Prostate-specific membrane antigen inhibitor, radionuclide marker thereof, and use thereof

Abstract

The present invention provides a PSMA-targeting compound having a novel structure as shown in formula (I), a racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt thereof or a prodrug compound thereof, and a radionuclide marker thereof. The compound and the radionuclide marker thereof can be widely used in the diagnosis, staging, treatment or efficacy assessment of prostate cancer.

Description

Inhibitors of prostate-specific membrane antigens, their radionuclide markers, and their uses

[0001] This application requests the following:

[0002] Priority rights to the earlier application filed with the China National Intellectual Property Administration on December 13, 2024, with patent application number 202411844250.3 and title "Radioactive element-labeled prostate-specific membrane antigen inhibitor and its use therein";

[0003] Priority rights to the earlier application filed with the China National Intellectual Property Administration on March 26, 2025, with patent application number 202510368391.0 and title "Radioactive element-labeled prostate-specific membrane antigen inhibitor and its use therein";

[0004] Priority rights to the earlier application filed with the China National Intellectual Property Administration on October 23, 2025, with patent application number 202511528963.3 and title "Radioactive element-labeled prostate-specific membrane antigen inhibitor and its use therein";

[0005] The full text of the prior application is incorporated herein by reference. Technical Field

[0006] This invention belongs to the field of radiopharmaceuticals and relates to prostate-specific membrane antigen inhibitors, their radionuclide markers, and their pharmaceutical uses. Background Technology

[0007] Prostate cancer is one of the most common cancers in men, second only to lung cancer in incidence and mortality. However, the mortality rate of prostate cancer has been declining, mainly due to the widespread use of prostate-specific antigen (PSA) blood tests. PSA testing is considered to have revolutionized prostate cancer (PCa) screening. Early detection of PSA leads to a better prognosis (5-year survival rate of over 95%). Initial treatments include total or partial resection of the primary lesion, or radiation therapy. Hormone therapy is also an effective treatment. However, recurrence or metastasis over many years is not uncommon. After recurrence, hormone therapy may be temporarily effective, but it gradually becomes resistant, developing into castration-resistant prostate cancer (CRPC), especially metastatic castration-resistant prostate cancer (mCRPC), which is very difficult to treat. Developing effective treatments and diagnostic drugs for CRPC is an urgent need. Prostate-specific membrane antigen (PSMA) is a target molecule for prostate cancer. PSMA is commonly found in primary lesions, recurrent lesions, lymph node metastases, and bone metastases of prostate cancer. Therefore, drugs that specifically bind to PSMA may be effective for the treatment and diagnosis of CRPC and mCRPC.

[0008] Over the past few decades, new diagnostic / prognostic tools, especially imaging examinations, have been introduced into clinical practice to better support the diagnosis and treatment of prostate cancer patients. Furthermore, PSMA is also found in normal tissues, including the kidneys and salivary glands; therefore, it is important that drugs that specifically bind to PSMA do not exhibit the side effect of accumulation in the kidneys and salivary glands. Novartis' Pluvicto was the first marketed radiopharmaceutical targeting PSMA. 177 Lu (a beta-emitting nuclide) is a radionuclide. Studies have shown that this drug has some effect in treating CRPC patients, but some cancer patients are still not treatable with this drug. Therefore, developing a new PSMA-targeted drug has broad application prospects in the treatment of CRPC patients. Summary of the Invention

[0009] To address the problems existing in the prior art, the present invention includes, but is not limited to, providing a novel PSMA-targeting compound and its radionuclide label, as well as its preparation method and uses.

[0010] This invention first provides a compound of formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0011] Wherein, Ch is selected from chelating agent residues;

[0012] L A It does not exist, or is selected from -AC (=O)-; where A is selected from unsubstituted or optionally by one, two or more R. a The following groups are substituted: C-16 3-10 Cycloalkyl, 3-10 membered heterocyclic, C-membered 6-14 Aryl, sub-5-14 quinone heteroaryl; each R a They may be the same or different, and are independently selected from H, halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0013] L B It does not exist, or it is selected from -NH-(CH2). p - 4-8 membered heterocyclic groups;

[0014] Q is selected from C(O), sub-C 1-10 Alkyl or C 1-6 Alkoxy-substituted C 1-10 alkyl;

[0015] R LSelected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-10 Alkyl, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L1 They may be identical or different, and are independently selected from X, H, halogen, oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R. L2 The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L2 They may be the same or different, and are independently selected from Y, H, halogen, borate group, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy;

[0016] X and Y may be the same or different, and are independently selected from radioactive isotopes of iodine, bromine, or astatine, preferably. 125 I, 131 I, 211 At;

[0017] n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;

[0018] p is selected from 1, 2, 3, 4, 5, 6, 7, or 8;

[0019] q is selected from 1, 2, 3, 4, 5, 6, 7 or 8.

[0020] According to an embodiment of the present invention, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-10 Alkyl, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L1 They may be identical or different, and are independently selected from H, halogen, oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R atoms. L2 The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L2 They may be the same or different, and are independently selected from H, halogen, borate group, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0021] According to an embodiment of the present invention, Ch is selected from the following groups: Where m is selected from 1, 2, 3, 4, 5, 6, 7 or 8.

[0022] According to an embodiment of the present invention, Ch is selected from

[0023] According to an embodiment of the present invention, L A When it does not exist, L B It does not exist.

[0024] According to an embodiment of the present invention, L A Selected from -AC(=O)-, L B Selected from -NH-(CH2) p - or 4-8 membered heterocyclic groups.

[0025] According to an embodiment of the present invention, L A When L is selected from -AC(=O)-, A The carbonyl group in the middle and the L group on the right side B Connected, forming -AC(=O)-L B .

[0026] According to an embodiment of the present invention, L B Selected from -NH-(CH2) p - or a 5-6 member nitrogen-containing sub-heterocyclic group; preferably, the N heteroatom in the 5-6 member nitrogen-containing sub-heterocyclic group is related to the L... A The carbonyl group is attached.

[0027] According to an embodiment of the present invention, L B Selected from -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5- or

[0028] According to an embodiment of the present invention, L A Selected from -AC(=O)-, where A is selected from unsubstituted or optionally by one, two or more Rs. a The following groups are substituted: C-16 3-6 cycloalkyl, C-ide 6-10 Aryl;

[0029] According to an embodiment of the present invention, A is selected from cyclohexylene and phenylene;

[0030] According to an embodiment of the present invention, A is selected from...

[0031] According to an embodiment of the present invention, Q is selected from C(O), C-sub-C 1-6 Alkyl or C1-3 Alkoxy-substituted C 1-6 alkyl.

[0032] According to an embodiment of the present invention, Q is selected from C(O), -CH2-, -CH2CH2-, -CH2CH2CH2-,

[0033] According to an embodiment of the present invention, Q is selected from C(O), C-sub-C 1-6 alkyl;

[0034] According to an embodiment of the present invention, Q is selected from C(O) and -CH2-;

[0035] According to an embodiment of the present invention, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-6 Alkyl, C 6- 10 Aryl;

[0036] According to an embodiment of the present invention, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: methyl, ethyl, phenyl;

[0037] According to an embodiment of the present invention, R L Selected from -C(O)-R L1 -C(O)-CH2-R L1 ,

[0038] According to an embodiment of the present invention, each R L1 They are either identical or different, and are independently selected from oxo (=O), -S(O)2F, 125 I, 211 At, without substitution or optionally by one, two or more R L2 The following groups are substituted: C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0039] According to an embodiment of the present invention, each R L1 They are either identical or different, and are independently selected from oxo (=O), -S(O)2F, 125 I, 211 At, without substitution or optionally by one, two or more R L2 The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl (e.g.) ), furanyl, (like: ), morpholino (e.g.) ), tetrahydropyranyl (e.g.) ), pyridyl (e.g.) );

[0040] According to an embodiment of the present invention, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0041] According to an embodiment of the present invention, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl (e.g.) ), furanyl, (like: ), morpholino (e.g.) ), tetrahydropyranyl (e.g.) ), pyridyl (e.g.) );

[0042] According to an embodiment of the present invention, each R L2 They may be the same or different, and are independently selected from halogens, borate groups, and C. 1-6 alkyl;

[0043] According to an embodiment of the present invention, each R L2 They may be the same or different, and are independently selected from F, Cl, Br, I, borate group, methyl group, 125 I, 211 At;

[0044] According to an embodiment of the present invention, each R L2 They may be the same or different, and are independently selected from F, Cl, Br, I, borate group, and methyl group;

[0045] According to an embodiment of the present invention, R L Selected from (like ),

[0046] According to an embodiment of the present invention, the compound shown in formula (I) has the structure shown in (I'):

[0047] In the aforementioned formula (I'),

[0048] R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-10 Alkyl, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L1 They may be identical or different, and are independently selected from H, halogen, oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R atoms. L2 The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L2 They may be the same or different, and are independently selected from H, halogen, borate group, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 alkoxy groups; wherein, the Ch, L A L B Q, n, p, and q have the definitions described above;

[0049] According to an embodiment of the present invention, the R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-6 Alkyl, C 6-10 Aryl;

[0050] According to an embodiment of the present invention, the R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: methyl, ethyl, phenyl;

[0051] According to an embodiment of the present invention, the R L Selected from -C(O)-R L1 -C(O)-CH2-R L1 , In some implementations, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl;

[0052] According to an embodiment of the present invention, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl (e.g.) ), furanyl, (like: ), morpholino (e.g.) ), tetrahydropyranyl (e.g.) ), pyridyl (e.g.) );

[0053] According to an embodiment of the present invention, each R L2 They may be the same or different, and are independently selected from halogens, borate groups, and C. 1-6 alkyl;

[0054] According to an embodiment of the present invention, each R L2 They may be the same or different, and are independently selected from F, Cl, Br, I, borate group, and methyl group.

[0055] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0056] Among them, A, Q, L A L B R L m, n, p, and q each have the definitions described above independently.

[0057] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0058] Among them, A, Q, L B R L m, n, p, and q each have the definitions described above independently.

[0059] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0060] Among them, A, Q, R L1 R L2 p, q, and q are independently defined as described above.

[0061] According to an embodiment of the present invention, the compound represented by formula (I') has the following structure:

[0062] Among them, A, Q, R L1 R L2 p, q have the definitions described in formula (I') above independently.

[0063] According to an embodiment of the present invention, the compound represented by formula (I) has the following structure:

[0064] The present invention also provides compounds of formula (II), their racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts, or prodrug compounds thereof.

[0065] Wherein, Ch' is selected from chelating agent residues containing M, and is formed by chelating Ch with M as described above;

[0066] L A L B Q, R L m, n, and q are independently defined as described above.

[0067] M is selected from radioactive or non-radioactive metals, such as Ga, Lu, Ac, Pd, Pb, Tc, Tb, Cu, Bi, Al, Zr, Y, In, Sm, Re, Ra, and Ho, and their radioactive isotopes, for example... 68 Ga、 89 Zr、 64 Cu、 86 Y、 99 Tc, 161 Tb, 111 In、 90 Y、 67 Ga、 175 Lu、 177 Lu、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213 Bi、 223 Ra、 212 Bior 212 Pb, preferred 175 Lu、 177 Lu、 225 Ac、 161 Tb, 212Pb.

[0068] According to an embodiment of the present invention, the compound of formula (I) in the compound of formula (II) is chelated with M.

[0069] According to an embodiment of the present invention, the compound represented by formula (II) has the following structure:

[0070] Among them, L A L B Q, R L , m, n, q, and M each have the definitions described above independently.

[0071] According to an embodiment of the present invention, the compound represented by formula (II) has the following structure:

[0072] Among them, A and L B Q, R L m, n, p, q, and M each have the definitions described above independently.

[0073] According to an embodiment of the present invention, the compound represented by formula (II) has the following structure:

[0074] Among them, A, Q, M, X, Y, p, and q independently have the definitions described above.

[0075] According to an embodiment of the present invention, the compound represented by formula (II) has the following structure:

[0076] According to an embodiment of the present invention, the radiochemical purity of the compound of formula (II), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound is greater than or equal to 85%, for example greater than or equal to 90%.

[0077] The present invention also provides a compound of formula (III), its racemate, stereoisomer, tautomer, solvate, polymorph, or pharmaceutically acceptable salt thereof:

[0078] R S1 Selected from H or R L ;

[0079] R S2 Selected from hydroxyl or -O-carboxyl protecting groups;

[0080] R L It has the definition described above;

[0081] Z is selected from any one, two or more Cs. 1-6 Alkoxy-substituted C 1-6 alkyl.

[0082] According to an embodiment of the present invention, R S2 Selected from OH or C 1-6 Alkyl group.

[0083] According to an embodiment of the present invention, R S2 Selected from OH or -O-tBu.

[0084] According to an embodiment of the present invention, Z is selected from C. 1-3 Alkoxy-substituted C 2-6 alkyl.

[0085] According to an embodiment of the present invention, Z is selected from methoxy-substituted C-type derivatives. 2-6 alkyl.

[0086] According to an embodiment of the present invention, Z is selected from...

[0087] According to an embodiment of the present invention, the compound represented by formula (III) has the following structure:

[0088] Among them, R S1 R S2 As defined above.

[0089] According to an embodiment of the present invention, the compound represented by formula (III) has the following structure:

[0090] The present invention also provides a compound of formula (IV), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound:

[0091] Ch”—L—B

[0092] Formula (IV)

[0093] "Ch" is selected from chelating agent residues and chelating agent residues containing radioactive or non-radioactive metals.

[0094] L is a divalent linker;

[0095] B is the targeting group, selected from the following groups:

[0096] Where R L Z has the definition described above.

[0097] According to an embodiment of the present invention, B is selected from the following groups:

[0098] According to an embodiment of the present invention, the compound shown in formula (IV) has the following structure:

[0099] Wherein, Ch” is selected from Ch or Ch';

[0100] Ch、Ch'、L A L B R L Z and n have the definitions described above.

[0101] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), formula (II) or formula (IV), a racemic mixture thereof, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a polymorph thereof, a pharmaceutically acceptable salt thereof, or a prodrug compound thereof.

[0102] According to embodiments of the present invention, the pharmaceutical composition further includes one or more pharmaceutically acceptable excipients.

[0103] According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0104] The present invention also provides the use of compounds of formula (I), formula (II) or formula (IV), their racemates, stereoisomers, tautomers, solvates, polymorphs, pharmaceutically acceptable salts or prodrug compounds in the preparation of pharmaceuticals.

[0105] According to an embodiment of the present invention, the drug is a drug for the prevention, treatment or diagnosis of prostate cancer, or the drug is a drug for imaging prostate cancer.

[0106] According to an embodiment of the present invention, the prostate cancer is castration-resistant prostate cancer.

[0107] According to an embodiment of the present invention, the prostate cancer is metastatic castration-resistant prostate cancer.

[0108] According to an embodiment of the present invention, the prostate cancer is PSMA-positive prostate cancer.

[0109] The present invention also provides a method for treating or diagnosing prostate cancer, comprising administering to a patient a preventive, therapeutic or diagnostic effective amount of a compound of formula (I), formula (II) or formula (IV), its racemic, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, or the pharmaceutical composition thereof.

[0110] In some implementations, the patient includes mammals, preferably humans. Beneficial effects

[0111] This invention provides a novel PSMA-targeting compound of formula (I), its racemic, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, and its radionuclide label. This invention further verifies that the compound of formula I exhibits good PSMA binding activity, while its radionuclide label demonstrates high cellular uptake and internalization of water, as well as high tumor uptake levels in a mouse model. Therefore, the PSMA-targeting compound and its radionuclide label can be widely used in the diagnosis, staging, prevention / treatment, or efficacy evaluation of prostate cancer. Attached Figure Description

[0112] Figure 1 shows the compounds. 177 Tissue distribution of Lu-02 in PC3-PSMA tumor-bearing mouse model.

[0113] Figure 2 shows the compounds. 177 Tissue distribution of Lu-05 in PC3-PSMA tumor-bearing mouse model.

[0114] Figure 3 shows the compounds. 177 Tissue distribution of Lu-49 in PC3-PSMA tumor-bearing mouse model.

[0115] Figure 4 shows the compounds. 177 Tissue distribution of Lu-50 in PC3-PSMA tumor-bearing mouse model.

[0116] Figure 5 shows the compounds. 177 Tissue distribution of Lu-51 in PC3-PSMA tumor-bearing mouse model.

[0117] Figure 6 shows the compounds. 177 Tissue distribution of Lu-54 in PC3-PSMA tumor-bearing mouse model.

[0118] Figure 7 shows the compounds. 177 Tissue distribution of Lu-56 in PC3-PSMA tumor-bearing mouse model.

[0119] Figure 8 shows the compounds. 177Tissue distribution of Lu-58 in LNCaP tumor-bearing mouse model.

[0120] Figure 9 shows the compounds. 177 Tissue distribution of Lu-59 in LNCaP tumor-bearing mouse model.

[0121] Figure 10 shows the compounds. 177 Tissue distribution of Lu-60 in LNCaP tumor-bearing mouse model.

[0122] Figure 11 shows the compounds. 177 Tissue distribution of Lu-61 in LNCaP tumor-bearing mouse model.

[0123] Figure 12 shows the compounds. 177 Tissue distribution of Lu-62 in LNCaP tumor-bearing mouse model.

[0124] Figure 13 shows the compounds. 177 Tissue distribution of Lu-63 in LNCaP tumor-bearing mouse model.

[0125] Terminology Definitions and Explanations

[0126] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0127] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1-14" is equivalent to describing each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14. Furthermore, when certain numerical ranges are defined as "numbers", it should be understood that they describe the two endpoints of the range, each integer within the range, and each decimal within the range.

[0128] In various parts of this invention, descriptions of linking substituents (e.g., A, Q) are included. Those skilled in the art will understand that when a linking group is clearly required in the structure of a compound, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively. Therefore, when used as a linking group, "*-" and "*-" are equivalently defined; for example, "alkyl" and "alkylene" are equivalently defined, and "aryl" and "arylene" are equivalently defined. Those skilled in the art will also understand that the term "*-" indicates a divalent group connected to other groups by two single bonds or one double bond. The "*-" is, for example, "*-" 1-10 Alkyl group, C-alkyl group 3-10 "cycloalkyl", "3-14 membered heterocyclic", "C-membered heterocyclic" 6-14 "Aromatic", "sub-5-14 aryl", where "C" 1-10 Alkyl", C 3-10 "cycloalkyl", "3-14 membered heterocyclic", "C" 6-14 When "aryl" or "5-14 heteroaryl" refers to a linking group, it has the definition described above for "sub-aryl".

[0129] The term "C(O)" represents the carbonyl group.

[0130] The term "integers from 0 to 10" refers to 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0131] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0132] “C 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers.

[0133] Term "C" 3-10 "Cycloalkyl" should be understood to refer to saturated monocyclic, bicyclic (e.g., bridged, spirocyclic) or tricyclic alkanes having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0134] Term "C" 6-14 "Aryl" should be understood to preferably represent an aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 6-14 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C 6-14 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0135] The term "3-14 membered heterocyclic group" refers to a saturated or unsaturated non-aromatic ring or ring system, for example, a 4-, 5-, 6-, or 7-membered monocyclic ring, a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring (such as a fused ring, bridged ring, or spirocyclic ring), or a 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, for example, 1, 2, 3, 4, 5, or more heteroatoms selected from O, S, and N, wherein N and S may optionally be oxidized to various oxidation states to form nitrides, -S(O)-, or -S(O)2- states. Preferably, the heterocyclic group may be selected from "3-10 membered heterocyclic groups". The term "3-10 membered heterocyclic group" means a saturated or unsaturated non-aromatic ring or ring system containing at least one heteroatom selected from O, S, and N. The heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 4-membered rings, such as azirrobutyl or oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolealkyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazineyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or the heterocyclic atom on the 3-14-membered heterocyclic ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine, the nitrogen atom on the piperazine group can be attached to other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinium, the nitrogen atom on the piperidinium ring and the carbon atom at its para position can be attached to other groups.

[0136] The term "5-14-membered heteroaryl" should be understood to include monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 5, 6, 9, or 10 carbon atoms, and comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, and in each case may be benzofused. "Heteroaryl" also refers to a group in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the root or point of the connection is on the heteroaryl ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indazinyl, 1-, 3-, 4-, 5-, 6- or 7-isoindoleyl, 2-, 3-, 4-, 5-, 6- or 7-indoleyl, 2-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 4-, 5-, 6-, 7- or 8-purineyl, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinazinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl, 2-, 3-, 4-, 5- or 6-naphthidyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-pyrrolinyl, 2-, 4-, 6- or 7-pteridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazole, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-carbazole, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbazole, 1-, 2-, 3- 4-, 6-, 7-, 8-, 9- or 10-phenanthidium, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-pyridyl, 2-, 3-, 4-, 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenazinyl, 2- 3, 4, 5, 6 or 1, 3, 4, 5, 6, 7, 8, 9 or 10-benzoisoquinolinyl, 2, 3, 4 or thieno[2,3-b]furanyl, 2, 3, 5, 6, 7, 8, 9, 10 or 11-7H-pyrazino[2,3-c]carbazoleyl, 2, 3, 5, 6 or 7-2H-furano[3,2-b]-pyranyl, 2, 3, 4, 5, 7 or 8-5H-pyrido[2,3-d]-o-azinyl, 1, 3 or 5-1H-pyrazolo[4,3-d]-azole, 2-, 4- or 54H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8- or 9-furano[3,4-c]cenolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]carbazole, 2-, 3-, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thiazolyl Phenoyl, 2-, 4-, 5-, 6- or 7-benzozozolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzoazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-4H-pyrrolo[1,2-b][2]benzozapinyl. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thiophene, 2-, 4-, 5-, 6-, or 7-benzozozolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl. When the 5-14-membered heteroaryl group is linked to other groups to form the compounds of the present invention, the carbon atom on the 5-14-membered heteroaryl ring may be linked to other groups, or the heteroatom on the 5-14-membered heteroaryl ring may be linked to other groups. When the 5-14-membered heteroaryl group is substituted, it may be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution sites; for example, hydrogen atoms bonded to carbon atoms on the heteroaryl ring can be substituted, or hydrogen atoms bonded to heteroatoms on the heteroaryl ring can be substituted.

[0137] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0138] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0139] The term "bridged ring" refers to a ring system in which two rings share three or more cyclic atoms.

[0140] Wavy lines intersecting chemical bonds Used to indicate the connection position of a group with other atoms or groups in a general formula.

[0141] Term "C" 1-10"Alkoxy" refers to -O-(C 1-10 Alkyl), wherein C 1-10 The definition of alkyl groups is as described above. C 1-10 Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. C 1-10 The alkoxy group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, or heterocycloalkyloxy.

[0142] Those skilled in the art will understand that The dashed lines in the structure represent coordinate bonds, indicating that the central atom (or ion, collectively called the central atom) and the surrounding molecules, atoms, or ions (called ligands) are completely or partially bonded together by coordinate bonds. For ease of description, the same interpretation applies when the central atom is not shown or the coordinate bonds are only partially shown, as in the structure... Unless otherwise specified, all are consistent with The same understanding applies. Similarly, other similar statements (such as nuclides) can also be interpreted in the same way. 177 The same interpretation applies to all nuclides (where Lu is replaced with other nuclides).

[0143] In this invention, the compounds involved also include isotopically labeled compounds, which are the same as those shown in Formula I, but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of H, C, N, O, S, F, and Cl, respectively such as 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 32 P, 35 S, 18 F and 36 Cl. Compounds of the present invention, their prodrugs, or pharmaceutically acceptable salts of said compounds or prodrugs containing the aforementioned isotopes and / or other isotopes are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Compounds in (C) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e. 14C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavier isotopes (such as deuterium, i.e., 2 Hydrogen (H or D) substitution can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement), and may therefore be preferred in certain circumstances. The compounds of the invention claimed in the claims are particularly defined as being substituted with deuterium or tritium. Furthermore, the presence of hydrogen in the substituents without a separate mention of the terms deuterium or tritium does not exclude deuterium or tritium, but may also include deuterium or tritium.

[0144] In this invention, "radioactive nuclide marker" can be understood as corresponding to "radioactive nuclide-conjugated drug (RDC)," a drug form designed and developed by conjugating a precisely targeting molecule (monoclonal antibody or peptide / small molecule) and a potent cytotoxic factor (nucleoside) together with a linker arm. Its mechanism of action utilizes antibody or small molecule-mediated specific targeting to deliver cytotoxic molecules or imaging molecules, such as radioactive nuclides, to the target site, thereby concentrating the radiation generated by the radioisotope on the local tissue, achieving highly efficient and precise treatment while reducing damage to other tissues caused by systemic exposure. The energy generated by the radioactive rays from the nuclide can damage the chromosomes of cells, causing cells to stop growing, thereby eliminating rapidly dividing and growing cancer cells. The RDC load is a radioactive nuclide, which can be used for both diagnostic and therapeutic purposes. Based on this, those skilled in the art will understand that the structure of the compound shown in Formula I that does not contain a nuclide (e.g., Formula I') corresponds to a targeting ligand + linker structure, such as the "radioactive nuclide marker" shown in Formula II, which is loaded with a radioactive nuclide (e.g., the "M" group in Formula II of this invention; e.g., ...). 175 Lu、 177 (Lu et al.). Therefore, the structure of the compound shown in Formula I that does not contain a nuclide (e.g., Formula I') can also be understood as the "precursor compound" of the "radioactive nuclide conjugate".

[0145] Those skilled in the art will understand that the compounds shown in formula (I) can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0146] The compounds of the present invention may exist as solvates (such as hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, may be stoichiometric or non-stoichiometric.

[0147] Depending on their molecular structure, the compounds of the present invention can be chiral, and therefore may exist in various enantiomeric forms. Thus, these compounds can exist in racemic or optically active forms. The compounds of the present invention encompass isomers of each chiral carbon in the R or S configuration, or mixtures thereof, and racemates. The compounds of the present invention or their intermediates can be isolated as enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in both R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0148] The corresponding stable isomers can be separated using known methods, such as extraction, filtration, or column chromatography.

[0149] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0150] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0151] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0152] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0153] Example 1: Preparation of (10S,14S)-5-(4-iodobenzoyl)-1,12-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,5,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 01)

[0154] Step 1:

[0155] Compound 01-1 (5 g, 25.6 mmol) and TEA (5.17 g, 51.2 mmol) were added to a solution of dichloromethane (50 mL) at room temperature, followed by cooling to 0 °C. Methylsulfonyl chloride (3.70 g, 27.1 mmol) was slowly added dropwise to the reaction solution, and the mixture was reacted at 0 °C for 2 hours under argon protection. The reaction was monitored by LC-MS. The reaction solution was diluted with water (50 mL), extracted with EA (3 x 50 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to give product 01-2 (6 g). MS m / z (ESI): 274.1 [M+H] + .

[0156] Step 2:

[0157] At room temperature, N,N-diisopropylethylamine (3.97 g, 30.75 mmol) was added to a tetrahydrofuran (50 mL) solution of 01-2 (3.64 g, 13.33 mmol) and 01-3 (5 g, 10.25 mmol), and the reaction mixture was then heated to 60 °C and reacted for 16 hours. The reaction was monitored by LC-MS. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (3 x 50 mL), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to give product 01-4 (1.9 g). MS m / z (ESI): 665.4 [M+H] + .

[0158] Step 3:

[0159] Sodium bicarbonate (2.02 g, 24.1 mmol) was added to a mixed solution of tetrahydrofuran (15 mL) and water (15 mL) of 01-4 (1.60 g, 2.41 mmol) and 01-5 (687 mg, 2.65 mmol) at room temperature. The reaction mixture was reacted at room temperature for 2 hours under argon protection. The reaction was monitored by LCMS. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 5–30%) to give product 01-6 (1.57 g). MS m / z (ESI): 839.3 [M+H] + .

[0160] Step 4:

[0161] Platinum dioxide (132 mg, 0.58 mmol) was added to a 30 mL solution of tetrahydrofuran containing 01-6 (1.57 g, 1.94 mmol). The reaction mixture was incubated at 60 °C for 5 hours under a hydrogen atmosphere. The reaction was monitored by LC-MS, and the solution was filtered and concentrated to give product 01-7 (1.12 g). MS m / z (ESI): 704.3 [M+H] + .

[0162] Step 5:

[0163] At room temperature, benzyl alcohol (0.68 g, 6.32 mmol) was added to a solution of 01-8 (2.00 g, 5.27 mmol), DCC (1.30 g, 6.32 mmol), and DMAP (0.64 g, 5.27 mmol) in dichloromethane (20 mL). The reaction mixture was reacted at room temperature under argon protection for 2 hours. The reaction was monitored by LCMS. The reaction mixture was diluted with water (50 mL), extracted with dichloromethane (20 mL), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 10–20%) to give product 01-9 (1.12 g). MS m / z (ESI): 470.4 [M+H] + .

[0164] Step 6:

[0165] Diethylamine (5 mL) was added to a solution of 01-9 (1.12 g, 2.39 mmol) in 10 mL of dichloromethane at room temperature. The reaction mixture was reacted at room temperature for 16 hours under argon protection. The reaction was monitored by LC-MS, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 30-50%) to give product 01-10 (510 mg). MS m / z (ESI): 248.1 [M+H] + .

[0166] Step 7:

[0167] At room temperature, TCFH (666 mg, 2.38 mmol) was added to 15 mL solutions of acetonitrile containing 01-10 (510 mg, 2.06 mmol), 01-11 (1247 mg, 2.18 mmol), and NMI (341 mg, 4.16 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LC-MS, and the reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain product 01-12 (497 mg). MS m / z (ESI): 802.6 [M+H] + .

[0168] Step 8:

[0169] At room temperature, 10% Pd / C (66 mg, 0.062 mmol) was added to 20 mL of tetrahydrofuran containing O1-12 (497 mg, 0.62 mmol). The reaction mixture was reacted at room temperature under hydrogen protection for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered and concentrated to obtain product O1-13 (440 mg). MS m / z (ESI): 712.5 [M+H] + .

[0170] Step 9:

[0171] At room temperature, TCFH (188 mg, 0.67 mmol) was added to 10 mL of acetonitrile solutions containing 01-13 (400 mg, 0.56 mmol), 01-7 (378 mg, 0.56 mmol), and NMI (45.9 mg, 0.56 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 10–50%) to obtain product 01-14 (510 mg). MS m / z (ESI): 1398.7 [M+H] + .

[0172] Step 10:

[0173] At room temperature, CsF (167.1 mg, 1.1 mmol) was added to a DMSO (2 mL) solution of 01-14 (150 mg, 0.11 mmol), and the reaction mixture was reacted at room temperature for 16 hours under argon protection. The reaction was monitored by LCMS, and the reaction solution was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain 01-15 (60 mg). MS m / z (ESI): 1224.7 [M+H] + .

[0174] Step 11:

[0175] At room temperature, 01-15 (60 mg, 0.05 mmol), 01-16 (15 mg, 0.06 mmol), and TCFH (21 mg, 0.07 mmol) were dissolved in 2 mL of acetonitrile, and NMI (12 μL, 0.15 mmol) was added. The reaction solution was stirred at room temperature for 1 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was purified by reverse preparative high-performance liquid chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain product 01-17 (28 mg). MS m / z (ESI): 1454.5 [M+H] + .

[0176] Step 12:

[0177] At room temperature, 01-17 (28 mg, 0.019 mmol) was dissolved in 2 mL of TFA and stirred at room temperature for 2 h. The reaction was monitored by LCMS, and the system was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15-25%, 0.05% TFA) to obtain compound 01 (5 mg).

[0178] MS m / z (ESI): 1118.4 [M+H] + .

[0179] 1 H NMR(400MHz,CD3OD)δ7.82(d,2H),7.16(d,2H),4.34–4.27(m,2H),4.22–4 .17(m,1H),3.92–3.72(m,8H),3.65–3.58(m,2H),3.36–3.56(m,8H),3.18 –3.13(m,1H),3.09–3.02(m,2H),2.44–2.38(m,2H),2.17–2.06(m,2H),1. 99–1.68(m,8H),1.65–1.40(m,6H),1.30–1.15(m,2H),1.06–0.94(m,2H).

[0180] Example 2: Preparation of (11S,15S)-6-(4-iodobenzoyl)-1,13-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylic acid (compound 02)

[0181] Step 1:

[0182] Oxaloyl chloride (0.57 mL, 6.73 mmol) was dissolved in 50 mL of anhydrous DCM. Under argon protection, the solution was cooled to -78 °C. Then, DMSO (0.96 mL, 13.46 mmol) dissolved in 5 mL of DCM was slowly added dropwise. The reaction mixture was stirred at -70 °C for 5 min. O2-1 (1.2 g, 6.41 mmol) was added in portions, and stirring continued for 15 min. TEA (4.66 mL, 33.65 mmol) was then slowly added dropwise, and the mixture was stirred at -70 °C for 10 min. The cooling bath was removed, and the mixture was heated and stirred for 45 min. The reaction was monitored by LCMS until complete. Water (30 mL) was added to the reaction mixture, and stirring continued for 15 min. The reaction mixture was then washed successively with 0.1 M HCl, saturated NaHCO3 solution, and brine (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 5–30%) to obtain product 02-2 (1.2 g). MS m / z (ESI): 296.0 [M+H] + .

[0183] Step 2:

[0184] At room temperature, 01-3 (1.2 g, 2.46 mmol) and 02-2 (650 mg, 2.21 mmol) were dissolved in 10 mL of anhydrous methanol, and 0.2 mL of acetic acid was added. The mixture was stirred at room temperature for 1 h. The reaction solution was then cooled to 0 °C, and NaBH3CN (464 mg, 7.38 mmol) was added in portions. The reaction solution was stirred at room temperature for 16 h under nitrogen protection. The reaction was monitored by LCMS. The mixture was diluted with water (30 mL), extracted three times with DCM (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 30–50%) to obtain 02-3 (400 mg). MS m / z (ESI): 767.6 [M+H] + .

[0185] Step 3:

[0186] At room temperature, 02-3 (400 mg, 0.52 mmol), 01-16 (150 mg, 0.62 mmol), and TCFH (219 mg, 0.78 mmol) were dissolved in 5 mL of acetonitrile, and NMI (0.12 mL, 1.56 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to determine the completion of the reaction. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 10–50%) to obtain product 02-4 (400 mg). MS m / z (ESI): 997.2 [M+H] + .

[0187] Step 4:

[0188] At room temperature, 02-4 (400 mg, 0.4 mmol) was dissolved in 2 mL of DCM, and 2 mL of diethylamine was added. The reaction mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to determine the completion of the reaction. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 02-5 (180 mg). MS m / z (ESI): 775.4 [M+H] + .

[0189] Step 5:

[0190] At room temperature, 02-5 (180 mg, 0.23 mmol), 01-8 (100 mg, 0.28 mmol), and TCFH (97 mg, 0.35 mmol) were dissolved in 2 mL of acetonitrile, and NMI (55 μL, 0.69 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to determine the completion of the reaction. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 02-6 (200 mg). MS m / z (ESI): 1158.4 [M+H] + .

[0191] Step 6:

[0192] At room temperature, 02-6 (200 mg, 0.17 mmol) was dissolved in 2 mL of DCM, and 2 mL of diethylamine was added. The reaction mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to indicate completion. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 02-7 (100 mg). MS m / z (ESI): 914.3 [M+H] + .

[0193] Step 7:

[0194] At room temperature, 02-7 (100 mg, 0.11 mmol), 01-11 (76 mg, 0.13 mmol), and TCFH (46 mg, 0.17 mmol) were dissolved in 4 mL of acetonitrile, and NMI (26 μL, 0.33 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was then purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain 02-8 (60 mg). MS m / z (ESI): 1468.7 [M+H] + .

[0195] Step 8:

[0196] At room temperature, 2 mL of TFA was added to O2-8 (60 mg, 0.04 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS, and the system was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15–25%, 0.05% TFA) to obtain compound O2 (20 mg).

[0197] MS m / z(ESI): 1133.0 [M+H] + .

[0198] 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),7.84–7.45(m,3H),7.12(s,2H),6.41–6.20(m,2H),4.17–3.99(m,3H),3.72 –3.60(m,8H),3.11–2.89(m,20H),2.34–2.18(m,3H),2.00–1.30(m,18H),1.18–1.03(m,2H),0.94–0.78(m,2H).

[0199] Example 3: Preparation of (10S,14S)-5-(3-iodobenzoyl)-1,12-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,5,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 03)

[0200] Step 1:

[0201] At room temperature, 01-15 (60 mg, 0.05 mmol), 03-1 (15 mg, 0.06 mmol), and TCFH (21 mg, 0.07 mmol) were dissolved in 2 mL of acetonitrile, and NMI (12 μL, 0.15 mmol) was added. The reaction solution was stirred at room temperature for 1 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain product 03-2 (60 mg). MS m / z (ESI): 1454.4 [M+H] + .

[0202] Step 2:

[0203] At room temperature, 03-2 (60 mg, 0.041 mmol) was dissolved in 2 mL of TFA and stirred at room temperature for 2 h. The reaction was monitored by LCMS, and the system was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15-25%, 0.05% TFA) to obtain compound 03 (17.6 mg).

[0204] MS m / z (ESI): 1118.4 [M+H] + .

[0205] 1 H NMR(400MHz,CD3OD)δ7.83–7.79(m,1H),7.76–7.73(m,1H),7.40–7.35(m,1H),7 .26–7.20(m,1H),4.35–4.15(m,2H),3.95–3.71(m,8H),3.64–3.57(m,2H),3.54 –3.36(m,8H),3.25(s,9H),3.20–2.97(m,3H),2.44–2.36(m,2H),2.21–2.03(m, 2H),1.95–1.62(m,8H),1.58–1.35(m,6H),1.27–1.13(m,2H),1.06–0.91(m,2H).

[0206] Example 4: Preparation of (11S,15S)-6-(3-iodobenzoyl)-1,13-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylic acid (compound 05)

[0207] Step 1:

[0208] At room temperature, 02-3 (400 mg, 0.52 mmol), 03-1 (150 mg, 0.62 mmol), and TCFH (219 mg, 0.78 mmol) were dissolved in 5 mL of acetonitrile, and NMI (0.12 mL, 1.56 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LCMS. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 05-1 (400 mg). MS m / z (ESI): 997.2 [M+H] + .

[0209] Step 2:

[0210] At room temperature, 05-1 (400 mg, 0.4 mmol) was dissolved in 2 mL of DCM, and 2 mL of diethylamine was added. The reaction mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to determine the completion of the reaction. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 05-2 (180 mg). MS m / z (ESI): 775.4 [M+H] + .

[0211] Step 3:

[0212] At room temperature, 05-2 (180 mg, 0.23 mmol), 01-8 (100 mg, 0.28 mmol), and TCFH (97 mg, 0.35 mmol) were dissolved in 2 mL of acetonitrile, and NMI (55 μL, 0.69 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 10-50%) to obtain product 05-3 (200 mg). MS m / z (ESI): 1158.4 [M+H] + .

[0213] Step 4:

[0214] At room temperature, 05-3 (200 mg, 0.17 mmol) was dissolved in 2 mL of DCM, and 2 mL of diethylamine was added. The reaction mixture was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LC-MS to determine the completion of the reaction. The reaction mixture was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane: 10%) to obtain product 05-4 (100 mg). MS m / z (ESI): 914.3 [M+H] + .

[0215] Step 5:

[0216] At room temperature, 05-4 (100 mg, 0.11 mmol), 01-11 (76 mg, 0.13 mmol), and TCFH (46 mg, 0.17 mmol) were dissolved in 4 mL of acetonitrile, and NMI (26 μL, 0.33 mmol) was added. The reaction solution was stirred at room temperature for 2 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was then purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain 05-5 (60 mg). MS m / z (ESI): 1468.7 [M+H] + .

[0217] Step 6:

[0218] At room temperature, 2 mL of TFA was added to 05-5 (60 mg, 0.04 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain a crude product, which was then purified by preparative high performance liquid chromatography (acetonitrile / water: 15–25%, 0.05% TFA) to obtain compound 05 (20 mg).

[0219] MS m / z (ESI): 1132.4 [M+H] + .

[0220] 1 H NMR(400MHz,CD3OD)δ7.81(d,J=7.9Hz,1H),7.71(s,1H),7.39–7.32(m,1H),7.27 –7.19(m,1H),4.34–4.17(m,2H),3.96–3.66(m,8H),3.58–3.46(m,3H),3.25–3.1 6(m,8H),3.08–2.96(m,3H),2.46–2.38(s,2H),2.23–2.05(m,2H),1.95–1.77(m, 6H),1.75–1.60(m,4H),1.57–1.43(m,4H),1.36–1.19(m,2H),1.05–0.89(m,2H).

[0221] Example 5: Preparation of (11S, 15S)-6-(4-methylbenzoyl)-1,13-dioxo-1-((1r, 4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexyl)-2,6,12,14-tetraazacycloheptadecane-11,15,17-tricarboxylic acid (compound 11)

[0222] Step 1:

[0223] At room temperature, 11-1 (20 g, 95.5 mmol) and TEA (19.3 g, 191 mmol) were added to a solution of dichloromethane (200 mL), followed by cooling to 0 °C. Methylsulfonyl chloride (11.4 g, 100 mmol) was slowly added dropwise to the reaction solution, and the mixture was reacted at 0 °C for 2 hours under argon protection. The reaction was monitored by LC-MS. The reaction solution was diluted with water (200 mL), extracted with EA (3 x 300 mL), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain 11-2 (27 g). MS m / z (ESI): 288.1 [M+H] + .

[0224] Step 2:

[0225] Under nitrogen protection, 01-3 (5 g, 10.60 mmol), DIEA (4.11 g, 31.80 mmol), and 11-2 (3.96 g, 13.78 mmol) were dissolved in THF (50 mL), and the mixture was heated to 55 °C and reacted for 16 hours. The reaction solution was concentrated, and the crude product was purified by reversed-phase column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 11-3 (1.5 g). MS m / z (ESI): 679.7 [M+H] + .

[0226] Step 3:

[0227] PyBOP (1072 mg, 2.06 mmol) was added to solutions of 11-3 (700 mg, 1.03 mmol), 11-4 (117 mg, 0.71 mmol), and DIEA (399 mg, 3.09 mmol) at room temperature. The reaction mixture was reacted at room temperature for 2 hours under argon protection. The reaction mixture was concentrated, and the crude product was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain product 11-5 (200 mg). MS m / z (ESI): 797.5 [M+H] + .

[0228] Step 4:

[0229] Platinum dioxide (400 mg, 1.80 mmol) was added to a mixed solution of 11-5 (200 mg, 0.25 mmol) in methanol (10 mL) and water (2 mL). The reaction mixture was then reacted at room temperature for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered and concentrated to give product 11-6 (120 mg).

[0230] MS m / z (ESI): 663.4 [M+H] + .

[0231] Step 5:

[0232] 11-6 (120 mg, 0.18 mmol), 01-13 (128 mg, 0.18 mmol), and NMI (44.3 mg, 0.54 mmol) were added to acetonitrile (15 mL) with TCFH (75.7 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was detected by LCMS. After concentration of the filtrate, the crude product was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain product 11-7 (35 mg). MS m / z (ESI): 1356.8 [M+H] + .

[0233] Step 6:

[0234] Under an argon atmosphere, 11-7 (30 mg, 0.022 mmol) was dissolved in TFA (1 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure, and the crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15–25%, 0.05% TFA) to give compound 11 (5.71 mg).

[0235] MS m / z (ESI): 1020.5 [M+H] + .

[0236] 1 H NMR (400MHz, CD3OD) δ7.67-7.60(m,2H),7.29-7.25(m,1H),7.17-7.07(m,1H),4.61–4.56(m,2H),4.32–4.27(m,2H),4.14–4.11(m,1H) ,3.87–3.41(m,7H),3.48–3.44(m,7H),3.31–3.13(m,8H),2.49–2.32(m,5H),2.15–2.00(m,1H),1.99–1.63(m,6H),1.43–1.17(m,2H).

[0237] Example 6: Preparation of (10S,14S)-5-(4-methylbenzoyl)-1,12-dioxo-1-(4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)phenyl)-2,5,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 17)

[0238] Step 1:

[0239] At room temperature, 17-1 (30 mg, 0.025 mmol), 17-2 (4 mg, 0.03 mmol), and TCFH (10 mg, 0.035 mmol) were dissolved in 1 mL of acetonitrile, and NMI (6 μL, 0.07 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction mixture was concentrated to obtain a crude product, which was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain compound 17-3 (15 mg). MS m / z (ESI): 1342.5 [M+H] + .

[0240] Step 2:

[0241] At room temperature, 17-3 (15 mg, 0.011 mmol) was dissolved in 1 mL of TFA and stirred at room temperature for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain a crude product, which was then purified by high-performance liquid chromatography (acetonitrile / water: 15–25%, 0.05% TFA) to obtain compound 17 (1.92 mg). MS m / z (ESI): 1006.5 [M+H] + .

[0242] Example 7 Preparation of (10S,14S)-5-(3-bromobenzoyl)-1,12-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,5,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 19)

[0243] Step 1:

[0244] At room temperature, 01-15 (15 mg, 0.012 mmol), 19-1 (2 mg, 0.015 mmol), and TCFH (5 mg, 0.018 mmol) were dissolved in 1 mL of acetonitrile, and NMI (3 μL, 0.036 mmol) was added. The reaction solution was stirred at room temperature for 1 h under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated to obtain a crude product, which was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain product 19-2 (8 mg). MS m / z (ESI): 1407.2 [M+H] + .

[0245] Step 2:

[0246] At room temperature, 19-2 (8 mg, 0.005 mmol) was dissolved in 1 mL of TFA and stirred at room temperature for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain a crude product, which was purified by preparative high-performance liquid chromatography (acetonitrile / water: 15–25%, 0.05% TFA) to obtain compound 19 (3.2 mg).

[0247] MS m / z (ESI): 1070.4 [M+H] + .

[0248] Example 8: Preparation of (10S,14S)-5-(3-fluorobenzoyl)-1,12-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)phenyl)-2,5,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 20)

[0249] Step 1:

[0250] At room temperature, 17-1 (30 mg, 0.025 mmol), 20-1 (4 mg, 0.03 mmol), and TCFH (10 mg, 0.035 mmol) were dissolved in 1 mL of acetonitrile, and NMI (6 μL, 0.07 mmol) was added. The reaction solution was stirred at room temperature for 1 h under nitrogen protection. The reaction was monitored by LCMS, and the reaction solution was concentrated to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–40%, 0.05% TFA) to obtain product 20-2 (15 mg). MS m / z (ESI): 1346.8 [M+H] + .

[0251] Step 2:

[0252] At room temperature, 20-2 (15 mg, 0.011 mmol) was dissolved in 1 mL of TFA and stirred at room temperature for 2 h. The reaction was monitored by LCMS, and the system was concentrated to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15-25%, 0.05% TFA) to obtain compound 20 (3.85 mg).

[0253] MS m / z (ESI): 10¹⁰.⁸ [M+H] + .

[0254] Example 9

[0255] Preparation of (10S,14S)-6-(2-(4-iodophenyl)acetyl)-1,12-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,6,11,13-tetraazahexahexadecane-10,14,16-tricarboxylic acid (compound 49)

[0256] Step 1:

[0257] At room temperature, 49-1 (8.24 g, 27.8 mmol) and triethylamine (8.46 g, 83.6 mmol) were dissolved in dichloromethane (50 mL), cooled to -78 °C, and stirred for 0.5 h. Triphosgene (2.75 g, 9.28 mmol) was dissolved in DCM (10 mL) and slowly added dropwise to the reaction mixture, which was then stirred at -78 °C for 0.5 h. Then, 49-2 (10 g, 27.8 mmol) was dissolved in DCM (50 mL) and slowly added dropwise to the reaction mixture, which was allowed to return to room temperature naturally and stirred overnight. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to obtain 49-3 (10 g). MS m / z (ESI): 608.3 [M+H] + .

[0258] Step 2:

[0259] At room temperature, 49-3 (10 g, 16.5 mmol) and palladium on carbon (2 g) were dissolved in tetrahydrofuran (40 mL) and stirred overnight at 40 °C under hydrogen balloon conditions. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to obtain 49-4 (6 g). MS m / z (ESI): 474.3 [M+H] + .

[0260] Step 3:

[0261] At room temperature, 49-4 (0.95 g, 4.56 mmol) and 49-5 (2.4 g, 5.07 mmol) were dissolved in methanol (20 mL) and stirred for 1 hour. Then, sodium cyanoborohydride (0.48 g, 7.61 mmol) was added to the reaction mixture and stirred for 1 hour. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (10% MeOH in DCM) to give 49-6 (2.0 g). MS m / z (ESI): 665.3 [M+H] + .

[0262] Step 4:

[0263] At room temperature, 49-6 (2 g, 3.01 mmol), N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (0.94 g, 3.61 mmol), and sodium bicarbonate (2.53 g, 30.1 mmol) were dissolved in water (10 mL) and tetrahydrofuran (20 mL), and stirred for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 49-7 (1.1 g). MS m / z (ESI): 810.1 [M+H] + .

[0264] Step 5:

[0265] 49-7 (1.1 g, 1.36 mmol) and palladium on carbon (0.3 g) were dissolved in tetrahydrofuran (10 mL) at room temperature and reacted at room temperature under hydrogen atmosphere at 40 °C for 18 hours. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure to obtain 49-8 (800 mg). MS m / z (ESI): 675.4 [M+H] + .

[0266] Step 6:

[0267] At room temperature, 49-8 (700 mg, 1.04 mmol), 1-13 (740 mg, 1.04 mmol), TCFH (440 mg, 1.56 mmol), and NMI (260 mg, 3.12 mmol) were dissolved in acetonitrile (3 mL) and stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated and purified by reversed-phase silica gel column chromatography (acetonitrile / water: 20–70%, 0.05% TFA) to obtain 49-9 (300 mg). MS m / z (ESI): 1368.6 [M+H] + .

[0268] Step 7:

[0269] 49-9 (300 mg, 0.22 mmol) and cesium fluoride (668 mg, 4.4 mmol) were dissolved in DMSO (5 mL), and the reaction mixture was reacted at 30 °C under argon protection for 18 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 20–70%, 0.05% TFA) to obtain 49-10 (90 mg). MS m / z (ESI): 1224.6 [M+H] + .

[0270] Step 8:

[0271] At room temperature, TCFH (24 mg, 0.086 mmol) was added to a solution of 49-10 (70 mg, 0.057 mmol), 2-(4-iodophenyl)acetic acid (22.4 mg, 0.086 mmol), and NMI (14 mg, 0.17 mmol) in acetonitrile (2 mL). The reaction mixture was reacted at room temperature under argon protection for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–70%, 0.05% TFA) to obtain 49-12 (35 mg). m / z (ESI): 1468.3 [M+H] + .

[0272] Step 9:

[0273] Compound 49-12 (35 mg, 0.024 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was reacted at 30 °C for 2 hours. LCMS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 20–70%, 0.05% TFA) to give compound 49 (12.7 mg).

[0274] MS m / z(ESI): 1132.1 [M+H] + .

[0275] 1H NMR(400MHz, CD3OD)δ:7.66-7.64(m,2H),7.05-7.01(m,2H),4.31-4.26(m,2H),3.82-3.68(m,10H),3.43-3. 04(m,24H),2.43-2.39(m,2H),2.17-2.09(m,2H),1.91-1.62(m,11H),1.49-1.40(m,3H),1.02-0.96(m,2H).

[0276] Example 10

[0277] Synthesis of (12S,16S)-7-(2-(4-iodophenyl)acetyl)-1,14-dioxo-1-((1r,4S)-4-((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexyl)-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 50)

[0278] Step 1:

[0279] 50-1 (5 g, 22.4 mmol) and triethylamine (4.53 g, 44.8 mmol) were dissolved in dichloromethane (20 mL). The reaction solution was cooled to 0 °C, and methanesulfonyl chloride (3.08 g, 26.8 mmol) was slowly added dropwise while stirring for 0.5 h. The reaction solution was then brought to room temperature and stirred for 16 h. LC-MS monitoring showed that the reaction was complete. The solvent was concentrated, washed with ethyl acetate and water, dried over saturated brine and anhydrous sodium sulfate, and the filtrate was concentrated to obtain 50-2 (6.5 g). MS m / z (ESI): 302.2 [M+H] + .

[0280] Step 2:

[0281] 50-2 (2 g, 6.96 mmol), 01-3 (3.40 g, 6.96 mmol), and N,N-diisopropylethylamine (2.70 g, 20.8 mmol) were dissolved in tetrahydrofuran (20 mL) and stirred at 55 °C for 48 hours. The reaction solution was filtered and concentrated, and the crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 50-3 (1.0 g). MS m / z (ESI): 693.4 [M+H] + .

[0282] Step 3:

[0283] At room temperature, 50-3 (380 mg, 1.44 mmol) was dissolved in N,N-dimethylformamide (3 mL), and HATU (657 mg, 1.73 mmol) and N,N-diisopropylethylamine (558 mg, 4.32 mmol) were added. After stirring for 1 hour, 49-11 (1.0 g, 1.44 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction solution was filtered, and the resulting solution was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 50-4 (572 mg). MS m / z (ESI): 937.2 [M+H] + .

[0284] Step 4

[0285] 50-4 (80 mg, 0.13 mmol) was dissolved in TFA (7 mL), and the reaction solution was reacted at 40 °C for 2 hours. The reaction solution was concentrated to give product 50-5 (130 mg). MS m / z (ESI): 635.0 [M+H] + .

[0286] Step 5:

[0287] 50-5 (120 mg, 0.11 mmol) and 01-13 (90.7 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (28.4 mg, 0.22 mmol) and HATU (104 mg, 0.38 mmol) were added. The reaction mixture was reacted at room temperature for 16 hours. The reaction mixture was filtered, and the resulting solution was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain 50-6 (30 mg). MS m / z (ESI): 1328.3 [M+H] + .

[0288] Step 6:

[0289] At room temperature, 5 mL of TFA was added dropwise to 50-6 (60 mg, 0.10 mmol), and the reaction mixture was stirred at 35 °C for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain compound 50 (4.91 mg).

[0290] MS m / z (ESI): 1160.3 [M+H] + .

[0291] 1H NMR (400MHz, CD3OD) δ7.66(d,J=8.0Hz,2H),7.03(d,J=8.0Hz,2H),4.31(s,2H),3.83(s,5H),3.70(s,3H),3.41-3.33(m,12H),3.29- 3.23(m,7H),3.21-3.14(m,3H),3.08-2.99(m,2H),2.41(t,J=4.0Hz,3H),2.11(s,2H),1.85(m,6H),1.70-1.26(m,13H),1.00(s,2H).

[0292] Example 11

[0293] Preparation of (((S)-1-carboxy-5-(2-(4-iodophenyl)-N-((S)-1-((1r,4S)-4-((2-(4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexane-1-carbonyl)pyrrolidine-3-yl)acetamido)pentyl)carbamoyl)-L-glutamic acid (compound 51)

[0294] Step 1:

[0295] At room temperature, 51-1 (5 g, 26.7 mmol) and TEA (7.42 mL, 53.4 mmol) were dissolved in dichloromethane (50 mL), then cooled to 0 °C. Methylsulfonyl chloride (4.13 mL, 53.4 mmol) was slowly added dropwise to the reaction solution, and the reaction was carried out at 0 °C for 2 hours under argon protection. TLC monitoring showed the reaction was complete. The reaction solution was diluted with water (50 mL), extracted with EA (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain 51-2 (4.5 g). MS m / z (ESI): 266.1 [M+H] + .

[0296] Step 2:

[0297] At room temperature, N,N-diisopropylethylamine (2.81 g, 27.7 mmol) was added to a solution of 51-2 (4.5 g, 16.96 mmol) and 01-3 (3.72 g, 7.63 mmol) in 10 mL of dimethyl sulfoxide. The reaction mixture was then heated to 80 °C and microwaved for 3 hours. The reaction was monitored by LC-MS. The reaction mixture was filtered, and the residue was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 51-3 (519 mg). MS m / z (ESI): 657.3 [M+H] + .

[0298] Step 3:

[0299] At room temperature, HATU (260 mg, 0.66 mmol) and DIEA (0.16 mL, 0.99 mmol) were added to a 3 mL solution of DMF containing 49-11 (173 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour under argon protection, and then 51-3 (219 mg, 0.33 mmol) was added. The reaction mixture was then reacted at room temperature for 2 hours under argon protection. The reaction was monitored by LCMS. The reaction mixture was filtered, and the residue was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 51-4 (200 mg). MS m / z (ESI): 901.1 [M+H] + .

[0300] Step 4:

[0301] At 0 °C, 2 mL of 4 M hydrochloric acid-ethyl acetate solution was added to a 2 mL solution of 51-4 (200 mg, 0.218 mmol) in ethyl acetate. The reaction mixture was reacted at 0 °C for 30 min under a hydrogen atmosphere. The reaction was monitored by LC-MS, and the reaction mixture was concentrated to obtain 51-5 (200 mg). MS m / z (ESI): 801.6 [M+H] + .

[0302] Step 5:

[0303] HATU (144 mg, 0.38 mmol) was added to a 3 mL solution of DMF containing 01-13 (270 mg, 0.38 mmol) at room temperature. The reaction mixture was reacted at room temperature under argon protection for 1 hour, followed by the addition of DIEA (73.7 mg, 0.57 mmol) and 51-5 (150 mg, 0.19 mmol). The reaction mixture was then reacted at room temperature under argon protection for 2 hours. The reaction was monitored by LCMS. The reaction mixture was filtered, and the residue was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 51-6 (29 mg). MS m / z (ESI): 1494.4 [M+H] + .

[0304] Step 6:

[0305] At room temperature, 51-6 (59 mg, 0.039 mmol) was dissolved in 2 mL of TFA and stirred at 40 °C for 2 h. The reaction was monitored by LCMS, and the system was concentrated to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography (acetonitrile / water: 15-25%, 0.05% TFA) to obtain compound 51 (3.09 mg).

[0306] MS m / z(ESI): 1158.1 [M+H] + .

[0307] 1 H NMR(400MHz,CD3OD)δ7.83-7.56(m,2H),7.12-6.92(m,2H),4.65-4.55(m,1H) ,4.55-4.43(m,1H),4.41-4.15(m,2H),4.04-3.64(m,12H),3.56-3.49(m,2H) ,3.43-3.34(m,6H),3.26-3.14(m,6H),3.11-2.96(m,2H),2.53-2.34(m,3H), 2.34-2.04(m,4H),2.01-1.72(m,8H),1.72-1.34(m,10H),1.17-0.93(m,2H).

[0308] Example 12

[0309] Synthesis of (13S,17S)-8-(2-(4-iodophenyl)acetyl)-1,15-dioxo-1-((1r,4r)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,8,14,16-tetraazanonadecane-13,17,19-tricarboxylic acid (compound 52)

[0310] Step 1:

[0311] At 0 °C, methanesulfonyl chloride (2.9 g, 25.2 mmol) was slowly added dropwise to a solution of 52-1 (3 g, 12.6 mmol) and DIEA (4.9 g, 37.9 mmol) in 20 mL of dichloromethane and stirred for 2 hours. The reaction was monitored by LC-MS until completion. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (10% MeOH in DCM) to give 52-2 (3.6 g). MS m / z (ESI): 316.5 [M+H] + .

[0312] Step 2:

[0313] At room temperature, 01-3 (9.44 g, 19.3 mmol), a-2 (5.5 g, 17.4 mmol), and DIEA (6.76 g, 52.3 mmol) were dissolved in tetrahydrofuran (100 mL) and stirred at 55 °C for 60 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 20–70%, 0.05% TFA) to give 52-3 (1.3 g). MS m / z (ESI): 707.7 [M+H] + .

[0314] Step 3:

[0315] HATU (859 mg, 2.26 mmol) was added to a DCM solution of 52-3 (800 mg, 1.13 mmol), 49-11 (444 mg, 1.69 mmol), and DIEA (292 mg, 2.26 mmol) in 10 mL at room temperature. The reaction mixture was reacted at room temperature under argon protection for 2 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–70%, 0.05% TFA) to obtain 52-4 (500 mg). MS m / z (ESI): 951.2 [M+H] + .

[0316] Step 4:

[0317] At room temperature, 52-4 (500 mg, 0.53 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at 45 °C for 1 hour. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated to obtain 52-5 (350 mg). MS m / z (ESI): 649.1 [M+H] + .

[0318] Step 5:

[0319] 52-5 (400 mg, 0.62 mmol), 52-6 (400 mg, 0.49 mmol), and DIEA (240.4 mg, 1.86 mmol) were dissolved in DMF (5 mL). The reaction mixture was reacted at 45 °C for 18 hours under argon protection. The reaction was monitored by LC-MS until completion. The reaction mixture was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.05% TFA) to obtain 52-7 (100 mg). MS m / z (ESI): 1342.2 [M+H] + .

[0320] Step 6:

[0321] Compound 52-7 (50 mg, 0.037 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was reacted at 35 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.05% TFA) to give compound 52 (30.0 mg).

[0322] MS m / z(ESI): 1174.0 [M+H] + .

[0323] 1 H NMR(400MHz,CD3OD)δ:7.67-7.65(m,2H),7.04-7.02(m,2H),4.33-4.24(m,2H),3.90-3.66(m,10H),3.31-3.29(m,17H),3.16-3 .12(m,2H),3.05-3.04(m,2H),2.43-2.38(m,2H),2.18-2.09(m,2H),1.91-1.79(m,6H),1.69-1.27(m,17H),1.02-0.89(m,2H).

[0324] Example 13

[0325] Preparation of ((13S,17S)-8-(2-(4-iodophenyl)acetyl)-2,15-dioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-3,8,14,16-tetraazanonadecane-13,17,19-tricarboxylic acid (compound 53)

[0326] Step 1:

[0327] 01-3 (20 g, 74.8 mmol), 53-1 (46.4 g, 98.0 mmol), and DIEA (29.0 g, 224 mmol) were dissolved in tetrahydrofuran (50 mL), and the mixture was stirred at 55 °C for 48 hours. The reaction was monitored by LC-MS, and the reaction solution was concentrated to give the crude product 53-2 (50 g) as indicated in the title. MS m / z (ESI): 659.6 [M+H] + .

[0328] Step 2:

[0329] In an ice bath, 49-11 (9.55 g, 36.4 mmol) was dissolved in N,N-dimethylformamide (100 mL), and 53-2 (13.8 g crude product, 20.6 mmol) was added. The mixture was stirred for 1 hour, followed by the addition of DIEA (11.7 g, 91.1 mmol) and HATU (20 g, 30.4 mmol). This mixture was reacted at room temperature for 2 hours. The reaction was monitored by LCMS. The reaction solution was concentrated, and the crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 53-3 (4 g). MS m / z (ESI): 903.4 [M+H] + .

[0330] Step 3:

[0331] 53-3 (200 mg, 0.22 mmol) was dissolved in trifluoroacetic acid (1 mL) at room temperature and reacted at 40 °C for 3 hours under argon protection. The reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure to obtain 50-5 (140 mg, crude product). MS m / z (ESI): 635.0 [M+H] +

[0332] Step 4:

[0333] Compound 50-5 (100 mg, 0.16 mmol), DIEA (41.3 mg, 0.32 mmol), and 53-4 (80.0 mg, 0.16 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The residue was purified by preparative high-performance liquid chromatography (acetonitrile / water: 20–70%, 0.05% TFA) to give compound 53 (40 mg).

[0334] MS m / z(ESI): 1021.1 [M+H] + .

[0335] 1 H NMR (400MHz, CD3OD) δ7.66(d,J=8.4Hz,2H),7.03(d,J=8.0Hz,2H),4.33-4.23(m,2H),3.86-3.70(m,1 0H),3.31-3.20(m,21H),2.43-2.39(m,2H),2.17-2.11(m,1H),1.92-1.81(m,2H),1.69-1.23(m,10H).

[0336] Example 14

[0337] Preparation of (12S,16S)-8-(2-(4-iodophenyl)acetyl)-2,14-dioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-3,8,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 54)

[0338] Step 1:

[0339] At room temperature, 49-4 (10.0 g, 21.1 mmol) and 53-1 (6.15 g, 23.0 mmol) were dissolved in tetrahydrofuran (100 mL), and N,N-diisopropylethylamine (8.18 g, 63.3 mmol) was added. The reaction was carried out overnight at 50 °C. The reaction was monitored by LCMS until completion. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 54-1 (2.3 g). MS m / z (ESI): 645.3 [M+H] + .

[0340] Step 2:

[0341] 54-1 (2.30 g, 3.51 mmol), N,N-diisopropylethylamine (1.36 g, 10.53 mmol), and 49-11 (0.92 g, 3.51 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature. Then, HATU (2.00 g, 5.26 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS until completion. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. After washing with saturated brine (50 mL), the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give 54-2 (377 mg). MS m / z (ESI): 889.4 [M+H] + .

[0342] Step 3:

[0343] 54-2 (377 mg, 0.42 mmol) was dissolved in trifluoroacetic acid (0.048 g, 0.42 mmol) at room temperature and reacted for 5 h. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure to obtain 54-3 (380 mg). MS m / z (ESI): 621.3 [M+H] + .

[0344] Step 4:

[0345] At room temperature and 0°C, 54-3 (380 mg, 0.48 mmol) and 53-4 (241 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (3 mL), and triethylamine (0.34 g, 3.36 mmol) was slowly added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LCMS until completion. The crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–70%, 0.05% TFA) to obtain 54 (15.47 mg).

[0346] MS m / z (ESI): 1007.2 [M+H] + .

[0347] 1 H NMR(400MHz,DMSO-d6)δ:12.76-11.74(m,6H),8.38-8.26(m,1H),7.66-7.6 3(m,2H),7.05-7.00(m,2H),6.39-6.30(m,2H),4.12-4.05(m,2H),3.70-3. 53(m,9H),3.50-3.33(m,4H),3.30-3.14(m,7H),3.10(m,3H),3.02(s,8H), 2.30-2.18(m,2H),1.98-1.87(m,1H),1.75-1.64(m,2H),1.55-1.31(m,8H).

[0348] Example 15

[0349] Preparation of (12S,16S)-7-(2-(4-iodophenyl)acetyl)-1,14-dioxo-1-(4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)phenyl)-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 55).

[0350] Step 1:

[0351] 53-3 (200 mg, 0.22 mmol) was dissolved in ethyl acetate (5 mL), and 4 M hydrochloric acid-ethyl acetate solution (5 mL) was added. The reaction mixture was reacted at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 50-5 (200 mg). MS m / z (ESI): 803.5 [M+H] + .

[0352] Step 2:

[0353] At room temperature, 53-4 (10 g, 14.9 mmol), 55-1 (2.35 g, 14.9 mmol), and DIEA (3.86 g, 29.8 mmol) were dissolved in DMF (30 ml), and the mixture was reacted at room temperature for 18 hours. The reaction was monitored by LC-MS until completion. The reaction solution was lyophilized to obtain 55-2 (11 g, crude product). MS m / z (ESI): 706.2 [M+H] + .

[0354] Step 3:

[0355] Under nitrogen protection, at room temperature, HATU (479 mg, 1.26 mmol) and DIEA (0.3 mL, 1.89 mmol) were added to a 4 mL DMF solution of 50-5, and the mixture was stirred for 1 hour. Then, 55-2 (500 mg, 0.63 mmol) was added. The reaction solution was reacted at 25 °C for 16 hours under argon protection. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain the crude product. The residue was dissolved in 2 mL DMF and purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 55-3 (80 mg). MS m / z (ESI): 1490.2 [M+H] + .

[0356] Step 4:

[0357] At room temperature, 2 mL of TFA was added to 55-3 (80 mg, 0.054 mmol), and the mixture was stirred at 40 °C for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain a crude product, which was purified by preparative high performance liquid chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain compound 55 (18.28 mg).

[0358] MS m / z (ESI): 1154.4 [M+H] + .

[0359] 1H NMR (400MHz, CD3OD) δ7.77(d,J=8.2Hz,2H),7.63(dd,J=8.3,3.9Hz,2H),7.41(dd,J=8.3 ,3.2Hz,2H),7.02(dd,J=8.3,3.0Hz,2H),4.43(s,2H),4.36-4.12(m,2H),3.86(s,4H),3. 70(d,J=2.4Hz,6H),3.46-3.32(m,14H),3.25-3.14(m,8H),2.39(d,J=9.6Hz,2H),2.21- 2.07(m,1H),1.95-1.83(m,1H),1.83-1.69(m,1H),1.67-1.43(m,7H),1.39-1.25(m,2H).

[0360] Example 16

[0361] Preparation of (13S,17S)-9-(2-(4-iodophenyl)acetyl)-2,15-dioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-3,9,14,16-tetraazanonadecane-13,17,19-tricarboxylic acid (compound 56).

[0362] Step 1:

[0363] At 0 °C, methanesulfonic anhydride (12.8 g, 73.8 mmol) was slowly added to a solution of 56-1 (10 g, 49.2 mmol) and TEA (20.5 mL, 147.6 mmol) in 100 mL of dichloromethane and stirred for 16 hours. The reaction was monitored by LC-MS until completion. The reaction solution was diluted with water (200 mL), extracted with dichloromethane (100 mL x 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain 56-2 (13 g). MS m / z (ESI): 282.1 [M+H] + .

[0364] Step 2:

[0365] At room temperature, 10 mL of TEA was added to a THF (150 mL) solution of 49-4 (14 g, 29.6 mmol) and 56-2 (8.3 g, 29.6 mmol). The reaction mixture was reacted at 55 °C for 48 hours under argon protection. The reaction was monitored by LCMS. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL x 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM: 0–10%) to obtain 56-3 (4.0 g). MS m / z (ESI): 659.6 [M+H] + .

[0366] Step 3:

[0367] At room temperature, DIEA (790 mg, 6.08 mmol) was added to a DMF (10 mL) solution of 56-3 (1 g, 1.52 mmol), 49-11 (480 mg, 1.82 mmol), and HATU (870 mg, 2.28 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LCMS. The mixture was diluted with water (50 mL), extracted three times with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 0–70%, 0.1% FA) to obtain 56-4 (1 g). MS m / z (ESI): 903.2 [M+H] + .

[0368] Step 4:

[0369] At room temperature, 56-4 (100 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 40 °C for 2 hours under nitrogen protection. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated to obtain 56-5 (70 mg). MS m / z (ESI): 635.0 [M+H] + .

[0370] Step 5:

[0371] At room temperature, DIEA (57 mg, 0.44 mmol) and 53-4 (66 mg, 0.13 mmol) were added to a 3 mL solution of DMF containing 56-5 (70 mg, 0.11 mmol). The reaction mixture was reacted at 25 °C for 16 hours under argon protection. The reaction was monitored by LCMS. The reaction mixture was concentrated to obtain a crude product, which was purified by preparative high-performance liquid chromatography (acetonitrile / water: 0–70%, 0.05% FA) to obtain compound 56 (20.06 mg).

[0372] MS m / z(ESI): 1021.0 [M+H] + .

[0373] 1 H NMR(400MHz, CD3OD)δ:7.70-7.62(m,2H),7.08-7.00(m,2H),4.35-4.25(m,2H),3.82-3.75(m,4H),3.74-3.53(m,6H),3.47-3. 27(m,12H),3.23-3.09(m,10H),2.47-2.37(m,2H),2.21-2.08(m,1H),1.97-1.84(m,2H),1.83-1.45(m,7H),1.37-1.23(m,2H).

[0374] Example 17

[0375] Preparation of (12S,16S)-8-(2-(4-iodophenyl)acetyl)-2,14-dioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)-3,8,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 57)

[0376] Step 1:

[0377] At room temperature, 49-4 (10.0 g, 21.1 mmol) and 53-1 (6.15 g, 23.0 mmol) were dissolved in tetrahydrofuran (100 mL), and N,N-diisopropylethylamine (8.18 g, 63.3 mmol) was added. The reaction was carried out overnight at 50 °C. The reaction mixture was monitored by LC-MS. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography (1% MeOH in DCM) to give 57-1 (2.3 g). MS m / z (ESI): 645.3 [M+H] + .

[0378] Step 2:

[0379] At room temperature, 57-1 (2.3 g, 3.5 mmol), sodium bicarbonate (2.9 g, 35 mmol), and 57-2 (1.0 g, 4.2 mmol) were dissolved in tetrahydrofuran (100 mL) and water (50 mL) and stirred overnight at room temperature. The reaction was monitored by LC-MS. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was subjected to silica gel column chromatography (1% MeOH in DCM) to give 57-3 (2.0 g). MS m / z (ESI): 779.2 [M+H] + .

[0380] Step 3:

[0381] At 0 °C, 10 mL of 4 M hydrochloric acid-ethyl acetate solution was added to a 10 mL solution of 57-3 (1.4 g, 1.8 mmol) in ethyl acetate. The reaction mixture was reacted at 0 °C for 30 min under a hydrogen atmosphere. The reaction was monitored by LC-MS, and the reaction mixture was concentrated to give 57-4 (1.2 g). MS m / z (ESI): 679.4 [M+H] + .

[0382] Step 4:

[0383] At room temperature, DIEA (1.2 mL, 7.08 mmol) was added to a 12 mL solution of DMF containing 57-4 (1.2 g, 1.77 mmol) and 53-4 (1.3 g, 1.95 mmol). The reaction mixture was reacted at room temperature under argon protection for 16 hours. The reaction was monitored by LCMS. The mixture was diluted with water (50 mL), extracted three times with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 0–70%, 0.1% FA) to obtain 57-5 (500 mg). MS m / z (ESI): 1233.5 [M+H] + .

[0384] Step 5:

[0385] At room temperature, 57-5 (500 mg, 0.41 mmol) and palladium on carbon (0.3 g) were dissolved in isopropanol (10 mL) and reacted at room temperature under hydrogen atmosphere at 40 °C for 3 hours. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure to obtain 57-6 (450 mg). MS m / z (ESI): 1099.5 [M+H] + .

[0386] Step 6:

[0387] At room temperature, DIEA (38 mg, 0.29 mmol) was added to a DMF (1 mL) solution of 57-6 (80 mg, 0.07 mmol), 57-7 (13 mg, 0.09 mmol), and HATU (42 mg, 0.11 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LCMS. The mixture was diluted with water (5 mL), extracted three times with ethyl acetate (5 mL x 3), and the organic phases were combined. After washing with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography (acetonitrile / water: 10–90%, 0.1% TFA) to obtain 57-8 (15 mg). MS m / z (ESI): 1231.8 [M+H] + .

[0388] Step 7:

[0389] At room temperature, 1 mL of TFA was added to 57-8 (15 mg, 0.012 mmol), and the mixture was stirred at 40 °C for 2 h. The reaction was monitored by LCMS to indicate completion. The system was concentrated to obtain the crude product, which was then purified by preparative high-performance liquid chromatography (acetonitrile / water: 10–30%, 0.05% TFA) to obtain compound 57 (7.57 mg). MS m / z (ESI): 895.3 [M+H] + .

[0390] Example 18

[0391] Preparation of (12S, 16S)-7-(2-(naphth-2-yl)acetyl)-1,14-dioxo-1-((1r, 4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexyl)-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 58)

[0392] Step 1:

[0393] At room temperature, cesium carbonate (151.94 g, 466.32 mmol) and benzyl bromide (39.88 g, 233.16 mmol) were added to a DMF (400 mL) solution of compound 58-1 (40 g, 155.44 mmol). The reaction solution was reacted at room temperature under argon protection for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was filtered to remove cesium carbonate, washed with water to remove DMF, dried, and evaporated to dryness to obtain compound 58-2 (53.2 g). MS (ESI) m / z = 292.3 [M+H-56] + .

[0394] Step 2:

[0395] Compound 58-2 (53.2 g, 153.12 mmol) was dissolved in 4 M ethyl hydrochloride solution (400 mL) at 0 °C, and the solution was slowly heated to room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was concentrated under reduced pressure to give compound 58-3 (45 g) as a white solid. MS (ESI) m / z = 248.4 [M+H] + .

[0396] Step 3:

[0397] At room temperature, N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate (63.8 g, 227.5 mmol) and 1-methyl-1H-imidazole (44.7, 54.6 mmol) were added to a 200 mL solution of acetonitrile containing compounds 58-3 (45.01 g, 182 mmol) and 58-4 (104 g, 182 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LCMS until completion. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase chromatography to give compound 58-5 (21 g). LCMS (ESI) m / z = 802.6 [M+H] + .

[0398] Step 4:

[0399] At room temperature, 10% Pd / C (2.1 g, 19.73 mmol) was added to tetrahydrofuran (210 mL) containing compound 58-5 (21 g, 26.18 mmol). The reaction mixture was reacted at 40 °C for 16 hours under argon protection. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated to give compound 58-6 (18.3 g). LCMS (ESI) m / z = 712.5 [M+H] + .

[0400] Step 5:

[0401] At 0 °C, methanesulfonyl chloride (9.0 g, 79.4 mmol) was slowly added dropwise to 100 mL of DCM containing compound 58-7 (10.0 g, 52.9 mmol) and DIEA (20.4 g, 158.8 mmol). The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LC-MS. The mixture was diluted with water (10 mL), extracted three times with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 58-8 (10 g). The crude product was directly added to the next reaction step. MS m / z (ESI): 268.2 [M+H] + .

[0402] Step 6:

[0403] Compound 58-8 (10 g, 37.4 mmol), compound 58-9 (18.2 g, 37.4 mmol), and DIEA (14.5 g, 112.3 mmol) were dissolved in THF (100 mL) at room temperature. The reaction mixture was heated to 50 °C and reacted at 50 °C for 48 hours. The reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase silica gel column chromatography to obtain compound 58-10 (3.0 g). MS m / z (ESI): 659.2 [M+H] + .

[0404] Step 7:

[0405] Compound 58-10 (3 g, 4.5 mmol), benzyl chloroformate (1.3 g, 5.2 mmol), and NaHCO3 (3.8 g, 45.0 mmol) were dissolved in THF (20 mL) at room temperature. The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LCMS. The mixture was diluted with water (20 mL), extracted three times with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography to give compound 58-11 (2 g). MS m / z (ESI): 793.2 [M+H] + .

[0406] Step 8:

[0407] Compound 58-11 (1 g, 1.26 mmol) was dissolved in 10 mL of 2 M ethyl acetate hydrochloride solution at 0 °C. The reaction solution was slowly heated to 10 °C and reacted at 10 °C for 2 hours. The reaction was monitored by LC-MS. The reaction solution was concentrated under reduced pressure to give compound 58-12 (800 mg). MS m / z (ESI): 693.4 [M+H] + .

[0408] Step 9:

[0409] Compounds 58-12 (800 mg, 1.2 mmol), 58-6 (850 mg, 1.2 mmol), TCFH (500 mg, 1.8 mmol), and NMI (196 mg, 2.4 mmol) were dissolved in acetonitrile (10 mL) at room temperature. The reaction mixture was reacted at room temperature for 1 hour under argon protection. The reaction was monitored by LC-MS. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase silica gel column chromatography to obtain compound 58-13 (500 mg). MS m / z (ESI): 1386.2 [M+H] + .

[0410] Step 10:

[0411] Compound 58-13 (500 mg, 0.36 mmol) and palladium on carbon (300 mg) were added to isopropanol (10 mL) at room temperature. After purging with nitrogen three times, hydrogen was introduced, and the reaction was carried out at 45 °C for 4 hours. The reaction was monitored by LC-MS. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 58-14 (400 mg). MS m / z (ESI): 1252.2 [M+H] + .

[0412] Step 11:

[0413] Compound 58-15 (12.5 mg, 0.067 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate (25.6 mg, 0.067 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 1 hour. Then, compound 58-14 (70 mg, 0.056 mmol) and DIEA (29 mg, 0.22 mmol) dissolved in dichloromethane (1 mL) were added dropwise to the above reaction solution. The reaction solution was reacted at room temperature for 1 hour under nitrogen protection. The reaction was monitored by LCMS to indicate completion. The reaction solution was concentrated under reduced pressure to obtain 58-16 (70 mg). No purification was required for the next step. MS m / z (ESI): 1421.5 [M+H] + .

[0414] Step 12:

[0415] Compound 58-16 (70 mg, 0.049 mmol) was dissolved in trifluoroacetic acid (3 mL). The mixture was reacted at 40 °C for 2 hours. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated under reduced pressure, and the crude product was purified by reverse-phase HPLC to obtain compound 58 (18.11 mg). MS m / z (ESI): 1084.6 [M+H] + .

[0416] 1 H NMR (400MHz, CD3OD) δ7.81(t,J=7.2Hz,3H),7.71(s,1H),7.49–7.42(m,2H),7.38(d,J=8.0Hz,1H),4.35–4.20(m,2H),3.92(s,2H),3.88(s,1H) ),3.82(s,4H),3.79–3.61(m,4H),3.50–3.33(m,13H),3.26–3.14(m,7H ),3.04(d,J=7.0Hz,2H),2.41(s,2H),2.10(s,3H),1.93–1.24(m,20H).

[0417] Example 19

[0418] Preparation of (12S,16S)-7-(2-(4-bromophenyl)acetyl)-1,14-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 59)

[0419] Step 1:

[0420] 59-1 (53.5 mg, 0.25 mmol) and HATU (93.5 mg, 0.25 mmol) were dissolved in DCM (1 mL) and stirred at room temperature for 1 hour. 58-14 (100 mg, 0.081 mmol) and DIEA (63.6 mg, 0.49 mmol) were dissolved in DCM (0.5 mL) and added to the above solution. The reaction mixture was reacted at room temperature for 1 hour under nitrogen protection. LC-MS monitoring showed the starting material had disappeared, indicating the product was the main component. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography to obtain 59-2 (55 mg). MS m / z (ESI): 1448.8 [M+H] + .

[0421] Step 2:

[0422] Tri-tert-butyl 59-2 (55 mg, 0.038 mmol) was dissolved in trifluoroacetic acid (2 mL) and reacted at 40 °C for 2 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC to obtain compound 59 (20 mg). MS m / z (ESI): 1112.5 / 1114.5 [M+H] + .

[0423] 1 H NMR (400MHz, CD3OD) δ7.46(d,J=8.4Hz,2H),7.17(d,J=8.4Hz,2H),4.36–4.19(m,2H),3.87–3.68(m,5H),3.32– 2.99(m,25H),2.43–2.39(m,2H),2.17–2.09(m,2H),1.92–1.78(m,6H),1.71–1.28(m,12H),1.03–0.97(m,2H).

[0424] Example 20

[0425] Preparation of (11S,15S)-6-(4-bromobenzene)-1,13-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carbonylmethyl)-1,4,7,10-tetracyclododecane-1-yl)acetamide)methyl)cyclohexyl)-2,6,12,14-tetracycloheptadecane-11,15,17-tricarbonate (compound 60)

[0426] Step 1:

[0427] Compounds 58-9 (25 g, 51.2 mmol), 60-1 (4.0 g, 76.8 mmol), and TEA (15.5 g, 153.6 mmol) were dissolved in methanol (100 mL) at room temperature. The reaction mixture was reacted at room temperature under argon protection for 18 hours. The reaction was monitored by LC-MS to indicate completion. The solvent was concentrated under reduced pressure to give compound 60-2 (27 g). MS m / z (ESI): 541.2 [M+H] + .

[0428] Step 2:

[0429] Compound 60-2 (27 g, 50 mmol), CbzOSu (15 g, 60 mmol), and sodium bicarbonate (21 g, 250 mmol) were dissolved in THF (100 mL) and water (50 mL), respectively, at room temperature. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LCMS. After dilution with water (100 mL), the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 60-3 (20 g). MS m / z (ESI): 675.2 [M+H] + .

[0430] Step 3:

[0431] Sodium borohydride (5.6 g, 148.1 mmol) was added in portions to a methanol (56 mL) solution containing compound 60-3 (20 g, 29.6 mmol) and CoCl2 (4.6 g, 35.5 mmol). The reaction mixture was reacted at 0 °C for 1 hour under argon protection. The reaction was monitored by LC-MS until completion. The reaction mixture was quenched with water (10 mL), and the residue was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 60-4 (12 g). MS m / z (ESI): 679.2 [M+H] + .

[0432] Step 4:

[0433] Compound 60-4 (10 g, 14.7 mmol), compound 58-6 (15.7 g, 22.1 mmol), HATU (8.3 g, 22.1 mmol), and DIEA (3.8 g, 29.4 mmol) were dissolved in DMF (50 mL) at room temperature. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS. After dilution with water (100 mL), the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 60-5 (6 g). MS m / z (ESI): 1372.2 [M+H] + .

[0434] Step 5:

[0435] Compound 60-5 (6 g, 4.3 mmol) and palladium on carbon (3 g) were added to isopropanol (50 mL) at room temperature. After purging with nitrogen three times, hydrogen was introduced, and the reaction was carried out overnight at 40 °C. The reaction was monitored by LC-MS. The reaction solution was filtered to remove the palladium on carbon, and the filtrate was concentrated under reduced pressure to give compound 60-6 (5 g). MS m / z (ESI): 1238.2 [M+H] + .

[0436] Step 6:

[0437] Compound 60-7 (19.5 mg, 0.097 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (36.9 mg, 0.097 mmol) were dissolved in dichloromethane (1 mL) and stirred at room temperature for 1 hour. 60-6 (100 mg, 0.081 mmol) and DIEA (20.9 mg, 0.16 mmol) were dissolved in dichloromethane (0.5 mL) and added dropwise to the above reaction solution. The reaction solution was reacted at room temperature for 1 hour under nitrogen protection. LC-MS monitoring showed the disappearance of the starting material. The reaction solution was quenched with water (10 mL), extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 60-8 (110 mg). No purification was required for the next step. MS m / z (ESI): 1422.8 [M+H] + .

[0438] Step 7:

[0439] Compound 60-8 (110 mg, 0.077 mmol) was dissolved in trifluoroacetic acid (2 mL). The mixture was reacted at 40 °C for 2 hours. LCMS monitoring showed the starting material had disappeared. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC to give compound 60 (7.51 mg). MS m / z (ESI): 1084.9 / 1086.9 [M+H] + .

[0440] Example 21

[0441] Preparation of (11S,15S)-6-(2-(4-bromophenyl)acetyl)-1,13-dioxo-1-((1r,4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamyl)methyl)cyclohexyl)-2,6,12,14-tetraazaheptadecane-11,15,17-tricarboxylic acid (compound 61)

[0442] Step 1:

[0443] Compound 59-1 (53 mg, 0.25 mmol) and compound 60-6 (100 mg, 0.081 mmol) were dissolved in DCM (2 mL), followed by the sequential addition of HATU (95 mg, 0.25 mmol) and DIEA (54.5 mg, 0.5 mmol). The reaction mixture was reacted at room temperature for 1 hour under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 61-1 (60 mg). No further purification was required for the next step.

[0444] MS m / z (ESI): 1434.4 [M+H] + .

[0445] Step 2:

[0446] Compound 61-1 (50 mg, 0.036 mmol) was dissolved in trifluoroacetic acid (2 mL). The mixture was reacted at 40 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC to obtain compound 61 (7.7 mg).

[0447] MS m / z(ESI):1098.5 / 1100.5[M+H] + .

[0448] Example 22

[0449] Preparation of (11S, 15S)-7-(2-(4-bromophenyl)acetyl)-1,13-dioxo-1-((1r, 4S)-4-((2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexyl)-2,7,12,14-tetraazacycloheptadecane-11,15,17-tricarboxylic acid (compound 62)

[0450] Step 1:

[0451] Compound 62-1 (8.24 g, 27.8 mmol) and triethylamine (8.46 g, 83.6 mmol) were dissolved in dichloromethane (50 mL) at room temperature, cooled to -78 °C, and stirred for 0.5 h. Triphosgene (2.75 g, 9.28 mmol) was dissolved in DCM (10 mL) and slowly added dropwise to the reaction mixture, which was then stirred at -78 °C for 0.5 h. Then, compound 62-2 (10 g, 27.8 mmol) was dissolved in DCM (50 mL) and slowly added dropwise to the reaction mixture, which was allowed to return to room temperature naturally and stirred overnight. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature. The residue was purified by silica gel column chromatography to obtain 62-3 (10 g). MS m / z (ESI): 608.3 [M+H] + .

[0452] Step 2:

[0453] Compound 62-3 (10 g, 16.5 mmol) and palladium on carbon (2 g) were dissolved in tetrahydrofuran (40 mL) at room temperature and stirred overnight at 40 °C under hydrogen balloon conditions. The reaction was monitored by LCMS until completion. The reaction solution was filtered and concentrated to give compound 62-4 (6 g). MS m / z (ESI): 474.3 [M+H] + .

[0454] Step 3:

[0455] Compound 62-4 (18 g, 38.01 mmol), compound 62-5 (10.72 g, 38.01 mmol), and potassium iodide (0.63 g, 3.80 mmol) were dissolved in DMF (100 mL) at room temperature. Potassium carbonate (15.76 g, 114.03 mmol) was added under nitrogen protection. The reaction mixture was heated to 40 °C and stirred for 16 hours under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction mixture was diluted with water (200 mL), and extracted three times with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography to give compound 62-6 (25 g). LCMS (ESI) m / z = 675.4 [M + H] +

[0456] Step 4:

[0457] Compound 62-6 (18 g, 26.67 mmol) and potassium carbonate (11.06 g, 80.01 mmol) were dissolved in DMF (100 mL) at room temperature, and benzyl chloroformate (9.10 g, 53.34 mmol) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 2 hours under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction mixture was quenched with saturated ammonium chloride aqueous solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 62-7 (7 g). MS (ESI) m / z = 809.5 [M+H] +

[0458] Step 5:

[0459] Compound 62-7 (7 g, 8.65 mmol) and hydrazine hydrate (7.21 g, 144.03 mmol) were dissolved in ethanol (70 mL) at room temperature. The mixture was heated to 50 °C and stirred for 3 hours under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction solution was filtered, and the filtrate was concentrated to give compound 62-8 (5 g). MS (ESI) m / z = 679.4 [M+H] +

[0460] Step 6:

[0461] Compounds 62-8 (5 g, 7.37 mmol), 58-6 (5.25 g, 7.37 mmol), and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (2.80 g, 7.37 mmol) were dissolved in DMF (20 mL) at room temperature. N,N-diisopropylethylamine (2.86 g, 22.11 mmol) was added under nitrogen protection. The reaction mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction was monitored by LC-MS until complete. The reaction mixture was quenched with saturated ammonium chloride solution, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give compound 62-9 (4.5 g). MS (ESI) m / z = 1374.1 [M+H] +

[0462] Step 7:

[0463] Compound 62-9 (1 g, 0.73 mmol) and Pd / C (120 mg, 1.13 mmol) were dissolved in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at 30 °C for 16 hours under hydrogen protection. The reaction was monitored by LCMS until complete, and the solution was directly concentrated by filtration to give compound 62-10 (0.9 g). No further purification was required for the next step. MS (ESI) m / z = 1239.5 [M+H] +

[0464] Step 8:

[0465] Compound 59-1 (54 mg, 0.25 mmol) and compound 62-10 (100 mg, 0.081 mmol) were dissolved in DCM (2 mL), followed by the sequential addition of HATU (95 mg, 0.25 mmol) and DIEA (65 mg, 0.5 mmol). The reaction mixture was reacted at room temperature under nitrogen protection for 1 hour. The reaction was monitored by LCMS. DCM (10 mL) and water (10 mL) were added to the reaction mixture for extraction, followed by washing with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 62-11 (60 mg). MS m / z (ESI): 1434.8 [M+H] + .

[0466] Step 9:

[0467] Compound 62-11 (50 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (2 mL). The mixture was reacted at 40 °C for 2 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated, and the crude product was purified by reverse-phase HPLC to give compound 62 (8.7 mg). MS m / z (ESI): 1098.5 / 1100.5 [M+H]+ .

[0468] 1 H NMR (400MHz, CD3OD) δ7.46(d,J=6.8Hz,2H),7.18–7.16(m,2H),4.32–4.26(m,2H),3.81–3.70(m,10H),3.41–3.11(m,24H ),3.05(d,J=6.4Hz,2H),2.43–2.39(m,2H),2.17–2.11(m,2H),1.91–1.79(m,6H),1.68–1.28(m,12H),1.07–0.83(m,2H).

[0469] Example 23

[0470] Preparation of (((10S, 12S, 16S)-7-(2-(4-bromophenyl)acetyl)-10-methoxy-1,14-dioxo-1-((1r, 4S)-4-(2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamido)methyl)cyclohexyl)-2,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylic acid (compound 63)

[0471] Step 1:

[0472] Compound 63-1 (100 g, 346 mmol) was dissolved in DCM (1 L), and EDCI (99.13 g, 519 mol), DMAP (63.32 g, 519 mol), and cycloisopropyl malonate (74.80 g, 519 mol) were added sequentially at -8 °C. The reaction was carried out at 25 °C for 16 hours. LCMS showed that the starting material had disappeared. The reaction solution was extracted with saturated potassium bisulfate (2 x 1 L) and saturated brine (2 x 1 L). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (3.70 L) and stirred at 25 °C for 16 hours. After cooling to room temperature, the mixture was washed with saturated brine and saturated KHSO4 aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 63-2 (89 g). MS (ESI) m / z = 258.3 [M+H-56] + .

[0473] Step 2:

[0474] Compound 63-2 (50 g, 159.7 mmol) was dissolved in DCM (500 mL), acetic acid (50 mL) was added, and NaBH4 (18.2 g, 479.2 mmol) was added in portions at 0 °C. The reaction was carried out at room temperature for 3 hours. LC-MS monitoring showed that the starting material disappeared. The reaction solution was quenched with water, and a saturated NaHCO3 aqueous solution was added. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried, and concentrated under reduced pressure to obtain compound 63-3 (30 g). MS (ESI) m / z = 216.2 [M+H-100] + .

[0475] Step 3:

[0476] At room temperature, silver oxide (33.06 g, 142.68 mmol), 4A molecular sieve (18 g), and iodomethane (56.26 mL, 903.64 mmol) were added to ultradry DCM (150 mL) containing compound 63-3 (15 g, 47.56 mmol). The reaction mixture was reacted under sealed conditions at 55 °C for 18 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product 63-4 (14 g). MS (ESI) m / z = 230.4 [M-Boc+H] + .

[0477] Step 4:

[0478] Sodium borohydride (3.22 g, 85 mmol) was added to 3 mL of ethanol containing 14 g (42.50 mmol) of compound 63-4 at 0 °C. The reaction mixture was slowly heated to 25 °C and stirred for 4 hours. The reaction was monitored by LC-MS until completion. The reaction mixture was quenched with water, extracted twice with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain product 63-5 (9 g). MS (ESI) m / z = 334.4 [M+H] + .

[0479] Step 5:

[0480] Compound 63-5 (9 g, 26.99 mmol) and triethylamine (11.25 mL, 80.97 mmol) were dissolved in DCM (90 mL) at room temperature. Methanesulfonic anhydride (4.70 g, 26.99 mmol) was slowly added dropwise at 0 °C, and the mixture was stirred at 25 °C for 1 hour. After the reaction was monitored by LCMS, the reaction solution was quenched with water, extracted twice with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude 63-6 (9 g). No further purification was required; it was used directly in the next step. MS (ESI) m / z = 412.2 [M+H] + .

[0481] Step 6:

[0482] At room temperature, crude product 63-6 (9 g, 21.87 mmol) was dissolved in DMF (90 mL), and sodium azide (7.11 g, 109.35 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain product 63-7 (5 g). MS (ESI) m / z = 359.2 [M+H] + .

[0483] Step 7:

[0484] At 0°C, 50 mL of 4M dioxane hydrochloride solution was added to compound 63-7 (5 g, 13.59 mmol). The reaction mixture was slowly heated to 25°C and stirred for 30 minutes. The reaction was monitored by LC-MS until completion. The reaction mixture was dried under nitrogen to obtain crude product 63-8 (4.2 g). No purification was required for the next step. MS (ESI) m / z = 259.2 [M+H] + .

[0485] Step 8:

[0486] At 0 °C, compound 62-2 (10 g, 33.81 mmol) was dissolved in DCM (100 mL), and triethylamine (8.7 g, 86.33 mmol) and 4-dimethylaminopyridine (166 mg, 1.36 mmol) were added. After stirring for 5 minutes, N,N'-carbonyldiimidazole (6 g, 37.00 mmol) was added, and the reaction mixture was slowly heated to 25 °C and stirred for 16 hours. The reaction was monitored by LCMS until completion. The reaction mixture was diluted with DCM (150 mL), washed with saturated sodium bicarbonate (60 mL), water (2 × 100 mL), and brine (100 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give compound 63-9 (12.2 g). No purification was required for the next step.

[0487] LCMS(ESI)m / z = 354.4[M+H] + .

[0488] Step 9:

[0489] Compound 63-9 (7.39 g, 20.91 mmol) and triethylamine (15.5 mL, 111.52 mmol) were dissolved in DCM (50 mL). Methyl trifluoromethanesulfonate (3.43 g, 20.91 mmol) was added dropwise at 0 °C, and the reaction mixture was reacted at 0 °C under nitrogen protection for 30 min. Then, compound 63-8 (3.6 g, 13.94 mmol) was added in portions, and the reaction was carried out at 25 °C for 16 h. After the reaction was monitored by LCMS, the reaction mixture was quenched with water, and extracted three times with DCM (500 mL * 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain product 63-10 (5.3 g). MS (ESI) m / z = 544.4 [M + H] + .

[0490] Step 10:

[0491] Compound 63-10 (2 g, 3.68 mmol) was dissolved in THF (40 mL), followed by the addition of Pd / C (2 g, 18.87 mmol). The mixture was purged three times with nitrogen, then three times with hydrogen. The reaction was carried out under hydrogen protection at 25 °C for 1 hour. LC-MS monitoring showed the starting material had disappeared. The reaction solution was filtered to remove Pd / C, and the filtrate was concentrated to obtain crude 63-11 (1.9 g). No further purification was required; it was used directly in the next step. MS (ESI) m / z = 518.6 [M+H] + .

[0492] Step 11:

[0493] Compound 63-11 (1.9 g, 3.68 mmol) was dissolved in DMF (40 mL), followed by the sequential addition of potassium carbonate (1.52 g, 11.04 mmol), compound 62-5 (1.03 g, 3.68 mmol), and potassium iodide (183 mg, 1.10 mmol). The reaction was carried out at 60 °C for 16 hours. LC-MS monitoring showed the starting material had disappeared. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product 63-12 (2.9 g). No further purification was required; it was used directly in the next step. MS (ESI) m / z = 719.6 [M+H] + .

[0494] Step 12:

[0495] Crude product 63-12 (2.9 g, 3.68 mmol) was dissolved in DMF (45 mL), and triethylamine (1.12 g, 11.04 mmol) and 63-13 (1.28 g, 5.52 mmol) were added. The reaction was carried out at 25 °C for 16 hours. LC-MS monitoring showed that the starting material disappeared. The reaction solution was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 63-14 (280 mg). MS (ESI) m / z = 915.5 / 917.5 [M+H] + .

[0496] Step 13:

[0497] Compound 63-14 (280 mg, 0.31 mmol) was dissolved in ethanol (6 mL), and hydrazine hydrate (155 mg, 3.10 mmol) was added. The reaction was carried out at 50 °C for 2 hours. LC-MS monitoring showed that the starting material disappeared. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product 63-15 (220 mg). MS (ESI) m / z = 785.5 / 787.5 [M+H] + .

[0498] Step 14:

[0499] Crude product 63-15 (220 mg, 0.28 mmol) was dissolved in acetonitrile (2.5 mL), followed by the addition of 58-6 (199 mg, 0.28 mmol), NMI (85 mg, 0.84 mmol), and TCFH (98 mg, 0.35 mmol). The reaction was carried out at 25 °C for 2 hours. LCMS monitoring showed that the starting material disappeared. The reaction solution was quenched with water, extracted three times with ethyl acetate, and the organic phases were combined, dried, concentrated under reduced pressure, and the residue was purified by reverse-phase synthesis to obtain compound 63-16 (130 mg).

[0500] LCMS(ESI)m / z=1479.0 / 1481.0[M+H] + .

[0501] Step 15:

[0502] Compound 63-16 (130 mg, 0.088 mmol) was dissolved in TFA (3 mL) and reacted at 40 °C for 2 hours. LCMS monitoring showed the starting material disappeared. The reaction solution was concentrated, and the residue was purified by reverse-phase HPLC to obtain compound 63 (39 mg). MS (ESI) m / z = 1142.5 / 1144.5 [M+H] + .

[0503] 1H NMR(400MHz,DMSO-d6)δ12.46(s,4H),8.38(s,1H),7.73–7.63(m,1H),7.48(dd,J=8.3,1.4Hz, 2H),7.17(t,J=7.8Hz,2H),6.39(dd,J=15.4,8.2Hz,1H),6.35–6.26(m,1H),4.19(d,J=9.1Hz, 1H), 4.09 (dd, J=11.0, 6.5Hz, 1H), 3.68 (t, J=50.2Hz, 12H), 3.23 (dd, J=25.6, 10.2Hz, 15H), 3. 14–2.85(m,13H),2.32–2.16(m,2H),2.05–1.53(m,11H),1.53–1.22(m,7H),0.99–0.80(m,2H).

[0504] Using conditions similar to those in the above embodiments, the compounds listed in Table 1 below were prepared, and their structural characterization data are listed in the table below.

[0505] Table 1

[0506] Preparation Example 1 175 Synthesis of Lu-02

[0507] At room temperature, compound O2 (10 mg, 8.8 μmol) was dissolved in ammonium acetate buffer solution (0.1 M, pH = 5.0), and 10 mg / mL of LuCl was added. 3· The reaction solution was prepared with 7.4 mg of 6H₂O (26 μmol) and reacted at 90 °C for 30 min. After the reaction was completed, the reaction solution was lyophilized to obtain the crude product. The crude product was purified by Prep-HPLC (15% to 25% of ACN in water, + 0.05% TFA in water) to obtain the final product. 175 Lu-02 (3.55mg).

[0508] LCMS(ESI)M / Z:1304.8[M+H] + .

[0509] Using conditions similar to those described in the preparation examples above, the following compounds were prepared, and their structural characterization data are listed in Table 2 below.

[0510] Table 2

[0511] Preparation of Compound Example 2 177 Preparation of Lu-01

[0512] Add 321 μL of acetate-sodium acetate buffer (0.1 M, pH 4.5) to a 1.5 mL centrifuge tube, then add 15 μL of 1 nM / μL physiological saline solution of compound 01, and take 7 μL of the radionuclide. 177 LuCl3 (activity: 15.23 mCi); placed on a constant-temperature mixer, shaken, reaction temperature 95℃, reaction time 15 min. After the reaction, the reaction tube was cooled to room temperature, and 500 μL of 30 mg / mL reaction termination solution (a mixture of 4 mg / mL gentian acid aqueous solution, 1 mg / mL DTPA aqueous solution, and 100 mg / mL sodium ascorbate aqueous solution in a volume ratio of 2:1.5:3.5) was added to obtain the radiolabeled product. 177 Lu-01. Activity: 15.15 mCi, HPLC radiochemical purity > 99%.

[0513] Preparation of Compound Example 3 177 Preparation of Lu-02

[0514] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-02; HPLC radiochemical purity result was 97.8%.

[0515] Preparation of Compound Example 4 177 Synthesis of Lu-05

[0516] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-05; HPLC radiochemical purity result was 96.3%.

[0517] Preparation of Compound Example 5 177 Synthesis of Lu-21

[0518] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-21; HPLC radiochemical purity > 99%.

[0519] Preparation of Compound Example 6 177 Synthesis of Lu-22

[0520] The compound was prepared according to the method disclosed in Preparation Example 2. 177Lu-22; HPLC radiochemical purity result >99%.

[0521] Preparation of Compound Example 7 177 Synthesis of Lu-30

[0522] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-30; HPLC radiochemical purity >99%.

[0523] Preparation of Compound Example 8 177 Synthesis of Lu-49

[0524] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-49; HPLC radiochemical purity result >98%.

[0525] Preparation of Compound Example 9 177 Synthesis of Lu-50

[0526] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-50; HPLC radiochemical purity result >98%.

[0527] Preparation of Compound Example 10 177 Synthesis of Lu-51

[0528] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-51; HPLC radiochemical purity >98%.

[0529] Preparation of Compound Example 11 177 Synthesis of Lu-52

[0530] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-52; HPLC radiochemical purity result >98%.

[0531] Preparation of Compound 12 177 Synthesis of Lu-53

[0532] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-53; HPLC radiochemical purity result >98%.

[0533] Preparation of Compound Example 13 177 Synthesis of Lu-54

[0534] The compound was prepared according to the method disclosed in Preparation Example 2.177 Lu-54; HPLC radiochemical purity >98%.

[0535] Preparation of Compound 14 177 Synthesis of Lu-55

[0536] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-55; HPLC radiochemical purity result >98%.

[0537] Preparation of Compound Example 15 177 Synthesis of Lu-56

[0538] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-56; HPLC radiochemical purity >98%.

[0539] Preparation of Compound 16 177 Synthesis of Lu-57

[0540] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-57; HPLC radiochemical purity result >98%.

[0541] Preparation of Compound Example 17 177 Synthesis of Lu-58

[0542] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-58; HPLC radiochemical purity result >98%.

[0543] Preparation of Compound 18 177 Synthesis of Lu-59

[0544] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-59; HPLC radiochemical purity result >98%.

[0545] Preparation of Compound 19 177 Synthesis of Lu-60

[0546] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-60; HPLC radiochemical purity result >98%.

[0547] Preparation of Compound 20 177 Synthesis of Lu-61

[0548] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-61; HPLC radiochemical purity >98%.

[0549] Preparation of Compound 21 177 Synthesis of Lu-62

[0550] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-62; HPLC radiochemical purity result >98%.

[0551] Preparation of Compound 22 177 Synthesis of Lu-63

[0552] The compound was prepared according to the method disclosed in Preparation Example 2. 177 Lu-63; HPLC radiochemical purity result >98%.

[0553] Biological evaluation

[0554] Test Example 1: Determination of the PSMA binding activity of the compounds of the present invention (cellular level)

[0555] I. Experimental Materials and Instruments

[0556] 1. Flow cytometer (BD, LSR Fortessa)

[0557] 2. Cells (PC3-PSMA+, Genomeditech, GM-C35469)

[0558] 3. PSMA-Cy5 (MediCy)

[0559] II. Experimental Procedure

[0560] This experiment evaluated the binding ability of the compound to the target protein by detecting the competitive binding activity of the compound of this invention and the fluorescent reference compound PSMA-Cy5 to PSMA protein on PC3-PSMA+ cells. PC3-PSMA+ cells were used at a concentration of 1.0 × 10⁻⁶ cells. 5 Cells were seeded at a density of 1:1 in each well of a 96-well plate. The compound of this invention was serially diluted 5-fold at an initial concentration of 4.0 μM to seven concentration points, and mixed with an equal volume of the fluorescent reference compound PSMA-Cy5 at a fixed concentration of 0.02 μM. The mixture was then added to the 96-well cell culture plate and incubated at 4°C in the dark for 1 hour. After incubation, cells were washed twice with pre-chilled DPBS buffer, and then 100 μL of cell fixation solution was added to the 96-well plate, incubated at 4°C in the dark for 15 minutes. After incubation, cells were washed twice with pre-chilled DPBS buffer, and then resuspended in 100 μL of FACS buffer for flow cytometry analysis.

[0561] III. Experimental Results

[0562] The data were analyzed using GraphPad Prism 10 software, and the dose-effect curve and IC were fitted. 50 The PSMA binding activity of the compounds in this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 3.

[0563] Table 3 IC50 of the compounds in this invention for PSMA binding activity 50 value

[0564] Test Example 2: Determination of the PSMA binding activity of the compounds of the present invention (protein level)

[0565] I. Experimental Materials and Instruments

[0566] 1. Multifunctional microplate reader (PE, Envision 2105)

[0567] 2.human PSMA His tag (CUSABIO, CSB-MP008782HU1)

[0568] 3. PSMA-Cy5 (MediCy)

[0569] 4.HTRF MAB ANTI-6HIS-EU GOLD (Revvity, 61HI2KLA)

[0570] 5.HTRF PPI-EUROPIUM DETECT.BUF. (Revvity, 61DB9RDF)

[0571] 6.PROXIPLATE-384PLUS (Revvity, 6008280)

[0572] 7. Low-speed refrigerated centrifuge (Beckman, AVANti J-15R)

[0573] II. Experimental Procedure

[0574] This experiment evaluated the binding ability of the compounds by detecting their competitive binding activity against PSMA protein with PSMA-Cy5. Human PSMA His tag protein was prepared to a final concentration of 5 nM using HTRF PPI-EUROPIUM DETECT.BUF, and 5 μL was added to each well of a 384-well plate. HTRF MAB ANTI-6HIS-EU GOLD reagent was prepared to a 100x stock solution according to the manufacturer's instructions, and then diluted to a 1x working solution using HTRF PPI-EUROPIUM DETECT.BUF, and 5 μL was added to each well of a 384-well plate. The competing compound PSMA-Cy5 was prepared to a final concentration of 20 nM using HTRF PPI-EUROPIUM DETECT.BUF, and 5 μL was added to each well of a 384-well plate. The compound of this invention was serially diluted 5-fold at an initial concentration of 2.0 μM to eight concentration points, and 5 μL was added to each well of a 384-well plate, resulting in a final total volume of 20 μL. The 384-well plate was centrifuged at 1000 rpm for 2 minutes, then incubated at room temperature in the dark for 2 hours. After incubation, the plate was used to detect the HTRF signal at wavelengths of 665 / 620 nm using a multi-functional microplate reader.

[0575] III. Experimental Results

[0576] The data were analyzed using GraphPad Prism 10 software, and the dose-effect curve and IC were fitted. 50 The PSMA binding activity of the compounds in this invention was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 4.

[0577] Table 4 IC50 values ​​of the PSMA binding activity of the compounds in this invention 50 value

[0578] Test Example 3: Determination of cellular uptake and internalization levels of the compounds of the present invention

[0579] I. Experimental Materials and Instruments

[0580] 1. ICP-MS (Agilent, 7850)

[0581] 2. Cells (LNCaP, Cobioer, CBP60346)

[0582] 3.Poly-L-lysine solution (Sigma-Aldrich, P4832)

[0583] II. Experimental Procedure

[0584] LNCaP cells were seeded at a density of 1.0e6 per well in poly-L-lysine-coated 6-well plates and incubated at 37°C in a 5% CO2 incubator for 24 hours. The chelating compounds were prepared into a 20 nM solution using serum-free RPMI 1640 medium, and 1.0 mL was reserved for ICP-MS analysis to detect the concentration of the chelating compounds. 175 Lu (nitrogen) content was determined. 2 mL of the solution was added to a 6-well cell plate washed with DPBS and incubated at 37°C (5% CO2) for 2 hours. For cell uptake, the solution in the 6-well plate was aspirated, and the plate was washed twice with pre-cooled DPBS. Then, 1.0 mL of 0.3 M NaOH solution was added to fully lyse the cells in the plate, and the lysate was collected. The Lu content in the lysate was detected using ICP-MS. 175 The Lu element content was determined. For cell internalization, the solution in the 6-well plate was aspirated, and the cells were washed twice with pre-chilled DPBS. Then, 1.0 mL of acidic stripping buffer (0.05 M glycine stripping buffer in 100 mM NaCl, pH 2.8) was added, and the plate was incubated at 4°C for 10 minutes. The solution in the plate was aspirated, and the cells were washed twice with pre-chilled DPBS. Then, 1.0 mL of 0.3 M NaOH solution was added to fully lyse the cells in the plate, and the lysate was collected. The Lu element content in the lysate was detected by ICP-MS. 175 The content of Lu element.

[0585] III. Experimental Results

[0586] According to the test 175 Lu content was used to calculate the uptake and internalization levels of the compounds of the present invention in LNCaP cells.

[0587] The uptake and internalization levels of the compounds of this invention in LNCaP cells were determined by the above experiments, and the measured uptake and internalization ratios are shown in Table 5.

[0588] Table 5. Uptake and internalization ratios of compounds in this invention.

[0589] Test Example 4: Tissue distribution experiment of the compound of the present invention in a PC3-PSMA tumor-bearing mouse model.

[0590] I. Experimental Materials and Instruments

[0591] 1. Cell line (PC3-PSMA, Cobioer, CBP74206)

[0592] 2. Mice (BALB / c Nude, male, 8-10 weeks old, from Zhejiang Vital River Pharmaceutical Group)

[0593] 3. HPLC (Shimadzu, LC-20AD)

[0594] 4.γ-counter (PerkinElmer, 3470)

[0595] II. Experimental Procedure

[0596] Male BALB / c Nude mice, approximately 8-10 weeks old, were subcutaneously inoculated with 5 × 10⁸ g of [unspecified substance]. 6 PC3-PSMA cells (50% matrix gel). Allow the tumor to grow to approximately 100-400 mm. 3 When the size is... 177 The Lu radiolabeled compound was injected intravenously into mice (approximately 100 μCi / mouse). Animals were euthanized at 1, 4, and 24 hours post-administration via carbon dioxide inhalation. After euthanasia, serum, urine, brain, heart, liver, lungs, kidneys (cortex of the right kidney), muscle, spleen, salivary glands, thyroid gland, bones, duodenum, rectum, pancreas, stomach, and tumors were collected. The %ID / g (per gram of tissue radioactivity count relative to the total injected radioactivity count) was calculated for each organ.

[0597] III. Experimental Results

[0598] Compounds in this invention 177 Lu-02 177 Lu-05 177 Lu-49 177 Lu-50, 177 Lu-51, 177 Lu-54 177 The results of tissue distribution experiments of Lu-56 in PC3-PSMA tumor-bearing mouse models are shown in Figures 1-7.

[0599] IV. Experimental Conclusions

[0600] Data shows that after the compound enters the body via the tail vein, it can be rapidly distributed to various organs and rapidly metabolized out of the body, primarily through the kidneys. One hour after administration, the compound of this invention exhibited a high level of tumor uptake in a PC3-PSMA tumor-bearing mouse model, and after one hour, the level of renal retention showed a rapid decreasing trend.

[0601] Test Example 5: Tissue distribution experiment of the compound of the present invention in a LNCaP tumor-bearing mouse model.

[0602] I. Experimental Materials and Instruments

[0603] 1. Cell lines (LNCaP, Cobioer, CBP60346)

[0604] 2. Mice (NOD SCID, male, 10-12 weeks old, Zhejiang Vital River Pharmaceutical Co., Ltd.)

[0605] 3. HPLC (Shimadzu, LC-20AD)

[0606] 4.γ-counter (PerkinElmer, 3470)

[0607] II. Experimental Procedure

[0608] Based on the optimized labeling method, the compound in the invention is... 177 Lu labeling. First, prepare a 0.5M sodium acetate buffer (pH 5.5): Weigh 3.402g of sodium acetate trihydrate, add 40mL of pure water, mix thoroughly, adjust the pH to 5.5 with glacial acetic acid, and then bring the volume to 50mL. Prepare the reaction termination solution: Mix 4mg / mL gentian acid aqueous solution, 1mg / mL DTPA aqueous solution, and 100mg / mL sodium ascorbate aqueous solution in a volume ratio of 2:1.5:3.5. Prepare a 1mM solution of the compound of the present invention: Weigh an appropriate amount of powder, add a certain volume of physiological saline, dissolve thoroughly, and use immediately. Dilute the 1mM solution of the compound of the present invention 10 times with 0.5M sodium acetate buffer, mix thoroughly, and use immediately. Then take a 1.5mL centrifuge tube as the reaction tube, and add 5mCi of [unclear text - possibly a specific ingredient or solution] sequentially. 177 LuCl3 (approximately 0.25 nmol) and 50 μL of a diluted solution of the compound of this invention (approximately 5 nmol) were added to the reaction tube. The reaction tube was placed at 90 °C and heated for 15 min. After the reaction, the reaction tube was cooled to room temperature, and 500 μL of 30 mg / mL reaction stop solution was added to each tube to obtain the radiolabeled product. Radiochemical purity was confirmed by online monitoring HPLC to meet the requirements of tissue distribution experiments. Male NOD-SCID mice aged approximately 10-12 weeks were subcutaneously inoculated with 5 × 10⁵ ppm of the solution. 6 LNCaP cells (50% matrix gel). Wait until the tumor grows to approximately 100-400 mm. 3 When the size is... 177 The Lu radiolabeled compound was injected intravenously into mice (approximately 100 μCi / mouse). Animals were euthanized at 1, 4, and 24 hours post-administration via carbon dioxide inhalation. After euthanasia, serum, urine, brain, heart, liver, lungs, kidneys (cortex of the right kidney), muscle, spleen, salivary glands, bones, duodenum, rectum, pancreas, stomach, and tumors were collected. The %ID / g (per gram of tissue radioactivity count relative to the total injected radioactivity count) was calculated for each organ.

[0609] III. Experimental Results

[0610] The results of the tissue distribution experiments of the compounds in the LNCaP tumor-bearing mouse model of the present invention are shown in Figures 8-13.

[0611] IV. Experimental Conclusions

[0612] Data shows that after the compound enters the body via the tail vein, it can be rapidly distributed to various organs and rapidly metabolized out of the body, primarily through the kidneys. One hour after administration, the compound of this invention exhibited a high level of tumor uptake in an LNCaP-bearing mouse model, and after one hour, the level of renal retention showed a rapid decreasing trend.

[0613] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. The compound represented by formula (I), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: in, Ch is selected from chelating agent residues; L A It does not exist, or is selected from -AC (=O)-; A is selected from no substitution or is optionally replaced by one, two or more R. a The following groups are substituted: C-16 3- 10 Cycloalkyl, 3-10 membered heterocyclic, C-membered 6-14 Aryl, sub-5-14 quinone heteroaryl; each R a They may be the same or different, and are independently selected from H, halogen, cyano, hydroxyl, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; L B It does not exist, or it is selected from -NH-(CH2). p - 4-8 membered heterocyclic groups; Q is selected from C(O), sub-C 1-10 Alkyl or C 1-6 Alkoxy-substituted C 1-10 alkyl; R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-10 Alkyl, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L1 They may be identical or different, and are independently selected from X, H, halogen, oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R. L2 The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L2 They may be the same or different, and are independently selected from Y, H, halogen, borate group, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; X and Y may be the same or different, and are independently selected from radioactive isotopes of iodine, bromine, or astatine, preferably. 125 I, 131 I, 211 At; n is selected from 1, 2, 3, 4, 5, 6, 7 or 8; p is selected from 1, 2, 3, 4, 5, 6, 7, or 8; q is selected from 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound of formula (I) according to claim 1, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, Ch is selected from the following groups: Where m is selected from 1, 2, 3, 4, 5, 6, 7 or 8; Preferably, Ch is selected from 3. The compound of formula (I) according to claim 1 or 2, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, When L A When it does not exist, L B It does not exist; Or, L A Selected from -AC(=O)-, L B Selected from -NH-(CH2) p -or 4-8 membered heterocyclic groups; Preferably, L A When L is selected from -AC(=O)-, A The carbonyl group in the middle and the L group on the right side B Connected, forming -AC(=O)-L B ; A is selected from unsubstituted or arbitrarily assigned to one, two or more R. a The following groups are substituted: C-16 3-6 cycloalkyl, C-ide 6-10 Aryl; Preferably, A is selected from cyclohexylene or phenylene; Preferably, A is selected from Preferably, L B Selected from -NH-(CH2) p -or 5-6 nitrogen-containing heterocyclic groups; Preferably, in the 5-6 member nitrogen-containing subheterocyclic group, the N heteroatom and L... A The carbonyl group is attached; More preferably, L B Selected from -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5- or Preferably, Q is selected from C(O) and C-sub-C. 1-6 Alkyl or C 1-3 Alkoxy-substituted C 1-6 alkyl; Preferably, Q is selected from C(O), -CH2-, -CH2CH2-, -CH2CH2CH2-, 4. The compound of formula (I) according to any one of claims 1-3, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-6 Alkyl, C 6-10 Aryl; Preferably, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: methyl, ethyl, phenyl; Preferably, R L Selected from -C(O)-R L1 -C(O)-CH2-R L1 , Preferably, each R L1 They are either identical or different, and are independently selected from oxo (=O), -S(O)2F, 125 I, 211 At, without substitution or optionally by one, two or more R L2 The following groups are substituted: C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; Preferably, each R L1 They are either identical or different, and are independently selected from oxo (=O), -S(O)2F, 125 I, 211 At, without substitution or optionally by one, two or more R L2 The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl (e.g.) ), furanyl, (like: ), morpholino (e.g.) ), tetrahydropyranyl (e.g.) ), pyridyl (e.g.) )； Preferably, each R L2 They may be the same or different, and are independently selected from halogens, borate groups, and C. 1-6 alkyl; Preferably, each R L2 They may be the same or different, and are independently selected from F, Cl, Br, I, borate group, methyl group, 125 I, 211 At; Preferably, R L Selected from (like )、 5. The compound of formula (I) according to any one of claims 1-4, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, in, R L Selected from unsubstituted or arbitrarily assigned to one, two or more R L1 The following groups are substituted: C 1-10 Alkyl, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L1 They may be identical or different, and are independently selected from H, halogen, oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R atoms. L2 The following groups are substituted: C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-14 Aryl, 5-14 quinone heteroaryl; each R L2 They may be the same or different, and are independently selected from H, halogen, borate group, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Preferably, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl; Preferably, each R L1 They may be identical or different, and are independently selected from oxo (=O), -S(O)2F, unsubstituted, or optionally substituted by one, two, or more R groups. L2 The following groups are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl (e.g.) ), furanyl, (like: ), morpholino (e.g.) ), tetrahydropyranyl (e.g.) ), pyridyl (e.g.) )； Preferably, each R L2 They may be the same or different, and are independently selected from halogens, borate groups, and C. 1-6 alkyl; Preferably, the compound shown in formula (I) has the following structure: Among them, A, Q, L A L B R L m, n, p, and q each have the definition as described in any one of claims 1-4; Preferably, the compound shown in formula (I) has the following structure: Among them, A, Q, L B R L m, n, p, and q each have the definition as described in any one of claims 1-4; Preferably, the compound shown in formula (I) has the following structure: Among them, A, Q, R L1 R L2 p, q, and p, q are each independently defined as described in any one of claims 1-4.

6. The compound of formula (I) according to any one of claims 1-5, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound represented by formula (I) has the following structure:

7. The compound of formula (II), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, in, Ch' is selected from chelating agent residues containing M, and is formed by chelating Ch with M according to any one of claims 1-6; L A L B Q, R L m, n, p, and q each have the definition as described in any one of claims 1-6; M is selected from radioactive or non-radioactive metals, such as Ga, Lu, Ac, Pd, Pb, Tc, Tb, Cu, Bi, Al, Zr, Y, In, Sm, Re, Ra, and Ho, and their radioactive isotopes, for example... 68 Ga、 89 Zr、 64 Cu、 86 Y、 99 Tc, 161 Tb, 111 In、 90 Y、 67 Ga、 175 Lu、 177 Lu、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb, 225 Ac、 213 Bi、 223 Ra、 212 Bior 212 Pb, preferred 175 Lu、 177 Lu、 225 Ac、 161 Tb, 212 Pb; Preferably, the compound of formula (II) is formed by chelating the compound of formula (I) according to any one of claims 1-6 with M.

8. The compound of formula (II) according to claim 7, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown in formula (II) has the following structure: Among them, L A L B A, Q, R L m, n, p, q, and M each have the definition as described in claim 7 independently; Preferably, the compound shown in formula (II) has the following structure: Among them, A and L B Q, R L m, n, p, q, and M each have the definition as described in claim 7 independently; Preferably, the compound shown in formula (II) has the following structure: Wherein, A, Q, M, X, Y, p, and q independently have the definitions described in claim 7.

9. The compound of formula (II) according to claim 7 or 8, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound, wherein the compound of formula (II) has the following structure:

10. The compound represented by formula (III), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: R S1 Selected from H or R L ; R S2 Selected from hydroxyl or -O-carboxyl protecting groups; preferably, R S2 Selected from hydroxyl or C 1-6 Alkyloxy; more preferably, R S2 Selected from OH or -O-tBu; R L It has the definition as described in any one of claims 1-5; Z is selected from any one, two or more Cs. 1-6 Alkoxy-substituted C 1-6 alkyl; Preferably, Z is selected from C. 1-3 Alkoxy-substituted C 2-6 alkyl; Preferably, Z is selected from methoxy-substituted C-type compounds. 2-6 alkyl; Preferably, Z is selected from Preferably, the compound shown in formula (III) has the following structure: Preferably, the compound shown in formula (III) has the following structure:

11. The compound represented by formula (IV), its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound: Ch”—L—B Formula (IV) "Ch" is selected from chelating agent residues and chelating agent residues containing radioactive or non-radioactive metals. L is a divalent linker; B is the targeting group, which is selected from the following groups: in, R L Z has the definition as described in any one of claims 1-6, and Z has the definition as described in claim 10; Preferably, B is selected from the following groups:

12. The compound of formula (IV) according to claim 11, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound, characterized in that, The compound shown has the following structure: Wherein, Ch” is selected from Ch or Ch'; Ch、Ch'、L A L B R L Z and n have the definitions as described in any one of claims 1-11.

13. A pharmaceutical composition comprising the compound of formula (I), formula (II), or formula (IV) as claimed in any one of claims 1-9, 11-12, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt, or prodrug compound.

14. Use of the compound of formula (I) according to any one of claims 1-6, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound in the preparation of a radiopharmaceutical.

15. Use of the compound of formula (I), formula (II), formula (IV) as claimed in any one of claims 1-9, 11-12, its racemate, stereoisomer, tautomer, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound or the pharmaceutical composition of claim 13 in the preparation of a medicament; Preferably, the drug is a drug for the prevention, treatment or diagnosis of prostate cancer, or the drug is a drug for imaging prostate cancer. Preferably, the prostate cancer is castration-resistant prostate cancer; Preferably, the prostate cancer is metastatic castration-resistant prostate cancer; Preferably, the prostate cancer is PSMA-positive prostate cancer.

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