At least one selected from Ga, preferably ６８ Ga or １７７ Lu, 14. The compound of formula (IV) according to claim 13, or a pharmaceutically acceptable salt thereof.

15. the below described: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof, wherein the chelating agent comprises a radionuclide, and the radionuclide is ６８ Ga, 15. A compound of formula (IV) according to claim 14 or a pharmaceutically acceptable salt thereof.

16. the below described: 【Chemistry 13】 or a pharmaceutically acceptable salt thereof, wherein the chelating agent comprises a radionuclide, and the radionuclide is １７７ Lu, 15. A compound of formula (IV) according to claim 14 or a pharmaceutically acceptable salt thereof.

17. A composition comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, diluents or vectors.

18. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a composition according to claim 17, in the preparation of a composition for imaging in a patient.

19. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a composition according to claim 17, in the preparation of a medicament for diagnosing and / or treating and / or preventing a PSMA-mediated disease or condition.

20. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a composition according to claim 17, in the preparation of a medicament for diagnosing and / or treating and / or preventing tumors and cancers, preferably wherein the tumors and cancers are prostate cancer.

21. A method for preparing a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IV) is a compound represented by formula v or a pharmaceutically acceptable salt thereof, the method comprising the steps of: removing tert-butyl from a compound represented by formula v-5; 【Chemistry 14】 Including, Preparation method.

22. a step of subjecting a compound represented by formula v-3 and a compound represented by formula v-4 to a condensation reaction to obtain a compound represented by formula v-5; the below described: 【Chemistry 15】 22. The method of claim 21 further comprising:

23. 23. A method of producing a compound of formula (IV) or a pharmaceutically acceptable salt thereof according to claim 21 or 22, further comprising the step of complexing a radionuclide with a chelating agent in the compound of formula (IV) or a pharmaceutically acceptable salt thereof. A method for preparing the compound of claim 13.

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