Compounds targeting neurotensin receptors and uses thereof

Abstract

The application provides a compound targeting a neurotensin receptor and an application thereof. The compound of the application is a compound shown in formula I or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown in formula I, has high selectivity and targeting, can accurately recognize and combine with an NTR1 receptor, reduces cross-reactions with non-target tissues, and improves the therapeutic effect of a drug.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and more specifically, to compounds that target neurotensive peptide receptors and their uses. Background Technology

[0002] Neurotensin (NTS) is a neuropeptide composed of 13 amino acids, widely distributed in the central nervous system and peripheral tissues, and has a variety of physiological functions, including regulating neurotransmission, blood pressure, body temperature, analgesia, and participation in immune responses. Neurotensin exerts its biological effects by interacting with three receptor subtypes, among which neurotensin receptor 1 (NTR1) is one of the most extensively studied receptors.

[0003] NTR1 belongs to the G protein-coupled receptor (GPCR) family. Neurotensin binds to NTR1, activating various intracellular signaling pathways, such as the GPCR signaling pathway, thereby regulating cell proliferation, differentiation, migration, and survival. Under pathological conditions, abnormal NTR1 expression is closely associated with various diseases, especially in the field of oncology. Studies have shown that NTR1 is highly expressed in various solid tumors, such as colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, small cell lung cancer, and non-small cell lung cancer. For example, in pancreatic ductal adenocarcinoma, the positive rate of NTR1 is as high as 75%-90%, while it is almost not expressed in normal pancreatic tissue. Furthermore, high NTR1 expression is also associated with tumor progression, invasion, and poor prognosis; for example, in early-stage non-small cell lung cancer, NTR1-positive patients have lower survival rates.

[0004] Given the crucial role of NTR1 in tumors, it has become a potential target for cancer treatment. Despite some progress in existing research, the development of NTR1-targeted drugs still faces numerous challenges. For example, further exploration is needed to improve drug targeting, reduce side effects, and optimize bioavailability. Therefore, developing novel NTR1-targeted drugs to meet clinical needs has significant scientific and practical value. Summary of the Invention

[0005] This invention aims to at least partially address one of the technical problems existing in the prior art. Therefore, this invention proposes a targeting compound against neurotensin receptor 1 (NTR1). This compound can specifically bind to tumor cells that highly express NTR1, achieving tumor diagnosis and treatment through precise targeting, effectively improving diagnostic sensitivity and treatment accuracy.

[0006] Therefore, in a first aspect, the present invention provides a compound. According to embodiments of the present invention, the compound is a compound of Formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula I:

[0007] Among them, AA-COOH is selected from amino acids of 2-amino-2-adamantane carboxylic acid and cyclohexylglycine; Ring A is selected from p R a Substituted phenylene or phenyl-5-6 heteroaryl groups, wherein R a Independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 Cycloalkyl, carboxyl, hydroxyl; p is an integer selected from 0, 1, 2, 3; R is selected from n R's. b Replacement C 1-6 Alkylene, amino, C 0-6 alkyleneamine, C 2-6 The R group consists of an alkynylamino group, a 5-8 membered heterocyclic group linked to a methylene group, or -O-, -S-, -NH-. b Independently selected from oxidized, halogenated, and C 1-6 Alkyl group; n is an integer selected from 0, 1, 2, or 3; L1 is selected from connectors, which are q R c The substituted carbon chain or heterochain, said R c Independently selected from oxidized, halogenated, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, carboxyl, hydroxyl; q is an integer selected from 0, 1, 2, 3, 4, 5; L2 is selected from an amino acid chain; Z is a chelating group derived from the chelating agent.

[0008] According to embodiments of the present invention, the compound represented by Formula I may further include at least one of the following additional technical features: According to an embodiment of the present invention, in the compound shown in Formula I, in ring A, the heteroatom in the phenyl 5-6-membered heteroaryl group is selected from one or two of N, O, and S, and the number of heteroatoms is one or two; undefined groups are as described in any embodiment of the present invention.

[0009] According to embodiments of the present invention, in the compound shown in Formula I, in R, the heteroatom in the 5-8 membered heterocyclic group linked by the methylene group is selected from N, and the number of heteroatoms is 1 or 2; undefined groups are as described in any embodiment of the present invention.

[0010] According to an embodiment of the present invention, in the compound shown in Formula I, in L1, the heteroatom in the heterochain is selected from one or two of N and O, and the number of heteroatoms is 1-8. Undefined groups are as described in any embodiment of the present invention.

[0011] According to an embodiment of the present invention, in the compound shown in Formula I, the number of heteroatoms in the heterochain in L1 can be 1, 2, 3, 4, 5, 6, 7, 8, or a range consisting of any of the above values.

[0012] According to an embodiment of the present invention, in the compound shown in Formula I, L1, the main chain of the carbon chain has 3-8 carbon atoms; undefined groups are as described in any embodiment of the present invention.

[0013] According to an embodiment of the present invention, in the compound shown in Formula I, the number of carbon atoms in the main chain of the carbon chain in L1 can be 3, 4, 5, 6, 7, 8, or a range consisting of any of the above values.

[0014] According to an embodiment of the present invention, in the compound shown in Formula I, L1, the total number of carbon atoms and heteroatoms in the main chain of the heterochain is 5-25; undefined groups are as described in any embodiment of the present invention.

[0015] According to an embodiment of the present invention, in the compound shown in Formula I, in L1, the total number of carbon atoms and heteroatoms in the main chain of the heterochain is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or a range consisting of any of the above values.

[0016] According to an embodiment of the present invention, in the compound shown in Formula I, L1, the main chain of the heterochain contains a 5-6 membered heterocyclic group; undefined groups are as described in any embodiment of the present invention.

[0017] According to embodiments of the present invention, in the compound shown in Formula I, L2, the amino acid chain includes at least two of arginine or a derivative thereof, glycine or a derivative thereof, lysine or a derivative thereof, glutamic acid or a derivative thereof, serine or a derivative thereof, alanine or a derivative thereof, tyrosine or a derivative thereof, aspartic acid or a derivative thereof, histidine or a derivative thereof, phenylalanine or a derivative thereof, and threonine or a derivative thereof; undefined groups are as described in any embodiment of the present invention.

[0018] According to embodiments of the present invention, in the compound shown in Formula I, L2, the amino acid chain includes at least two of the following: arginine or a derivative thereof, glycine or a derivative thereof, lysine or a derivative thereof, glutamic acid or a derivative thereof, serine or a derivative thereof, alanine or a derivative thereof, tyrosine or a derivative thereof, aspartic acid or a derivative thereof, histidine or a derivative thereof, phenylalanine or a derivative thereof, and threonine or a derivative thereof; undefined groups are as described in any embodiment of the present invention.

[0019] According to embodiments of the present invention, in the compound shown in Formula I, the chelating agent in Z is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazononon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7-triazacyclononane Alkane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxy-Do3A), p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), (R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-hydrazinopyridine-3-carboxylic acid (HYNIC), 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); undefined groups are as described in any of the embodiments of the present invention.

[0020] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a The substituted phenylene, wherein p is 1 or 2, and R a Independently selected from halogens, C 1-6 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0021] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a The substituted phenylene, wherein p is 1 or 2, and R a Independently selected from halogens, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0022] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a The substituted phenylene, wherein p is 1 or 2, and R a The group is independently selected from halogen, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of the present invention.

[0023] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a Substituted phenyl-5-6-membered heteroaryl, wherein p is 0 or 1, wherein R a Selected from halogens, C 1-6 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0024] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a Substituted phenyl-5-6-membered heteroaryl, wherein p is 0 or 1, wherein R a Selected from halogens, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0025] According to an embodiment of the present invention, in the compound shown in Formula I, when ring A is selected from p R a Substituted phenyl-5-6-membered heteroaryl, wherein p is 0 or 1, wherein R a Selected from halogens, methyl, ethyl, n-propyl, isopropyl; undefined groups are as described in any embodiment of the invention. According to an embodiment of the invention, in the compound of formula I, when R is selected from n R... b Replacement C 0-6 alkylamino group, wherein n is 0, 1 or 2, and R b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0026] According to an embodiment of the present invention, in the compound shown in Formula I, when R is selected from n R b Replacement C 0-6 alkylamino group, wherein n is 0, 1 or 2, and R b The groups are independently selected from oxo, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of this invention.

[0027] According to an embodiment of the present invention, in the compound shown in Formula I, when R is selected from n R b The substituted methylene-linked 5-8 membered heterocyclic group, wherein n is 0 or 1, and R b Selected from oxo groups; undefined groups are as described in any embodiment of this invention.

[0028] According to an embodiment of the present invention, in the compound shown in Formula I, when R is selected from n R b Replacement C 2-6 Imynylamino, wherein n is 0, 1 or 2, wherein R b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0029] According to an embodiment of the present invention, in the compound shown in Formula I, when R is selected from n R b Replacement C 2-6 Imynylamino, wherein n is 0, 1 or 2, wherein R b The groups are independently selected from oxo, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of this invention.

[0030] According to an embodiment of the present invention, in the compound shown in Formula I, when L1 is selected from q R c The substituted carbon chain, wherein q is 0 or 1, and R c Selected from oxo, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0031] According to an embodiment of the present invention, in the compound shown in Formula I, when L1 is selected from q R c The substituted carbon chain, wherein q is 0 or 1, and R c The radicals are selected from oxo, methyl, ethyl, n-propyl, and isopropyl; undefined radicals are as described in any embodiment of this invention.

[0032] According to an embodiment of the present invention, in the compound shown in Formula I, when L1 is selected from q R c The substituted heterochain, wherein q is 0, 1, 2, 3 or 4, wherein R c Selected from oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; undefined groups as described in any embodiment of the invention.

[0033] According to an embodiment of the present invention, in the compound shown in Formula I, when L1 is selected from q R c The substituted heterochain, wherein q is 0, 1, 2, 3 or 4, wherein R cThe radicals are selected from oxo, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-propyl, and haloisopropyl; undefined radicals are as described in any of the embodiments of this invention.

[0034] According to embodiments of the present invention, in the compound shown in Formula I, the 5-6 membered heteroaryl group in ring A is selected from pyridyl, furanyl, pyrroleyl, imidazolyl, thiopheneyl, or pyrimidinyl; undefined groups are as described in any embodiment of the present invention.

[0035] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 1-6 The alkylene group is selected from -CH2-, where n is 0 or 1, and R... b Independently selected from oxygen, C 1-3 alkyl.

[0036] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 0-6 The alkylene amino group is selected from -CH2-NH-, where n is 1 or 2, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0037] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 0-6 The alkylamino group is selected from -CH2-NH-, where n is 1 or 2, and R... b The groups are independently selected from oxo, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of this invention.

[0038] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 0-6 The alkylene amino group is selected from amino groups, where n is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0039] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 0-6 The alkylene amino group is selected from amino groups, where n is 0 or 1, and R... b Selected from methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any of the embodiments of this invention.

[0040] According to an embodiment of the present invention, in the compound shown in Formula I, the 5-8 membered heterocyclic group in R is selected from... , , , , Undefined groups are as described in any embodiment of this invention.

[0041] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 1 or 2, r is 0, 1, 2 or 3, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0042] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The alkynylamino group is selected from -C≡C-CH2-NH-, where n is 1 or 2, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0043] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The alkynylamino group is selected from -C≡C-CH2-NH-, where n is 1 or 2, and R... b The groups are independently selected from oxo, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of this invention.

[0044] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 0 or 1, r is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0045] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The ynylamino group is selected from -C≡C-NH-, where n is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0046] According to an embodiment of the present invention, in the compound shown in Formula I, R contains C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 0 or 1, r is 0 or 1, and R... b Selected from methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any of the embodiments of this invention.

[0047] According to an embodiment of the present invention, in the compound represented by Formula I, in L1, the carbon chain is selected from... , , Undefined groups are as described in any embodiment of this invention.

[0048] According to an embodiment of the present invention, in the compound represented by Formula I, in L1, the heterochain is selected from... , , , , , , , , , , , , , , , Undefined groups are as described in any embodiment of this invention.

[0049] According to embodiments of the present invention, the compound is a compound of Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula II.

[0050] R is selected from n R's. b Replacement C 1-6 Alkylene, C 0-6 alkyleneamine, C 2-6 The R group consists of an alkynylamino group, a 5-8 membered heteroaryl group linked to a methylene group, and -O-, -S-, or -NH-. b Independently selected from oxidized, halogenated, and C 1-6 Alkyl group; n is an integer selected from 0, 1, 2, or 3; L1 is selected from connectors, which are q R c The substituted carbon chain or heterochain, said R c Independently selected from oxidized, halogenated, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, carboxyl, hydroxyl; q is an integer selected from 0, 1, 2, 3, 4, 5; L2 is selected from an amino acid chain; Z is a chelating group derived from the chelating agent; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl; m is an integer selected from 0, 1, and 2.

[0051] According to an embodiment of the present invention, in the compound represented by Formula II, R1 is selected from halogens, C 1-3 Alkyl, C1-3 Halogenated alkyl, cyano, C 3-6 Cycloalkyl groups; undefined groups as described in any embodiment of the invention.

[0052] According to embodiments of the present invention, in the compound represented by Formula II, R1 is selected from halogen, methyl, ethyl, n-propyl, and isopropyl; undefined groups are as described in any embodiment of the present invention.

[0053] According to embodiments of the present invention, the compound is a compound of Formula III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula III.

[0054] R is selected from n R's. b Replacement C 1-6 Alkylene, C 0-6 alkyleneamine, C 2-6 The R group consists of an alkynylamino group, a 5-8 membered heterocyclic group linked to a methylene group, or -O-, -S-, -NH-. b Independently selected from oxidized, halogenated, and C 1-6 Alkyl group; n is an integer selected from 0, 1, 2, or 3; L1 is selected from connectors, which are q R c The substituted carbon chain or heterochain, said R c Independently selected from oxidized, halogenated, and C 1-6 Alkyl, C 1-6 Haloalkyl; q is an integer selected from 0, 1, 2, 3, 4, 5; L2 is selected from an amino acid chain; Z is a chelating group derived from the chelating agent.

[0055] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, R is selected from n R... b Replacement C 1-6 Alkylene, C 0-6 alkyleneamine, C 2-6 The group consists of an alkynylamino group, a 5-8 membered heterocyclic group linked to a methylene group, or a -O-, -S-, or -NH- group, wherein the heteroatom in the 5-8 membered heterocyclic group linked to the methylene group is selected from N, and the number of heteroatoms is 1 or 2. The R group... b Independently selected from oxidized, halogenated, and C 1-6 Alkyl group; n is an integer selected from 0, 1, 2, 3; undefined groups are as described in any embodiment of the present invention.

[0056] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, L1 is selected from linkers, said linkers being formed by q R cThe substituted carbon chain or heterochain, wherein the heteroatoms in the heterochain are selected from one or two types of N and O, and the number of heteroatoms is 1-8, and the number of carbon atoms in the main chain of the carbon chain is 3-8; the R c Independently selected from oxidized, halogenated, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, carboxyl, hydroxyl; q is an integer selected from 0, 1, 2, 3, 4, 5; undefined groups are as described in any embodiment of the present invention.

[0057] According to embodiments of the present invention, in the compounds shown in Formula II or Formula III, L2 is selected from an amino acid chain, said amino acid chain including at least two of the following: arginine or a derivative thereof, glycine or a derivative thereof, lysine or a derivative thereof, glutamic acid or a derivative thereof, serine or a derivative thereof, alanine or a derivative thereof, tyrosine or a derivative thereof, aspartic acid or a derivative thereof, histidine or a derivative thereof, phenylalanine or a derivative thereof, and threonine or a derivative thereof; undefined groups are as described in any embodiment of the present invention.

[0058] According to embodiments of the present invention, in the compounds shown in Formula II or Formula III, in R, the heteroatom in the 5-8 membered heterocyclic group linked by the methylene group is selected from N, and the number of heteroatoms is 1 or 2; undefined groups are as described in any embodiment of the present invention.

[0059] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, in L1, the heteroatoms in the heterochain are selected from one or two of N and O; undefined groups are as described in any embodiment of the present invention.

[0060] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, in L1, the main chain of the carbon chain has 3-8 carbon atoms; undefined groups are as described in any embodiment of the present invention.

[0061] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, in L1, the total number of carbon atoms and heteroatoms in the main chain of the heterochain is 5-25; undefined groups are as described in any embodiment of the present invention.

[0062] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, L1 contains a 5-6 membered heterocyclic group in the main chain of the heterochain; undefined groups are as described in any embodiment of the present invention.

[0063] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when R is selected from n R b Replacement C 1-6 Alkylene, wherein n is 0, 1 or 2, wherein Rb Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0064] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when R is selected from n R b Replacement C 0-6 alkylamino group, wherein n is 0, 1 or 2, and R b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0065] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 1-6 The alkylene group is selected from -CH2-, where n is 0 or 1, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0066] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 0-6 The alkylamino group is selected from -CH2-NH-, where n is 1 or 2, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0067] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 0-6 The alkylene amino group is selected from amino groups, where n is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0068] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when R is selected from n R... b The substituted methylene-linked 5-8 membered heterocyclic group, wherein n is 0 or 1, and R b Selected from oxo groups; undefined groups are as described in any embodiment of this invention.

[0069] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when R is selected from n R... b Replacement C 2-6 Imynylamino, wherein n is 0, 1 or 2, wherein R b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0070] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 1 or 2, r is 0, 1, 2 or 3, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0071] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 2-6 The imine-alkynylamino group is selected from -C≡C-CH2-NH-, where n is 1 or 2, and R... b Independently selected from oxygen, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0072] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 0 or 1, r is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0073] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when C 2-6 The ynylamino group is selected from -C≡C-NH-, where n is 0 or 1, and R... b Selected from C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0074] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when L1 is selected from q R c The substituted carbon chain, wherein q is 0 or 1, and R c Selected from oxo, C 1-3 Alkyl groups; undefined groups as described in any embodiment of the invention.

[0075] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, when L1 is selected from q R c The substituted heterochain, wherein q is 0, 1, 2, 3 or 4, wherein R c Selected from oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; undefined groups as described in any embodiment of the invention.

[0076] According to embodiments of the present invention, in the compounds represented by Formula II or Formula III, the 5-8 membered heterocyclic group in R is selected from... , , , , Undefined groups are as described in any embodiment of this invention.

[0077] According to embodiments of the present invention, in the compound represented by Formula II or Formula III, in L1, the carbon chain is selected from... , , Undefined groups are as described in any embodiment of this invention.

[0078] According to embodiments of the present invention, in the compound represented by Formula II or Formula III, in L1, the heterochain is selected from... , , , , , , , , , , , , , , , Undefined groups are as described in any embodiment of this invention.

[0079] According to embodiments of the present invention, the compound is a compound of Formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula IV.

[0080] L2 is selected from an amino acid chain; L3 is selected from chemical bonds or by t R. d The substituted heterochain, wherein the heteroatoms in the heterochain are N or O, and the R d Independently selected from oxidative oxidation; q is an integer selected from 0, 1, and 2; Z is a chelating group derived from the chelating agent.

[0081] It should be noted that when L3 is selected from chemical bonds, L2 is directly connected to -C(=O)-.

[0082] According to embodiments of the present invention, in the compound shown in Formula IV, in L2, the amino acid chain includes at least two of arginine or a derivative thereof, glycine or a derivative thereof, lysine or a derivative thereof, glutamic acid or a derivative thereof, serine or a derivative thereof, alanine or a derivative thereof, tyrosine or a derivative thereof, aspartic acid or a derivative thereof, histidine or a derivative thereof, phenylalanine or a derivative thereof, and threonine or a derivative thereof; undefined groups are as described in any embodiment of the present invention.

[0083] According to embodiments of the present invention, in the compound shown in Formula IV, L2, the amino acid chain includes at least two of the following: arginine or a derivative thereof, glycine or a derivative thereof, lysine or a derivative thereof, glutamic acid or a derivative thereof, serine or a derivative thereof, alanine or a derivative thereof, tyrosine or a derivative thereof, aspartic acid or a derivative thereof, histidine or a derivative thereof, phenylalanine or a derivative thereof, and threonine or a derivative thereof; undefined groups are as described in any embodiment of the present invention.

[0084] According to embodiments of the present invention, in the compounds shown in Formula II, Formula III, or Formula IV, in Z, the chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid (DOTAGA), 1,4,7-triazacyclononanephosphonic acid (TRAP), 1,4,7- Triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphonic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecano-1(15),11,13-trien-3,6,9-triacetic acid (PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (O-Do3A), p-isocyanothiobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isocyanothiobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isocyanothiobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isocyanothiobenzyl-DTPA (MX-DTPA), (R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), 6-hydrazinopyridine-3-carboxylic acid (HYNIC), 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA); undefined groups are as described in any of the embodiments of the present invention.

[0085] According to embodiments of the present invention, in the compounds represented by Formula I, Formula II, or Formula III, R is selected from... , , , -NH- , , -O-, -S-; undefined groups are as described in any embodiment of this invention.

[0086] According to embodiments of the present invention, in the compounds represented by Formula I, Formula II, or Formula III, L1 is selected from... , , , , , , , , , , , , , , , , , , , , Undefined groups are as described in any embodiment of this invention.

[0087] According to embodiments of the present invention, in the compounds shown in Formula I, Formula II, Formula III or Formula IV, L2 is selected from... , , , , , , , , , , , , Undefined groups are as described in any embodiment of this invention.

[0088] According to embodiments of the present invention, in the compounds shown in Formula I, Formula II, Formula III or Formula IV, Z is selected from... , , , , , , , Undefined groups are as described in any embodiment of this invention.

[0089] According to embodiments of the present invention, the compound represented by Formula I, Formula II, Formula III, or Formula IV, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound represented by Formula I, Formula II, Formula III, or Formula IV, may be any of the following compounds or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0090] According to embodiments of the present invention, the compound represented by Formula I, Formula II, Formula III, or Formula IV, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound represented by Formula I, Formula II, Formula III, or Formula IV, may be any of the following compounds or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs of any of the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0091] In a second aspect of the invention, a complex is provided. According to an embodiment of the invention, the complex is formed by complexing the compound described in the first aspect, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs, with M; wherein M is selected from at least one of radionuclides or non-radioactive elements.

[0092] According to an embodiment of the present invention, the radionuclide is selected from at least one of diagnostic radionuclides or therapeutic radionuclides.

[0093] According to an embodiment of the present invention, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb、 86 Y.

[0094] According to an embodiment of the present invention, the therapeutic radionuclide is selected from... 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac、 227 Th.

[0095] According to an embodiment of the present invention, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc, 177 Lu、 225 Ac、 161 Tb.

[0096] According to an embodiment of the present invention, the radionuclide 18 F is through 18 FAl is formed by complexing the compound with the compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

[0097] According to an embodiment of the present invention, M is complexed with a chelating group in the compound or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound.

[0098] In a third aspect, the present invention provides a pharmaceutical composition. According to embodiments of the invention, the pharmaceutical composition comprises the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or a complex described in the second aspect.

[0099] According to embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0100] In a fourth aspect of the invention, the invention provides for the use of the compound of the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex of the second aspect, or a pharmaceutical composition of the third aspect, in the preparation of a medicament for the diagnosis and / or treatment of a disease characterized by overexpression of neurotensin receptor 1.

[0101] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0102] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0103] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0104] According to an embodiment of the present invention, the disease is selected from at least one of tumors, neuropsychiatric diseases, metabolic diseases, and cardiovascular diseases.

[0105] According to an embodiment of the present invention, the disease is selected from at least one of colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, and breast cancer.

[0106] In a fifth aspect, the present invention provides a method for imaging tissue expressing neurotensin receptor 1. According to embodiments of the invention, the method comprises: administering to the tissue a compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex described in the second aspect, or a pharmaceutical composition described in the third aspect, and imaging the tissue after administration.

[0107] According to an embodiment of the present invention, the imaging is performed by positron emission tomography or single-photon emission computed tomography.

[0108] In a sixth aspect of the invention, a method for diagnosing and / or treating a disease characterized by overexpression of neurotensin receptor 1 is provided. According to embodiments of the invention, the method comprises administering to a patient a pharmaceutically acceptable dose of the compound of the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or the complex of the second aspect, or the pharmaceutical composition of the third aspect.

[0109] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0110] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0111] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0112] According to an embodiment of the present invention, the disease is selected from at least one of tumors, neuropsychiatric diseases, metabolic diseases, and cardiovascular diseases.

[0113] According to an embodiment of the present invention, the disease is selected from at least one of colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, and breast cancer.

[0114] In a seventh aspect of the invention, the invention provides for the use of the compound described in the first aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a complex described in the second aspect, or a pharmaceutical composition described in the third aspect, in the diagnosis and / or treatment of diseases characterized by overexpression of neurotensin receptor 1.

[0115] According to an embodiment of the present invention, the diagnostic method is selected from radionuclide imaging.

[0116] According to an embodiment of the present invention, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography.

[0117] According to an embodiment of the present invention, the treatment is selected from radiotherapy.

[0118] According to an embodiment of the present invention, the disease is selected from at least one of tumors, neuropsychiatric diseases, metabolic diseases, and cardiovascular diseases.

[0119] According to an embodiment of the present invention, the disease is selected from at least one of colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, and breast cancer.

[0120] Beneficial effects: 1. High selectivity and targeting The compounds of this invention exhibit high selectivity and targeting, precisely recognizing and binding to the NTR1 receptor while reducing cross-reactivity with non-target tissues (such as NTR2, NTR3, or other GPCR family receptors). This high selectivity not only improves the therapeutic effect of the drug but also significantly reduces side effects, providing patients with greater safety.

[0121] 2. Strong diagnostic and therapeutic effects The radionuclide-labeled NTR1 receptor-targeting drugs of this invention can be used not only for treatment but also for disease diagnosis and staging. For example, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) imaging techniques can be used to monitor the expression level and distribution of NTR1 receptors in tumors or other lesions in real time, providing important evidence for precision medicine. Simultaneously, the therapeutic effects of radionuclides (such as β or α particle radiation) can directly kill tumor cells with high NTR1 receptor expression, achieving integrated diagnosis and treatment (i.e., "therapeutic integration").

[0122] 3. Good drug stability and bioavailability This invention significantly improves drug stability and bioavailability by optimizing the binding mechanism between radionuclides and ligands, as well as the drug delivery system. Radionuclide-labeled ligands exhibit longer half-lives and higher target tissue uptake rates in vivo, thereby enhancing the therapeutic effect of the drug.

[0123] 4. Potential for personalized treatment Because the expression level of the NTR1 receptor varies across different diseases and individuals, the drug developed in this invention can be individually dosed based on the patient's NTR1 receptor expression status. By using imaging technology to monitor drug distribution and treatment efficacy in real time, doctors can dynamically adjust treatment plans, achieving precise and personalized treatment.

[0124] 5. Reduce treatment costs and resource waste Through its integrated diagnostic and therapeutic design, the drug of this invention can achieve both diagnosis and treatment in a single administration, reducing the need for multiple examinations and treatments for patients and lowering medical costs. Furthermore, precise targeting reduces drug waste and damage to normal tissues, further improving the economy and sustainability of treatment.

[0125] 6. Higher targeting and affinity The drug of this invention achieves a significantly higher binding affinity for NTR1 by optimizing the ligand structure, which is superior to existing drugs. This higher affinity allows the drug to more precisely target NTR1-positive tumor cells, reduce uptake by non-target tissues, thereby improving therapeutic efficacy and reducing side effects.

[0126] 7. Broader indications The drug of this invention is not only applicable to tumor types with high NTR1 expression, such as pancreatic cancer and colorectal cancer, but its effectiveness in various other solid tumors, such as head and neck squamous cell carcinoma and breast cancer, has also been verified through preclinical studies. This gives the invention broader potential for clinical application.

[0127] 8. Higher antitumor activity In various tumor xenograft models, the radiopharmaceutical of this invention exhibited significant antitumor activity. Compared with existing drugs, it achieved a higher tumor shrinkage rate and prolonged the survival of model animals at the same dose.

[0128] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0129] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 1 according to an embodiment of the present invention; Figure 2 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 1 according to an embodiment of the present invention; Figure 3This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 2 according to an embodiment of the present invention; Figure 4 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 2 according to an embodiment of the present invention; Figure 5 This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 3 according to an embodiment of the present invention; Figure 6 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 3 according to an embodiment of the present invention; Figure 7 This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 4 according to an embodiment of the present invention; Figure 8 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 4 according to an embodiment of the present invention; Figure 9 This is a graph showing the LCMS (liquid chromatography-mass spectrometry) detection results of compound 5 according to an embodiment of the present invention; Figure 10 This is a chromatogram of the HPLC (high performance liquid chromatography) detection results of compound 5 according to an embodiment of the present invention; Figure 11 Compound 1 according to an embodiment of the present invention is used. 68 Image of radioactive thin-layer chromatography scan results after Ga radiolabeling; Figure 12 Compound 2 according to an embodiment of the present invention is used. 68 Image of radioactive thin-layer chromatography scan results after Ga radiolabeling; Figure 13 Compound 3 according to an embodiment of the present invention is used. 68 Image of radioactive thin-layer chromatography scan results after Ga radiolabeling; Figure 14 Compound 4 according to an embodiment of the present invention is used. 68 Image of radioactive thin-layer chromatography scan results after Ga radiolabeling; Figure 15 Compound 5 according to an embodiment of the present invention is used. 68 Image of radioactive thin-layer chromatography scan results after Ga radiolabeling; Figure 16 Compound 1 according to an embodiment of the present invention is used. 18 HPLC test results after F radioactive labeling; Figure 17 Compound 2 according to an embodiment of the present invention is used. 177 Image of radioactive thin-layer chromatography scan after Lu radiolabeling; Figure 18 Compound 3 according to an embodiment of the present invention is used. 177 HPLC test results after Lu radiolabeling; Figure 19 Compound 5 according to an embodiment of the present invention is used. 177 Image of radioactive thin-layer chromatography scan after Lu radiolabeling; Figure 20 Different time intervals after drug administration according to embodiments of the present invention 68 PET / CT imaging results of Ga-compound 1 on HT29 model mice; Figure 21 Different time intervals after drug administration according to embodiments of the present invention 68 Figure 1 shows the uptake of Ga-compound 1 in different tissues of HT29 model mice; Figure 22 Different time intervals after drug administration according to embodiments of the present invention 68 PET / CT imaging results of Ga-compound 2 on HT29 model mice; Figure 23 Different time intervals after drug administration according to embodiments of the present invention 68 Figure 1. Uptake of Ga-compound 2 in different tissues of HT29 model mice; Figure 24 Different time intervals after drug administration according to embodiments of the present invention 18 PET / CT imaging results of compound F-1 on HT29 model mice; Figure 25 Different time intervals after drug administration according to embodiments of the present invention 18 Figure 1 shows the uptake of F-compound 1 in different tissues of HT29 model mice; Figure 26 Different time intervals after drug administration according to embodiments of the present invention 68 PET / CT imaging results of Ga-compound 1 on AsPC-1 model mice; Figure 27 Different time intervals after drug administration according to embodiments of the present invention 68 Figure 1 shows the uptake results of Ga-compound 1 in different tissues of AsPC-1 model mice; Figure 28 Different time intervals after drug administration according to embodiments of the present invention 18 PET / CT imaging results of compound F1 on AsPC-1 model mice; Figure 29 Different time intervals after drug administration according to embodiments of the present invention 18 Figure 1 shows the uptake results of F-compound 1 in different tissues of AsPC-1 model mice; Figure 30 According to an embodiment of the present invention 68 Ga-compound 1 and 68 Distribution of Ga-compound 2 in HT29 model ex vivo tissues 1 hour and 4 hours after administration; Figure 31 According to the embodiments of the present invention 177 Distribution of Lu-compound 2 in HT29 model ex vivo tissues 4 hours, 24 hours and 48 hours after administration; Figure 32 According to the embodiments of the present invention 177 Distribution of Lu-compound 5 in ex vivo tissues of the AsPC-1 model 4 hours, 24 hours and 48 hours after administration. Detailed Implementation

[0130] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0131] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0132] To facilitate understanding of the invention, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0133] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0134] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0135] Terms and Definitions Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures shall fall within the scope of this application specification.

[0136] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have one substituent at each substituted position of the group. When more than one position in a given structural formula can be replaced by one or more substituents selected from a specific group, then the substituents may be substituted at each substituted position in the same or different ways.

[0137] The term "unsubstituted" means that the specified group does not have substituents.

[0138] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that the hydrogen atoms in the given structure are not substituted or that one or more hydrogen atoms are substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.

[0139] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0140] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR, and UV / Vis spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the descriptions of this application. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on the descriptions in several summary and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0141] When a substituent is described using a conventional chemical formula written from left to right, that substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, CH2O is equivalent to OCH2. As used herein, or Indicates the linking site of a functional group.

[0142] Unless otherwise specified, use wedge-shaped solid line keys ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, using a straight solid line key ( ) and straight dashed key ( ) indicates the relative configuration of the center of the solid.

[0143] The numerical ranges described in this application specification and claims, when interpreted as "integers," should be understood to include both endpoints of the range and every integer within that range. For example, "integers from 1 to 6" should be understood to include every integer of 1, 2, 3, 4, 5, and 6. When the numerical range is interpreted as "numbers," it should be understood to include both endpoints of the range, every integer within that range, and every decimal within that range. For example, "numbers from 1 to 10" should be understood to include not only every integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9.

[0144] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0145] Depending on the choice of raw materials and methods, the compounds of the present invention can exist as one or a mixture of possible isomers, for example as purely optical isomers, or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are symbols used to specify the plane-polarized rotation induced by the compound, where (–) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0146] When the bonds of the chiral carbon in the formulas of this invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the resulting enantiomerically pure compounds and mixtures thereof are included within the scope of the general formula. The illustration of racemic or enantiomerically pure compounds in this document is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. The absolute configuration of a stereocenter is represented by wedge-shaped and dashed bonds.

[0147] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0148] The term "solvent" refers to a compound of the present invention or a salt thereof comprising a stoichiometric or nonstoichiometric solvent bound by intermolecular noncovalent forces, and a hydrate when the solvent is water.

[0149] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0150] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0151] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts. These may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts, or may be used for the identification, characterization, or purification of the compounds of the present invention.

[0152] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of the present invention are prepared by modifying functional groups in the compound; this modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group within the compound of the present invention. When a prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0153] The term "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0154] The term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0155] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0156] In this document, the term "treatment" refers to the use of a drug to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in individuals susceptible to disease but not yet diagnosed with it; (b) suppression of disease, such as inhibiting disease progression; or (c) alleviating disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any use of a drug to treat, cure, alleviate, improve, reduce, or suppress a disease in an individual, including but not limited to the administration of the drugs described herein to individuals in need.

[0157] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0158] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.

[0159] For pharmaceuticals or pharmacologically active agents, the terms "effective dose," "effective amount," or "therapeutic effective amount" refer to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0160] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium. 2 H), tritium ( 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0161] Term "C" 1-6 "Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. Such alkyl groups are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and 2-ethylbutyl. 1-Ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. In particular, the group has 1, 2, or 3 carbon atoms (“C1-C3 alkyl”), such as methyl, ethyl, n-propyl, or isopropyl. “Alkylene” refers to a divalent saturated aliphatic hydrocarbon group formed by removing two hydrogen atoms from the same carbon atom of an alkane, with the general formula -C n H 2n -

[0162] Term "C" 3-6 "Cycloalkyl" should be understood as referring to a saturated monovalent monocyclic, bicyclic, or bridged ring hydrocarbon ring having 3-6 carbon atoms, including fused or bridged polycyclic systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, and bicyclo[3.1.0]hexane.

[0163] The term "oxo" refers to =O. When oxo is a substitution on the carbon chain, they together form the carbonyl moiety [-C(=O)-]. When oxo is a substitution on the ring, one or more atoms on the ring are replaced by -C(O)-, such as the 2-pyridone group.

[0164] The term "5-6 membered heteroaryl" should be understood as referring to a monovalent monocyclic aromatic ring group having 5-6 ring atoms and containing 1-5 heteroatoms independently selected from N, O, and S. Examples of 5-6 membered heteroaryl groups include, but are not limited to, furanyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isozolyl, oxazolyl, diazolyl, imidazoleyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.

[0165] The terms "halogen" or "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0166] The term "haloalkyl" refers to a saturated aliphatic hydrocarbon group (such as -CvFw, where v = 1 to 3 and w = 1 to (2v+1)) that has a specific number of carbon atoms and is substituted with one or more halogens, and is either branched or straight-chain. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.

[0167] The term "heterocyclic group" should be understood to refer to a saturated heterocyclic compound having 5-8 ring atoms, with 5-6 ring atoms containing 1-5 heteroatoms independently selected from N, O and S.

[0168] The term "alkynylamino" refers to an organic group containing an alkynyl group (-C≡C) and an amino group (-NH₂ or -NH⁻), wherein the alkynyl group and the amino group are linked by a carbon chain or other linkage. For example, when the structure of a C2 alkynylamino group is -C≡C-NH⁻, the structure of a C3 alkynylamino group can be -C≡C-CH₂-NH⁻ or -CH₂-C≡C-NH⁻, and the structure of a C4 alkynylamino group can be -C≡C-CH₂-CH₂-NH⁻. The term "imynylamino" refers to an organic group containing an imynylyl group (-C≡C-) and an amino group (-NH₂ or -NH⁻), wherein the alkynyl group and the amino group are linked by a carbon chain or other linkage.

[0169] The term "alkylamino" refers to a substance containing an alkyl group (-C). n H 2n+1Alkylamino groups (i.e., saturated hydrocarbon groups) and amino groups (-NH2 or -NH-). For example, the structure of a C0 alkylamino group is -NH-, the structure of a C1 alkylamino group is -CH2-NH-, and the structure of a C2 alkylamino group can be -CH2-CH2-NH-, etc. The term "alkyleneamino" refers to a group containing an alkylene group (-C...). n H 2n -) and amino (-NH2 or -NH-) groups.

[0170] The term "amino acid chain" refers to a linear chain structure formed by the condensation of one or more identical or different amino acid units (natural amino acids and / or non-natural amino acids) through peptide bonds (amide bonds). The types, numbers, and connection order of the amino acid residues may be the same or different.

[0171] The term "natural amino acids" refers to the 20 α-amino acids that are widely found in nature and participate in the formation of natural proteins. These include glycine (Gly), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), serine (Ser), threonine (Thr), cysteine ​​(Cys), methionine (Met), asparagine (Asn), glutamine (Gln), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), and proline (Pro).

[0172] The term "non-natural amino acid" refers to amino acids other than the 20 α-amino acids that constitute natural proteins, or their derivatives. These derivatives include compounds obtained by alkylation, acetylation, sulfonation, phosphorylation, hydroxylation, and nitration. They also include D-isomers of natural amino acids, derivatives with substituted, modified, extended, or shortened side chains, amino acids with substituents introduced on their carbon skeletons, non-α-amino acids such as β-amino acids and γ-amino acids, as well as artificially synthesized amino acids such as cyclic amino acids, N-substituted amino acids, and C-substituted amino acids, and rare amino acids that exist in nature but do not participate in the formation of natural proteins.

[0173] The term "amino acid residue" refers to the group obtained by subtracting a water molecule from the original amino acid structure after the amino acid molecule forms a peptide bond through dehydration condensation. The term "amino acid or its derivative compound residue" refers to the group obtained by subtracting a water molecule from the original amino acid or its derivative compound structure after the amino acid or its derivative compound molecule forms a peptide bond through dehydration condensation.

[0174] The compounds and preparation methods of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the content of the present invention are covered within the scope of protection intended by the present invention.

[0175] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples are all commercially available.

[0176] The full names of the chemical substances used in this embodiment are shown in Table 1: Table 1: Compound Abbreviations and Corresponding Full Names

[0177] The following peptides were used in the synthesis of polypeptides: Fmoc-D-Lys(Dde)-OH (CAS: 333973-51-6), Fmoc-D-Tyr(tBu)-OH (CAS: 118488-18-9), Fmoc-D-Lys(Alloc)-OH (CAS: 214750-75-1), Fmoc-D-Glu(tBu)-OH (CAS: 104091-08-9), Fmoc-2-Nal-OH (CAS: 112883-43-9), Fmoc-D-Lys(Alloc)-OH (CAS: 214750-75-1), BOC-D-Glu(OtBu)-OH (CAS: 104719-63-3), Nota(OtBu*2), and Fmoc-PEG4-propionic. Fmoc-D-Arg(Pbf)-OH (CAS: 187618-60-6), Fmoc-Gly-OH (CAS: 29022-11-5), Fmoc-Phe-OH (CAS: 35661-40-6), Fmoc-Gly-Gly-OH (CAS: 35665-38-4), and DOTA(OtBu*3) are all available for purchase. The structures of Fmoc-D-Lys(Dde)-OH, Fmoc-D-Tyr(tBu)-OH, Fmoc-D-Lys(Alloc)-OH, Fmoc-D-Glu(tBu)-OH, Fmoc-2-Nal-OH, Nota(OtBu*2), and DOTA(OtBu*3) are as follows: , , , , , , .

[0178] Example 1: Synthesis of the compound 1. Synthesis of Compound 1

[0179] Step 1:

[0180] Compound 1b (3.18 mmol, 1.00 eq) was dissolved in DMF (13.5 mL), and HOBt (4.77 mmol, 1.50 eq), EDCI (4.77 mmol, 1.50 eq), DIEA (1.57 mL, 3.00 eq), and compound 2b (5.08 mmol, 1.60 eq, HCl) were added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was directly purified by reverse phase to give compound 3b (1.74 g, purity 99.8%).

[0181] Step Two:

[0182] Compound 3b (2.92 mmol, 1.00 eq) was dissolved in THF (18.0 mL), and LiOH•H2O (3.80 mmol, 1.30 eq) dissolved in H2O (18.0 mL) was added at 0 °C. The reaction mixture was stirred at 25 °C for 6 hours. The pH of the reaction mixture was adjusted to 2–3 with 1N HCl, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (20.0 mL), dried over Na2SO4, and concentrated by vacuum filtration to obtain the crude product. Compound 4b (972 mg) was prepared by reverse phase reaction.

[0183] Step 3:

[0184] Compound 4b (591 μmol, 1.00 eq) was dissolved in DMF (10.0 mL), and DIEA (293 μL, 3.00 eq) and HATU (710 μmol, 1.20 eq) were added. The reaction was stirred at 25 °C for 0.5 h. Then, compound 5b (1.18 mmol, 2.00 eq) was added to the reaction solution, and the reaction was stirred at 35 °C for 3 h. Compound 6b (360 mg) was prepared by reverse phase reaction.

[0185] Step Four:

[0186] Compound 6b (762 μmol, 1.00 eq) was dissolved in DMF (6.00 mL), and K₂CO₃ (1.52 mmol, 2.00 eq) and AllylBr (1.14 mmol, 1.50 eq) were added. The reaction was stirred at 25 °C for 2.5 h. The reaction was quenched with 20.0 mL of water, extracted with ethyl acetate, washed with brine (20.0 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated to dryness to give unpurified compound 7b (607 mg). This was used directly in the next reaction.

[0187] Step 5:

[0188] Compound 7b (761 μmol, 1.00 eq) was dissolved in DCM (3.00 mL), and TFA (3.00 mL, 53.0 eq) was added. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was then reacted with hydrochloric acid to prepare Int A (301 mg, purity 99.6%).

[0189] Step Six:

[0190] Peptide synthesis: The peptide was synthesized using standard Fmoc chemical methods, the specific process of which is as follows: 1) Weigh 0.15 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.15 mmol, 1.00 eq) into a reaction column. Add 20.0 mL of DCM, then add DIEA (0.60 mmol, 4.00 eq) dropwise. Purge the resin with nitrogen to ensure uniform bubbling. After reacting at 20 °C for 2 hours, add MeOH (1.00 mL) dropwise into the reaction column. Purge with nitrogen for 30 minutes, then purge until no liquid flows out. Add DMF to wash, then purge again until no liquid flows out.

[0191] 2) Deprotection: Add DMF (V:V) (20.0 mL) containing 20% ​​piperidine to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0192] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.45 mmol, 3.00 eq) and HBTU (0.42 mmol, 2.85 eq) into the above resin. Add 20.0 mL of DMF and then add DIEA (0.90 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20 °C for 45 minutes, remove the reaction solution, wash with DMF, and drain the waste until no liquid flows out.

[0193] Repeat steps 2) and 3) to condense the amino acids (1-4) in Table 2: Table 2: Amino Acids and Coupling Reagents

[0194] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0195] 4) Peptide cleavage: At room temperature, the dried resin was added to the prepared cleavage solution (containing 90.0% TFA, 2.5% H2O, 5.0% TIS and 2.5% 3-Mpr, 10.0 mL), and agitated with nitrogen for 1.5 hours. Frozen isopropyl ether was added to the reaction solution, and after centrifugation and precipitation, the unpurified compound 1 (140 mg) was obtained.

[0196] 5) Purification of peptides: The unpurified compound from the previous step was purified by preparative high performance liquid chromatography to obtain the final product, compound 1 (33.0 mg, purity 95.6%).

[0197] LCMS of compound 1 as follows Figure 1 As shown; HPLC of compound 1 as follows Figure 2 As shown.

[0198] 2. Synthesis of Compound 2

[0199] Synthesis process:

[0200] Peptide synthesis: The peptide was synthesized using standard Fmoc chemical methods, the specific process of which is as follows: 1) Weigh 0.10 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.10 mmol, 1.00 eq) into the reaction column. Add 10.0 mL of DCM, then add DIEA (0.40 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure the resin bulges evenly. After reacting at 20 °C for 2 hours, add MeOH (0.20 mL) dropwise into the reaction column. After purging with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0201] 2) Deprotection: Add 20.0 mL of DMF (V:V) containing 20% ​​piperidine to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the resin.

[0202] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.30 mmol, 3.00 eq) and HBTU (0.28 mmol, 2.85 eq) into the above resin. Add 10.0 mL of DMF, then add DIEA (0.60 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes. Remove the reaction solution, wash with DMF, and drain the waste until no liquid flows out.

[0203] Repeat steps 2-3 above to couple amino acids (1-5) in Table 3: Table 3: Amino Acids and Coupling Reagents

[0204] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0205] 4) Peptide cleavage: At room temperature, the dried resin was added to the prepared cleavage solution (containing 90% TFA, 2.5% H2O, 5% TIS and 2.5% 3-Mpr, 10 mL) and sonicated for 2 h. After filtration, the filtrate was added to ice-cold isopropyl ether for precipitation and centrifugation, and dried to obtain unpurified compound 2 (100 mg).

[0206] 5) Purification of peptide: The unpurified compound 2 from the previous step was purified by preparative high performance liquid chromatography to obtain the final product compound 2 (11.9 mg, purity: 97.1%).

[0207] LCMS of compound 2 as follows Figure 3 As shown; HPLC analysis of compound 2 Figure 4 As shown.

[0208] 3. Synthesis of Compound 3

[0209] Synthesis process:

[0210] Peptide synthesis: The peptide was synthesized using standard Fmoc chemical methods, the specific process of which is as follows: 1) Weigh 0.10 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.10 mmol, 1.00 eq) into the reaction column. Add 10.0 mL of DCM, then add DIEA (0.40 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure the resin bulges evenly. After reacting at 20 °C for 2 hours, add MeOH (0.20 mL) dropwise into the reaction column. After purging with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0211] 2) Deprotection: Add 20.0 mL (V:V) of DMF containing 20% ​​piperidine to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0212] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.30 mmol, 3.00 eq) and HBTU (0.28 mmol, 2.85 eq) into the above resin. Add 10.0 mL of DMF, then add DIEA (0.60 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes. Remove the reaction solution, wash with DM, and drain the waste until no liquid flows out.

[0213] Repeat steps 2-3 above to couple amino acids (1-8) in Table 4: Table 4: Amino Acids and Coupling Reagents

[0214] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0215] 4) Peptide cleavage: At room temperature, the dried resin was added to the prepared cleavage solution (containing 90% TFA, 2.5% H2O, 5% TIS and 2.5% 3-Mpr, 10 mL), sonicated for 2 h, filtered, and the filtrate was added to ice-cold isopropyl ether for precipitation and centrifugation. The filtrate was dried to obtain unpurified compound 3 (200 mg).

[0216] 5) Purification of peptide: The unpurified compound 3 from the previous step was purified by preparative high performance liquid chromatography to obtain the final product compound 3 (16.0 mg, purity: 95.7%).

[0217] LCMS of compound 3 as follows Figure 5 As shown; HPLC analysis of compound 3, such as Figure 6 As shown.

[0218] 4. Synthesis of Compound 4

[0219] Synthesis process:

[0220] Peptide synthesis: The peptide was synthesized using standard Fmoc chemical methods, the specific process of which is as follows: 1) Weigh 0.10 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.10 mmol, 1.00 eq) into a reaction column. Add 10.0 mL of DCM, then add DIEA (0.40 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20 °C for 2 hours, add MeOH (1.00 mL) dropwise into the reaction column. After agitating with nitrogen for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0221] 2) Deprotection: Add 10.0 mL (V:V) of DMF containing 20% ​​piperidine to the resin and agitate under nitrogen for 15 minutes. Wash the resin and dry it to obtain the final resin.

[0222] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.30 mmol, 3.00 eq) and HATU (0.28 mmol, 2.85 eq) into the above resin. Add 10.0 mL of DMF and then add DIEA (0.30 mmol, 3.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 30 minutes, then remove the reaction solution, add DMF to wash, and discharge waste until no liquid flows out.

[0223] Repeat steps 2-3 above to couple amino acids (1-7) in Table 5: Table 5: Amino Acids and Coupling Reagents

[0224] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0225] 4) Peptide cleavage: At room temperature, the dried resin was added to the prepared cleavage solution (containing 92.5% TFA, 2.5% H2O, 2.5% TIS and 2.5% 3-Mpr, 10 mL), and cleaved for 2 hours. After filtration, unpurified compound 4 (150 mg) was obtained.

[0226] 5) Purification of peptide: The unpurified compound 4 from the previous step was purified by preparative high performance liquid chromatography to obtain the final product compound 4 (13.50 mg, purity: 98.1%).

[0227] LCMS of compound 4, such as Figure 7 As shown; HPLC analysis of compound 4, such as Figure 8 As shown.

[0228] 5. Synthesis of Compounds

[0229] Synthesis process:

[0230] Peptide synthesis: The peptide was synthesized using standard Fmoc chemical methods, the specific process of which is as follows: 1) Weigh 0.15 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-D-Lys(Dde)-OH (0.15 mmol, 1.00 eq) into a reaction column. Add 20.0 mL of DCM, then add DIEA (0.60 mmol, 4.00 eq) dropwise. Adjust the nitrogen atmosphere to ensure uniform resin agitation. After reacting at 20 °C for 2 hours, add MeOH dropwise into the reaction column. After a nitrogen atmosphere for 30 minutes, purge the column until no liquid flows out. Add DMF to wash the column, then purge again until no liquid flows out.

[0231] 2) Deprotection: Add 20.0 mL (V:V) of DMF containing 20% ​​piperidine to the resin and agitate under nitrogen for 15 minutes. Wash the resin with DMF and dry it to obtain the final resin.

[0232] 3) Coupling of amino acids: Weigh Fmoc-D-Tyr(tBu)-OH (0.45 mmol, 3.00 eq) and HBTU (0.42 mmol, 2.85 eq) into the above resin. Add 20.0 mL of DMF, then add DIEA (0.90 mmol, 6.00 eq) dropwise into the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin agitation. React at 20 °C for 45 minutes. Remove the reaction solution, wash with DMF, and drain the waste until no liquid flows out.

[0233] Repeat steps two and three to condense the amino acids (1-6) in Table 6: Table 6: Amino Acids and Coupling Reagents

[0234] Shrink the resin with MeOH, discharge the waste until no more liquid flows out, pour out the resin and dry it for later use.

[0235] 4) Peptide cleavage: At room temperature, the dried resin was added to the prepared cleavage solution (containing 90.0% TFA, 2.5% H2O, 0.0% TIS and 2.5% 3-Mpr, 10.0 mL) and reacted for 1.5 hours. Frozen isopropyl ether was added to the reaction solution, and the mixture was centrifuged, precipitated and dried to obtain unpurified compound 5 (140 mg, crude product).

[0236] 5) Purification of peptide: The unpurified compound 5 from the previous step was purified by preparative high performance liquid chromatography to obtain the final product compound 5 (13.0 mg, purity: 95.1%).

[0237] LCMS of compound 5 as follows Figure 9 As shown; HPLC analysis of compound 5, such as Figure 10 As shown.

[0238] Example 2: Radioactive Labeling 1. 68 Labeling process of Ga-compounds 1-5 Add 1 mL of sodium acetate / acetic acid buffer solution (pH=7.2) to a vial, then add 60 μL of aqueous solution of the precursor of compounds 1-5 (containing 60 μg), mix thoroughly, and add 1 mL of... 68 The reaction solution of GaCl3 in 0.1M hydrochloric acid was reacted at a specific temperature. The reaction was then terminated, and the solution was purified using a C18 column. The C18 column was washed with 1 mL of 70% ethanol, and the eluent was collected into a vial. The eluent was then diluted with 6 mL of physiological saline and filtered through a sterile membrane into a sterile vacuum bottle. Sampling and testing. The radiochemical purity of the product was determined by Radio-iTLC, as shown in Table 7. 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4 and 68 The radiometric thin-layer chromatography (TLC) results of Ga-compound 5 are shown in the figure below. Figure 11-15 As shown.

[0239] Table 7: Labeling results of compounds 1-4

[0240] 2. 18 F-compound 1 labeling process Add 3.6 mL of DMSO solution, 27 μL of AlCl3, 5 μL of glacial acetic acid, and 20 μL of an aqueous solution of precursor compound 1 (containing 100 μg of precursor compound 1) to a vial and then add to the reaction flask. Shake well. Take a certain amount of the generated fluorine... 18The F] aqueous solution was taken out and its radioactivity was measured using an activity meter, and the result was recorded as the reaction activity value of the experiment (fluorine [ 18 [F] aqueous solution can be produced by a cyclotron (F) to fluorine [ 18 The F] aqueous solution was added to the pretreated QMA column, followed by elution with 0.5 mL of physiological saline. The eluent flowed directly into the reaction flask, which was then capped with a rubber stopper. The reaction flask was placed at 80°C for 15 min. After cooling to room temperature, the reaction solution was diluted with sterile water for injection and purified using a C18 column. The eluent was discarded, and the C18 column was slowly eluted with 1.5 mL of 70% ethanol solution. The eluent was collected into the product bottle, diluted with 9 mL of physiological saline, and filtered through a sterile membrane into a sterile vacuum bottle. Samples were taken for testing, and the radiochemical purity of the product was determined to be 99.95% by HPLC. Figure 16 As shown.

[0241] 3. 177 Lu-compound 2, 177 Lu-compound 3, 177 Lu-compound 5 labeling process Add 0.5 mL of sodium acetate / acetic acid buffer solution (pH=7.2) to the reaction flask, add 60 μL of aqueous solution (containing 60 μg) of the precursor of compound 2, compound 3, or compound 5, mix thoroughly, and add 0.5 mL of […]. 177 The pH of the reaction solution was adjusted to 4-5 using a 0.05M hydrochloric acid solution of Lu-LuCl3. The reaction was carried out at 80℃ for 15 min, and then the reaction was terminated. Samples were taken for analysis, and the radiochemical purity of the product was determined by HPLC or Radio-iTLC. The results are shown in Table 8. 177 The radiometric thin-layer chromatography results of Lu-compound 2 are shown in the figure below. Figure 17 As shown, 177 The HPLC test results of Lu-compound 3 are shown in the figure below. Figure 18 As shown, 177 The radiometric thin-layer chromatography (TLC) results of Lu-compound 5 are shown below. Figure 19 As shown.

[0242] Table 8: TLC labeling rates of compounds 3 and 5

[0243] Example 3: Preclinical Experiment 1. Affinity Test The affinity of compounds 1-5 for neurotensin receptor 1 (CAIX) was determined using the Biacore 8K protein interaction system. His-NTSR1 (purchased from Cusabio) was coupled to the surface of a CM5 chip, and a series of analyte solutions of different concentrations were prepared. The analyte compounds were injected, and their affinity for CAIX was measured. The run buffer used in the experiment was: 1X PBS (10 mM phosphate, 2.7 mM KCl, 137 mM NaCl), 0.05% DDM (dodecyl maltodextrin). The affinity of the analyte compounds for CAIX was determined by the equilibrium dissociation constant KD (K0). d / K a The value represents K, where K is the number of K. d K is the dissociation constant. a As the binding constant, the smaller the KD value, the higher the affinity between the compound and the protein.

[0244] The test results are shown in Table 9. The results show that compounds 1-5 have good affinity for neurotensin receptor 1, among which compounds 1 and 5 have better affinity for neurotensin receptor 1.

[0245] Table 9: KD values ​​of compounds 1-5

[0246] 2. MicroPET / CT Imaging Results of Drug Effects in Tumor Model Mice Mouse animal model: purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd. The HT29 mouse model is a xenograft model constructed based on the human colon cancer cell line HT29.

[0247] The AsPC-1 mouse model is a xenograft model constructed based on the human pancreatic cancer cell line AsPC-1.

[0248] (1) MicroPET / CT imaging results of the drug in HT29 model mice Four HT29 tumor model mice were randomly selected and divided into groups for the experiment. All animals in each group received the same drug. 68 Ga-compound 1, 68 Ga-compound 2, 68 Ga-compound 3. 68 Ga-compound 4, 18Compound F-1. Each animal was administered 80 μCi of the drug. The pre-anesthetized animals were placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and underwent MicroPET / CT scans after drug administration. 68 Ga-compound 1, 68 Ga-compound 3 and 68 Ga-compound 4 was subjected to dynamic scanning at 30 min after drug administration, and static MicroPET / CT scanning at 1 h and 2 h after drug administration. 68 Ga-compound 2 was subjected to static MicroPET / CT scans at 30 min, 2 h, and 4 h after administration; 18 Compound F-1 underwent static MicroPET / CT scans at 1 h, 2 h, 4 h, and 6 h post-administration. After reconstruction using the device software, the scanned images were obtained, and the regions of interest (ROIs) were analyzed to determine the uptake of the radiotracer and obtain the %ID / g value.

[0249] 68 The results of administration of Ga-compound 1 are shown in Table 10. Figure 20 (The arrow indicates the location of the tumor) and Figure 21 As shown, it can be seen 68 Ga-compound 1 drugs can be rapidly enriched at the tumor site, and the uptake at the tumor site did not decrease significantly 2 hours after administration. The uptake in non-target organs can be rapidly metabolized by the kidneys through circulation. 2 hours after administration, the ratio of tumor uptake to muscle uptake can reach 5-6, which has a high target-to-substrate ratio, and the tumor imaging is more obvious and clear.

[0250] 68 The results of administration of Ga-compound 2 are shown in Table 11. Figure 22 (The arrow indicates the location of the tumor) and Figure 23 As shown, it can be seen 68 Ga-compound 2 drugs can be rapidly enriched at the tumor site, and the uptake at the tumor site did not decrease significantly 4 hours after administration. The uptake in non-target organs can be rapidly metabolized by the kidneys through circulation. 4 hours after administration, the ratio of tumor uptake to muscle uptake can reach 5-6, which has a high target-to-substrate ratio, and the tumor imaging is more obvious and clearer.

[0251] 68 The results after administration of Ga-compound 3 are shown in Table 12. 68 Ga-compound 3 drugs can be rapidly enriched at the tumor site, and the uptake in non-target organs can be rapidly metabolized by the kidneys through circulation. Two hours after administration, the ratio of tumor uptake to muscle uptake can reach 9, which has a high target-to-substrate ratio, and the tumor imaging is more obvious and clearer.

[0252] 68 The results after administration of Ga-compound 4 are shown in Table 13. 68 Ga-compound 4 drugs can rapidly accumulate at the tumor site, and the uptake at the tumor site continues to increase 1 or 2 hours after administration. Uptake in non-target organs can be rapidly metabolized by the kidneys through circulation. The ratio of tumor uptake to muscle uptake gradually increases 1 or 2 hours after administration.

[0253] 18 The results of administration of compound F-1 are shown in Table 14. Figure 24 (The arrow indicates the location of the tumor) and Figure 25 As shown, it can be seen 18 Compound F-1 can rapidly accumulate at the tumor site, and maintains high uptake at the tumor site 4 or 6 hours after administration. Uptake in non-target organs can be rapidly metabolized by the kidneys through circulation. The ratio of tumor uptake to muscle uptake gradually increases 2-6 hours after administration. At 6 hours after administration, the ratio of tumor uptake to muscle uptake can reach 8-9, which has a high target-to-substrate ratio, and the tumor imaging is more obvious and clear.

[0254] Table 10: 68 %ID / g value after administration of Ga-compound 1

[0255] Table 11: 68 %ID / g value after administration of Ga-compound 2

[0256] Table 12: 68 %ID / g value after administration of Ga-compound 3

[0257] Table 13: 68 %ID / g value after administration of Ga-compound 4

[0258] Table 14: 18 %ID / g value after administration of compound F-1

[0259] (2) MicroPET / CT imaging results of the drug in AsPC-1 model mice Four mice with the AsPC-1 tumor model were randomly selected and divided into groups for the experiment. All animals in each group were given the same drug. 68 Ga-compound 1, 18 F-compound 1, 68Ga-compound 4, 68 Ga-compound 5. Each animal was administered 80 μCi of the drug. The pre-anesthetized animals were placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and underwent MicroPET / CT scans after drug administration. 68 Ga-compound 1, 68 Ga-compound 4 and 68 Ga-compound 5 was subjected to dynamic scanning at 1 hour after drug administration, and static MicroPET / CT scanning at 2 hours and 4 hours after drug administration. 18 Compound F-1 underwent static MicroPET / CT scans at 1 h, 2 h, 4 h, and 6 h post-administration. After reconstruction using the device software, the scanned images were obtained, and the regions of interest (ROIs) were analyzed to determine the uptake of the radiotracer and obtain the %ID / g value.

[0260] 68 The results of administration of Ga-compound 1 are shown in Table 15. Figure 26 (The arrow indicates the location of the tumor) and Figure 27 As shown, it can be seen 68 Ga-compound 1 drugs can rapidly accumulate at the tumor site, and the uptake at the tumor site continues to increase at 57.5 min and 120 min after administration, maintaining high uptake at the tumor site at 240 min. Four hours after administration, the ratio of tumor uptake to muscle uptake gradually increases, reaching 5-6, indicating a high target-to-substrate ratio and more obvious and clear tumor imaging.

[0261] 18 The results of administration of compound F-1 are shown in Table 16. Figure 28 (The arrow indicates the location of the tumor) and Figure 29 As shown, it can be seen 18 Compound F-1 can rapidly accumulate at the tumor site. Four hours after administration, the ratio of tumor uptake to muscle uptake gradually increases. Six hours after administration, the uptake ratio can reach 6-7, exhibiting a high target-to-substrate ratio, resulting in more obvious and clearer tumor imaging.

[0262] 68 The results after administration of Ga-compound 4 are shown in Table 17. 68 Ga-compound 4 drugs rapidly accumulate at the tumor site, and the uptake at the tumor site continues to increase over time. Four hours after administration, the ratio of tumor uptake to muscle uptake also gradually increases.

[0263] 68 The results after administration of Ga-compound 5 are shown in Table 18. 68Ga-compound 5 drugs rapidly accumulate at the tumor site and maintain high uptake at the tumor site for 4 hours after administration. The ratio of tumor uptake to muscle uptake gradually increases over time.

[0264] Table 15: 68 %ID / g value after administration of Ga-compound 1

[0265] Table 16: 18 %ID / g value after administration of compound F-1

[0266] Table 17: 68 %ID / g value after administration of Ga-compound 4

[0267] Table 18: 68 %ID / g value after administration of Ga-compound 5

[0268] Example 4: Drug distribution experiment in isolated tissues of model mice 1. Drug distribution experiment in isolated tissues of HT29 model mice Model mice were randomly selected and divided into two groups, with animals in each group receiving the same drug. Six HT29 tumor model mice were randomly selected from each group, and four mice from each group received the same drug. 68 Ga-compound 1, 68 Ga-compound 2. Each animal was administered 100 μCi of the drug. 68 Three animals in Group 1 (Ga-compound group) were dissected at 1 hour and 4 hours after drug administration. 68 Two animals from each of the two Ga-compound groups were dissected at 1 hour and 4 hours after administration. Blood, brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumors were collected for gamma radiation counting.

[0269] The results of the radioactivity of different tissues at different time points are as follows: Figure 30 As can be seen from Table 19, 68 Ga-compound 1, 68 Ga-compound 2 was enriched at the tumor site 1 hour after administration and 4 hours after administration. 68 Ga-compound 1 and 68 Ga-compound 2 still exhibits high uptake at the tumor site.

[0270] Table 19: 68 Ga-compound 1, 68 %ID / g value after administration of Ga-compound 2

[0271] 2. Drug distribution experiment in isolated tissues of HT29 model mice Nine HT29 tumor model mice were randomly selected and administered the drug. 177 Lu-compound 2. Each animal was given 300 μCi of the drug. Three animals were dissected at 4h, 24h and 48h after administration. Fifteen tissues and organs were collected, including the brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat and tumor, and gamma radiation counts were measured.

[0272] The results of the radioactivity of different tissues at different time points are as follows: Figure 31 As can be seen from Table 20, 177 Four hours after administration of Lu-compound 2, high uptake was observed at the tumor site, and no significant decrease was observed at the tumor site until 48 hours later. Uptake at other non-target organs gradually decreased.

[0273] Table 20: 177 %ID / g value of Lu-compound 2 after administration

[0274] 3. Drug distribution experiment in isolated tissues of AsPC-1 model mice Eight AsPC-1 tumor model mice were randomly selected and administered the drug. 177 Lu-compound 5. Each animal was given 300 μCi of the drug. Two, three, and three animals were dissected at 4h, 24h, and 48h after administration, respectively. Fifteen tissues and organs were collected, including the brain, thyroid gland, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor, and gamma radiation counts were measured.

[0275] The results of the radioactivity of different tissues at different time points are as follows: Figure 32 As can be seen from Table 21, 177 Lu-compound 5 reaches high uptake at the tumor site 4 hours after administration, while uptake at other non-target organs decreases significantly within 24 hours.

[0276] Table 21: 177 %ID / g value after administration of Lu-compound 5

[0277] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0278] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a compound of formula II or III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: 、 ； R is selected from n R's. b Replacement C 1-6 Alkylene, C 0-6 alkyleneamine, C 2-6 The group consists of an alkynylamino group, a 5-8 membered heterocyclic group linked to a methylene group, or a -O-, -S-, or -NH- group, wherein the heteroatom in the 5-8 membered heterocyclic group linked to the methylene group is selected from N, and the number of heteroatoms is 1 or 2. The R group... b Independently selected from oxidized, halogenated, and C 1-6 Alkyl group; n is an integer selected from 0, 1, 2, or 3; L1 is selected from connectors, which are q R c The substituted carbon chain or heterochain, wherein the heteroatoms in the heterochain are selected from one or two types of N and O, and the number of heteroatoms is 1-8, and the number of carbon atoms in the main chain of the carbon chain is 3-8; the R c Independently selected from oxidized, halogenated, and C 1-6 Alkyl, C 1-6 Halogenated alkyl, carboxyl, hydroxyl; q is an integer selected from 0, 1, 2, 3, 4, 5; L2 is selected from an amino acid chain, wherein the amino acid chain includes at least two of the following: arginine or its derivative residues, glycine or its derivative residues, lysine or its derivative residues, glutamic acid or its derivative residues, serine or its derivative residues, alanine or its derivative residues, tyrosine or its derivative residues, aspartic acid or its derivative residues, histidine or its derivative residues, phenylalanine or its derivative residues, and threonine or its derivative residues; R1 is selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl; m is an integer selected from 0, 1, and 2; Z is a chelating group derived from the chelating agent.

2. The compound according to claim 1, characterized in that, The compound satisfies one or more of the following conditions: (1) In L1, the total number of carbon atoms and heteroatoms in the main chain of the heterochain is 5-25; (2) In L1, the main chain of the heterochain contains 5-6 member heterocyclic groups; (3) In Z, the chelating agent is selected from 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid, N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazononon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid, 1,4,7-triazacyclononanephosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-hydroxy) [Methyl)phosphonic acid], 3,6,9,15-tetraazabicyclo[9.3.1.]pentadecan-1(15),11,13-trien-3,6,9-triacetic acid, N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, p-isocyanothiobenzyl-DTPA, 1-(p-isocyanothiobenzyl)-3-methyl-DTPA, 2-(p-isocyanothiobenzyl)-4-methyl-DTPA 1-(2)-methyl-4-isocyanothiobenzyl-DTPA, (R)-2-amino-3-(4-isothiocyanophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid, 6-hydrazylpyridine-3-carboxylic acid, 2-(4-isothiocyanophenyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid or 2-[(4-isothiocyanophenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

3. The compound according to claim 2, characterized in that, The compound satisfies one or more of the following conditions: (1) When R is selected from n R b Replacement C 1-6 Alkylene, wherein n is 0, 1 or 2, wherein R b Independently selected from oxygen, C 1-3 alkyl; (2) When R is selected from n R b Replacement C 0-6 alkylamino group, wherein n is 0, 1 or 2, and R b Independently selected from oxygen, C 1-3 alkyl; (3) When R is selected from n R b The substituted methylene-linked 5-8 membered heterocyclic group, wherein n is 0 or 1, and R b Selected from oxo; (4) When R is selected from n R b Replacement C 2-6 Imynylamino, wherein n is 0, 1 or 2, wherein R b Independently selected from oxygen, C 1-3 alkyl; (5) When L1 is selected from q R c The substituted carbon chain, wherein q is 0 or 1, and R c Selected from oxo, C 1-3 alkyl; (6) When L1 is selected from q R c The substituted heterochain, wherein q is 0, 1, 2, 3 or 4, wherein R c Selected from oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups.

4. The compound according to claim 3, characterized in that, The compound satisfies one or more of the following conditions: (1) In R, the C 1-6 The alkylene group is selected from -CH2-, where n is 0 or 1, and R... b Independently selected from oxygen, C 1-3 alkyl; (2) In R, the C 0-6 The alkylene amino group is selected from -CH2-NH-, where n is 1 or 2, and R... b Independently selected from oxygen, C 1-3 alkyl; (3) In R, the C 0-6 The alkylene amino group is selected from amino groups, where n is 0 or 1, and R... b Selected from C 1-3 alkyl; (4) In R, the 5-8 member heterocyclic group is selected from , , , , ; (5) In R, the C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 1 or 2, r is 0, 1, 2 or 3, and R... b Independently selected from oxygen, C 1-3 alkyl; (6) In R, the C 2-6 The ynylamino group is selected from -C≡C-(CH2)r-NH-, where n is 0 or 1, r is 0 or 1, and R... b Selected from C 1-3 alkyl; (7) In L1, the carbon chain is selected from , , ; (8) In L1, the heterochain is selected from , , , , , , , , , , , , , , , .

5. The compound according to any one of claims 1-4, characterized in that, The R is selected from , , , -NH- , , -O-, -S-; Optionally, L1 is selected from , , , , , , , , , , , , , , , , , , , , .

6. The compound according to any one of claims 1-5, characterized in that, L2 is selected from , , , , , , , , , , , , ; Optionally, Z is selected from , , , , , , , .

7. The compound according to claim 1, characterized in that, The compound is a compound of Formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of a compound of Formula IV. Wherein, L2 and Z are defined as described in any one of claims 1-6; L3 is selected from chemical bonds or by t R. d The substituted heterochain, wherein the heteroatoms in the heterochain are N or O, and the R d Independently selected from oxygen; t is an integer selected from 0, 1, and 2.

8. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 9. The compound according to claim 1, characterized in that, It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 10. A complex, characterized in that, The complex is formed by complexing M with the compound of any one of claims 1-9, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug; Wherein, M is selected from at least one of a radioactive nuclide or a non-radioactive element; Optionally, the radionuclide is selected from at least one of diagnostic or therapeutic radionuclides; Optionally, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99m Tc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94m Tc, 67 Ga、 71 / 72 / 74 As、 82m Rb、 86 Y; Optionally, the therapeutic nuclide is selected from... 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac、 227 Th; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc, 177 Lu、 225 Ac、 161 Tb; Preferably, the radionuclide 18 F is through 18 FAl is formed by complexing the compound with the compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs.

11. The complex according to claim 10, characterized in that, The M complexes with the chelating group in the compound or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts, or prodrugs.

12. A pharmaceutical composition, characterized in that, include: The compound of any one of claims 1-9, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex of any one of claims 10-11; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

13. Use of the compound of any one of claims 1-9, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the complex of any one of claims 10-11, or the pharmaceutical composition of claim 12, in the preparation of a medicament for the diagnosis and / or treatment of a disease characterized by overexpression of neurotensin receptor 1.

14. The use according to claim 13, characterized in that, The diagnostic method is selected from radionuclide imaging; Optionally, the diagnostic method is selected from positron emission tomography or single-photon emission computed tomography. Optionally, the treatment is selected from radiotherapy.

15. The use according to claim 14, characterized in that, The disease is selected from at least one of the following: tumors, neuropsychiatric disorders, metabolic diseases, and cardiovascular diseases; Optionally, the disease is selected from at least one of colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, pancreatic ductal adenocarcinoma, small cell lung cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, glioblastoma, and breast cancer.

16. A method for imaging tissues expressing neurotensin receptor 1, characterized in that, include: Applying to the tissue the compound of any one of claims 1-9, or its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the complex of any one of claims 10-11, or the pharmaceutical composition of claim 12. And to image the tissue after drug administration.

17. The method according to claim 16, characterized in that, The imaging was performed using positron emission tomography or single-photon emission computed tomography.

Images