Fap compound and use thereof

Abstract

The present application discloses a compound of formula I or a pharmaceutically acceptable salt, ester, or solvate thereof. Formula I is (RW)m11—L—X, wherein each group is as defined herein. The present application also disclose a pharmaceutical composition comprising the compound and a use of the compound.

Description

FAP compounds and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of radiopharmaceuticals, and particularly relates to a new FAP compound and uses thereof. BACKGROUND

[0002] Cancer is one of the major diseases that endanger people's life and health safety. According to the data released by the National Cancer Center, there were more than 4.8 million new cases of malignant tumors in China in 2022, and the incidence rate of men was higher than that of women in general. Based on tumor registration and follow-up monitoring, the top ten cancer types in terms of incidence rate are: lung cancer, colorectal cancer, thyroid cancer, liver cancer, gastric cancer, breast cancer, esophageal cancer, cervical cancer, prostate cancer, and pancreatic cancer.

[0003] In recent years, fibroblast activation protein (FAP) as a marker of cancer-associated fibroblasts (CAFs) is a suitable marker for radiopharmaceutical diagnosis and a suitable target for radiopharmaceutical treatment, and has attracted more and more attention (see: CN114341158A, CN114341159A, CN116940585A, etc.).

[0004] It is reported that FAP is generally not expressed in normal tissues, while more than 90% of stromal fibroblasts in epithelial malignant tumors are detected to have high expression of FAP, including breast cancer, esophageal cancer, thyroid cancer, ovarian cancer, lung cancer, colon cancer, gastric cancer, and pancreatic cancer, etc. (see: CN113621021A, CN115260160A, etc.). At present, FAP-targeted drugs have become a hot topic in the medical field.

[0005] FAP-targeted drugs are mainly composed of FAP compounds and radionuclides. For targeted drugs, there are mainly two performance indicators: ① effectiveness, higher tumor site uptake; ② less toxic side effects, lower kidney and other tissue uptake.

[0006] However, the existing FAP compounds and targeted drugs are still not very satisfactory in terms of effectiveness and / or toxic side effects, and therefore it is necessary to further develop new FAP compounds and / or their targeted drugs.

[0007] SUMMARY

[0008] The main purpose of the present application is to provide a new FAP compound, which has higher tumor uptake and / or lower kidney uptake, can greatly reduce the risk of kidney damage while improving the targeting effect of the drug, and thus is beneficial to better meet the medication needs of patients.

[0009] According to a first aspect, the present application provides a compound of the following formula I or a pharmaceutically acceptable salt, ester or solvate thereof, (R W ) m11 —L—X I

[0010] wherein,

[0011] L is a linker comprising nitrogen (N) and / or sulfur (S);

[0012] X is hydrogen or a chelator, and X is connected to the N-terminal end (e.g. NH or N) of L;

[0013] R w is (preferably, R w is

[0014] ) ;

[0015] m 11 is 1 or 2; when m 11 is 2, R w are the same or different;

[0016] said -Xaa2-Xaa3-Xaa4-Xaa5-Xaa6- is a residue of an amino acid and / or a peptide, the sequence of which is drawn from left to right in the direction of the N-terminal end to the C-terminal end;

[0017] Y 1 is CH or N;

[0018] m is 1 or 2;

[0019] n is 0 or 1;

[0020] R a is selected from the group consisting of hydrogen, deuterium, tritium, OH, COOH, CONH2, -CO-X 1 or -CO-NH-X 1 , wherein X 1 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl, X 1 is unsubstituted, or, optionally X 1 is substituted with one or more substituents selected from the group consisting of deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, CONH2, halogen, cyano (CN), OH, NH2and -NH-CO-R a1 -CO-NH-R a2 -(O-R a3 ) u -NH-CO-R a4 -R d ;

[0021] Ra1 R a2 R a3 and R a4 Each is independently selected from 1-6 methylene (CH2) groups, wherein R a1 R a2 R a3 and R a4 All methylene groups (CH2) in the form are not substituted, or, optionally, the R group is not substituted. a1 R a2 R a3 and R a4 One or two hydrogens of one, two, three, four or five methylene (CH2) groups are independently replaced by deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, azide, C1-C6 alkyl, azide-substituted C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl;

[0022] u can be 0, 1, 2, 3, 4 or 5;

[0023] R d Selected from C5-C6 aryl, X 2 Substituted C5-C6 aryl, C2-C6 heteroaryl or X 2 Substituted C2-C6 heteroaryl groups, wherein X 2 Selected from deuterium, tritium, methyl, halomethyl, methoxy, halomethoxy, ethyl, haloethyl, ethoxy, haloethoxy, propyl, halopropyl, propoxy, halopropoxy, COOH, CONH2, halogen, cyano (CN), NH2 or OH;

[0024] R b Selected from hydrogen, deuterium, tritium, methyl, OH, NH2, or F;

[0025] R c Selected from COOH, CONH2, -CO-NH-Z a -CO-NH-CO-Z a -CO-NH-Z b -CO-NH-Z a -CO-NH-Z b -NH-CO-Z a or -CO-Z c ;

[0026] in,

[0027] Z a Selected from C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl, C2-C6 heteroaryl or Z aunsubstituted, or, optionally Z a is substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, COOH, CONH2, OH, halogen, cyano (CN), NH2, X 0 is selected from hydrogen, deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, pyrazolyl, C1-C6 alkyl substituted pyrazolyl, COOH, CONH2, OH, or NH2(wherein, when X 0 is hydrogen, it means that the phenyl group is not substituted with X 0 );

[0028] Z b is selected from 1-6 methylene groups (CH2), wherein all methylene groups (CH2) in said Z b are unsubstituted, or, optionally one or two hydrogens in 1, 2, 3, 4, or 5 methylene groups (CH2) in said Z b are each independently substituted with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, azido, C1-C6 alkyl, azido substituted C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl, or C2-C6 heteroaryl;

[0029] Z c is selected from 4-7 membered nitrogen heterocycle, wherein Z c is unsubstituted, or, optionally Z c is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, COOH, CONH2, OH, and NH2;

[0030] m1, m2, m3, and m4 are each independently selected from 1 or 2;

[0031] m 21 and m 22 are each independently selected from 1 or 2;

[0032] n 11 is 0 or 1;

[0033] X 11 is selected from S or O;

[0034] R zcselected from COOH, CONH2, -CH2-COOH, -CH2-CONH2, C1-C6alkyl, C1-C6alkoxy, C1-C6alkyl-substituted phenyl, C1-C6alkoxy-substituted phenyl, or halogen-substituted phenyl;

[0035] R za1 , R za2 , R za3 , and R za4 are each independently selected from hydrogen, deuterium, tritium, C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, C2-C6heteroaryl, or

[0036] Xaa2and Xaa3are each independently selected from an amino acid residue as depicted in formula AA1, AA2, or AA3:

[0037] (preferably, Xaa2and Xaa3are each independently selected from an amino acid residue as depicted in formula:

[0038] )

[0039] wherein,

[0040] R 2a , R 2b , and R 2c are each independently selected from hydrogen, deuterium, tritium, C1-C3alkyl, or substituted C1-C3alkyl, wherein the substituents of the C1-C3alkyl are selected from OH, NH2, halogen, cyano (CN), carboxyl (COOH), or C5-C7cycloalkyl;

[0041] R 2d is selected from hydrogen, deuterium, tritium, methyl, OH, NH2, or F;

[0042] X 3 is selected from CH2, CF2, CH-R 2e , S, O, or NH;

[0043] R 2e is selected from deuterium, tritium, methyl, OH, NH2, or F;

[0044] p is 0, 1, or 2;

[0045] v is 1 or 2;

[0046] w is 1, 2, or 3;

[0047] Xaa4is an amino acid residue as depicted in formula AA4:

[0048] (preferably, Xaa4is an amino acid residue as depicted in formula: )

[0049] wherein,

[0050] R 4a is selected from hydrogen, deuterium, tritium, OH, COOH, CONH2, X 4 , -CO-NH-X 4 , -NH-CO-X 4 or -NH-X 5 , wherein X 4 is selected from C1-C6alkyl, C1-C6alkoxy, C5-C6aryl or C2-C6heteroaryl, X 4 is unsubstituted, or, optionally, X 4 is substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxyl (COOH), CONH2, OH, halogen, cyano (CN) and -NH-X 5 ; X 5 is selected from hydrogen, deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, OH or

[0051] q is selected from an integer from 1 to 10 (e.g., q is 1, 2, 3, 4 or 5), wherein all methylene groups (CH2) in said q are unsubstituted, or, optionally, one or two hydrogens in 1, 2, 3, 4 or 5 methylene groups (CH2) in said q are each independently substituted with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, C1-C6alkyl, C1-C6alkyl substituted with azido, C1-C6alkoxy, C5-C6aryl or C2-C6heteroaryl;

[0052] R 4b is selected from hydrogen, deuterium, tritium or methyl;

[0053] Xaa5is an amino acid residue of formula AA5:

[0054] (preferably, Xaa5is an amino acid residue of formula: )

[0055] R 5a is selected from COOH, CONH2, -CO-X 6 , -oxadiazole-X 6 or -S(=O)(=O)-X 6 (i.e.: ), wherein X 6 is selected from C1-C6alkyl, C1-C6alkoxy, C5-C6aryl or C2-C6heteroaryl, X 6unsubstituted, or, optionally, X 6 substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxyl (COOH), CONH2, OH, cyano (CN), halogen, and NH2;

[0056] r is 1, 2, 3, 4, or 5; wherein all methylene groups (CH2) in said r are unsubstituted, or, optionally, one or two hydrogens in 1, 2, 3, 4, or 5 methylene groups (CH2) in said r are each independently substituted with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, C1-C6 alkyl, C1-C6 alkyl substituted with azido, C1-C6 alkoxy, C5-C6 aryl, or C2-C6 heteroaryl;

[0057] Xaa6 is an amino acid residue selected from an aromatic alpha-amino acid, a halogen-substituted aromatic alpha-amino acid, X 7 substituted aromatic alpha-amino acid, a heteroaromatic alpha-amino acid, a halogen-substituted heteroaromatic alpha-amino acid, X 7 substituted heteroaromatic alpha-amino acid, which can be in the S- or R-configuration, wherein X 7 is selected from C5-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl, or C2-C6 heteroaryl, X 7 unsubstituted, or, optionally, X 7 substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, CONH2, halogen, cyano (CN), NH2, and OH.

[0058] In a preferred embodiment,

[0059] L is selected from L xa1 , L xa3 ,

[0060] wherein,

[0061] L xa1 is

[0062] L xa2 is

[0063] L xa3 is

[0064] z1, z2, z3, and z4 are each independently selected from 0, 1, 2, or 3;

[0065] t0 is 1, 2 or 3;

[0066] m5, m6, m7 and m8 are each independently selected from 0, 1, 2 or 3;

[0067] m 31 and m 32 are each independently selected from 1 or 2;

[0068] R za5 , R za6 and R za7 are each independently selected from hydrogen, deuterium, tritium, C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl, C2-C6 heteroaryl or

[0069] L xb1 , L xb2 and L xb3 are each independently selected from -CO-(Rx1-O) t1 -Rx2-NH-CO-, -CO-(Rx1-O) t1 -Rx2-NH-CO-(Rx3-O) t2 -Rx4-CO-, -CO-(Rx1-O) t1 -Rx2-CO-NH-(Rx3-O) t2 -Rx4-CO-, -CO-(Rx1-O) t1 -Rx2-CO-NH-(Rx3-O) t2 -Rx4-NH-CO- or -CO-(Rx1-O) t1 -Rx2-NH-CO-(Rx3-O) t2 -Rx4-NH-CO-;

[0070] R x11 is selected from hydrogen, deuterium, tritium or C1-C6 alkyl;

[0071] R x1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 are each independently selected from 1-6 methylene groups (CH2), wherein all methylene groups of said R x1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 are unsubstituted, or, optionally, one or more methylene groups of said Rx1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 one or two hydrogens in one or two of the methylene groups (CH2) in R x5 -Z d , -CO-NH-R x5 -Z d , C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl;

[0072] R x5 is selected from 1-6 methylene groups (CH2), wherein all methylene groups (CH2) in R x5 are unsubstituted, or, optionally, one or two hydrogens in one or two of the methylene groups (CH2) in R x5 are each independently replaced with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl;

[0073] Z d is

[0074] t1, t2, t 11 , t 12 , t 13 , and t 14 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0075] Yaabbis a cyclic peptide group condensed from 3-8 amino acids (substituted or unsubstituted), and L xb2 is attached to the N-terminus (e.g., NH or N) of Yaabb;

[0076] Yaaccis

[0077] z5and z6are each independently selected from 1 or 2;

[0078] R x16 is selected from 1-6 methylene groups (CH2), wherein all methylene groups (CH2) in R x16 are unsubstituted, or, optionally, one or two hydrogens in one or two of the methylene groups (CH2) in Rx16 one or two hydrogens in one, two, three, four or five methylene groups (CH2) are each independently replaced with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl;

[0079] R 9a selected from C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl;

[0080] Z e is a 4-7 membered nitrogen heterocycle, wherein Z e is unsubstituted, or, optionally, Z e substituted with one or more substituents selected from deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, COOH, CONH2, OH, and NH2.

[0081] In a preferred embodiment,

[0082] X is hydrogen or a chelator, and X is attached to the N-terminus (e.g., NH or N) of L; said chelator is 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA, ), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, , 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-pentanedioic acid (DOTAGA: , N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 2-(4,7-bis(carboxymethyl)-1,4,7-triazol-N-alkyl)pentanedioic acid (NODAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)- phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15- tetraazabicyclo[9,3,1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N4, N2S2, N3S, Hynic, diethylenetriaminepentaacetic acid (DTPA: wherein X 12 , X 13 and X 14 are each independently selected from S or O;

[0083] Alternatively, the chelator is PYTA, PY3A-NH2, PY3A-NH2-SQ, PYTAGA, PYTAGA-NH2 or PYTAGA-NH2-SQ;

[0084] wherein,

[0085] NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N4, N2S2, N3S, Hynic, have the same definition as in CN 114341158 A, CN 116940586 A or its homologous patent application WO 2022 / 148851 A1;

[0086] For example,

[0087] Macropa means

[0088] PYTA means

[0089] ​PY3A-NH2 refers to

[0090] PY3A-NH2-SQ refers to

[0091] PYTAGA refers to PYTAGA1 and PYTAGA2,

[0092] PYTAGA-NH2 refers to

[0093] PYTAGA-NH2-SQ refers to Preferably, the chelator is DOTA or DOTAGA;

[0094] Alternatively, the chelator is PYTA or PYTAGA

[0095] In a preferred embodiment,

[0096] R w is

[0097] wherein,

[0098] X 6 is selected from C1-C6 alkyl, C1-C6 alkoxy or C5-C6 aryl; X 6 is unsubstituted, or, optionally X 6 is substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxyl (COOH), CONH2, OH, cyano (CN), halogen and NH2, and r is 1, 2 or 3;

[0099] Preferably,

[0100] X 6 is C1-C6 alkyl (e.g., X 6 is methyl, ethyl or propyl), and r is 1, 2 or 3.

[0101] More preferably,

[0102] X 6 is methyl or ethyl, and r is 2,

[0103] wherein Y 1m, n, R a R b R c Xaa2, Xaa3, Xaa6, R 4a R 4b and q are defined as above.

[0104] In a preferred embodiment,

[0105] R c selected from COOH, CONH2, -CO-NH-Z a -CO-NH-CO-Z a -CO-NH-Z b -CO-NH-Z a -CO-NH-Z b -NH-CO-Z a or -CO-Z c ;

[0106] wherein,

[0107] Z a selected from C1-C6 alkyl, C1-C6 alkoxy or Z a is unsubstituted or, optionally, Z a is substituted with one or more substituents selected from deuterium, tritium, COOH, CONH2, OH, halogen, cyano (CN), NH2and X 0 selected from hydrogen, deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, COOH, CONH2, OH or NH2;

[0108] Z b selected from 1-6 methylenes (CH2), wherein all methylenes (CH2) in said Z b are unsubstituted or, optionally, one or two hydrogens in one of the methylenes (CH2) in said Z b are each independently substituted with deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, azido, C1-C6 alkyl, azido-substituted C1-C6 alkyl or C1-C6 alkoxy;

[0109] Z c is a 4-6 membered nitrogen heterocycle, wherein Z c is unsubstituted or, optionally, Z csubstituted with one or more substituents selected from the group consisting of deuterium, tritium, halogen, cyano (CN), -B(OH)2, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-haloalkyl, COOH, CONH2, OH and NH2;

[0110] R zc is selected from the group consisting of COOH, CONH2, Ci-C6-alkyl, Ci-C6-alkoxy, Ci-C6-alkyl-substituted phenyl, Ci-C6-alkoxy-substituted phenyl or halogen-substituted phenyl;

[0111] R za1 , R za2 , R za3 and R za4 are each independently selected from the group consisting of hydrogen, deuterium, tritium or Ci-C6-alkyl;

[0112] Preferably,

[0113] R c is selected from the group consisting of COOH, CONH2, -CO-NH-Z a , -CO-NH-CO-Z a , -CO-NH-Z b -CO-NH-Z a , -CO-NH-Z b -NH-CO-Z a or -CO-Z c ;

[0114] wherein,

[0115] Z a is selected from the group consisting of Ci-C6-alkyl or Z a is unsubstituted or, optionally, Z a is substituted with one or more substituents selected from the group consisting of deuterium, tritium, COOH, CONH2, NH2, X 0 is selected from the group consisting of hydrogen, deuterium, tritium, halogen, cyano (CN), -B(OH)2or Ci-C6-alkyl;

[0116] Z b is selected from 1 to 6 methylenes (CH2), wherein all methylenes (CH2) in said Z b are unsubstituted or, optionally, one or two hydrogens in one methylene (CH2) in said Z b are each independently substituted with deuterium, tritium, carboxyl (COOH), CONH2or Ci-C6-alkyl;

[0117] Z c is selected from the group consisting of piperazinyl, piperidinyl, pyrrolidinyl, wherein Z c is unsubstituted, or, optionally, Z c is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6alkyl, COOH, and CONH2;

[0118] R zc is selected from C1-C3alkyl, C1-C3alkoxy, or C1-C3alkyl-substituted phenyl;

[0119] R za1 , R za2 , R za3 , and R za4 are each independently selected from hydrogen or C1-C3alkyl.

[0120] In one preferred embodiment,

[0121] The compounds described herein are shown in Formula IA or Formula IB:

[0122] wherein,

[0123] L in Formula IA is as defined above;

[0124] L in Formula IB is as defined above; xa3 as defined above;

[0125] X is hydrogen or a chelator, and X is attached to the N-terminal end (e.g., NH or N) of L; wherein the chelator is DOTA or

[0126] R a is -CO-X 1 or -CO-NH-X 1 , wherein X 1 is C1-C6alkyl;

[0127] R b is hydrogen, deuterium, or tritium;

[0128] R c is as defined above;

[0129] Xaa2and Xaa3are each independently selected from the following amino acid residues:

[0130] (preferably, Xaa2and Xaa3are each independently selected from the following amino acid residues: )

[0131] wherein,

[0132] R2a and R 2b Each is independently selected from hydrogen, deuterium, tritium, C1-C3 alkyl, or C1-C3 alkyl groups substituted with carboxyl;

[0133] R 2c Selected from hydrogen, deuterium, or tritium;

[0134] R 2d Selected from hydrogen, deuterium, or tritium;

[0135] R 4a Selected from hydrogen, deuterium, tritium, OH, COOH, CONH2, X 4 -CO-NH-X 4 or -NH-X 5 , where X 4 It is a C1-C6 alkyl or phenyl group, X 4 Not replaced, or, optionally X 4 Selected from deuterium, tritium, carboxyl (COOH), CONH2 and -NH-X 5 One or more substituents are substituted; X 5 Selected from hydrogen, deuterium, tritium or

[0136] q is selected from integers from 1 to 6, wherein all methylene (CH2) in q are unsubstituted, or, optionally, one or both hydrogens of one or two methylene (CH2) in q are independently substituted by deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, or C1-C6 alkyl.

[0137] r is 1, 2, 3, 4 or 5; wherein all methylene groups in r are unsubstituted, or, optionally, one or both hydrogens of one or two methylene groups in r are independently substituted by deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6.

[0138] R 4b It can be hydrogen, deuterium, or tritium;

[0139] Xaa6 is selected from aromatic α-amino acids, halogen-substituted aromatic α-amino acids, and X... 7 Substituted aromatic α-amino acids, amino acid residues, of which X 7 It is a C1-C6 alkyl group, X 7 Not replaced, or, optionally X 7 It is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano (CN), NH2 and OH; the aromatic α-amino acid is phenylalanine, and the halogen is fluorine, chlorine, bromine or iodine;

[0140] Preferably,

[0141] R a For -CO-X 1 or -CO-NH-X 1 , where X 1 It is a C3-C5 alkyl group;

[0142] R b It is hydrogen;

[0143] R c As defined above;

[0144] R 4a Selected from OH, COOH, CONH2, X 4 -CO-NH-X 4 or -NH-X 5 , where X 4 It is a C1-C3 alkyl or phenyl group, X 4 Not replaced, or, optionally X 4 Selected from carboxyl (COOH), CONH2 and -NH-X 5 One or more substituents are substituted; X 5 For hydrogen or

[0145] q is 1, 2, 3, 4 or 5, wherein all methylene (CH2) in q are unsubstituted, or, optionally, one or both hydrogens of one methylene (CH2) in q are independently substituted by deuterium, tritium, carboxyl (COOH), CONH2, OH, halogen, cyano (CN), NH2, C1-C3 alkyl;

[0146] r is 1, 2, 3 or 4; wherein all methylene groups in r are unsubstituted, or, optionally, one or both hydrogens of one or two methylene groups in r are independently substituted by deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6.

[0147] R 4b It is hydrogen;

[0148] Xaa6 is (For example, phenylalanine or residues that substitute for phenylalanine; preferably, ), where X 0a A is hydrogen, a halogen, or a methyl group substituted with 1-3 halogen molecules, wherein the halogen is fluorine, chlorine, bromine, or iodine; 环 It is phenyl, anthracene, naphthyl, pyridyl, or benzopyridyl; t 21 The value is 0, 1, 2, 3, 4, 5, or 6 (where X is the inequality). 0a When it is hydrogen, it represents A. 环 Not X 0areplace).

[0149] In a preferred embodiment

[0150] The compounds are shown as those of formula IA1 or IB1:

[0151] (In Formula IA1 or Formula IB1, * indicates a chiral carbon, which can be either R or S configuration)

[0152] in,

[0153] In equation ⅠA1, L is as defined above;

[0154] In formula IB1, L xa3 As defined above;

[0155] Xaa2 and Xaa3 are each independently selected from the amino acid residues shown below:

[0156] (Preferably, Xaa2 and Xaa3 are each independently selected from the amino acid residues shown below:) )

[0157] R a For -CO-X 1 or -CO-NH-X 1 The X 1 Selected from n-propyl, n-butyl, or n-pentyl;

[0158] R c As defined above;

[0159] R 4a Selected from OH, COOH, CONH2, X 4 -CO-NH-X 4 or -NH-X 5 , where X 4 It is a C1-C2 alkyl or phenyl, and optionally X 4 Selected from carboxyl (COOH), CONH2 and -NH-X 5 One or more substituents are substituted; X 5 for

[0160] q is 1, 2, 3, 4 or 5, wherein all methylene (CH2) in q are unsubstituted, or, optionally, one or both hydrogens of one methylene (CH2) in q are each independently substituted by a C1-C3 alkyl group;

[0161] X 0aIt is hydrogen, halogen, or methyl group substituted with 1-3 halogen molecules, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine;

[0162] A 环 It is phenyl, anthracene, or naphthyl; t 21 It can be 1 or 2;

[0163] Preferably,

[0164] X 0a Connected in A 环 The opposite or intermediate position.

[0165] In a preferred embodiment

[0166] R 4a For X 4 or -NH-X 5 , where X 4 It is phenyl, and X 4 by -NH-X 5 Replace; X 5 for

[0167] q is 1, 2, 3, 4 or 5, wherein all methylene (CH2) in q are not substituted.

[0168] In a preferred embodiment

[0169] In formula ⅠA1, L is Where t0 is 2 or 3; m5, m6, m7, and m8 are each independently selected from 1 or 2; m 31 and m 32 Each is independently selected from 1 or 2; R za5 and R za7 Each is independently selected from hydrogen or methyl (e.g., wait);

[0170] Preferably, the compounds of the present invention are selected from:

[0171] In a preferred embodiment

[0172] L is (Preferred) ),

[0173] L xa3 for

[0174] in,

[0175] L xa1 for

[0176] L xa2 for

[0177] L xb1 is -CO-(CH2)2-CO-NH-(CH2)4-CH(NH-CO-(CH2)3-Z d )-CO-, -CO-Rx2-NH-CO-Rx4-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-(CH2-CH2-O)2-(CH2)2-CO-, -CO-CH2-NH-CO-, -CO-(CH2)3-CO-NH-CH(COOH)-(CH2)4-NH-CO-, -CO-(CH2-CH2-O)4-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-;

[0178] L xb2 is -CO-(CH2-CH2-O)2-(CH2)2-NH-CO;

[0179] L xb3 It is -CO-CH(CH3)-NH-CO-,

[0180] Z d for

[0181] Rx2 is

[0182] Rx4 is

[0183] Rx 11 for

[0184] Z ePyrroleyl groups substituted with -B(OH)2;

[0185] Yaacc Z e Pyrroleyl groups substituted with halogen and / or cyano (CN);

[0186] Yaabb is a cyclic peptide composed of 3-5 amino acids condensed together, and L... xb2 The amino acid in Yaabb is selected from aspartic acid (Asp), phenylalanine (Phe), lysine (Lys), glycine (Gly), or arginine (Arg) and is attached to the N-terminus (e.g., NH or N).

[0187] X 0 It can be hydrogen, deuterium, tritium, halogen, or cyano (CN);

[0188] Preferably,

[0189] L is

[0190] L xa3 for

[0191] In a preferred embodiment, the compounds of the present invention are selected from:

[0192] In a preferred embodiment, the compound of the present invention is shown as formula IA2 or formula IB2:

[0193] (In formula IA2 or formula IB2, * indicates a chiral carbon, which can be either R or S configuration)

[0194] Among them, X and R c L, L xa3 Xaa2, Xaa3, R a R 4a , q, X 0a A 环 and t 21 As defined above.

[0195] In a preferred embodiment, the -S(=O)(=O)-CH3(R) in each of claims 9 and 11 is respectively... 5a Replace with The resulting compound;

[0196] Preferably, the compound is selected from:

[0197] In a preferred embodiment, the compound is shown as formula IA3 or formula IB3:

[0198] (In Formula IA3 or Formula IB3, * indicates a chiral carbon, which can be either R or S configuration)

[0199] Among them, X and R c L, L xa3 Xaa2, Xaa3, R 4a And q as defined above;

[0200] R a For -CO-X 1 or -CO-NH-X 1 , where X 1 It is a C1-C6 alkyl or phenyl group; X 1 Not replaced, or, optionally X 1 Composed of methyl or -NH-CO-R a1 -CO-NH-R a2 -(OR a3 ) u -NH-CO-R a4 -R d replace;

[0201] R a1 R a2 R a3 R a4 Each is independently selected from 1 to 6 methylene (CH2) molecules, wherein R a1 R a2 R a3 and R a4 All the methylene groups (CH2) in the compound were not replaced;

[0202] u can be 0, 1, 2, 3, 4 or 5;

[0203] R d A phenyl group that is substituted with a phenyl or halogen;

[0204] R 5a It is COOH or CONH2;

[0205] r is 1 or 2;

[0206] A 环 It is phenyl, anthracene, naphthyl, pyridyl, or benzopyridyl;

[0207] t 21It can be 0, 1, 2, 3, 4, 5, or 6;

[0208] X 0 Selected from hydrogen, deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, pyrazolyl, C1-C6 alkyl-substituted pyrazolyl, COOH or CONH2;

[0209] Preferably,

[0210] A 环 It is phenyl, anthracene, naphthyl, or pyridyl;

[0211] t 21 It can be 1 or 2;

[0212] X 0 It is selected from hydrogen, deuterium, tritium, halogen, cyano (CN), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, pyrazolyl or C1-C6 alkyl-substituted pyrazolyl.

[0213] In a preferred embodiment

[0214] L is

[0215] Among them, z1, z2, z3, and z4 are each independently selected from 1 or 2; t0 is 2 or 3; m5, m6, m7, and m8 are each independently selected from 1 or 2; m 31 and m 32 Each is independently selected from 1 or 2; and R za5 and R za7 Each is independently selected from hydrogen or methyl (e.g., wait).

[0216] In a preferred embodiment, the compound is selected from:

[0217] In a preferred embodiment

[0218] L is (Preferred) ),

[0219] L xa3 for

[0220] in,

[0221] L xa1 for

[0222] L xa2 for

[0223] L xb1 is -CO-(CH2)2-CO-NH-(CH2)4-CH(NH-CO-(CH2)3-Z d )-CO-, -CO-Rx2-NH-CO-Rx4-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-(CH2-CH2-O)2-(CH2)2-CO-, -CO-CH2-NH-CO-, -CO-(CH2)3-CO-NH-CH(COOH)-(CH2)4-NH-CO-, -CO-(CH2-CH2-O)4-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-;

[0224] L xb2 is -CO-(CH2-CH2-O)2-(CH2)2-NH-CO;

[0225] L xb3 It is -CO-CH(CH3)-NH-CO-,

[0226] Z d for

[0227] Rx2 is

[0228] Rx4 is

[0229] Rx 11 for

[0230] Z e Pyrroleyl groups substituted with -B(OH)2;

[0231] Yaacc Z e Pyrroleyl groups substituted with halogen and / or cyano (CN);

[0232] Yaabb is a cyclic peptide composed of 3-5 amino acids condensed together, and L... xb2 The amino acid in Yaabb is selected from aspartic acid (Asp), phenylalanine (Phe), lysine (Lys), glycine (Gly), or arginine (Arg) and is attached to the N-terminus (e.g., NH or N).

[0233] X 0 It can be hydrogen, deuterium, tritium, halogen, or cyano (CN);

[0234] Preferably,

[0235] L is

[0236] L xa3 for

[0237] In a preferred embodiment, the compound is selected from:

[0238] In a preferred embodiment

[0239] L is L xa1 or

[0240] L xa1 for

[0241] L xb1 For -CO-; and, L xb1 With L xa1 The N-terminal connection;

[0242] R x99 It is hydrogen, C1-C6 alkyl or

[0243] Xaa6 is

[0244] T 环 For A 环 or

[0245] A 环 It can be phenyl, anthracene, or naphthyl;

[0246] X 0a Connected in A 环 Opposite or intermediate;

[0247] X 0a It is hydrogen, halogen, or methyl group substituted with 1-3 halogen molecules, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine;

[0248] t 97 t 98 and t 99 Each can be independently selected from 0, 1, 2, 3, 4, 5, or 6;

[0249] Preferably, the compound is selected from:

[0250] In a preferred embodiment, the compound comprises a nuclide;

[0251] Preferably, the radionuclide is a diagnostically active radionuclide or a therapeutically active radionuclide;

[0252] More preferably, the nuclide is selected from... 94 Tc, 99m Tc, 90 In、 111 In、 67 Ga、 68 Ga、 86 Y、 90 Y、 177 Lu、 151 Tb, 152 Tb, 155 Tb, 51 Mn, 52 Mn, 76 Br、 77 Br、 201 Tl、 203 Pb, 186 Re、 188 Re、 64 Cu、 67 Cu、 55 Co、 57 Co、 43 Sc、 44 Sc、 47 Sc、 225 Ac、 213 Bi、 212 Bi、 212 Pb, 227 Th、 153 Sm、 166 Ho、 152 Gd, 153 Gd, 157 Gd, 166 Dy、 55 Fe、 18 F, 11 C 89 Zr、 123 I, 124 I, 125 I, 131 I or 211 At;

[0253] More preferably, the nuclide is 68 Ga or177 Lu.

[0254] According to a second aspect, the present invention also provides the use of the compound according to the first aspect or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a medicament for diagnosing and / or treating a disease; for example, said disease is cancer; further, said disease is glioma (e.g., brain glioma, etc.), colon cancer, breast cancer, esophageal cancer, thyroid cancer, ovarian cancer, lung cancer, gastric cancer, pancreatic cancer or sarcoma, etc.

[0255] According to a third aspect, the present invention also provides a pharmaceutical composition comprising the compound according to the first aspect or a pharmaceutically acceptable salt, ester or solvate thereof and a pharmaceutically acceptable excipient (an excipient is an additive in a pharmaceutical preparation other than the active pharmaceutical ingredient, also known as an excipient).

[0256] According to a fourth aspect, the present invention also provides a kit comprising the compound according to the first aspect or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more optional excipients and one or more optional devices, wherein the devices are selected from labeling devices, purification devices, operating devices, radiation protection devices, analytical devices or administration devices.

[0257] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0258] "Aryl" can be a bridged ring or a spiro ring, and non-limiting examples include phenyl, naphthyl, or anthracene.

[0259] "C1-C6 alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group with 1 to 6 carbon atoms, preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and their various branched isomers.

[0260] "C1-C6 alkoxy" refers to RO, where R is a C1-C6 alkyl group and O is oxygen. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. Preferably, it is a C1-C4 alkoxy.

[0261] "Deuteration" refers to the replacement of some or all of the hydrogen atoms in a substituted group with deuterium atoms.

[0262] "Halogenation" refers to the replacement of some or all of the hydrogen atoms in the substituted group with halogens.

[0263] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0264] "Heteroaryl" can be a bridged ring or a spiro ring. Non-limiting examples include pyridyl, furanyl, thiophene, pyranyl, pyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, oxazolyl, thiazolyl, thiaranyl, benzimidazolyl, benzoxazolyl, benzopyridinyl (including indole, isoindole), benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzothiaranyl, pyrrolopyridyl, and purinyl.

[0265] A "solvent" is a compound or its pharmaceutically acceptable salt in which molecules of a suitable solvent are bound in a crystal lattice. The suitable solvent is physiologically permissible at the administered dose. Examples of suitable solvents include ethanol and water. When water is used as the solvent, the molecule is called a "hydrate".

[0266] "Ester" refers to the esterification of free acid groups in the compounds of this invention. Suitable esters include various alkyl esters, such as C1-C10 alkyl esters of saturated or unsaturated C1-C18 fatty acids.

[0267] In the chemical structure of the compound described in this invention, the configuration of "bond" is not specified, i.e., bond It can be an S configuration, R configuration, D configuration, L configuration, Z configuration, or E configuration, or it can contain multiple configurations (e.g., two, three, four, etc.).

[0268] Compared to existing known FAP compounds, the novel FAP compounds provided by this invention have higher tumor uptake and / or lower renal uptake, thus improving drug targeting efficacy while significantly reducing the risk of kidney damage, thereby better meeting patients' medication needs. Attached Figure Description

[0269] Figure 1 shows the experimental example 1. 177 Representative visualizations at 1h, 4h, 8h, 24h and 48h after administration of Lu-VWT047000.

[0270] Figure 2 shows the experimental example 1. 177 Representative visualizations at 1h, 4h, 8h, 24h and 48h after administration of Lu-VWT047200.

[0271] Figure 3 shows the drug administration in Experiment Example 1. 177 Lu-VWT047200 and 177 Tumor volume comparison curve of Lu-FAP-2286.

[0272] Figure 4 shows the drug administration in Experiment Example 1. 177 Lu-VWT047200 and 177 A curve showing the weight comparison of mice treated with Lu-FAP-2286.

[0273] Figure 5 shows the treatment group 1 (administration) in Experiment 2. 177 Lu-FAP-2286, 0.3 mcg / animal), treatment group 2 (administered). 177 The relative change of tumor volume (RTV) in Lu-VWT053800 (0.3 mci / mouse) and control mice.

[0274] Figure 6 shows the treatment group 1 (administration) in Experiment 2. 177 Lu-FAP-2286, 0.3 mcg / animal), treatment group 2 (administered). 177 The relative tumor proliferation rate (T / C) changes (%) between Lu-VWT053800 (0.3 mci / mouse) and control mice. Detailed Implementation

[0275] The present invention will be clearly and completely described below with reference to specific embodiments. Those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as a limitation on the scope of protection of the present invention.

[0276] In this invention, unless otherwise specified, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0277] Regarding the definitions of terms used in this invention, unless otherwise stated, the initial definitions provided herein apply to the term throughout the text; for terms not specifically defined herein, the meanings that a person skilled in the art can give them may be given based on the disclosure and / or context.

[0278] Compound VWT005700 (a known compound, namely: WO2021005131 A1 and its Chinese patent family CN 114341158 A, etc., which describes compound 3BP-3554): obtained by purchase or prepared according to methods in the prior art.

[0279] For example, compound VWT005700 can be prepared according to the following synthetic route:

[0280] in,

[0281] Fmoc-L-Cys(Trt)-OH, Fmoc-L-Phe-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Pro-OH, 1,3,5-tris(bromomethyl)benzene, cysteamine (also known as mercaptoethylamine), DOTA-NHS, etc., are all known.

[0282] Compound VWT005700 and 177 Clinical drugs can be prepared by reacting LuCl3 solution. 177 Lu-FAP-2286 is used as a control compound in this application.

[0283] in,

[0284] The main raw materials and additives involved are shown in Table 1 below.

[0285] Table 1. Main Raw Materials and Additives

[0286] in,

[0287] Intermediates containing amino groups (NH or NH2) (e.g., VWT012511, VWT012705, VWT078402, etc.) react with chelating agents (DOTA-NHS, DOTA(tBu)3, or DOTA(tBu)3-NHS) to attach DOTA.

[0288] Typically, chelating agents (DOTA-NHS, DOTA(tBu)3, or DOTA(tBu)3-NHS) can be obtained by purchasing commercially available products or by known methods in the prior art.

[0289] For example,

[0290] One method for preparing DOTA(tBu)3 (or DOTA(tBu)3-OH) can be described by referring to the method in Chinese patent application CN1295578A (Example 18A) or its family patent WO 99 / 58162A2 (CN2025-1 removes the Bn group to obtain DOTA(tBu)3; Bn refers to benzyl):

[0291] One method for preparing DOTA(tBu)3-NHS is to refer to the method in US Patent 6,838,557 B1 (DOTA(tBu)3-OH reacts with N-hydroxysuccinimide (N-Hydroxysuccinimide, NHS) to obtain DOTA(tBu)3-NHS).

[0292] One method for preparing DOTA-NHS is to refer to the method in US Patent 7,514,078 B2 or its family of patents WO 02 / 098897 A2 (DOTA reacts with N-hydroxysuccinimide (NHS) to obtain DOTA-NHS); or, DOTA(tBu)3-NHS can also be obtained by removing the (tBu)3 group from DOTA.

[0293] akin,

[0294] One method for preparing DOTA-GA(tBu)4 (also written as DOTAGA(tBu)4, CAS No.: 306776-79-4) can be referred to the method in US Patent 8,048,906 B2 or its family of patents WO 2005 / 001415 A2; if EP2104-05 is replaced with benzyl 2-hydroxyacetate (CAS No.: 30379-58-9), the aforementioned CN2025-1 and / or DOTA(tBu)3 can be obtained.

[0295] as well as,

[0296] DOTAGA(tBu)4-NHS and / or DOTAGA-NHS can also be prepared by similar methods described above.

[0297] PYTA can be obtained by purchasing commercially available products or by known methods in the prior art (e.g., C. Harriswangler, L. et al., Inorg. Chem., 2022, 61, 6209–6222.); and, Cyclen in US Patent 8,048,906B2 or its family of patents WO 2005 / 001415 A2 is replaced with PYTAGA(tBu)4 can be prepared; and PYTAGA(tBu)4-NHS and / or PYTAGA-NHS, PYTAGA, etc. can also be prepared. (Source: C. Harriswangler, L. et al., Inorg. Chem., 2022, 61, 6209-6222.)

[0298] Furthermore, PYTA reacts with ethylenediamine (or Boc-ethylenediamine, etc.) to give PY3A-NH2; PY3A-NH2 reacts with diethyl squarate (CAS No.: 5231-87-8) to give PY3A-NH2-SQ. Similarly, PYTAGA-NH2, PYTAGA-NH2-SQ, etc., can also be obtained.

[0299] Example 1

[0300] Preparation of compound VWT012500

[0301] (1.1) Preparation of VWT012501

[0302] CTC resin (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, then washed with DMF (30 mL), and then treated with a mixture of Fmoc-L-Cys(Trt)-OH (5.69 g) and DIPEA (2.51 g) in DMF (18 mL) for 4 hours. MeOH (3 mL) was then added and reacted for 1 hour. The resin was then washed with DMF (24 mL) to obtain VWT012501.

[0303] (1.2) Preparation of VWT012502

[0304] VWT012501 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-Ala(9-Anth)-OH (2.36 g), PyAOP (1.84 g), HOAT (0.66 g), and DIPEA (1.25 g) in DMF (18 mL) for 5 hours. The resin was then washed with DMF to obtain VWT012502.

[0305] Here, 20% piperidine / DMF refers to a DMF solution of piperidine (with a concentration of 20%, which is a commonly used reagent for removing the Fmoc group).

[0306] (1.3) Preparation of VWT012503

[0307] VWT012502 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Gln(Trt)-OH (5.93 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 5 hours. The resin was then washed with DMF to obtain VWT012503.

[0308] (1.4) Preparation of VWT012504

[0309] VWT012503 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Thr(tBu)-OH (6.43 g), DIC (8.42 g), and HOBT (2.19 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT012504.

[0310] (1.5) Preparation of VWT012505

[0311] VWT012504 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of Fmoc-L-Pro-OH (2.36 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT012505.

[0312] (1.6) Preparation of VWT012506

[0313] VWT012505 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of Fmoc-L-Pro-OH (2.36 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT012506.

[0314] (1.7) Preparation of VWT012507

[0315] VWT012506 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of Fmoc-L-Cys(Trt)-OH (5.77 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT012507.

[0316] (1.8) Preparation of VWT012508

[0317] VWT012507 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of hexanoic acid (1.30 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT012508.

[0318] (1.9) Preparation of VWT012509

[0319] VWT012508 was treated in TFA-DTT-H2O-TIPS (volume ratio = 94:2.5:2.5:1) lysis buffer (210 mL) for 3 hours, crystallized by methyl tert-butyl ether, and after centrifugation and drying, crude VWT012509 (white solid, 2.67 g) was obtained. After preparative HPLC purification, 158 mg of VWT012509 was obtained.

[0320] (1.10) Preparation of VWT012510

[0321] VWT012509 (158 mg) was dissolved in ethanol-acetonitrile (volume ratio = 1:1; 80 mL), then DIPEA (103.42 mg) and 1,3,5-tris(bromomethyl)benzene (73.82 mg) were added and reacted for 3 hours. Then 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (94.51 mg) was added and reacted overnight. The mixture was concentrated to obtain VWT012510 (solid, 444 mg).

[0322] (1.11) Preparation of VWT012511

[0323] VWT012510 (444 mg) was treated in 95% TFA / 5% H2O solution for 3 hours, then crystallized with methyl tert-butyl ether, centrifuged and dried to obtain crude VWT012511 (white solid, 353 mg), which was then purified by preparative HPLC to obtain 27 mg of VWT012511.

[0324] (1.12) Preparation of VWT012500

[0325] VWT012511 (27 mg) was dissolved in DMSO (1 mL), followed by the addition of DOTA-NHS (16.85 mg) and DIPEA (8.74 mg). The mixture was reacted overnight at room temperature. After preparative HPLC purification, 6.2 mg of VWT012500 was obtained; LCMS: [M / 2+H] + =796.70.

[0326] In this invention,

[0327] DOTA in the structure is

[0328] The chirality of VWT012500 and its intermediates is consistent with that of the raw materials such as Fmoc-L-Cys(Trt)-OH, Fmoc-Ala(9-Anth)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Thr(tBu)-OH, and Fmoc-L-Pro-OH.

[0329] Example 2

[0330] Preparation of compound VWT012400

[0331] VWT012400 was synthesized following the method described in Example 1 (VWT012500) (by replacing Fmoc-Ala(9-Anth)-OH with Fmoc-1-Nal-OH); LCMS: [M+H] + =1541.70, HPLC purity is 95.94% (peak area normalization method).

[0332] Example 3

[0333] Preparation of compound VWT012600

[0334] (3.1) Preparation of VWT012602

[0335] VWT012601 (21.8 mmol, same as VWT012501) was swollen in DMF (160 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (112 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Phe-OH (17.73 g), PyBOP (23.82 g), HOBT (6.18 g) and DIPEA (11.83 g) in DMF (112 mL) for 6 hours. The resin was then washed with DMF to obtain VWT012602.

[0336] (3.2) Preparation of VWT012609

[0337] Following the method of Example 1, VWT012609 was synthesized from VWT012602 through multiple steps.

[0338] (3.3) Preparation of VWT012610

[0339] VWT012609 (1.34 g) was dissolved in ethanol-acetonitrile (volume ratio = 1:1; 680 mL), then DIPEA (0.97 g) and 1,3,5-tris(bromomethyl)benzene (0.70 g) were added and reacted overnight. Then 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane was added and the mixture was concentrated to obtain VWT012610 (solid, 3.9 g).

[0340] (3.4) Preparation of VWT012600

[0341] Following the method described in Example 1, VWT012600 was synthesized from VWT012610 through two steps (① removal of the Boc protecting group; ② reaction with DOTA-NHS); LCMS: [M+H] + =1519.70, HPLC purity is 98.14% (peak area normalization method).

[0342] Example 4

[0343] Preparation of compound VWT012700

[0344] (4.1) Preparation of VWT012701

[0345] CTC resin (1.09 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with a mixture of Fmoc-Lys(ivDde)-OH (1.26 g) and DIPEA (0.57 g) in DMF (8 mL) for 4 hours. Then MeOH (1 mL) was added and reacted for 1 hour. The resin was washed with DMF to obtain VWT012701.

[0346] (4.2) Preparation of VWT012702

[0347] VWT012701 (1.09 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (8 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of 4-(p-iodophenyl)butyric acid (0.95 g), PyBOP (1.75 g) and HOBT (0.45 g) in DMF (8 mL) for 4 hours. The resin was then washed with DMF to obtain VWT012702.

[0348] (4.3) Preparation of VWT012703

[0349] VWT012702 (1.58 g) was treated in 1% TFA / 99% DCM lysis buffer (15 mL) for 3 hours. The lysis buffer was washed with saturated sodium bicarbonate aqueous solution. The organic phase was concentrated and redissolved with ethyl acetate. The organic phase was washed with saturated brine and concentrated to obtain VWT012703 (510 mg).

[0350] (4.4) Preparation of VWT012704

[0351] VWT012703 (500 mg), HATU (334.44 mg), and DIPEA (311.85 mg) were dissolved in DMF (5 mL), and then N-tert-butoxycarbonyl-1,3-propanediamine (0.15 g) was added and reacted overnight. The mixture was washed with saturated brine, extracted with EA, and the organic phase was concentrated to obtain VWT012704 (513 mg).

[0352] (4.5) Preparation of VWT012705

[0353] VWT012704 (513 mg) was reacted in a TFA / DCM solution (volume ratio = 1 / 2) for 3 hours. The organic phase was washed with saturated brine and concentrated to obtain VWT012705 (422 mg).

[0354] (4.6) Preparation of VWT012706

[0355] VWT012705 (370 mg) was reacted with DOTA(tBu)3 (465.35 mg), HATU (309.70 mg), and DIPEA (311.85 mg) in DMF (10 mL) overnight, and then concentrated to obtain VWT012706 (812 mg).

[0356] (4.7) Preparation of VWT012707

[0357] VWT012706 (0.752 g) was treated in 2% hydrazine hydrate / DMF (8 mL) for 3 hours. The reaction system was diluted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain VWT012707 (640 mg).

[0358] (4.8) Preparation of VWT012708

[0359] After the reaction of VWT012707 (640 mg), succinic anhydride (186.59 mg) and DIPEA (323.42 mg) in DMF (5 mL) at room temperature was completed, the reaction system was diluted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain VWT012708 (1.027 g).

[0360] (4.9) Preparation of VWT012700

[0361] VWT012708 (50 mg), DIC (10.10 mg), and HOSu (10.19 mg) were reacted in DMF (2 mL) at room temperature overnight. The reaction system was diluted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain VWT012709.

[0362] VWT012709 (55 mg), DIPEA (17.50 mg), and compound A (53.45 mg) were reacted in DMF (1 mL) at room temperature overnight. The reaction system was diluted with ethyl acetate, the organic phase was washed with saturated brine, and the organic phase was concentrated to obtain VWT012710.

[0363] VWT012710 (112 mg) was treated with 95% TFA / 5% H2O (1 mL) for 3 hours, then methyl tert-butyl ether (MTBE) was added, precipitating a solid. The solid was centrifuged and dried to obtain 101 mg of crude product. This crude product was then purified by preparative HPLC to obtain VWT012700 (9.4 mg); LCMS: [M / 2+H] + =1014.30.

[0364] Example 5

[0365] Preparation of compound VWT022800

[0366] (5.1) Preparation of VWT022801

[0367] CTC resin (2.16 mmol) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with a mixture of Fmoc-Orn(Dde)-OH (2.24 g) and DIPEA (1.12 g) in DMF (12 mL) for 5 hours. Then MeOH (2 mL) was added and reacted for 1 hour. The resin was washed with DMF to obtain VWT022801.

[0368] (5.2) Preparation of VWT022802

[0369] VWT022801 (2.16 mmol) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (16 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-Gly-OH (19.18 g), PyAOP (3.38 g) and DIPEA (1.67 g) in DMF (12 mL) for 2 hours. The resin was then washed with DMF to obtain VWT022802.

[0370] (5.3) Preparation of VWT022803

[0371] VWT022802 (2.16 mmol) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (16 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of 4-(4-cyanophenyl)butyric acid (0.41 g), PyAOP (1.12 g) and DIPEA (0.56 g) in DMF (12 mL) for 4 hours. The resin was then washed with DMF to obtain VWT022803.

[0372] (5.4) Preparation of VWT022804

[0373] VWT022803 (1.67 g) was treated in TFA / DCM (volume ratio = 3 / 97) lysis buffer for 3 hours, the resin was removed by filtration, the pH was adjusted to neutral (approximately 7.0) with 3% ammonia, 15 ml of purified water was added for washing, the mixture was separated, and the organic phase was concentrated to obtain VWT022804 (0.41 g).

[0374] (5.5) Preparation of compound B

[0375] Compound B was prepared according to the method in Example 1.

[0376] (5.6) Preparation of VWT022805

[0377] VWT022804 (63.71 mg), HATU (42.00 mg), DIPEA (43.06 mg) and compound B (122 mg) were reacted overnight at room temperature in DCM (5 mL). H2O and EA were added, the mixture was separated, and the organic phase was concentrated to obtain VWT022805 (200 mg).

[0378] (5.7) Preparation of VWT022806

[0379] After VWT022805 (200 mg) was reacted completely in 8% hydrazine hydrate / DMF (2.5 mL) at room temperature, H2O (10 mL) was added, and the pH was adjusted to 7 with 2% TFA aqueous solution. VWT022806 (25 mg) was obtained by preparative HPLC purification.

[0380] (5.8) Preparation of VWT022800

[0381] VWT022806 (25 mg), DIPEA (11.15 mg), and DOTA-NHS (34.64 mg) were reacted overnight in DMSO (2.5 mL) at room temperature. The mixture was purified by preparative HPLC to obtain 6.1 mg of VWT022806. LCMS: [M / 2+H] + =917.70.

[0382] Example 6

[0383] Preparation of compound VWT022700

[0384] VWT022700 was synthesized following the method described in Example 5 (VWT022800) (by replacing 4-(4-cyanophenyl)butyric acid with 4-(4-iodophenyl)butyric acid); LC-MS: [M / 2+H] + = 968.1 [M / 3 + H] + =645.9.

[0385] Example 7

[0386] Preparation of compound VWT026900

[0387] (7.1) Preparation of VWT026902

[0388] VWT026901 (3.24 mmol, same as VWT012501) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-D-Tic-OH (2.58 g), PyAOP (3.38 g), HOAT (0.88 g) and DIPEA (1.68 g) in DMF (18 mL) for 3 hours. The resin was then washed with DMF to obtain VWT026902.

[0389] (7.2) Preparation of VWT026909

[0390] Following the method of Example 1, VWT026909 was synthesized from VWT026902 through multiple steps.

[0391] (7.3) Preparation of VWT026910

[0392] VWT026909 (245 mg) was dissolved in ethanol-acetonitrile (volume ratio = 1:1; 124 mL), then DIPEA (175.97 mg) and 1,3,5-tris(bromomethyl)benzene (125.60 g) were added and reacted for 2 hours. Then cysteamine (also known as mercaptoethylamine, 104.43 mg) was added and reacted for 2 hours. The mixture was concentrated to obtain crude VWT026910 (solid, 542 mg). VWT026910 (35 mg) was purified by preparative HPLC.

[0393] (7.4) Preparation of VWT026900

[0394] VWT026910 (35 mg) was dissolved in DMSO (1 mL), followed by the addition of DIPEA (20.76 mg) and DOTA-NHS (32.00 mg) and reacted overnight. After preparative HPLC purification, 4.7 mg of the target product VWT026900 was obtained; LCMS: [M+H] + =1483.20.

[0395] Example 8

[0396] Preparation of compound VWT027000

[0397] VWT027000 was synthesized using the method described in Example 7 (with Fmoc-D-Tic-OH replaced by Fmoc-L-Tic-OH); LCMS: [M+H] + =1483.20, HPLC purity is 95.97% (peak area normalization method).

[0398] Example 9

[0399] Preparation of compound VWT027100

[0400] (9.1) Preparation of VWT027103

[0401] VWT027102 (3.24 mmol, same as VWT012602) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (24 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-MET(O2)-OH (2.61 g), DIC (0.810 g) and HOBT (0.96 g) in DMF (18 mL) for 3 hours. The resin was then washed with DMF to obtain VWT027103.

[0402] (9.2) Preparation of VWT027100

[0403] Following the method described in Example 7, VWT027100 was synthesized from VWT027103; LCMS: [M+H] + =1506.20.

[0404] Example 10

[0405] Preparation of compound VWT027200

[0406] VWT024902: Obtained by purchase or prepared according to the methods described in documents such as Chinese Patent Application 202311428064.7 (application date: October 31, 2023).

[0407] The synthetic route for intermediate VWT024902 is shown below:

[0408] (10.1) Preparation of VWT027203

[0409] VWT027202 (0.55 mmol, same as VWT012602) was treated with 2% piperidine / 2% DBU / DMF (4 mL) for 30 minutes, washed with DMF, and then VWT024902 (286 mg), DIC (91 mg), and HOBT (108 mg) were added to DMF (4 mL) and reacted for 3 h. The resin was washed with DMF to obtain VWT027203.

[0410] (10.2) Preparation of VWT027200

[0411] Following the method described in Example 7, VWT027200 was synthesized from VWT027203; LC-MS: [M+H] + =1510.00, HPLC purity is 96.31% (peak area normalization method).

[0412] Example 11

[0413] Preparation of compound VWT028700

[0414] (11.1) Preparation of VWT028702

[0415] Synthesis of compound H11-2 (H1)

[0416] Compound H11-1 ((2S)-2-amino-3-(4-bromophenyl)propionate methyl ester: 1.00 g, 3.87 mmol) and di-tert-butyl dicarbonate (1.69 g, 7.75 mmol) and triethylamine (1.18 g, 11.62 mmol) were reacted in dichloromethane (10 mL) at room temperature for 4 hours. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether-ethyl acetate = 10:1, v / v) to give compound H11-2 (1.10 g, 79%) as a colorless liquid.

[0417] Synthesis of compound H11-4 (H2)

[0418] Compounds H11-2 (1.0 g, 2.78 mmol, 1.0 eq) and H11-3 (580 mg, 2.78 mmol), cesium carbonate (2.72 g, 8.35 mmol), and Pd(dppf)Cl2 (204 mg, 0.28 mmol, 0.1 eq) were reacted in water (10 mL) and DMF (10 mL) at 80 °C for 2 hours under nitrogen protection. Ethyl acetate was added, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether-ethyl acetate = 3:1, v / v) to give compound H11-4 (880 mg, 88%) as a yellow solid.

[0419] Synthesis of compound H11-5 (H3)

[0420] Compound H11-4 (880 mg, 2.44 mmol) reacted with sodium hydroxide (488 mg, 12.2 mmol) in water (2 mL) and methanol (10 mL) at room temperature for 2 hours. The methanol was removed by concentration, and the pH was adjusted to neutral or weakly acidic by adding dilute hydrochloric acid. The mixture was then concentrated to give compound H11-5 (720 mg, 85%) as a pale yellow solid; LCMS: [M+H] + =346.2. Used directly in the next step without purification.

[0421] Synthesis of compound H11-6 (H4)

[0422] Compound H11-5 (720 mg, 2.08 mmol) was reacted in trifluoroacetic acid (5 mL) and dichloromethane (5 mL) at room temperature for 4 hours (removal of the Boc group), and the mixture was concentrated to give compound H11-6 (500 mg, 98%) as a brown liquid; LCMS: [M+H] + =246.1.

[0423] Synthesis of compound VWT028702 (H5)

[0424] Compound H11-6 (400 mg, 1.63 mmol) was reacted with Fmoc-Cl (422 mg, 1.63 mmol), sodium carbonate (519 mg, 4.89 mmol), and water (10 mL) and tetrahydrofuran (10 mL) at room temperature for 4 hours. Ethyl acetate was added, followed by washing with water and saturated brine, drying over anhydrous sodium sulfate, concentration, and purification by silica gel column chromatography (dichloromethane-methanol = 10:1, v / v) to give compound VWT028702 (493.7 mg, 64%) as a light brown solid; LCMS: [M+H] + =468.2.

[0425] (11.2) Preparation of VWT028700

[0426] Referring to the method in Example 7, VWT028700 was synthesized from VWT028701 (identical to VWT012501) and VWT028702 through multiple steps; LCMS: [M+H] + =1551.4, LCMS:[M / 2+H] + =776.4, HPLC purity is 97.91% (peak area normalization method).

[0427] Example 12

[0428] Preparation of compound VWT028800

[0429] (12.1) Preparation of VWT028801

[0430] VWT028801 was synthesized using the method described in Example 7.

[0431] (12.2) Preparation of VWT030700

[0432] Preparation of I1)VWT030701

[0433] CTC resin (22 mmol) was swollen in DMF (160 mL) for 30 minutes, washed with DMF, and then treated with a mixture of Fmoc-L-Gln(Trt)-OH (40.29 g) and DIPEA (17.03 g) in DMF (160 mL) for 4 hours. Then MeOH (20 mL) was added and reacted for 1 hour. The resin was washed with DMF to obtain VWT030701.

[0434] Preparation of I2)VWT030702

[0435] VWT030701 (22 mmol) was swollen in DMF (120 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (160 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Thr(tBu)-OH (26.23 g), PyAOP (34.41 g), and HOAT (8.99 g) in DMF (160 mL) for 4 hours. The resin was then washed with DMF to obtain VWT030702.

[0436] Preparation of I3)VWT030703

[0437] VWT030702 (22 mmol) was swollen in DMF (160 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (160 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Pro-OH (22.26 g), DIC (8.34 g), and OXYMA PURE (9.38 g) in DMF (160 mL) for 3 hours. The resin was then washed with DMF to obtain VWT030703.

[0438] Preparation of I4)VWT030704

[0439] VWT030703 (22 mmol) was swollen in DMF (160 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (160 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Pro-OH (22.26 g), DIC (8.34 g), and OXYMA PURE (9.38 g) in DMF (160 mL) for 3 hours. The resin was then washed with DMF to obtain VWT030704.

[0440] Preparation of I5)VWT030705

[0441] VWT030704 (22 mmol) was swollen in DMF (160 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (160 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Cys(Trt)-OH (38.84 g), DIC (8.34 g), and OXYMA PURE (9.38 g) in DMF (160 mL) for 3 hours. The resin was then washed with DMF to obtain VWT030705.

[0442] Preparation of I6)VWT030706

[0443] VWT030705 (22 mmol) was swollen in DMF (120 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (120 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of hexanoic acid (7.73 g), DIC (8.34 g) and OXYMA PURE (9.38 g) in DMF (160 mL) for 3 hours. The resin was then washed with DMF to obtain VWT030706.

[0444] Preparation of I7)VWT030700

[0445] VWT030706 was treated in 1% TFA / 99% DCM lysis buffer (440 mL) for 3 hours, the resin was removed by filtration, the filtrate was added to purified water (200 mL), the pH was adjusted to neutral with 3% ammonia, the liquid was separated, and the organic phase was concentrated to obtain VWT030700 (21.99 g).

[0446] (12.3) Preparation of VWT028802

[0447] VWT028801 (2.2 mmol) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (16 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of VWT030700 (3.91 g), Pyoxime (8.34 g) and DIPEA (0.85 g) in DMF (16 mL) for 26 hours. The resin was then washed with DMF to obtain VWT028802.

[0448] (12.4) Preparation of VWT028800

[0449] Referring to the method in Example 7, VWT028800 was synthesized from VWT028802 through multiple steps; LCMS: [M+H] + =1471.80, HPLC purity is 95.61% (peak area normalization method).

[0450] Example 13

[0451] Preparation of compound VWT029000

[0452] Following the method of Example 7 (replacing Fmoc-D-Tic-OH with Fmoc-Phe(3-Br)-OH), VWT029000 was synthesized; LCMS: [M+H] + =1550.80, HPLC purity is 99.26% (peak area normalization method).

[0453] Example 14

[0454] Preparation of compound VWT029200

[0455] Following the method of Example 7 (replacing Fmoc-D-Tic-OH with Fmoc-Phe(4-Br)-OH), VWT029200 was synthesized; LCMS: [M+H] + =1550.80, HPLC purity is 98.86% (peak area normalization method).

[0456] Example 15

[0457] Preparation of compound VWT029400

[0458] Following the method of Example 12 (replacing Fmoc-3-Pal-OH with Fmoc-Tyr(Me)-OH), VWT029400 was synthesized; LCMS: [M+H] + =1501.00.

[0459] Example 16

[0460] Preparation of compound VWT029500

[0461] Following the method of Example 12 (replacing Fmoc-3-Pal-OH with Fmoc-Phe(3-OMe)-OH), VWT029500 was synthesized; LCMS: [M] + =1500.90, HPLC purity is 97.93% (peak area normalization method).

[0462] Example 17

[0463] Preparation of compound VWT051000

[0464] Following the method of Example 9 (or Example 12) (replacing Fmoc-Phe-OH with Fmoc-Phe(4-Br)-OH and n-hexanoic acid with n-butyric acid), VWT051000 was synthesized; LC-MS: [M+H] + =1557.80.

[0465] Example 18

[0466] Preparation of compound VWT051100

[0467] Following the method of Example 9 (or Example 12) (replacing Fmoc-Phe-OH with Fmoc-D-Phe(4-Br)-OH and n-hexanoic acid with n-pentanoic acid), VWT051100 was synthesized through multiple steps; LC-MS: [M+H] +=1571.90, HPLC purity is 97.89% (peak area normalization method).

[0468] Example 19

[0469] Preparation of compound VWT051600

[0470] Following the method of Example 9 (or Example 12) (replacing one of the Fmoc-Pro-OH groups with Fmoc-Val-OH, replacing hexanoic acid with valeric acid, and replacing Fmoc-Phe-OH with Fmoc-Phe(4-Br)-OH), VWT051600 was synthesized through multiple steps; LC-MS: [M+H] + =1573.80.

[0471] Example 20

[0472] Preparation of compound VWT051700

[0473] Following the method of Example 9 (or Example 12) (replacing one of the Fmoc-Pro-OH groups with Fmoc-Val-OH, replacing hexanoic acid with valeric acid, and replacing Fmoc-Phe-OH with Fmoc-Phe(4-Br)-OH), VWT051700 was synthesized through multiple steps; LC-MS: [M+H] + =1573.80, HPLC purity is 95.34% (peak area normalization method).

[0474] Example 21

[0475] Preparation of compound VWT051800

[0476] Following the method of Example 9 (or Example 12) (replacing Fmoc-Phe-OH with Fmoc-Phe(4-Br)-OH, replacing hexanoic acid with valeric acid, and replacing VWT012601 with VWT051801), VWT051800 was synthesized; LC-MS: [M+H] + =1670.90, HPLC purity is 96.15% (peak area normalization method).

[0477] Example 22

[0478] Preparation of compound VWT052000

[0479] Following the method of Example 17 (VWT051000) (replacing Fmoc-L-Cys(Trt)-OH with Fmoc-D-Cys(Trt)-OH and n-butyric acid with n-valeric acid), VWT052000 was synthesized; LC-MS: [M / 2+H] + =786.50.

[0480] Example 23

[0481] Preparation of compound VWT052400

[0482] VWT052400 was synthesized according to the method of Example 21 (VWT051800) or Example 41 (replacing CTC resin with Rink amide resin); LC-MS: [M+H] + =1669.90, HPLC purity is 98.03% (peak area normalization method).

[0483] Example 24

[0484] Preparation of compound VWT052600

[0485] VWT052600 was synthesized according to the method of Example 21 (VWT051800) or Example 41; LC-MS: [M / 2+H] + =895.70, HPLC purity is 96.46% (peak area normalization method).

[0486] Example 25

[0487] Preparation of compound VWT047000

[0488] (25.1) Preparation of VWT047002

[0489] VWT047001 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Phe(4-Cl)-OH (1.962 g), PyAOP (2.423 g), HOAT (0.632 g), and DIPEA (1.215 g) in DMF (18 mL) for 3 hours. The resin was then washed with DMF to obtain VWT047002.

[0490] (25.2) Preparation of VWT047003

[0491] VWT047002 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-MET(O2)-OH (1.871 g), DIC (0.588 g), and OXYMA PURE (0.658 g) in DMF (18 mL) for 2.5 hours. The resin was then washed with DMF to obtain VWT047003.

[0492] (25.3) Preparation of VWT047004

[0493] VWT047003 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Thr(tBu)-OH (3.652 g), DIC (0.596 g), and OXYMA PURE (0.662 g) in DMF (18 mL) for 3 hours. The resin was then washed with DMF to obtain VWT047004.

[0494] (25.4) Preparation of VWT047005

[0495] VWT047004 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Pro-OH (3.131 g), DIC (0.593 g), and OXYMA PURE (0.662 g) in DMF (18 mL) for 2 hours. The resin was then washed with DMF to obtain VWT047005.

[0496] (25.5) Preparation of VWT047006

[0497] VWT047005 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Pro-OH (3.127 g), DIC (0.585 g) and OXYMA PURE (0.659 g) in DMF (18 mL) for 16 hours. The resin was then washed with DMF to obtain VWT047006.

[0498] (25.6) Preparation of VWT047007

[0499] VWT047006 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Cys(Trt)-OH (5.430 g), DIC (0.585 g), and OXYMA PURE (0.659 g) in DMF (18 mL) for 3 hours. The resin was then washed with DMF to obtain VWT047007.

[0500] (25.7) Preparation of VWT047008

[0501] VWT047007 (3.09 mmol) was swollen in DMF (18 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (18 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of n-valeric acid (0.947 g), DIC (0.585 g) and OXYMA PURE (0.659 g) in DMF (18 mL) for 18 hours. The resin was then washed with DMF to obtain VWT047008.

[0502] (25.8) Preparation of VWT047009

[0503] VWT047008 was treated in TFA-DTT-H2O-TIPS (volume ratio = 88:5:5:2) lysis buffer (78 mL) for 3 hours, and methyl tert-butyl ether was used to crystallize it. After centrifugation and drying, crude VWT047009 (white solid, 2.270 g) was obtained. Then, it was purified by preparative HPLC to obtain 0.740 g of the target product VWT047009.

[0504] (25.9) Preparation of VWT047000

[0505] Following the method described in Example 7, VWT047000 was synthesized from VWT047009; LCMS: [M+H] + =1525.80, HPLC purity is 95.69% (peak area normalization method).

[0506] Example 26

[0507] Preparation of compound VWT047100

[0508] Following the method of Example 25 (Fmoc-L-Phe(4-Cl)-OH was replaced with Fmoc-L-4-trifluoromethylphenylalanine), VWT047100 was synthesized; LCMS: [M / 2+H]+=780.50, HPLC purity was 98.12% (peak area normalization method).

[0509] Example 27

[0510] Preparation of VWT047200

[0511] Following the method of Example 25 (replacing Fmoc-L-Phe(4-Cl)-OH with Fmoc-L-Phe(4-Br)-OH), VWT047200 was synthesized; LCMS: [M+H] + =1571.70, HPLC purity is 98.54% (peak area normalization method).

[0512] Example 28

[0513] Preparation of VWT013200

[0514] (28.1) Preparation of VWT013200-10

[0515] Synthesis of Compound 3 (J1)

[0516] Compound 1 (1 g, 6.2 mmol) and compound 2 (0.66 g, 12.4 mmol) were reacted at room temperature for 16 hours in dioxane (20 mL) and sodium hydroxide aqueous solution (5 mL, 40%). The reaction mixture was then extracted with water (20 mL) and ethyl acetate (60 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether-ethyl acetate = 3:1, v / v) to give compound 3 (1.26 g, 93.5%) as a colorless oily liquid; LCMS: [M+Na]. + =237.2.

[0517] Synthesis of Compound 4 (J2)

[0518] Compound 3 (600 mg, 2.7872 mmol) and Raney nickel (60 mg) were added to methanol (30 mL), and the mixture was reacted with hydrogen gas continuously at room temperature for 16 hours. The mixture was filtered and concentrated to give compound 4 (560 mg, 90.7%) as a colorless oily liquid; LCMS: [M+H] + =219.1.

[0519] Synthesis of Compound 6 (J3)

[0520] Compound 4 (560 mg, 2.5536 mmol) and compound 5 (337.37 mg, 2.5536 mmol) were reacted in a DMF (20 mL) solution of HATU (1455.55 mg, 3.8304 mmol) and DIPEA (988.24 mg, 7.6608 mmol) at room temperature for 6 hours. Then, water (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (60 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether-ethyl acetate = 1:2, v / v) to give compound 6 (650 mg, 75.5%) as a colorless oily liquid; LCMS: [M+H] + =333.2.

[0521] Synthesis of Compound 7 (J4)

[0522] Compound 6 (650 mg, 1.9496 mmol) was reacted with 1,4-dioxane / hydrogen chloride (15 mL) at room temperature to remove the Boc group, and the mixture was concentrated to give compound 7 (450 mg, 98.3%) as a colorless oily liquid; LCMS: [M+H] + =233.1.

[0523] Synthesis of Compound 9 (J5)

[0524] Compound 7 (400 mg, 1.7221 mmol) and compound 8 (499.58 mg, 1.7221 mmol) were reacted in 20 mL of DMF solution containing HATU (981.60 mg, 2.5832 mmol) and DIPEA (666.45 mg, 5.1663 mmol) at room temperature for 6 hours. The mixture was then extracted with 20 mL of water and 60 mL of ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane-methanol = 50:1, v / v) to give compound 9 (640 mg, 72.9%) as a colorless oily liquid; LCMS: [M+H] + =505.2.

[0525] Synthesis of J6)VWT013200-10

[0526] Compound 9 (600 mg, 1.1896 mmol) was dissolved in methanol (15 mL), and reacted with lithium hydroxide (142.75 mg, 5.948 mmol) and water (5 mL) at room temperature for 16 hours. The pH was adjusted to neutral (e.g., by adding dilute hydrochloric acid), the solution was concentrated, and purified by C18 reversed-phase silica gel column chromatography to give VWT013200-10 (213.6 mg, 36.2%) as a white solid; LCMS: [M+H] + =491.1.

[0527] (28.2) Preparation of VWT013208

[0528] VWT013207 (0.298 mmol) was swollen in DMF (3 mL) for 30 minutes, washed with DMF, treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, washed with DMF, and then treated with a mixture of Fmoc-Nle-OH (0.31 g), DIC (0.12 g) and HOBT (0.13 g) in DMF (3 mL) for 6 hours. The resin was washed with DMF to obtain compound VWT013208.

[0529] (28.3) Preparation of VWT013209

[0530] VWT013208 (0.298 mmol) was swollen in DMF (3 mL) for 30 minutes, washed with DMF, treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, washed with DMF, and then treated with a mixture of VWT013200-10 (0.17 g), PyAOP (0.18 g), HOAT (0.048 g) and DIPEA (0.09 g) in DMF (3 mL) for 9 hours. The resin was washed with DMF to obtain VWT013209.

[0531] (28.4) Preparation of VWT013200

[0532] Following the method described in Example 1, VWT013200 was synthesized from VWT013209; LCMS: [M / 2+H] + =989.70, HPLC purity is 95.40% (peak area normalization method).

[0533] Example 29

[0534] Preparation of VWT013300

[0535] Referring to the method of Example 28 (to Replace with VWT013300 was synthesized; LCMS: [M / 2+H] + =1012.20, HPLC purity is 97.82% (peak area normalization method).

[0536] Example 30

[0537] Preparation of VWT013400

[0538] Referring to the method of Example 28 (to Replace with The synthesis yielded VWT013400; [M / 2+H] + =1034.20, HPLC purity is 96.35% (peak area normalization method).

[0539] Example 31

[0540] Preparation of VWT037700

[0541] Following the method of Example 25 (replacing Fmoc-L-Phe(4-Cl)-OH with Fmoc-L-Phe(4-Br)-OH and replacing n-pentanoic acid with n-hexanoic acid), VWT037700 was synthesized; LCMS: [M+H]+ =1585.80, HPLC purity is 95.13% (peak area normalization method).

[0542] Example 32

[0543] Preparation of VWT051300

[0544] (32.1) Preparation of compound M

[0545] n-Butylamine (1.0 g), DSC (1 g) and TEA (1.15 g) were reacted in acetonitrile (25 ml) for 4 hours. The acetonitrile was removed by concentration, and the residue was redissolved in ethyl acetate, washed with citric acid aqueous solution, and the ethyl acetate organic phase was concentrated to give compound M.

[0546] (32.2) Preparation of VWT051300

[0547] Following the method of Example 25 (replacing Fmoc-L-Phe(4-Cl)-OH with Fmoc-L-Phe(4-Br)-OH and replacing n-valeric acid with compound M), VWT051300 was synthesized; LC-MS: [M+H] + =1586.80.

[0548] Example 33

[0549] Preparation of VWT051500

[0550] Following the method described in Example 25, VWT051500 was synthesized; LC-MS: [M+H] + =1617.80.

[0551] Example 34

[0552] Preparation of VWT051900

[0553] Following the method of Example 27 (Fmoc-L-MET(O2)-OH replaced with Fmoc-D-MET(O2)-OH), VWT051900 was synthesized; LC-MS: [M+H] + =1571.90, HPLC purity is 98.31% (peak area normalization method).

[0554] Example 35

[0555] Preparation of VWT052800

[0556] VWT052800 was synthesized according to the method of Example 21 or Example 41; LC-MS: [M+H] + =1714.00, HPLC purity is 96.93% (peak area normalization method).

[0557] Example 36

[0558] Preparation of VWT047400

[0559] VWT047400 was synthesized by referring to the method of Example 14 (replacing n-valeric acid or n-hexanoic acid with 3-methylbenzoic acid).

[0560] Example 37

[0561] Preparation of VWT030300

[0562] (37.1) Preparation of VWT030301

[0563] CTC resin (1.10 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and treated with a mixture of Fmoc-Lys(N3)-OH (523 mg) and DIPEA (351 mg) in DMF (8 mL) for 4 hours. Then MeOH (0.5 mL) was added and reacted for 1 hour. The resin was washed with DMF to obtain VWT030301.

[0564] (37.2) Preparation of VWT030302

[0565] VWT030301 (1.10 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of Fmoc-Val-OH (1.12 g), PyAOP (1.72 g) and DIPEA (0.86 g) in DMF (8 mL) for 2 hours. After washing with DMF, VWT030302 was obtained.

[0566] (37.3) Preparation of VWT030303

[0567] VWT030302 (1.10 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, Fmoc-Nle-OH (1.17 g), DIC (0.42 g), and HOBT (0.49 g) were added to DMF (8 mL) and reacted for 2.5 h. The resin was then washed with DMF to obtain VWT030303.

[0568] (37.4) Preparation of VWT030304

[0569] VWT030303 (1.10 mmol) was treated with 20% piperidine / DMF for 30 minutes, washed with DMF, and DOTA(tBu)3 (0.95 g), DIC (0.21 g), and HOBT (0.25 g) were added to DMF (8 mL) and reacted for 3 h. The resin was washed with DMF to obtain VWT030304.

[0570] (37.5) Preparation of VWT030305

[0571] VWT030304 (1.10 mmol) was treated with 1% TFA / 99% DCM lysis buffer (20 mL) for 3 h, filtered, washed with saturated sodium bicarbonate solution, and the organic phase was concentrated to obtain VWT030305.

[0572] (37.6) Preparation of VWT030300

[0573] After VWT030305 (100 mg) reacted completely with compound A in a DMF (5 ml) solution of DIPEA (41 mg) and HATU (53 mg), it was added dropwise to MTBE (100 ml) and stirred to crystallize. After centrifugation and drying, VWT030306 was obtained.

[0574] VWT030306 was deprotected by the protecting group (tBu)3 to obtain crude VWT030300; after purification, 1.8 mg of VWT030300 was obtained. LC-MS: [M+H] + =1837.5, [M / 2+H] + =919.4, [M / 3+H] + =613.4.

[0575] Example 38

[0576] Preparation of VWT016900

[0577] (38.1) Preparation of VWT016901

[0578] Wang resin (4.4 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, and treated with a mixture of Fmoc-β-Ala-OH (4.11 g), PyBOP (6.86 g), HOBT (1.78 g) and DIPEA (3.43 g) in DMF (15 mL) for 4 hours. Then, acetic anhydride (8.98 g) and pyridine (6.96 g) were added and reacted for 1 hour. The resin was washed with DMF to obtain VWT016901.

[0579] (38.2) Preparation of VWT016902

[0580] VWT016901 (4.4 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the resin was treated with a mixture of Fmoc-L-Cys(mmt)-OH (5.42 g), PyBOP (5.10 g), HOBT (1.96 g), and DIPEA (1.31 g) in DMF (15 mL) for 2 hours. The resin was then washed with DMF to obtain VWT016902.

[0581] (38.3) Preparation of VWT016903

[0582] VWT016902 (4.4 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, washed with DMF, and then treated with a mixture of Fmoc-L-Phe-OH (5.20 g), PyBOP (7.60 g), HOBT (2.02 g) and DIPEA (3.50 g) in DMF (15 mL) for 2 hours. The resin was washed with DMF to obtain VWT016903.

[0583] (38.4) Preparation of VWT016907

[0584] Following the method in Example 1, VWT016903 was reacted sequentially with Fmoc-L-Gln(Trt)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Pro-OH and Fmoc-L-Pro-OH to synthesize VWT016907.

[0585] (38.5) Preparation of VWT016908

[0586] VWT016907 (4.4 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, washed with DMF, and then treated with a mixture of Fmoc-L-Cys(mmt)-OH (5.50 g), HATU (3.70 g) and DIPEA (2.30 g) in DMF (15 mL) for 2 hours. The resin was washed with DMF to obtain VWT016908.

[0587] (38.6) Preparation of VWT016909

[0588] VWT016908 (4.4 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, washed with DMF, and then treated with a mixture of hexanoic acid (1.54 g), PyBOP (7.60 g), HOBT (2.02 g) and DIPEA (3.50 g) in DMF (15 mL) for 2 hours. The resin was washed with DMF to obtain VWT016909.

[0589] (38.7) Preparation of VWT016900

[0590] VWT016909 (4.0 mmol) was swollen in DMF (40 mL) for 30 minutes, washed with DMF, and treated with 2% TFA / DCM (0.5 mL) for 30 minutes to remove the MMT protecting group. The resin was then washed with DMF and treated overnight with a mixture of 1,3,5-tris(bromomethyl)benzene (1.43 g) and DIPEA (1.14 g) in DMF (40 mL). The resin was washed with DMF to obtain VWT016910.

[0591] Subsequently, VWT016910 was reacted sequentially with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate and DOTA-NHS to synthesize VWT016900; LC-MS: [M+H] + =1563.00.

[0592] Example 39

[0593] Preparation of VWT016500

[0594] (39.1) Preparation of VWT016501

[0595] Rink amide Resin (0.90 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and the Fmoc protecting group was removed with 20% piperidine / DMF solution. Then, it was reacted with Fmoc-Asp(OtBu)-OH (1.11 g), DIC (0.39 g) and HOBT (0.40 g) in DMF (6 mL) for 6 h. The resin was washed with DMF to obtain VWT016501.

[0596] (39.2) Preparation of compound C

[0597] Compound C was synthesized from VWT016501 through multiple steps, following the method described in Example 1.

[0598] (39.3) Preparation of VWT016512

[0599] Compound C (150 mg) was reacted with t-Boc-N-amido-PEG2-NHS ester (69 mg), DIPEA in MeOH (1 ml) and DCM (10 ml) for 26 h. The mixture was concentrated, and the concentrated residue was reacted with 95% TFA / 5% H2O (5 ml) for 2 h. Methyl tert-butyl ether (MTBE) was added, and the solid precipitated was centrifuged and dried to obtain VWT016512.

[0600] (39.4) Preparation of VWT016515

[0601] CTC resin (2.20 mmol) was swollen in DMF (16 mL) for 30 minutes, washed with DMF, and then Fmoc-NH-PEG2-CH2CH2COOH (1.32 g) and DIPEA (0.86 g) were added and reacted in DMF (16 mL) for 4 h. The resin was washed with DMF to obtain VWT016513.

[0602] Then, the resin was treated with 20% piperidine / DMF for 30 minutes, washed with DMF, and Fmoc-Glu-OAll (1.80 g), HATU (1.60 g) and DIPEA (1.14 g) were added to DMF (16 mL) and reacted for 1.5 h. The resin was then washed with DMF to obtain VWT016514.

[0603] Subsequently, VWT016514 was treated in 1% TFA / 99% DCM lysis buffer (35 mL) for 4 h, filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain VWT016515.

[0604] (39.5) Preparation of VWT016516

[0605] CTC resin (8.8 mmol) was swollen in DMF (64 mL) for 30 minutes, washed with DMF, and then Fmoc-Gly-OH (7.85 g) and DIPEA (6.83 g) were added and reacted in DMF (48 mL) for 5 h. The resin was washed with DMF to obtain VWT016516.

[0606] (39.6) Preparation of VWT016517

[0607] VWT016516 (8.80 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, Fmoc-Arg(Pbf)-OH (17.14 g), PyAOP (13.78 g), and DIPEA (6.83 g) were added to DMF (48 mL) and reacted for 15 h. The resin was then washed with DMF to obtain VWT016517.

[0608] (39.7) Preparation of VWT016518

[0609] VWT016517 (8.80 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, Fmoc-Lys(ivDde)-OH (7.60 g), DIC (1.66 g), and HOBT (1.97 g) were added to DMF (48 mL) and reacted for 3 h. The resin was washed with DMF to obtain VWT016518.

[0610] (39.8) Preparation of VWT016519

[0611] VWT016518 (8.80 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, Fmoc-D-Phe-OH (5.13 g), DIC (1.66 g), and HOBT (1.97 g) were added to DMF (48 mL) and reacted for 2.5 h. The resin was then washed with DMF to obtain VWT016519.

[0612] (39.9) Preparation of VWT016520

[0613] VWT016519 (8.80 mmol) was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group. After washing with DMF, Fmoc-Asp(OtBu)-OH (10.88 g), DIC (3.32 g), and HOBT (3.93 g) were added to DMF (48 mL) and reacted for 2.5 h. The resin was then washed with DMF to obtain VWT016520.

[0614] (39.10) Preparation of VWT016521

[0615] VWT016520 was treated with 20% piperidine / DMF for 30 minutes to remove the Fmoc protecting group, and then treated in 1% TFA / 99% DCM lysis buffer for 3 hours to remove the resin, thus generating VWT016521.

[0616] (39.11) Preparation of VWT016523

[0617] VWT016521 (10.5 g) was reacted with DIPEA (3.5 g) and HATU (3.7 g) in DCM for 6 h. The mixture was washed with purified water, dried over anhydrous sodium sulfate, and concentrated to obtain VWT016522. Then, 4% hydrazine hydrate / DMF (100 ml) was added and reacted for 6 h. Purified water (500 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and purified to obtain VWT016523.

[0618] (39.12) Preparation of VWT016525

[0619] VWT016523 (1.68 g) was reacted with VWT016515 (0.9 g), DIPEA (0.67 g), and PyAOP (1.05 g) in DMF (10 ml) for 5 h. Then, purified water (50 ml) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain VWT016524. Then, tetrakis(triphenylphosphine)palladium (197 mg), phenylsilane (923 mg), and DMF (10 ml) were added and reacted for 2 h. After that, 0.02 mol / L copper reagent aqueous solution (50 ml) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by pre-HPLC to obtain VWT016525.

[0620] (39.13) Preparation of VWT016526

[0621] VWT016525 (100 mg) was reacted with HOSu (25 mg) and DIC (27 mg) in DMF (5 ml) for 24 h and concentrated. Then, DIPEA (26 mg), VWT016512 (92 mg) and DMF (5 ml) were added and reacted for 6 h. The reaction solution was added to MTBE (100 ml), and a solid precipitated. The solid was dried to obtain VWT016526 (approximately 140 mg).

[0622] (39.14) Preparation of VWT016500

[0623] VWT016526 (140 mg) was treated with 20% piperidine / DMF (3 mL) for 60 minutes to remove the Fmoc protecting group. Then the reaction solution was added to MTBE (60 mL), and a solid was precipitated. After drying, VWT016527 was obtained.

[0624] VWT016527 (125 mg) was reacted with DIPEA (19 mg) and DOTA-NHS (37 mg) in DMF (5 ml) for 48 h, and then added to MTBE (100 ml), precipitating a solid, which was dried to obtain VWT016528.

[0625] VWT016528 (110 mg) was treated with 95% TFA / 5% H2O lysis buffer (5 mL) for 4 hours, and then purified by pre-HPLC to obtain compound VWT016500; LC-MS: [M / 2+H] + =1320.5, [M / 3+H] + =880.6, [M / 4+H] + =660.7.

[0626] Example 40

[0627] Preparation of VWT016200

[0628] (40.1) Preparation of VWT016205

[0629] Preparation of K1)VWT016201

[0630] CTC resin (1.08 mmol) was swollen in DMF (8 ml) for 30 minutes, washed with DMF, and then treated with a mixture of Fmoc-NH-PEG4-CH2CH2COOH (1.05 g) and DIPEA (0.58 g) in DMF (8 ml) for 3 hours. Then MeOH (1 mL) was added and reacted for 1 hour, followed by washing with DMF to obtain VWT016201.

[0631] Preparation of K2)VWT016202

[0632] VWT016201 (1.08 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (8 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Lys(ivDde)-OH (1.86 g), HATU (1.18 g), and DIPEA (0.84 g) in DMF (8 mL) for 10 hours, and then washed with DMF to obtain VWT016202.

[0633] Preparation of K3)VWT016203

[0634] VWT016202 (1.08 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (8 mL) to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of DOTA(tBu)3 (1.23 g), HATU (0.78 g) and DIPEA (0.56 g) in DMF (8 mL) for 10 hours, washed with DMF, to obtain VWT016203.

[0635] Preparation of K4)VWT016204

[0636] VWT016203 (1.08 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with 8% hydrazine hydrate / DMF solution (8 mL) for 30 minutes to remove the ivDde protecting group. After washing with DMF, the reaction was treated with a mixture of 4-(p-iodophenyl)butyric acid (0.63 g), HATU (0.78 g) and DIPEA (0.56 g) in DMF (8 mL) for 10 hours, and then washed with DMF to obtain VWT016204.

[0637] Preparation of K5)VWT016205

[0638] VWT016204 (2.45 g) was treated in 1% TFA / DCM solution (25 ml) at room temperature for 3 hours, filtered, purified water (40 ml) was added to the filtrate, the pH was adjusted to 7 with ammonia, the mixture was separated, the aqueous phase was extracted twice with DCM, and the organic phase was concentrated to obtain VWT016205 (1.22 g).

[0639] (40.2) Preparation of VWT016206

[0640] After VWT016205 (240 mg), HATU (82.23 mg), DIPEA (76.72 mg), and VWT016512 (240 mg) were reacted in DMF (3 ml) at room temperature, the mixture was washed with saturated brine and ethyl acetate, and the organic phase was concentrated to obtain VWT016206.

[0641] (40.3) Preparation of VWT016200

[0642] Following the method in Example 4, VWT016206 was deprotected by removing the tBu protecting group in 95% TFA / 5% H2O to prepare VWT016200 (72 mg); LC-MS: [M / 2+H] + =1127.70.

[0643] The following compounds can also be prepared by referring to the preparation methods described above and / or existing technologies: for example, VWT053100, VWT053200, etc.

[0644] Example 41

[0645] Preparation of VWT053100

[0646] (41.1) Preparation of compound 41-5

[0647] Preparation of compound 41-2 (L1)

[0648] Compound 41-1 (((benzyloxy)carbonyl)-L-lysine: 17.8 mmol, 1.0 eq) was dissolved in tert-butyl acetate (30 mL), and perchloric acid (1.5 eq) was added. The reaction was carried out at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give compound 41-2 (approximately 4 g, 66%) as a colorless liquid; LCMS: [M+H] + =337.2.

[0649] Here, eq refers to equivalent (molar ratio).

[0650] Preparation of L2) compound 41-4

[0651] Compound 41-3 (2-(4-isobutylphenyl)acetic acid: 12.5 mmol, 1.2 eq) and HATU (1.5 eq) were dissolved in DMF (50 mL), and compound 41-2 (10.4 mmol, 1.0 eq) and DIPEA (3.0 eq) were added. The mixture was reacted at room temperature for 3 hours. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 × 3 mL). The organic phase was washed three times with saturated brine (200 mL). The organic phase was concentrated to obtain the residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to give compound 41-4 (4.3 g, 80%) as a colorless liquid; LCMS: [M+H] + =511.3.

[0652] Preparation of L3 compound 41-5

[0653] Compound 41-4 (8.2 mmol, 1.0 eq) was dissolved in methanol (50 mL), and palladium on carbon catalyst (0.5 g) was added. The reaction was carried out under hydrogen gas continuously at room temperature for 16 hours to remove the amino protecting group. The mixture was filtered, and the filtrate was concentrated to obtain compound 41-5 (3.0 g, 96%), which was a dark brown liquid.

[0654] (41.2) Preparation of VWT053102

[0655] Following the method of Example 25, VWT053101 was synthesized. VWT053101 was deresinated in a TFE / DCM pyrolysis buffer of 1 / 5 (volume ratio), crystallized by methyl tert-butyl ether, centrifuged and dried to obtain VWT053102.

[0656] (41.3) Preparation of VWT053103

[0657] VWT053102 and compound 41-5 undergo a condensation reaction in a DIC condensation system (e.g., DIC and HOBT), and after treatment in TFA-DTT-H2O-TIPS lysis buffer, VWT053103 is obtained.

[0658] (41.4) Preparation of VWT053100

[0659] Following the method described in Example 25, VWT053100 was synthesized from VWT053103; LC-MS: [M+H] +

[0660] =1873.70, HPLC purity is 98.17% (peak area normalization method).

[0661] Example 42

[0662] Preparation of VWT053200

[0663] (42.1) Preparation of compound 42-4

[0664] Preparation of compound 42-3 (M1)

[0665] Compound 42-2 (2-(4-isobutylphenyl)acetic acid: 15.0 mmol, 1.2 eq) and HATU (1.5 eq) were dissolved in DMF (50 mL), and compound 42-1 (2-aminoethylcarbamate tert-butyl ester: 12.5 mmol, 1.0 eq) and DIPEA (3.0 eq) were added. The mixture was reacted at room temperature for 3 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane / methanol = 50 / 1, v / v) to give compound 42-3 (3.8 g, 90%) as a colorless liquid; LCMS: [M+Na] + =357.2.

[0666] Preparation of compound 42-4 (M2)

[0667] Compound 42-3 (11.1 mmol, 1.0 eq) was dissolved in ethyl acetate solution of hydrogen chloride (50 mL, 4 M), and reacted at room temperature for 2 hours; concentration under reduced pressure gave compound 42-4 (2.35 g, 89%) as a white solid; LCMS: [M+H] + =235.2.

[0668] (42.2) Preparation of VWT053200

[0669] VWT053200 was synthesized following the method of Example 41 (replacing compound 41-5 with compound 42-4); LCMS: [M+H] + =1787.90, HPLC purity is 96.41% (peak area normalization method).

[0670] Example 43

[0671] Preparation of VWT053700

[0672] Following the method of Example 27 (Fmoc-L-Thr(tBu)-OH replaced with Fmoc-Asn(Trt)-OH), VWT053700 was synthesized; LC-MS: [M+H] + =1584.90.

[0673] Example 44

[0674] Preparation of VWT053800

[0675] Following the method of Example 27 (Fmoc-L-Thr(tBu)-OH was replaced with Fmoc-L-Asp(OtBu)-OH), VWT053800 was synthesized; LC-MS: [M+H] + =1585.90.

[0676] Example 45

[0677] Preparation of VWT054900

[0678] Following the method of Example 31 (replacing Fmoc-L-MET(O2)-OH with Fmoc-D-MET(O2)-OH), VWT054900 was synthesized; LCMS: [M+H] + =1585.50.

[0679] Example 46

[0680] Preparation of VWT055800

[0681] VWT055800 was synthesized following the method of Example 41 (with compounds 41-5 replaced by D-alanine hydrochloride); LCMS: [M+H] + =1641.70.

[0682] Example 47

[0683] Preparation of VWT057600

[0684] (47.1) Preparation of VWT057603

[0685] VWT057603 was synthesized using the method of Example 27 (using Fmoc-D-MET(O2)-OH).

[0686] (47.2) Preparation of VWT057604

[0687] Refer to the method in Example 27:

[0688] VWT057603 (1.03 mmol) was swollen in DMF (8 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (8 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, the reaction was treated with a mixture of Fmoc-L-Lys(Alloc)-OH (0.94 g), DIC (0.26 g), and OXYMA PURE (0.30 g) in DMF (6 mL) for 3 hours. The resin was then washed with DMF to obtain VWT057604.

[0689] (47.3) Preparation of VWT057608

[0690] VWT057608 was synthesized using the method described in Example 27.

[0691] (47.4) Preparation of VWT057609

[0692] VWT057608 (1.03 mmol) was swollen in DMF (8 mL) for 30 minutes, followed by washing with DMF, methyl tert-butyl ether and DCM sequentially. Then, the resin was treated with phenylsilane (0.61 g) and tetrakis(triphenylphosphine)palladium (0.11 g) in DCM (8 mL) for 2 hours to remove the Alloc protecting group. The resin was then washed with DCM, methyl tert-butyl ether and DMF sequentially. The reaction was then treated with a mixture of D-hydrogenated orotic acid (0.49 g), DIC (0.39 g) and OXYMA PURE (0.44 g) in DMF (8 mL) for 3 hours. The resin was then washed with DMF to obtain VWT057609.

[0693] (47.5) Preparation of VWT057600

[0694] Following the method described in Example 27, VWT057600 was synthesized from VWT057609; LCMS: [M+H] + =1756.80, purity is 99.94% (peak area normalization method).

[0695] Example 48

[0696] Preparation of VWT057400

[0697] Following the method of Example 47 (replacing Fmoc-Asp(OtBu)-OH and Fmoc-L-Lys(Alloc)-OH with Fmoc-L-Pro-OH and Fmoc-L-HLys(Alloc)-OH respectively), VWT057400 was synthesized; LCMS: [M+H]+ =1752.90, purity is 95.94% (peak area normalization method).

[0698] Example 49

[0699] Preparation of VWT057500

[0700] Following the method of Example 47 (replacing Fmoc-L-Lys(Alloc)-OH with Fmoc-L-HLys(Alloc)-OH), VWT057500 was synthesized; LCMS: [M+H] + =1770.80, purity is 95.01% (peak area normalization method).

[0701] Example 50

[0702] Preparation of VWT058800

[0703] VWT058800 was synthesized following the method of Example 41 (with compounds 41-5 replaced by L-alanine hydrochloride); LCMS: [M+H] + =1641.90.

[0704] Example 51

[0705] Preparation of VWT058900

[0706] Following the method of Example 48 (replacing Fmoc-Phe(4-Br)-OH with Fmoc-Phe(4-I)-OH), VWT058900 was synthesized; LC-MS: [M / 2+H] + =899.90.

[0707] Example 52

[0708] Preparation of VWT059000

[0709] (52.1) Preparation of compound 52-1

[0710] Compound 52-1 was synthesized by referring to the method of Example 42 (replacing compound 42-2 with D-hydrogenated orotic acid).

[0711] (52.2) Preparation of VWT059000

[0712] VWT059000 was synthesized following the method of Example 41 (by replacing compounds 41-5 and Fmoc-Phe(4-Br)-OH with compounds 52-1 and Fmoc-Phe(4-I)-OH, respectively); LCMS: [M+H] + =1800.00.

[0713] Example 53

[0714] Preparation of VWT059200

[0715] VWT059200 was synthesized following the method of Example 41 (by replacing compounds 41-5 and Fmoc-Phe(4-Br)-OH with D-alanineamide hydrochloride and Fmoc-Phe(4-I)-OH, respectively); LC-MS: [M] + =1687.50.

[0716] Example 54

[0717] Preparation of VWT059300

[0718] (54.1) Preparation of VWT059301

[0719] Rink amide Resin (1.35 mmol) was swollen in DMF (12 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (12 mL) for 30 minutes to remove the Fmoc protecting group. The resin was then washed with DMF (12 mL) and reacted with Fmoc-D-MET(O2)-OH (0.65 g), DIC (0.24 g) and OXYMA PURE (0.27 g) in DMF (9 mL) for 4 hours. The resin was washed with DMF to obtain VWT059301.

[0720] (54.2) Preparation of VWT059302

[0721] VWT059301 (1.35 mmol) was swollen in DMF (12 mL) for 30 minutes, washed with DMF, and then treated with 20% piperidine / DMF (12 mL) for 30 minutes to remove the Fmoc protecting group. After washing with DMF, it was reacted with Fmoc-Cys(Trt)-OH (2.41 g), PyAOP (2.35 g), HOAT (0.62 g) and DIPEA (1.07 g) in DMF (9 mL) for 7 hours. The resin was washed with DMF to obtain compound VWT059302.

[0722] (54.3) Preparation of VWT059300

[0723] Following the method of Example 21 (replacing VWT051801 with VWT059302), VWT059300 was synthesized; LC-MS: [M+H] + =1733.90.

[0724] Example 55

[0725] Preparation of VWT059500

[0726] VWT059500 was synthesized according to the method of Example 33 (replacing Fmoc-L-Thr(tBu)-OH and Fmoc-L-MET(O2)-OH with Fmoc-Aph(Hor)-OH and Fmoc-D-MET(O2)-OH, respectively) or Example 25; LC-MS: [M] + =1818.60.

[0727] Example 56

[0728] Preparation of VWT066600

[0729] VWT066600 was synthesized according to the methods of Example 33 (replacing Fmoc-L-Thr(tBu)-OH with Fmoc-L-Asp(OtBu)-OH) or Example 25; LC-MS: [M+H] + =1631.70, HPLC purity is approximately 100% (peak area normalization method).

[0730] Example 57

[0731] Preparation of VWT069000

[0732] (57.1) Preparation of VWT069001

[0733] VWT069001 was synthesized by referring to the method of Example 33 (replacing Fmoc-L-Phe(4-I)-OH with Fmoc-Lys(Alloc)-OH) or Example 25.

[0734] (57.2) Preparation of VWT069002

[0735] VWT069001 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes, washed with DMF, methyl tert-butyl ether and dichloromethane, respectively. Then, the Alloc protecting group was removed by reacting tetrakis(triphenylphosphine)palladium (374.5 mg) and phenylsilane (2.103 g) in dichloromethane (24 mL) for 1 hour. The resin was then washed with dichloromethane, methyl tert-butyl ether and DMF, respectively, to obtain VWT069002.

[0736] (57.3) Preparation of VWT069003

[0737] VWT069002 (3.24 mmol) was swollen in DMF (24 mL) for 30 minutes and washed with DMF. Then, it was reacted with 4-(p-iodophenyl)butyric acid (2.82 g), DIC (1.34 g) and HOBT (1.44 g) in DMF (18 mL) for 2 hours. The resin was washed with DMF to obtain VWT069003.

[0738] (57.4) Preparation of VWT069000

[0739] VWT069000 was synthesized from VWT069003 according to the method of Example 33 or Example 25; LC-MS: [M+H] + =1744.70, HPLC purity is 99.29% (peak area normalization method).

[0740] Example 58

[0741] Preparation of VWT069200

[0742] (58.1) Preparation of VWT069201

[0743] VWT069201 was synthesized by referring to the method of Example 33 or Example 25.

[0744] (58.2) Preparation of VWT069202

[0745] Fmoc-Ala-OH (16.06 mmol, 1.0 eq) was dissolved in dichloromethane (50 mL), and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 1.5 eq) and HOSu (1.5 eq) were added. The mixture was reacted at room temperature for 3 hours. Dichloromethane (100 mL) was added, and the mixture was washed with water. The organic phase was dried and concentrated to obtain VWT069202 (5.3 g); LCMS: [M+H] + =408.

[0746] (58.3) Preparation of VWT069203

[0747] VWT069201 (100 mg) was dissolved in DMF (3.0 mL), then DIPEA (314.63 mg) and VWT069202 (87.80 mg) were added and reacted for 3 hours. Then 0.5 mL of piperidine was added and stirred for 1 hour to remove the Fmoc protecting group. After purification by preparative HPLC, VWT069203 (30 mg) was obtained.

[0748] (58.4) Preparation of VWT069200

[0749] Refer to the method of Example 33 or Example 25:

[0750] VWT069203 (30 mg) was dissolved in DMSO (1 mL), followed by the addition of DOTA-NHS (20.73 mg) and DIPEA (89.14 mg). The mixture was reacted overnight at room temperature. After preparative HPLC purification, WT069200 (5.6 mg) was obtained. LC-MS: [M] + =1688.50, HPLC purity is 97.51% (peak area normalization method).

[0751] Example 59

[0752] Preparation of VWT072200

[0753] VWT072200 was synthesized following the methods of Example 33 (where Fmoc-L-Thr(tBu)-OH and Fmoc-Phe(4-I)-OH were replaced with Fmoc-D-Asp(OtBu)-OH and Fmoc-Phe(4-Br)-OH, respectively) or Example 25; LC-MS: [M+H] + =1585.40, HPLC purity is 99.72% (peak area normalization method).

[0754] Example 60

[0755] Preparation of VWT072300

[0756] VWT072300 was synthesized according to the method of Example 33 (replacing Fmoc-L-Thr(tBu)-OH and Fmoc-Phe(4-I)-OH with Fmoc-Glu(OtBu)-OH and Fmoc-Phe(4-Br)-OH, respectively) or Example 25; LC-MS: [M+H] +=1599.40, HPLC purity is approximately 100% (peak area normalization method).

[0757] Example 61

[0758] Preparation of VWT078400

[0759] (61.1) Preparation of VWT078401

[0760] VWT078401 was synthesized by referring to the method of Example 33 (replacing Fmoc-L-Thr(tBu)-OH and Fmoc-Phe(4-I)-OH with Fmoc-L-Asp(OtBu)-OH and Fmoc-Phe(4-Br)-OH respectively) or Example 25.

[0761] (61.2) Preparation of VWT078402

[0762] VWT078401 (190 mg) was dissolved in DMF (5 mL), then DIPEA (10.0 eq) and VWT069202 (3.0 eq) were added and reacted for 3 hours. After that, 1 mL of piperidine was added and stirred for 1 hour to remove the Fmoc protecting group. VWT078402 was then obtained by preparative HPLC purification.

[0763] (61.3) Preparation of VWT078400

[0764] VWT078402 (30 mg) was dissolved in DMF (1 mL), followed by the addition of DOTA(tBu)3-NHS (3.0 eq) and DIPEA (5.0 eq), and the mixture was reacted at room temperature for 3 h. After removing the DMF, 95% TFA (5 mL) was added and the mixture was reacted for 3 h (to remove the tBu group). VWT078400 (1.3 mg) was obtained after purification. LC-MS: [M] + =1656.70, HPLC purity is 99.27% ​​(peak area normalization method).

[0765] Example 62

[0766] Preparation of VWT078500

[0767] (62.1) Preparation of VWT078501

[0768] VWT078501 was synthesized by referring to the method of VWT069202 in Example 58 (replacing Fmoc-Ala-OH with Fmoc-Phe-OH).

[0769] (62.2) Preparation of VWT078500

[0770] Following the method described in Example 61, VWT078500 was synthesized; LC-MS: [M] + =1732.80, HPLC purity is 97.64% (peak area normalization method).

[0771] Example 63

[0772] Preparation of VWT096600

[0773] in,

[0774] PYTAGA1 refers to

[0775] Following the method of Example 27 (Fmoc-L-Thr(tBu)-OH and the chelating reagent were replaced with Fmoc-L-Asp(OtBu)-OH and PYTAGA-NHS, respectively), VWT096600 was synthesized; LCMS: [M+H] + =1811.50.

[0776] The preparation of PYTAGA-NHS is as follows:

[0777] (63.1) Preparation of PYTAGA(tBu)4

[0778] Referring to the method in US Patent 8,048,906 B2 or its family of patents WO 2005 / 001415 A2, Cyclen is replaced with PYTAGA(tBu)4 can be prepared.

[0779] (63.2) Preparation of PYTAGA-NHS

[0780] in,

[0781] NHS refers to

[0782] PYTAGA(tBu)4 (35 mg, 1.0 eq) was dissolved in dichloromethane (3.0 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.0 mg, 1.5 eq) and N-hydroxysuccinimide (7.06 mg, 1.5 eq) were added. The mixture was reacted at room temperature for 3 hours. Dichloromethane (10 mL) was added, and the mixture was washed three times with water (20 × 3 mL). The organic phase was dried and concentrated to obtain a solid. Then, trifluoroacetic acid (3.0 mL) was added, and the mixture was stirred at room temperature for 12 hours (to remove the tBu group). The solid was then added to methyl tert-butyl ether, precipitated, and dried to obtain PYTAGA-NHS.

[0783] Example 64

[0784] Preparation of VWT100800

[0785] VWT100800 was prepared according to the method in Example 63.

[0786] in,

[0787] PYTAGA2 refers to

[0788] Experimental Example 1: Study on Biological Distribution

[0789] 1. Experimental Materials and Methods

[0790] 1.1 Experimental instruments and reagents

[0791] Radioactivity meter (CRC-55tR, Capintec, USA); Thermostat (TS100); Electronic balance (ME104E, Mettler Toledo Instruments (Shanghai) Co., Ltd.); Electronic balance (BT457A10, Shenzhen Botu Electronic Technology Co., Ltd.); Small animal SPECT-CT imaging system (U-SPECT+ / CT, MI Labs); Radioactive thin-layer chromatography scanner (Scan-RAM MCA, Lablogic); Sodium acetate (250g / bottle, SIGMA); 177 LuCl3 (100mCi, China Isotope & Radiation Corporation); physiological saline (250mL / bag, Sichuan Kelun Pharmaceutical Co., Ltd.).

[0792] 1.2 Tumor Mouse Model

[0793] The mice were U87 mice (BALB / C nude mice), supplied by Heyuan Biotechnology (Shanghai) Co., Ltd., 6-8 weeks old, female.

[0794] 1×10 70.1 mL of 10^7 U87 cells (PBS: Matrigel = 1:1) were subcutaneously inoculated into the right dorsal side of each mouse, when the average tumor volume reached 200–400 mm. 3 These mice were used for research. The specific feeding conditions for the mice are shown in Table 2.

[0795] Table 2. Environmental conditions of the experimental animal housing room

[0796] 2. Experiments on biological distribution

[0797] 2.1 Preparation of the test injection solution

[0798] The properties of the test compounds are shown in Table 3.

[0799] Table 3. Compounds to be tested

[0800] A precursor solution with a concentration of 1 μmol / mL (1 nM) was prepared using physiological saline and the test compound (i.e., the compound prepared in Examples 1-64). 100 μL of the precursor solution was diluted in 900 μL of acetic acid solution (pH = 4.5, 0.4 mol / L). 10 μL (or 20 μL) of the diluted precursor solution was then added to… 177 LuCl3 solution and 40 μL acetic acid solution (pH = 4.5, 0.4 mol / L). The above solution was heated at 95 °C for 30 min. After the reaction was complete, it was cooled to room temperature to obtain various [products / reagents]. 177 Lu - the compound to be tested, for example 177 Lu-VWT028800 177 Lu-VWT047000, etc. Clinical drugs prepared using compound VWT005700. 177 Lu-FAP-2286 or purchased externally 177 Lu-FAP-2286 was used as a comparison.

[0801] Similarly,

[0802] Referring to the aforementioned method, 177 LuCl3 solution replaced with 225 AcCl3 solution can be used to obtain various solutions. 225 Ac-The compound to be tested.

[0803] For example,

[0804] (can also be drawn as ), wait.

[0805] The purity of radioactive compounds was determined using chromatography paper (Merck TLC Silica gel 60 F254, size: 1cm × 10cm). The developing solvent used in the determination was 1% EDTA.

[0806] 2.2 Drug administration and detection

[0807] Inject the aforementioned drug solution into tumor-bearing mice: the dosage was 0.2 mL, 200 μCi / nmol; administered via tail vein injection (consistent with the intended clinical administration); a single dose.

[0808] SPECT / CT scans were performed using a small animal SPECT-CT imaging system (U-SPECT+ / CT, MI Labs). Data acquisition was performed by static SPECT for 10 minutes, followed by a low-resolution whole-body CT scan.

[0809] Record animal weight, injection dose, injection time, and residual dose, and separately record the time for measuring injection dose and the time for measuring residual dose. Dissect and collect tissue samples, obtaining the heart, liver, spleen, lungs, kidneys, and tumors. First, weigh the net tissues, then perform radioactivity counting on the collected tissues to determine the distribution of the radioisotope label in different tissues and organs of the mice. Additionally, dilute the test sample 100-fold, take 0.1 mL in a counting tube as the standard 1% ID (i.e., one percent of the administered dose), and measure the radioactivity count of the 1% ID standard and the collected biological samples on a gamma counter to determine the biodistribution of the drug in the mice.

[0810] 3. Results Analysis

[0811] 3.1 Labeling efficiency

[0812] The labeling efficiency of each test compound was greater than 95%, indicating that the compounds did not require purification.

[0813] 3.2 Distribution of organisms

[0814] SPECT / CT was used to observe the tissue distribution of each drug, and the tissue distribution was visualized and quantified. The data on biological tissue distribution was expressed as the percentage of radioactivity count per gram of tissue or organ relative to the total administered dose (radioactivity count) (%ID / g).

[0815] The results of the quantitative analysis are shown in Table 4; where T / K refers to the ratio of tumor uptake to renal uptake.

[0816] Table 4. Tumor-bearing mice 177 Lu-FAP-2286 and 177Biodistribution of Lu-analyte (number of mice, n=3)

[0817] Among them, compounds 177 Lu-VWT047000 and 177 Representative visualizations after administration of Lu-VWT047200 are shown in Figures 1 and 2, respectively.

[0818] The results showed that, compared with existing known FAP compounds, the FAP compounds of this application have higher tumor uptake and / or lower renal uptake; where higher tumor uptake means better targeting effect, and lower renal uptake means lower nephrotoxicity of the drug; T / K (the ratio of tumor uptake to renal uptake) is an important indicator for screening drugs and / or clinical drug selection, and generally the higher the T / K value, the better.

[0819] In addition, select 177 Lu-VWT047200 (administered concentration (dose) of 0.2 mL, 0.3 mCi / nmol) is used as a representative compound. 177 The Lu-FAP-2286 group (dosage concentration: 0.2 mL, 1 mCi / nmol) and the solvent control group (physiological saline) served as controls. The drug was administered once via tail vein injection on day 1 (no further administration on subsequent days). Tumor volume and mouse weight were further assessed. The tumor volume was calculated using the formula: TV = 0.5a × b. 2 , where a is the long axis of the tumor and b is the short axis of the tumor; the results are shown in Figures 3 and 4 (number of mice, n=5).

[0820] The results showed that 177 Lu-VWT047200, at a dose of 0.3 mCi, can interact with... 177 The comparable efficacy of Lu-FAP-2286 at a 1mCi dose further demonstrates that the FAP compound of this application has superior targeting efficacy and / or better therapeutic effect on tumors.

[0821] The FAP compound of this application can improve the drug targeting effect while greatly reducing the risk of kidney damage, which is conducive to better meeting the medication needs of patients and has broad prospects for clinical promotion and higher application value.

[0822] Experimental Example 2: HT-1080 hFAP (human fibrosarcoma cells) subcutaneous tumor model

[0823] HT-1080hFAP subcutaneous tumor model mice (null / null nude mice, Wuxi Saifu Guotong Pharmaceutical Technology Co., Ltd.). Mice were randomly assigned to various experimental groups. Mouse weight and tumor size were measured. On the day of grouping, mice were divided into a negative control group (saline) and a treatment group (administered medication). 177 Lu-FAP-2286, 0.3 mcg / animal), treatment group 2 (administered with the drug prepared in Example 44 of this application). 177 Mice were initially administered Lu-VWT053800 (0.3 mcg / mouse). Health and appearance were observed daily thereafter, and body weight and tumor size were measured twice weekly. Relative change of tumor volume (RTV) and relative tumor proliferation rate (T / C%) are shown in Figures 5 and 6. RTV = Vt / V0

[0824] Vt: refers to the tumor volume measured each time (after drug administration); V0: the initial tumor volume (before drug administration).

[0825] The relative tumor proliferation rate (T / C%) is the percentage of tumor volume in the treatment group and the control group at a certain time point; its calculation formula is:

[0826] T / C (%) = TRTV / CRTV × 100% (where TRTV: refers to the average RTV in the treatment group; CRTV: refers to the average RTV in the negative control group)

[0827] Experimental results show that the compound of this application 177 The efficacy of Lu-VWT053800 is superior to 177 The efficacy of Lu-FAP-2286 (at a dose of 0.3 mCi) also demonstrates that the FAP compound of this application has superior targeting effects and / or better efficacy against tumors.

[0828] Of course, the present invention can also have other various embodiments. Without departing from the spirit and essence of the present invention, those skilled in the art can make various corresponding changes and / or modifications according to the present invention, and these corresponding changes and / or modifications should all fall within the protection scope of the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, ester, or solvate thereof, (R W ) m11 —L—XI wherein L is a linker comprising N and / or S; X is hydrogen or a chelator, and X is attached to the N-terminus of L; R w For (preferably, R w to )； m 11 is 1 or 2; when m 11 is 2, R w are the same or different; said -Xaa2-Xaa3-Xaa4-Xaa5-Xaa6- is a residue of an amino acid and / or a peptide, the sequence of which is drawn from left to right in the direction of the N-terminus to the C-terminus; Y 1 is CH or N; m is 1 or 2; n is 0 or 1; R a selected from hydrogen, deuterium, tritium, OH, COOH, CONH2, -CO-X 1 or -CO-NH-X 1 , wherein X 1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl, X 1 is unsubstituted, or, optionally, X 1 is substituted by one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, CONH2, halogen, cyano, OH, NH2and -NH-CO-R a1 -CO-NH-R a2 -O-R a3 ) u -NH-CO-R a4 -R d ; R a1 , R a2 , R a3 and R a4 are each independently selected from 1-6 methylene groups, wherein all methylene groups in R a1 , R a2 , R a3 and R a4 are unsubstituted, or, optionally, one or two hydrogens in one, two, three, four or five of the methylene groups in R a1 , R a2 , R a3 and R a4 are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl; u is 0, 1, 2, 3, 4 or 5; R d C5-C6aryl, X 2 substituted C5-C6aryl, C2-C6heteroaryl or X 2 substituted C2-C6heteroaryl, wherein X 2 is selected from the group consisting of deuterium, tritium, methyl, halogenated methyl, methoxy, halogenated methoxy, ethyl, halogenated ethyl, ethoxy, halogenated ethoxy, propyl, halogenated propyl, propoxy, halogenated propoxy, COOH, CONH2, halogen, cyano, NH2or OH; R b selected from hydrogen, deuterium, tritium, methyl, OH, NH2, or F; R c selected from COOH, CONH2, -CO-NH-Z a , -CO-NH-CO-Z a , -CO-NH-Z b -CO-NH-Z a , -CO-NH-Z b -NH-CO-Z a or -CO-Z c ; wherein Z a selected from C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, C2-C6heteroaryl or Z a unsubstituted, or, optionally Z a is selected from the group consisting of deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, COOH, CONH2, OH, halogen, cyano, NH2, One or more substituents are substituted, X 0 Selected from hydrogen, deuterium, tritium, halogen, cyano (CN), -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, pyrazolyl, C1-C6 alkyl-substituted pyrazolyl, COOH, CONH2, OH or NH2; Z b is selected from 1-6 methylene groups, wherein all methylene groups in said Z b are unsubstituted, or, optionally one or two hydrogens in one, two, three, four or five methylene groups in said Z b are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl; Z c selected from 4-7 membered nitrogen heterocycles, wherein Z c is unsubstituted, or, optionally, Z c is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano, -B(OH)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, COOH, CONH2, OH, and NH2; m1, m2, m3 and m4 are each independently selected from 1 or 2; m 21 and m 22 each independently is selected from 1 or 2; n 11 is 0 or 1 ; X 11 selected from S or O; R zc selected from COOH, CONH2, -CH2-COOH, -CH2-CONH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl substituted phenyl, C1-C6 alkoxy substituted phenyl or halogen substituted phenyl; R za1 , R za2 , R za3 , and R za4 are each independently selected from hydrogen, deuterium, tritium, C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, C2-C6heteroaryl, or Xaa2and Xaa3are each independently selected from an amino acid residue as depicted by formula AA1, AA2or AA3: (preferably, Xaa2and Xaa3are each independently selected from the group consisting of amino acid residues as shown below: )； wherein R 2a , R 2b , and R 2c are each independently selected from hydrogen, deuterium, tritium, C1-C3alkyl, or substituted C1-C3alkyl, wherein the substituents of the C1-C3alkyl are selected from OH, NH2, halogen, cyano, carboxyl, or C5-C7cycloalkyl; R 2d selected from hydrogen, deuterium, tritium, methyl, OH, NH2, or F; X 3 is selected from CH2, CF2, CH-R 2e , S, O or NH; R 2e selected from deuterium, tritium, methyl, OH, NH2, or F; p is 0, 1 or 2; v is 1 or 2; w is 1, 2 or 3; Xaa4is an amino acid residue of formula AA4: (preferably, Xaa4 is an amino acid residue as shown below: ) wherein R 4a selected from hydrogen, deuterium, tritium, OH, COOH, CONH2, X 4 , -CO-NH-X 4 , -NH-CO-X 4 or -NH-X 5 , wherein X 4 is selected from C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl, X 4 is unsubstituted or, optionally, X 4 is substituted by one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxy, CONH2, OH, halogen, cyano and -NH-X 5 , wherein X 5 is selected from hydrogen, deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, OH or q is an integer from 1 to 10 (preferably, q is an integer from 1 to 5), wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1, 2, 3, 4 or 5 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl, azido-substituted C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl; R 4b selected from hydrogen, deuterium, tritium or methyl; Xaa5is an amino acid residue of Formula AA5: (preferably, Xaa5 is an amino acid residue as shown below: )； R 5a selected from COOH, CONH2, -CO-X 6 , -oxadiazole-X 6 or -S(=O)(=O)-X 6 wherein X 6 is selected from C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl, X 6 is unsubstituted or, optionally, X 6 is substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxy, CONH2, OH, cyano, halogen and NH2; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1, 2, 3, 4 or 5 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl, azido-substituted C1-C6 alkyl, C1-C6 alkoxy, C5-C6 aryl or C2-C6 heteroaryl; and Xaa6is an amino acid residue selected from the group consisting of an aromatic alpha- amino acid, a halogen substituted aromatic alpha-amino acid, X 7 a substituted aromatic alpha-amino acid, a heteroaromatic alpha-amino acid, a halogen substituted heteroaromatic alpha-amino acid, X 7 a substituted heteroaromatic alpha-amino acid (in the S- or R-configuration), wherein X 7 is selected from the group consisting of C5-C7cycloalkyl, C1-C6alkyl, C1-C6alkoxy, C5-C6aryl or C2-C6heteroaryl, X 7 is unsubstituted, or, optionally, X 7 is substituted with one or more substituents selected from the group consisting of deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, CONH2, halogen, cyano, NH2and OH.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, L is selected from the group consisting of xa1 L xa3 , wherein L xa1 for L xa2 For L xa3 for z1, z2, z3 and z4 are each independently selected from 0, 1, 2 or 3; t0 is 1, 2 or 3; m5, m6, m7 and m8 are each independently selected from 0, 1, 2 or 3; m 31 and m 32 each independently is selected from 1 or 2; R za5 , R za6 , and R za7 are each independently selected from hydrogen, deuterium, tritium, C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, C2-C6heteroaryl, or L xb1 , L xb2 and L xb3 are each independently selected from -CO-(Rx1-O) t1 -Rx2-NH-CO-, -CO-(Rx1-O) t1 -Rx2-NH-CO-(Rx3-O) t2 -Rx4-CO-, -CO-(Rx1-O) t1 -Rx2-CO-NH-(Rx3-O) t2 -Rx4-CO-, -CO-(Rx1-O) t1 -Rx2-CO-NH-(Rx3-O) t2 -Rx4-NH-CO- or -CO-(Rx1-O) t1 -Rx2-NH-CO-(Rx3-O) t2 -Rx4-NH-CO-; R x11 selected from hydrogen, deuterium, tritium or Ci-C6alkyl; R x1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 are each independently selected from 1-6 methylene groups, wherein all methylene groups of R x1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 are unsubstituted, or, optionally, one or two hydrogens of 1, 2, 3, 4 or 5 methylene groups of R x1 , R x2 , R x3 , R x4 , R x12 , R x13 and R x14 are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, -NH-CO-R x5 -Z d , -CO-NH-R x5 -Z d , C1-C6alkoxy, C5-C6aryl or C2-C6heteroaryl; R x5 is selected from 1-6 methylenes, wherein all methylenes in said R x5 are unsubstituted, or, optionally one or two hydrogens in one, two, three, four or five methylenes in said R x5 are each independently replaced by deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl; Z d for t1, t2, t 11 , t 12 , t 13 and t 14 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; Yaabb is a cyclic peptide group condensed from 3 to 8 substituted or unsubstituted amino acids, and L xb2 is connected to the N-terminal of Yaabb; Yaacc is z5 and z6 are each independently selected from 1 or 2; R x16 is selected from 1-6 methylenes, wherein all methylenes in said R x16 are unsubstituted, or, optionally, one or two hydrogens in one, two, three, four or five methylenes in said R x16 are each independently replaced with deuterium, tritium, carboxy, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl; R 9a selected from C1-C6alkyl, C1-C6alkoxy, C5-C6aryl, or C2-C6heteroaryl; Z e is 4-7 membered nitrogen heterocycle, wherein Z e is unsubstituted, or, optionally Z e is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano, -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, COOH, CONH2, OH, and NH2.

3. The compound of claim 1, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, X is hydrogen or a chelator, and X is attached to the N-terminus of L; the chelator is 1,4,7-triazacyclononane-1,4,7-triacetic acid (N OTA, ), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA, ), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-pentanedioic acid (DOTAGA: ), N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 2-(4,7-bis(carboxymethyl)-1,4,7-triazolN-yl)pentanedioic acid (NODAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)- phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15- tetraazabicyclo[9,3,1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), NODA-MPAA, HBED, TETA, CB-TE2A, DTPA, Macropa, HOPO, TRAP, THP, DATA, NOTP, sarcophagine, FSC, NETA, H4octapa, Pycup, N4, N2S2, N3S, Hynic, diethylenetriaminepentaacetic acid (DTPA: ), wherein X 12 , X 13 and X 14 are each independently selected from S or O; or said chelator is PYTA, PY3A-NH2, PY3A-NH2-SQ, PYTAGA, PYTAGA-NH2 or PYTAGA-NH2-SQ; wherein PYTA is PY3A-NH2 is and / or PY3A-NH2-SQ is and / or PYTAGA is and / or PYTAGA-NH2 is and / or PYTAGA-NH2-SQ is and / or Preferably, the chelating agent is DOTA or DOTAGA; Alternatively, the chelator is PYTA or PYTAGA; wherein PYTAGA is and / or 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein R w for wherein X 6 is selected from C1-C6alkyl, C1-C6alkoxy, or C5-C6aryl;X 6 is unsubstituted, or, optionallyX 6 substituted with one or more substituents selected from deuterium, tritium, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, carboxy, CONH2, OH, cyano, halogen, and NH2, and r is 1, 2, or 3; preferably X 6 Ci-C6-alkyl and r is 1, 2 or 3. more preferably X 6 R1is H, methyl, or ethyl, and r is 2; and Y 1 , m, n, R a , R b , R c , Xaa2, Xaa3, Xaa6, R 4a , R 4b and q are as defined in claim 1.

5. The compound of claim 1 or 4, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, R c selected from COOH, CONH2, -CO-NH-Z a , -CO-NH-CO-Z a , -CO-NH-Z b -CO-NH-Z a , -CO-NH-Z b -NH-CO-Z a or -CO-Z c ; wherein Z a selected from C1-C6 alkyl, C1-C6 alkoxy or Z a unsubstituted, or, optionally Z a is selected from deuterium, tritium, COOH, CONH2, OH, halogen, cyano, NH2and One or more substituents are substituted, X 0 Selected from hydrogen, deuterium, tritium, halogen, cyano, -B(OH)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, COOH, CONH2, OH or NH2; Z b is selected from 1-6 methylene groups, wherein all methylene groups in said Z b are unsubstituted, or, optionally, one or two hydrogens in one methylene group in said Z b is each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, azido, C1-C6alkyl, azido-substituted C1-C6alkyl, or C1-C6alkoxy; Z c is 4-6 membered nitrogen heterocycle, wherein Z c is unsubstituted, or, optionally, Z c is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano, -B(OH)2, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, COOH, CONH2, OH, and NH2; R zc selected from COOH, CONH2, C1-C6alkyl, C1-C6alkoxy, C1-C6alkyl- substituted phenyl, C1-C6alkoxy-substituted phenyl, or halogen-substituted phenyl; R za1 , R za2 , R za3 and R za4 are each independently selected from hydrogen, deuterium, tritium or C1-C6alkyl; preferably R c selected from COOH, CONH2, -CO-NH-Z a , -CO-NH-CO-Z a , -CO-NH-Z b -CO-NH-Z a , -CO-NH-Z b -NH-CO-Z a or -CO-Z c ; wherein Z a selected from C1-C6alkyl or Z a unsubstituted, or, optionally Z a is selected from deuterium, tritium, COOH, CONH2, NH2, One or more substituents are substituted, X 0 Selected from hydrogen, deuterium, tritium, halogen, cyano, -B(OH)2 or C1-C6 alkyl; Z b is selected from 1-6 methylene groups (CH2), wherein all methylene groups in said Z b are unsubstituted, or, optionally, one or two hydrogens in one of the methylene groups in said Z b is each independently replaced with deuterium, tritium, carboxyl (COOH), CONH2, or C1-C6 alkyl; Z c selected from piperazinyl, piperidinyl, pyrrolidinyl, wherein Z c is unsubstituted, or, optionally, Z c is substituted with one or more substituents selected from deuterium, tritium, halogen, cyano, -B(OH)2, C1-C6alkyl, COOH, and CONH2; R zc selected from C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkyl substituted phenyl; R za1 , R za2 , R za3 and R za4 are each independently selected from hydrogen or C1-C3alkyl.

6. The compound of claim 1 or 5, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is as shown in Formula IA or Formula IB: wherein L in Formula IA is as defined in claim 2; L in formula IB xa3 as defined in claim 2; X is hydrogen or a chelator, and X is attached to the N-terminus of L; wherein the chelator is DOTA or R a -CO-X 1 or -CO-NH-X 1 wherein X 1 is C1-C6 alkyl; R b is hydrogen, deuterium or tritium; R c As defined in claim 1 or 5; Xaa2and Xaa3are each independently selected from the group of amino acid residues consisting of: (preferably, Xaa2and Xaa3are each independently selected from the group consisting of amino acid residues as shown below: )； wherein R 2a and R 2b each independently is selected from hydrogen, deuterium, tritium, C1-C3alkyl, or carboxyl-substituted C1-C3alkyl; R 2c selected from hydrogen, deuterium, or tritium; R 2d selected from hydrogen, deuterium, or tritium; R 4a selected from the group consisting of hydrogen, deuterium, tritium, OH, COOH, CONH2, X 4 , -CO-NH-X 4 or -NH-X 5 , wherein X 4 is C1-C6 alkyl or phenyl, X 4 is unsubstituted or, optionally, X 4 is substituted with one or more substituents selected from the group consisting of deuterium, tritium, carboxyl, CONH2and -NH-X 5 , wherein X 5 is selected from the group consisting of hydrogen, deuterium, tritium or q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; R 4b is hydrogen, deuterium or tritium; Xaa6is an amino acid residue selected from the group consisting of an aromatic alpha-amino acid, a halogen-substituted aromatic alpha-amino acid, X 7 a substituted aromatic alpha-amino acid, wherein X 7 is C1-C6alkyl, X 7 is unsubstituted, or, optionally, X 7 is substituted with one or more substituents selected from the group consisting of deuterium, tritium, halogen, cyano, NH2, and OH; said aromatic alpha-amino acid is phenylalanine, and said halogen is fluorine, chlorine, bromine, or iodine; preferably more preferably wherein DOTA or DOTAGA; 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein wherein preferably more preferably wherein preferably wherein wherein L in Formula IA is as defined in claim 2; wherein q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; preferably more preferably wherein DOTA or DOTAGA; 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein wherein preferably more preferably wherein preferably wherein wherein L in Formula IA is as defined in claim 2; wherein q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; preferably more preferably wherein DOTA or DOTAGA; 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein wherein preferably more preferably wherein preferably wherein wherein L in Formula IA is as defined in claim 2; wherein q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; preferably more preferably wherein DOTA or DOTAGA; 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein wherein preferably more preferably wherein preferably wherein wherein L in Formula IA is as defined in claim 2; wherein q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; r is 1, 2, 3, 4 or 5; wherein all methylene groups in said r are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; preferably more preferably wherein DOTA or DOTAGA; 4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein wherein preferably more preferably wherein preferably wherein wherein L in Formula IA is as defined in claim 2; wherein q is selected from an integer from 1 to 6, wherein all methylene groups in said q are unsubstituted, or, optionally one or two hydrogens in 1 or 2 methylene groups in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, R a -CO-X 1 or -CO-NH-X 1 wherein X 1 is C3-C5alkyl; R b is hydrogen; R c As defined in claim 5; R 4a selected from OH, COOH, CONH2, X 4 , -CO-NH-X 4 or -NH-X 5 wherein X 4 is C1-C3 alkyl or phenyl, X 4 is unsubstituted, or, optionally, X 4 is substituted with one or more substituents selected from carboxyl, CONH2, and -NH-X 5 ; X 5 is hydrogen or q is 1, 2, 3, 4 or 5, wherein all methylene groups in said q are unsubstituted or, optionally, one or two hydrogens in one methylene group in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C3 alkyl; r is 1, 2, 3 or 4; wherein all methylene groups in said r are unsubstituted or, optionally, one or two methylene groups in said r are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C6 alkyl; R 4b is hydrogen; Xaa6is (e.g., phenylalanine or a substituted phenylalanine residue; preferably, ), wherein X 0a is hydrogen, halogen or methyl substituted with 1-3 halogen molecules, which are fluorine, chlorine, bromine or iodine; A 环 is phenyl, anthracenyl, naphthyl, pyridyl or benzopyridyl; t 21 is 0, 1, 2, 3, 4, 5 or 6.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is shown as formula IA1 or formula IB1: wherein, L in formula IA1 is as defined in claim 2; L in formula IB1 xa3 as defined in claim 2; Xaa2and Xaa3are each independently selected from the group of amino acid residues consisting of: (preferably, Xaa2and Xaa3are each independently selected from the group consisting of amino acid residues as shown below: )； R a -CO-X 1 or -CO-NH-X 1 , said X 1 is selected from n-propyl, n-butyl or n-pentyl; R c As defined in claim 5; R 4a selected from OH, COOH, CONH2, X 4 , -CO-NH-X 4 or -NH-X 5 , wherein X 4 is Ci-C2alkyl or phenyl, and optionally X 4 is substituted with one or more substituents selected from carboxyl, CONH2and -NH-X 5 ; X 5 is q is 1, 2, 3, 4 or 5, wherein all methylene groups in said q are unsubstituted or, optionally, one or two hydrogens in one methylene group in said q are each independently replaced with deuterium, tritium, carboxyl, CONH2, OH, halogen, cyano, NH2, C1-C3 alkyl; X 0a is hydrogen, halogen or methyl substituted with 1-3 halogen molecules, the halogen being selected from fluorine, chlorine, bromine or iodine; A 环 is phenyl, anthryl or naphthyl; t 21 is 1 or 2; Preferably, X 0a connected in para or meta position to A 环 .

8. The compound according to claim 1 or 7, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, R 4a is X 4 or -NH-X 5 wherein X 4 is phenyl and X 4 is substituted with -NH-X 5 ; X 5 is q is 1, 2, 3, 4 or 5, wherein all methylene groups in said q are unsubstituted.

9. The compound according to claim 1 or 7, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, L in formula IA1 is wherein t0 is 2 or 3; each of m5, m6, m7, and m8 is independently selected from 1 or 2; m 31 and m 32 each independently selected from 1 or 2; R za5 and R za7 each independently selected from hydrogen or methyl (e.g., )； Preferably, the compound is selected from the group consisting of:

10. The compound according to claim 2, 6 or 7, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, L is (preferably )、 L xa3 for wherein, L xa1 for L xa2 for L xb1 -CO-(CH2)2-CO-NH-(CH2)4-CH(NH-CO-(CH2)3-Z d -CO-, -CO-Rx2-NH-CO-Rx4-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-CO-, -CO-CH2-NH-CO-, -CO-(CH2)3-CO-NH-CH(COOH)-(CH2)4-NH-CO-, -CO-(CH2-CH2-O)4-(CH2)2-NH-CO-, or -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-; L xb2 -CO-(CH2-CH2-O)2-(CH2)2-NH-CO; L xb3 -CO-CH(CH3)-NH-CO-, Z d for Rx2is Rx4is Rx 11 for Z e pyrrolidinyl substituted with -B(OH)2; Yaacc is Z e pyrrolidinyl substituted by halogen and / or cyano (CN); Yaabb is a cyclic peptide group condensed from 3-5 amino acids, and L xb2 The amino acid in Yaabb connected to the N-terminal is selected from aspartic acid, phenylalanine, lysine, glycine or arginine; X 0 R is hydrogen, deuterium, tritium, halogen or cyano; Preferably, L is L xa3 for 11. The compound of claim 10, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is selected from:

12. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compounds are shown as Formula IA2 or Formula IB2: wherein, X is as defined in claim 3; R c As defined in claim 5; L, L xa3 , Xaa2, Xaa3, R a , R 4a , q, X 0a , A 环 and t 21 as defined in claim 7.

13. The compound according to claim 12, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, replace -S(=0)(=0)-CH3(R 5a ) with the resulting compound; Preferably, the compound is selected from the group consisting of:

14. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is shown as formula IA3 or formula IB3: wherein, X is as defined in claim 3; R c As defined in claim 5; L, L xa3 Xaa2, Xaa3, R 4a q is as defined in claim 7; R a -CO-X 1 or -CO-NH-X 1 wherein X 1 is C1-C6 alkyl or phenyl; X 1 is unsubstituted, or, optionally, X 1 is substituted by methyl or -NH-CO-R a1 -CO-NH-R a2 -(O-R a3 ) u -NH-CO-R a4 -R d substituted; R a1 , R a2 , R a3 , R a4 are each independently selected from 1-6 methylene groups, wherein all methylene groups in R a1 , R a2 , R a3 and R a4 are unsubstituted; u is 0, 1, 2, 3, 4 or 5; R d is phenyl or halogen-substituted phenyl; R 5a is COOH or CONH2; r is 1 or 2; A 环 is phenyl, anthryl, naphthyl, pyridyl or benzopyridyl; t 21 is 0, 1, 2, 3, 4, 5, or 6; X 0 selected from hydrogen, deuterium, tritium, halogen, cyano, -B(OH)2, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, pyrazolyl, Ci-C6alkyl substituted pyrazolyl, COOH, or CONH2; Preferably, A 环 is phenyl, anthryl, naphthyl or pyridyl; t 21 is 1 or 2; X 0 selected from hydrogen, deuterium, tritium, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, pyrazolyl, or C1-C6alkyl substituted pyrazolyl.

15. The compound according to claim 14, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, L is wherein each of z1, z2, z3, and z4 is independently selected from 1 or 2; t0 is 2 or 3; each of m5, m6, m7, and m8 is independently selected from 1 or 2; m 31 and m 32 are each independently selected from 1 or 2; and R za5 and R za7 are each independently selected from hydrogen or methyl (e.g., )。 16. The compound of claim 15, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is selected from:

17. The compound according to claim 14, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, L is (preferably )、 L xa3 for wherein, L xa1 for L xa2 for L xb1 -CO-(CH2)2-CO-NH-(CH2)4-CH(NH-CO-(CH2)3-Z d -CO-, -CO-Rx2-NH-CO-Rx4-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)2-(CH2)2-CO-, -CO-CH2-NH-CO-, -CO-(CH2)3-CO-NH-CH(COOH)-(CH2)4-NH-CO-, -CO-(CH2-CH2-O)4-(CH2)2-NH-CO-, -CO-(CH2-CH2-O)3-(CH2)2-NH-CO-; L xb2 -CO-(CH2-CH2-O)2-(CH2)2-NH-CO; L xb3 -CO-CH(CH3)-NH-CO-, Z d for Rx2is Rx4is Rx 11 for Z e pyrrolidinyl substituted with -B(OH)2; Yaacc is Z e pyrrolidinyl substituted by halogen and / or cyano (CN); Yaabb is a cyclic peptide group condensed from 3-5 amino acids, and L xb2 The amino acid in Yaabb connected to the N-terminal (e.g., NH or N) of Yaabb is selected from aspartic acid (Asp), phenylalanine (Phe), lysine (Lys), glycine (Gly), or arginine (Arg); X 0 R is hydrogen, deuterium, tritium, halogen or cyano (CN); Preferably, L is L xa3 for 18. The compound of claim 17, or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein, The compound is selected from:

19. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester or solvate thereof, wherein, L is L xa1 or L xa1 for L xb1 -CO-; and, L xb1 is attached to the N-terminus of xa1 ​ R x99 is hydrogen, Ci-C6alkyl or Xaa6 is T 环 for A 环 or A 环 is phenyl, anthryl or naphthyl; X 0a connected in para or meta position to A 环 ; X 0a is hydrogen, halogen or methyl substituted with 1-3 halogen molecules, said halogen being selected from fluorine, chlorine, bromine or iodine; t 97 , t 98 , and t 99 are each independently selected from 0, 1, 2, 3, 4, 5, or 6; Preferably, the compound is selected from:

20. The compound or pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1-19, wherein, the compound comprises a nuclide; Preferably, the nuclide is a diagnostically active radionuclide or a therapeutically active radionuclide; More preferably, the radionuclide is selected from 94 Tc, 99m Tc, 90 In, 111 In, 67 Ga, 68 Ga, 86 Y, 90 Y, 177 Lu, 151 Tb, 152 Tb, 155 Tb, 51 Mn, 52 Mn, 76 Br, 77 Br, 201 Tl, 203 Pb, 186 Re, 188 Re, 64 Cu, 67 Cu, 55 Co, 57 Co, 43 Sc, 44 Sc, 47 Sc, 225 Ac, 213 Bi, 212 Bi, 212 Pb, 227 Th, 153 Sm, 166 Ho, 152 Gd, 153 Gd, 157 Gd, 166 Dy, 55 Fe, 18 F, 11 C, 89 Zr, 123 I, 124 I, 125 I, 131 I or 211 At; Further preferably, the radionuclide is 68 Ga or 177 Lu.

21. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester or solvate thereof, for the manufacture of a medicament for the diagnosis and / or treatment of a disease; For example, the disease is cancer.

22. A pharmaceutical composition comprising, The pharmaceutical composition comprises a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable excipient.

23. A kit comprising a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, ester or solvate thereof, and one or more optional excipients and, optionally, one or more devices selected from the group consisting of a labeling device, a purification device, an administration device, a radiation protection device, an analysis device or an application device.

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