Targeted carbonic anhydrase radiopharmaceuticals

Abstract

The invention relates to a targeted carbonic anhydrase radiopharmaceutical, in particular to a compound which is a compound as shown in a formula I or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula I, the compounds are capable of inhibiting carbonic anhydrase IX or diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a carbonic anhydrase-targeted radiopharmaceutical. Background Art

[0002] There are many types of α-carbonic anhydrases (α-CAs) distributed in most organs and tissues of the human body, and one type of CA is dominant in some organs and tissues. CAIX / XII is dominant in most hypoxic solid tumors, and CAI / II is one of the main protein components of red blood cells in the blood. Tumor-specifically expressed CAIX / XII is a type of transmembrane protein. CAIX is stably expressed in tumors such as RCC (renal cell carcinoma). CAIX is not expressed in normal kidney tissue, and is only partially weakly expressed in organs and tissues other than kidney tissue. Therefore, CAIX is a potential excellent target for the diagnosis and treatment of ccRCC (renal clear cell carcinoma). CAIX is also overexpressed in many other types of tumors, such as lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, oral cancer, etc.

[0003] Tumor-overexpressed CAIX can catalyze the hydration reaction of carbon dioxide, converting carbon dioxide into bicarbonate ions and protons, and regulating the pH of the cell environment. The increased acidity of the local microenvironment of the cell can activate the VEGF signaling pathway, promote new angiogenesis, and play an important role in the occurrence and development of tumors. In addition, most CA-targeted inhibitors bind to the metal active center of the CAIX extracellular enzyme catalytic domain to block its catalytic activity. The structure of CAIX-specific inhibitors is mostly based on the sulfonamide structure, with ionization, hypoxia-activated structuring, glycosylation, and nanoparticle inclusion. The labeling of small molecules of CAIX inhibitors with nuclides can be used for the treatment and diagnosis of tumors.

[0004] Currently, the effective treatment for RCC is surgical resection, but the limitation of surgery is that the recurrence rate is 30% (or about 50%) 5 years after surgery, and surgery is not possible for advanced or metastatic RCC. The classic effective drug for metastatic RCC is high-dose interleukin 2, but it can only produce a sustained complete response in 7-10% of patients. Therefore, for patients with a high risk of recurrence, the development of more sensitive and accurate early diagnosis strategies, as well as effective systemic therapeutic drugs for advanced and metastatic RCC, is a challenge that needs to be continued and resolved. The development of better CAIX targeted drugs and CAIX inhibitors with high affinity and specificity for the treatment of tumors has important scientific research value and broad application prospects. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

[0006] In the first aspect of the present invention, the present invention provides a compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I:

[0007]

[0008] Wherein, Y1 and Y2 are independently selected from C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkyleneoxy, C optionally substituted by R1 1～10 Alkylene-C(O)-NH-C 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkylene, -NH-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 2～10 Alkenylene or C optionally substituted by R1 2～10 Alkyne;

[0009] Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy;

[0010] X is selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0011] Z is selected from the group consisting of chelating agent residues;

[0012] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0013] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 Heteroaryl.

[0014] According to an embodiment of the present invention, X of the compound represented by Formula I is selected from carboxyl, phenyl, tolyl, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Alkoxy.

[0015] According to an embodiment of the present invention, R2 of the compound shown in Formula I is selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN or N3.

[0016] According to an embodiment of the present invention, the compound is a compound represented by Formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula II:

[0017]

[0018] wherein Y1 is selected from C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkyleneoxy, C optionally substituted by R1 1～10 Alkylene-C(O)-NH-C 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkylene, -NH-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 2～10 Alkenylene or C optionally substituted by R1 2～10 Alkyne;

[0019] Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy;

[0020] X is selected from halogen, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0021] Z is selected from the group consisting of chelating agent residues;

[0022] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0023] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0024] n is an integer selected from 1 to 6.

[0025] According to an embodiment of the present invention, X of the compound represented by Formula II is selected from carboxyl, phenyl, tolyl, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Alkoxy.

[0026] According to an embodiment of the present invention, R2 of the compound represented by Formula II is selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN or N3.

[0027] According to an embodiment of the present invention, the compound is a compound represented by Formula III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by Formula III:

[0028]

[0029] Wherein, Y4 is selected from -NR2-, -NR2-(C=O)-, -NR2-(C=S)-, (CH2) p -(C=O)-NR2-, -(C=O)-NR2-, -(C=S)-NR2- or a bond, p is selected from an integer between 1 and 4;

[0030] Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy;

[0031] X is selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl;

[0032] Z is selected from the group consisting of chelating agent residues;

[0033] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0034] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0035] n is selected from an integer between 1 and 6;

[0036] m is selected from an integer between 1 and 6.

[0037] According to an embodiment of the present invention, X of the compound represented by Formula III is selected from carboxyl, phenyl, tolyl, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Alkoxy.

[0038] According to an embodiment of the present invention, R2 of the compound represented by formula III is selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN or N3.

[0039] According to an embodiment of the present invention, Y3 is selected from -NH-C(O)-C optionally substituted by R1 1～10 Alkylene.

[0040] According to an embodiment of the present invention, Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1. 1～10 Alkylene.

[0041] It should be noted that the R1 can replace "-NH-C(O)-C 1～10 The "H" in "-NH-" in "alkylene" can also replace "-C 1～10 "H" of any "-CH2" in "alkylene".

[0042] According to an embodiment of the present invention, the R1 is selected from

[0043] According to an embodiment of the present invention, the R1 is selected from

[0044] According to an embodiment of the present invention, Y3 is selected from

[0045] According to an embodiment of the present invention, X is selected from carboxyl, phenyl, tolyl or C 1-4 alkyl.

[0046] According to an embodiment of the present invention, X is selected from carboxyl, phenyl, phenolic hydroxyl, naphthyl, tolyl or C 1-4 alkyl.

[0047] According to an embodiment of the present invention, Z is derived 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-triazononan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10 -tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'- {5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-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-isocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1 -(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA), [R]-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

[0048] According to an embodiment of the present invention, Z is selected from

[0049] According to an embodiment of the present invention, when Y4 is selected from a bond, Z is selected from

[0050] According to an embodiment of the present invention, when Y4 is selected from -NR2-, Z is selected from

[0051] In the second aspect of the present invention, the present invention provides a compound, which is a compound of formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula IV:

[0052]

[0053] Wherein, Y4 is selected from -NR2-, -NR2-(C=O)-, -NR2-(C=S)-, (CH2) p -(C=O)-NR2-, -(C=O)-NR2-, -(C=S)-NR2- or a bond, p is selected from an integer between 1 and 4;

[0054] Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy;

[0055] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0056] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0057] X is selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C5-10 heteroaryl;

[0058] Z1 is selected from

[0059] m is selected from an integer between 1 and 6.

[0060] According to an embodiment of the present invention, X of the compound represented by Formula IV is selected from carboxyl, phenyl, phenolic hydroxyl, naphthyl, tolyl, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Alkoxy.

[0061] According to an embodiment of the present invention, X of the compound represented by Formula IV is selected from carboxyl, phenyl, tolyl, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 1-4 Alkoxy.

[0062] According to an embodiment of the present invention, R2 of the compound represented by formula IV is selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN or N3.

[0063] According to an embodiment of the present invention, Y3 is selected from

[0064] According to an embodiment of the present invention, the X is selected from a carboxyl group or a phenyl group.

[0065] According to an embodiment of the present invention, when Y4 is selected from a bond, Z1 is selected from According to an embodiment of the present invention, when Y4 is selected from -NR2-, Z1 is selected from

[0066] In the third aspect of the present invention, the present invention provides a compound, whose structure is selected from the following:

[0067]

[0068]

[0069]

[0070] In the fourth aspect of the present invention, the present invention provides a compound. According to an embodiment of the present invention, the compound is formed by complexing the compound described in the first aspect, the second aspect or the third aspect with M.

[0071] According to an embodiment of the present invention, the M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0072] According to an embodiment of the present invention, the radioactive nuclide includes at least one of a diagnostic nuclide or a therapeutic nuclide.

[0073] According to an embodiment of the present invention, the diagnostic nuclide 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 or 86 Y.

[0074] According to an embodiment of the present invention, the therapeutic nuclide is selected from 177 Lu, 161 Tb, 90 Y. 131 I. 153 Sm, 67 Cu, 89 Sr, 166Ho, 177 Yb, 47 Sc, 186 / 188 Re, 212 / 213 Bi, 149 Pm, 212 Pb, 211 At 223 Ra, 225 Ac or 227 Th.

[0075] According to an embodiment of the present invention, the radionuclide is selected from 68 Ga, 18 F. 89 Zr, 99 mTc or 177 Lu.

[0076] According to an embodiment of the present invention, the radionuclide 18 F is through 18 FAl is complexed.

[0077] According to an embodiment of the present invention, the M is selected from 68 Ga, 18F or 177 Lu.

[0078] According to an embodiment of the present invention, the compound structure is selected from the following:

[0079]

[0080]

[0081]

[0082] In a fifth aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound described in the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

[0083] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0084] In the sixth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the fifth aspect for inhibiting carbonic anhydrase IX.

[0085] In a seventh aspect of the present invention, the present invention provides a method for imaging a tissue expressing carbonic anhydrase IX protein. According to an embodiment of the present invention, the method comprises administering the compound of the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of the fifth aspect to the tissue, and imaging the tissue after administration.

[0086] According to an embodiment of the present invention, the imaging is performed by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0087] In the eighth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the fifth aspect in the preparation of reagents and / or drugs for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX.

[0088] In the eighth aspect of the present invention, the present invention provides a method for inhibiting carbonic anhydrase IX, or diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX, comprising the steps of administering to a subject in need thereof the compound described in the first, second, third or fourth aspect of the present invention, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the fifth aspect.

[0089] According to an embodiment of the present invention, the diagnosis modality is selected from optical imaging and / or nuclear imaging.

[0090] According to an embodiment of the present invention, the diagnosis modality is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0091] According to an embodiment of the present invention, the treatment is selected from radiotherapy and / or assisted surgery with fluorescent surgical navigation.

[0092] According to an embodiment of the present invention, the tumor expressing carbonic anhydrase CAIX includes: renal cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma or oral cancer.

[0093] Beneficial effects:

[0094] The targeted carbonic anhydrase radiopharmaceutical disclosed in the present invention has a high affinity for carbonic anhydrase IX, and exhibits good specific targeted uptake, rapid enrichment, and long-term uptake maintenance in tissues, tumors or cells that highly express carbonic anhydrase IX in vivo, and is rapidly cleared in non-target tissues, with a high uptake ratio of tumors to normal tissues, clear imaging boundaries, and good safety. The diseased tissue can be quickly detected, and the tumor tissue has a long retention time, showing the potential possibility of treatment, and has clinical diagnosis and treatment significance.

[0095] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0096] Terms and Definitions

[0097] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combination and combination shall fall within the scope recorded in the specification of this application.

[0098] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

[0099] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0100] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and / or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

[0101] Definitions of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are 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, the manufacturer's instructions for use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or in accordance with the description of the present invention. The above-mentioned techniques and methods can usually be implemented according to the descriptions in the multiple summaries and more specific documents cited and discussed in this specification, according to conventional methods well known in the art. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.

[0102] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, then the substituents may be the same or different at each substitutable position.

[0103] The term "unsubstituted" means that the designated group bears no substituents.

[0104] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as specifically exemplified in the examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted with one or more substituents selected from a specific group, the substituents may be substituted the same or differently at each position.

[0105] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0106] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, CH2O is equivalent to OCH2. As used herein, Indicates the attachment site of a group.

[0107] The section headings used herein are only for the purpose of organizing the article and should not be interpreted as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.

[0108] In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0109] The numerical ranges recorded in the specification and claims of this application, when the numerical range is understood as an "integer", should be understood as recording the two endpoints of the range and each integer in the range. For example, "an integer from 1 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6. When the numerical range is understood as a "number", it should be understood as recording the two endpoints of the range and each integer in the range and each decimal in the range. For example, "a number from 1 to 10" should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

[0110] As used herein, the term "halogen" alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

[0111] The term "alkyl", when used alone or as part of other substituents, refers to a saturated linear or branched monovalent hydrocarbon group of 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein, including but not limited to deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

[0112] The term "alkylene" when used alone or as part of other substituents is understood to mean a straight-chain or branched saturated, unsaturated or partially saturated divalent hydrocarbon group. 1-10 "Alkylene" or "C 1- C 10 The term "alkylene" refers to a straight or branched divalent hydrocarbon group having 1 to 10 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, and butylene.

[0113] When alone or as part of other substituents, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to forty carbon atoms (e.g., C2-C6 alkenyl, for example, C2-C4 alkenyl) with at least one carbon-carbon sp2 double bond, and includes groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl include, but are not limited to, vinyl and allyl.

[0114] When alone or as part of other substituents, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of two to forty carbon atoms (e.g., C2-C6 alkynyl, and also C2-C4 alkynyl) having at least one carbon-carbon sp triple bond. Examples of alkynyl include, but are not limited to, ethynyl and propynyl.

[0115] The term "alkoxy" by itself or as part of another substituent refers to the group -OR Q , where R Q is "alkyl" as defined above.

[0116] When alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible). When one of the rings is a non-aromatic ring, the group may be connected through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring", "heteroaryl" or "heteroaromatic cyclyl".

[0117] The term "bicyclic" when used alone or as part of another substituent refers to a group having two connected rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin).

[0118] The term "naphthyl" when used alone or as part of another substituent is

[0119] The "chelating group" mentioned in the present disclosure for the compound of general formula (I) refers to a molecular fragment derived from a chelating agent. For example, the chelating group is a molecular fragment derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA) It can be introduced into the compound of general formula (I) by connecting one carboxyl group of DOTA to other groups through a bond, such as an amide bond.

[0120] In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

[0121] In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0122] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0123] Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, 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 center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0124] When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

[0125] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0126] The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

[0127] The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0128] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0129] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0130] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and / or adhesion.

[0131] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0132] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0133] The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present 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., preferably humans.

[0134] The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0136] Figure 1 is the LCMS spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0137] Figure 2 is a HPLC spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0138] Figure 3 is the nuclear magnetic spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0139] Figure 4 is the LCMS spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0140] Figure 5 is a HPLC spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0141] Figure 6 is the nuclear magnetic spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0142] Figure 7is the LCMS spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0143] Figure 8 is a HPLC spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0144] Fig. 9 is the nuclear magnetic spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0145] Fig.10 is the LCMS spectrum of the NYM048 molecule according to an embodiment of the present invention;

[0146] Fig.11 is a HPLC spectrum of the NYM048 molecule according to an embodiment of the present invention;

[0147] Fig.12 is the nuclear magnetic spectrum of the NYM048 molecule according to an embodiment of the present invention;

[0148] Fig.13 is the LCMS spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0149] Fig.14 is a HPLC spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0150] Fig.15 is the nuclear magnetic spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0151] Fig.16 is an LCMS spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0152] Fig.17 is a HPLC spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0153] Fig.18 is the nuclear magnetic spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0154] Fig.19 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM045 molecule;

[0155] Fig. 20 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM046 molecule;

[0156] Fig.21 According to an embodiment of the present invention 68Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM047 molecule;

[0157] Fig. 22 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM048 molecule;

[0158] Fig.23 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM049 molecule;

[0159] Fig.24 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM050 molecule;

[0160] Fig.25 According to an embodiment of the present invention 68 Radioactive thin layer chromatography scanning purity analysis result diagram of Ga-NYM074 molecule;

[0161] Fig.26 According to an embodiment of the present invention 18 Radioactive thin layer chromatography scanning purity analysis result diagram of F-NYM070 molecule;

[0162] Fig. 27 According to an embodiment of the present invention 18 Radioactive thin layer chromatography scanning purity analysis result diagram of F-NYM071 molecule;

[0163] Fig.28 According to an embodiment of the present invention 177 Radioactive thin layer chromatography scanning purity analysis result diagram of Lu-NYM073 molecule;

[0164] Fig.29 According to an embodiment of the present invention 177 Radioactive thin layer chromatography scanning purity analysis result diagram of Lu-NYM074 molecule;

[0165] Fig.30 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM045 / 046 / 047 in OS-RC-2 tumor-bearing mouse model;

[0166] Fig.31 FIG. 1 is a diagram of an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM048 / 049 / 050 in OS-RC-2 tumor-bearing mouse model;

[0167] Fig.32 According to an embodiment of the present invention 68 The uptake values ​​of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 in different organs and parts, as well as the uptake ratio between tumor and non-target organs;

[0168] Fig.33 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM045 in OS-RC-2 tumor-bearing mouse model;

[0169] Fig.34 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM046 in OS-RC-2 tumor-bearing mouse model;

[0170] Fig.35 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM047 in OS-RC-2 tumor-bearing mouse model;

[0171] Fig.36 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM048 in OS-RC-2 tumor-bearing mouse model;

[0172] Fig.37 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM049 in OS-RC-2 tumor-bearing mouse model;

[0173] Fig.38 According to different time periods of the embodiment of the present invention 68 PET / CT imaging results of Ga-NYM050 in OS-RC-2 tumor-bearing mouse model;

[0174] Fig.39 According to an embodiment of the present invention 68 The uptake of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 in the tumor site changes over time;

[0175] Fig.40 According to an embodiment of the present invention 68 PET / CT scans of Ga-NYM074 drug in mice;

[0176] Fig.41 According to an embodiment of the present invention 68 The uptake values ​​of Ga-NYM074 drug in different tissues of mice;

[0177] Fig.42 According to an embodiment of the present invention 68 The ratio of Ga-NYM074 drug in mouse tumors to muscle and tumors to heart;

[0178] Fig.43 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM050 in OS-RC-2 tumor-bearing mouse model;

[0179] Fig.44 According to an embodiment of the present invention 68 Scanning image of the competitive inhibition experiment of Ga-NYM050 in OS-RC-2 tumor-bearing mouse model;

[0180] Fig.45 According to an embodiment of the present invention 68 The uptake values ​​of Ga-NYM050 in different organs and parts at different times in the OS-RC-2 tumor-bearing mouse model;

[0181] Fig.46 According to an embodiment of the present invention 68 Ga-NYM050 blocking experiment in OS-RC-2 tumor-bearing mouse model with different organs and parts at different times;

[0182] Fig.47 According to an embodiment of the present invention 177 Lu-NYM073 / 177 SPECT / CT scans of Lu-NYM074 drug in mice;

[0183] Fig.48 is a graph showing changes in tumor volume of mice according to an embodiment of the present invention;

[0184] Fig.49 is a graph showing changes in mouse body weight according to an embodiment of the present invention;

[0185] Fig.50 According to an embodiment of the present invention 177 Distribution diagram of Lu-NYM074 in vitro tissues of mice;

[0186] Fig.51 Patient 1 is injected according to an embodiment of the present invention 18 MIP (maximum intensity projection) image after F-FDG;

[0187] Fig.52 Patient 1 is injected according to an embodiment of the present invention 68 MIP map after Ga-NYM046;

[0188] Fig.53 Patient 1 is injected according to an embodiment of the present invention 18 F-FDG and 68 CT and PET / CT cross-sectional images of Ga-NYM046;

[0189] Fig.54 Patient 1 is injected according to an embodiment of the present invention 18 F-FDG and 68 SUVmax and SUVmean plots after Ga-NYM046.

[0190] Fig.55 Patient 2 is injected according to an embodiment of the present invention 18 MIP image after F-FDG;

[0191] Fig.56 Patient 2 is injected according to an embodiment of the present invention 68 MIP map after Ga-NYM046;

[0192] Fig.57 Patient 2 is injected according to an embodiment of the present invention 18 F-FDG and 68 CT and PET / CT cross-sectional images of Ga-NYM046;

[0193] Fig.58 Patient 2 is injected according to an embodiment of the present invention 18 F-FDG and 68 SUVmax and SUVmean graphs after Ga-NYM046;

[0194] Fig.59 is an LCMS spectrum of the NYM070 molecule according to an embodiment of the present invention;

[0195] Fig.60 is a HPLC spectrum of the NYM070 molecule according to an embodiment of the present invention;

[0196] Fig.61 is the LCMS spectrum of the NYM071 molecule according to an embodiment of the present invention;

[0197] Fig.62 is a HPLC spectrum of the NYM071 molecule according to an embodiment of the present invention;

[0198] Fig.63 is the LCMS spectrum of the NYM073 molecule according to an embodiment of the present invention;

[0199] Fig.64 is a HPLC spectrum of the NYM073 molecule according to an embodiment of the present invention;

[0200] Fig.65 is the LCMS spectrum of the NYM074 molecule according to an embodiment of the present invention;

[0201] Fig.66 is a HPLC spectrum of the NYM074 molecule according to an embodiment of the present invention. DETAILED DESCRIPTION

[0202] 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. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product instructions are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0203]

[0204] Example 1: Preparation of the compound

[0205] 1. Synthesis steps of Int 1:

[0206]

[0207] Compound 2 (3.00 g, 1.00 eq) and pyridine (2.63 g, 2.00 eq) were dissolved in DMF (30.0 mL), and compound 4a (2.97 g, 1.00 eq) in DCM (20.0 mL) was added at 0°C. The reaction was stirred at 25°C for 14 hours. The reaction solution was concentrated in vacuo, and the residue was washed with 45.0

[0208] mL of water and 45.0 mL of saturated NaHCO 3 were diluted and filtered to obtain compound 4 (5.00 g).

[0209]

[0210] Compound 4 (5.00 g, 1.00 eq) and NaOH (3.45 g, 5.76 eq) were dissolved in H2O (70.0 mL). The reaction was stirred at 60°C for 1 hour. The reaction solution was cooled and the pH was adjusted to 4 with 1N HCl, filtered and washed with water to obtain compound Int 1 (2.00 g, 6.22 mmol, purity 95.9%).

[0211] 2. Synthesis steps of NYM045

[0212]

[0213] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0214] 1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol / g), Fmoc-Asp-OALL (Fmoc-L-aspartic acid alpha-allyl ester) (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, and drain until no liquid flows out. Add DMF for washing and drain.

[0215] 2) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0216] 3) Condensation: Fmoc-Apa-OH (Fmoc-5-aminopentanoic acid-OH, 1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0217] 4) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0218] 5) Reductive amination: Benzaldehyde (0.60mmol, 1.20eq) and trimethyl orthoformate (3.00mmol, 6.00eq) were dissolved in THF (20.0mL), and acetic acid (0.01mmol, 0.02eq) was added. The reaction was stirred with nitrogen at 20℃ for 0.50h. Sodium triacetoxyborohydride (3.00mmol, 6.00eq) was dissolved in methanol (1.00mL), and slowly added dropwise to the reaction column. The reaction was stirred with nitrogen at 20℃ for 1.00h. The resin was washed with DMF.

[0219] 6) Condensation: Int 1 (0.60 mmol, 1.20 eq) and HOAt (0.60 mmol, 1.20 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.60 mmol, 1.20 eq), and the reaction was stirred with nitrogen at 20°C for 12.0 h. The resin was washed with DMF.

[0220] 7) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

[0221] 8) Condensation: N-Fmoc-1,4-butanediamine hydrochloride (0.75 mmol, 1.50 eq) and DIEA (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were added to the resin, and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was treated with DMF.

[0222] 9) Deprotection: 20% piperidine (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0223] 10) Condensation: DOTA(tBu*3) (tri-tert-butyl 1,4,7,10-tetraazacyclododecane-tetraacetic acid, 0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (0.75 mmol, 1.50 eq) was added. The reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

[0224] Peptide cleavage and purification:

[0225] The resin was shrunk with MeOH (30.0 mL) and was drained until no liquid flowed out. The resin was poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of a prepared cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H2O and 2.5% 3-MPR) and shaken for 2 h. After filtration, the filtrate was added to ice isopropyl ether (100 mL) for sedimentation centrifugation and then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain a crude peptide.

[0226] NYM045 (15.0 mg, purity 97.52%) was obtained directly by reverse phase preparation (A: H2O containing 0.075% TFA, B: ACN acetonitrile).

[0227] LCMS:MS:[M+H] + =1069.7( Figure 1 (shown)

[0228] HPLC: Purity: 97.52% ( Figure 2 (shown)

[0229] 1 H NMR: 400 MHz, DMSO-d6( Figure 3 (shown)

[0230] δ:13.02-12.98(m,1H),8.32(s,1H),8.07-8.03(t,J=7.6Hz,1H),7.84-7.78 (m,1H),7.37-7.17(m,5H),4.55(s,1H),4.52-4.89(m,2H),3.74-3.59(m,6H ),3.22-3.04(m,24H),2.64-2.54(m,2H),2.44-2.40(m,1H),3.32-2.29(t,J =7.6Hz,1H),2.12-2.07(dd,J1=12.8Hz,J2=6.8Hz,2H),1.69-1.39(m,12H).

[0231] 3. Synthesis steps of NYM046

[0232]

[0233] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0234] 1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol / g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing, drain until no liquid flows out.

[0235] 2) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0236] 3) Condensation: Fmoc-Apa-OH (Fmoc-5-aminopentanoic acid-OH, 1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DM.

[0237] 4) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0238] 5) Protecting group: DIEA (3.00 mmol, 6.00 eq) was dissolved in THF (20.0 mL), added to the reaction column and agitated with nitrogen. Then, NsCl (1.50 mmol, 3.00 eq) was dissolved in THF (10.0 mL), slowly dripped into the reaction column, and the reaction was agitated with nitrogen at 20 °C for 1.00 h.

[0239] 6) Mitsunobu reaction: PPh3 (2.50 mmol, 5.00 eq) was dissolved in THF (30.0 mL), 2-naphthalenemethanol (1.00 mmol, 2.00 eq) was added to the resin and nitrogen was agitated for 5 min, and DEAD (2.50 mmol, 5.00 eq) was slowly added dropwise to the reaction column, and the reaction was agitated with nitrogen at 20°C for 12.0 h.

[0240] 7) Deprotection: Sodium thiophenolate (1.25 mmol, 2.50 eq) was dissolved in DMF (30.0 mL), added to the resin and stirred with nitrogen for 1 h. The resin was washed with DMF and dried.

[0241] 8) Condensation: Int 1 (0.60 mmol, 1.20 eq) and HOAt (0.60 mmol, 1.20 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.60 mmol, 1.20 eq), and the reaction was stirred with nitrogen at 20°C for 12.0 h. The resin was washed with DMF.

[0242] 9) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

[0243] 10) Condensation: N-Fmoc-1,4-butanediamine hydrochloride (0.75 mmol, 1.50 eq) and DIEA (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were added to the resin, and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

[0244] 11) Deprotection: 20% piperidine (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0245] 12) Condensation: DOTA(tBu*3) (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq), and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

[0246] Peptide cleavage and purification:

[0247] The resin was shrunk with MeOH (30.0 mL) for 3 min each time, and the waste was discharged until no liquid flowed out. The resin was poured out and dried for use. At room temperature, the dried resin was added to the prepared 20.0 mL cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H2O and 2.5% 3-MPR) and shaken on a shaking table for 2 h. After filtering, the filtrate was added to ice isopropyl ether for sedimentation centrifugation, and then washed with isopropyl ether (100 mL). Dry under vacuum for 2 hours to obtain the crude peptide.

[0248] NYM046 (15.0 mg, purity 95.74%) was obtained directly by reverse phase preparation (A: water containing 0.075% TFA, B: ACN acetonitrile).

[0249] LCMS:MS:[M / 2+H] + =1119.5( Figure 4 (shown)

[0250] HPLC: Rt = 7.72 min, purity: 95.74% ( Figure 5 (shown)

[0251] 1 H NMR: 400 MHz, DMSO-d6( Figure 6 (shown)

[0252] δ:13.05-12.97(m,1H),8.33(s,2H),8.08-8.07(m,1H),7.91-7.80(m,3H),7.69-7.66(m,1H),7.49-7.35-(m,3H),4.73-4.67(m,2H) ,4.51(brs,1H),3.70-3.60(m,6H),3.31-3.03(m,24H),2.65-2.59(m,3H),2.40-2.37(m,1H),2.12-2.08(m,2H),1.70-1.39(m,12H).

[0253] 4. Synthesis steps of NYM047

[0254] Step 1:

[0255]

[0256] At 20°C, HOBt (3.39 g, 1.50 eq), DIEA (8.73 mL, 3.00 eq), EDCI (4.80 g, 1.50 eq) and compound 2b (3.30 g, 1.05 eq) were slowly added to a solution of compound 1b (5.00 g, 1.00 eq) in DMF (50.0 mL). The reaction solution was stirred at 20°C for 2 hours. Compound 3b (3.10 g, purity 90.5%) was obtained by purification.

[0257] Step 2:

[0258]

[0259] Compound 3b (2.00 g, 1.00 eq) was dissolved in DCM (10.0 mL), and TFA (9.06 mL, 31.6 eq) was added thereto. The mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 4b.

[0260] Step 3:

[0261]

[0262] At 20°C, HOBt (719 mg, 1.50 eq), DIEA (3.09 mL, 5.00 eq), EDCI (1.02 g, 1.50 eq) and compound 5b (2.03 g, 1.00 eq) were slowly added to a solution of compound 4b (2.06 g, 1.20 eq) in DMF (20.0 mL). The reaction solution was stirred at 20°C for 12 hours. Compound 6b (2.40 g, purity 100%) was obtained by purification.

[0263] Step 4:

[0264]

[0265] Compound 6b (2.00 g, 1.00 eq) was dissolved in methanol (40.0 mL), and wet palladium carbon (200 mg, purity 10%, 8.68e-2 eq) was added thereto. The reaction was stirred at 20°C and H2 (15.0 Psi) for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 7b.

[0266] Step 5:

[0267]

[0268] At 20°C, HOBt (100 mg, 1.50 eq), DIEA (259 μL, 3.00 eq), EDCI (143 mg, 1.50 eq) and compound 8b (131 mg, 1.05 eq) were slowly added to a solution of compound 7b (393 mg, 1.00 eq) in DMF (4.00 mL). The reaction solution was stirred at 20°C for 12 hours. Compound 9b (360 mg) was obtained by purification.

[0269] Step 6:

[0270]

[0271] Compound 9b (360 mg, 1.00 eq) was dissolved in methanol (8.00 mL), and wet palladium carbon (36.0 mg, purity 10%, 9.62e-2 eq) was added thereto. The reaction was stirred at 20°C and H2 (15.0 Psi) for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 10b.

[0272]

[0273] At 20°C, slowly add Int1 (250 mg, 1.10 eq), BOP (113 mg, 1.00 eq), and DIEA (133 μL, 3.00 eq) to a solution of compound 10b (78.8 mg, 1.00 eq) in DMF (3.00 mL). The reaction solution was stirred at 20°C for 1 hour. The reaction solution was prepared with reverse phase (hydrochloric acid) to obtain compound 11b (180 mg).

[0274] Step 8:

[0275]

[0276] At 20°C, TFA / TIS / H2O (V:V=95%:2.5%:2.5, 2.00 mL) was added to compound 11b (180 mg, 1.00 eq). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was prepared by reverse phase (hydrochloric acid) to obtain NYM047 (12.0 mg, purity 96.0%).

[0277] LCMS:MS:[M] + =1011.4( Figure 7 (shown)

[0278] HPLC: Rt = 13.1 min, purity: 96.0% ( Figure 8 (shown)

[0279] 1 H NMR: 400MHz, D2O( Fig. 9 (shown)

[0280] δ:7.27-7.24(m,2H),7.21-7.19(m,1H),7.15-1.13(m,2H),4.50-4.45(m,1H),3.87-3.84(m,8H),3.33-3.11(m,17H),3.14-3 .12(m,5H),3.06-3.04(m,1H),2.62-2.60(m,2H),2.27-2.25(m,2H),2.24-2.18(m,2H),1.68-1.43(m,4H),135-1.34(m,9H).

[0281] 5. Synthesis steps of NYM048

[0282] Step 1:

[0283]

[0284] At 20°C, Int1 (200 mg, 1.10 eq), BOP (101 mg, 1.00 eq), and DIEA (120 μL, 3.00 eq) were slowly added to a solution of compound 7b (70.9 mg, 1.00 eq) in DMF (2.00 mL). The reaction solution was stirred at 20°C for 2 hours. Compound 12b (280 mg) was obtained by purification.

[0285] Step 2:

[0286]

[0287] At 20°C, TFA / TIS / H2O (V:V=95%:2.5%:2.5, 2.00 mL) was added to compound 12b (100 mg, 1.00 eq). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was prepared by reverse phase (hydrochloric acid) to obtain NYM048 (12.0 mg, 13.0 μmol, purity 99.0%).

[0288] LCMS:MS:[M] + =912.3( Fig.10 (shown)

[0289] HPLC: Rt = 6.17 min, purity: 99.0% ( Fig.11 (shown)

[0290] 1 H NMR: 400MHz, D2O( Fig.12 (shown)

[0291] δ:7.29-7.21(m,4H),7.16-7.14(m,1H),4.52–4.51(m,1H),4.74-4.73(m,8H),3.31-3.25( m,14H),3.12-3.09(m,6H),2.95-2.91(m,1H),2.50(m,2H),2.23(m,2H),1.48-1.36(m,9H).

[0292] 6. Synthesis steps of NYM049

[0293] Step 1:

[0294]

[0295] At 0°C, slowly dropwise add compound 1c (22.0 g, 1.00 eq) dissolved in THF (200 mL) to a THF solution of LiAlH4 (139 mL, 3.96 eq), and stir the reaction solution at 40°C for 0.5 hours. At 0°C, with N2 blowing, slowly dropwise add H2O (13.2 mL), 15% NaOH (13.2 mL) solution and H2O (40.0 mL) to the reaction solution in sequence to quench the reaction, and purify to obtain compound 2c (11.5 g, purity 91.0%).

[0296] Step 2:

[0297]

[0298] TsCl (48.0 g, 4.00 eq) and TEA (26.2 mL, 3.00 eq) were added to a solution of compound 2c (11.5 g, 1.00 eq) in DCM (250 mL), and the reaction solution was stirred at 25° C. for 12 hours. Compound 3c (23.0 g, purity 93.3%) was obtained by purification.

[0299] Step 3:

[0300]

[0301] KCN (8.43 g, 5.07 eq) was added to a stirred solution of compound 3c (13.0 g, 1.00 eq) in DMSO (140 mL) at 25°C, and the mixture was heated to 80°C and stirred for 3.5 hours to obtain compound 4c (4.70 g, purity 87.7%).

[0302] Step 4:

[0303]

[0304] Compound 4c (7.60 g, 1.00 eq) was dissolved in MeOH (140 mL), HCl gas (12.0 M, 114 mL, 33.2 eq) was passed into the solution at 0°C for 0.25 hours, and then the reaction mixture was stirred at 80°C for 10 hours. The mixture was concentrated in vacuo to obtain compound 5c (10.1 g, 40.3 mmol).

[0305] Step 5:

[0306]

[0307] Compound 5c (4.00 g, 1.00 eq) was dissolved in a mixed solution of THF (60.0 mL) and H2O (60.0 mL), and LiOH·H2O (670 mg, 1.00 eq) was added, and stirred at 0°C for 1 hour. Compound 6c (1.30 g, purity 93.3%) was obtained by purification.

[0308] Step 6:

[0309]

[0310] Compound 6c (0.90 g, 3.55 mmol, 1.00 eq) was added to a mixed solution of DCM (16 mL) and DMF (0.16 mL), (COCl) 2 (902 mg, 2.00 eq) was added at 0°C, stirred at 25°C for 0.5 h, concentrated in vacuo, and the residue was dissolved in DCM (16.0 mL). The solution was then added to a solution of compound 2a (704 mg, 1.10 eq) and Py (573 μL, 2.00 eq) in DMF (16.0 mL), and stirred at 0°C for 8 h. Compound 7c (1.20 g) was obtained after purification.

[0311] Step 7:

[0312]

[0313] Compound 7c (1.10 g, 1.00 eq) was dissolved in a mixed solution of H2O (12.0 mL) and THF (12.0 mL), and then LiOH·H2O (278 mg, 2.40 eq) was added and stirred at 25°C for 1 h. Int 2 (1.00 g, purity 96.2%) was obtained after purification.

[0314] Step 8:

[0315]

[0316] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0317] 1) Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol / g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing, drain until no liquid flows out.

[0318] 2) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0319] 3) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

[0320] 4) Condensation: Alloc-Cl (1.00 mmol, 2.00 eq) was dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (2.00 mmol, 4.00 eq), and the reaction was stirred with nitrogen at 20°C for 20.0 min, and this step was repeated twice. The resin was washed with DMF.

[0321] 5) Condensation: N-Fmoc-1,4-diaminobutane HCl (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were added to the resin, and DMF (30.0 mL) was added, followed by dropwise addition of DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0322] 6) Deprotection: 20% piperidine (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0323] 7) Condensation: DOTA(tBu*3) (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0324] 8) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

[0325] 9) Condensation: Fmoc-Apa-OH (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL), added to the resin, and then DIEA (3.00 mmol, 6.00 eq) was added, and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0326] 10) Deprotection: 20% piperidine (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0327] 11) Condensation: Int 2 (0.75 mmol, 1.50 eq) and HOAt (0.73 mmol, 1.45 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq), and the reaction was stirred with nitrogen at 20°C for 30.0 min. The resin was washed with DMF.

[0328] Peptide cleavage and purification:

[0329] The resin was shrunk with MeOH (30.0 mL) and was drained until no liquid flowed out. The resin was poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of the prepared cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H2O and 2.5% 3-MPR) and shaken on a shaker for 2 h. After filtration, the filtrate was added to ice isopropyl ether (100 mL) for sedimentation centrifugation and then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain the crude peptide.

[0330] Compound NYM049 (15.0 mg, 12.8 μmol, purity 95.42%) was obtained directly by reverse phase preparation (A: H2O containing 0.075% TFA, B: ACN acetonitrile).

[0331] LCMS:MS:[M+H] + =1055.6( Fig.13 (shown)

[0332] HPLC: Rt = 10.2 min, purity: 95.42% ( Fig.14 (shown)

[0333] 1 H NMR: 400 MHz, D2O.( Fig.15 (shown)

[0334] δ:7.12-7.19(m,4H),7.01(m,1H),4.55(t,J=7.6Hz,1H),3.72(m,6H),3.02-3.46(m,24H),2. 64-2.86(m,5H),2.52-2.56(m,2H),2.20-2.36(m,4H),1.50-1.57(m,2H),1.39-1.47(m,6H).

[0335] 7. Synthesis steps of NYM050

[0336] Step 1:

[0337]

[0338] NaNO2 (7.77 g, 112 mmol, 2.00 eq) was dissolved in H2O (15.0 mL) and added dropwise to compound 2b (15.0 g, 56.3 mmol, 1.00 eq), KBr (24.8 g, 208 mmol, 9.02 mL, 3.7 eq), HBr (28.4 g, 140 mmol, 19.1 mL, purity 40%, 2.50 eq) in H2O (300 mL) at 0°C. The reaction solution was stirred at 20°C for 12 h. Compound 1d-1 (3.30 g, purity 100%) was obtained after purification.

[0339] Step 2:

[0340]

[0341] Compound 1d-1 (5.30 g, 1.00 eq) and then O-tert-butyl-N,N'-diisopropylisourea (6.43 g, 2.00 eq) were added to DCM (55.0 mL), and stirred at 25° C. for 12 h. Compound 2d-1 (4.75 g, purity 98.7%) was obtained by purification.

[0342]

[0343] Compound 2d-2 (1.05 g, 1.50 eq) and K2CO3 (375 mg, 2.00 eq) were added to a DMF (10.0 mL) solution, and then compound 2d-1 (700 mg, 1.00 eq) was added. The mixture was then stirred at 50°C for 12 h. Compound 3d-1 (1.00 g, purity 98.1%) was obtained by purification.

[0344] Step 4:

[0345]

[0346] Compound 3d-1 (700 mg, 1.00 eq) was added to a mixed solution of THF (7.00 mL) and deionized water (0.05 mL), and Pd / C (70.0 mg, 10% purity, 0.10 eq) was added under nitrogen protection. The suspension was degassed and replaced with hydrogen. The reaction solution was stirred at H2 (15 psi) and 35°C for 12 h. The suspension was filtered, and the filtrate was filtered out under reduced pressure to obtain compound Int 3 (500 mg, purity 84.6%).

[0347] Step 5:

[0348]

[0349] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0350] 1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol / g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

[0351] 2) Deprotection: 20% piperidine / DMF (V:V) (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0352] 3) Condensation: Fmoc-Apa-OH (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were added to the resin, DMF (30.0 mL) was added, and DIEA (3.00 mmol, 6.00 eq) was added dropwise, and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0353] 4) Deprotection: 20% piperidine (30.0 mL) was added to the resin and stirred with nitrogen for 30 min. The resin was washed with DMF and dried.

[0354] 5) Condensation: Int 2 (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq), and the reaction was stirred with nitrogen at 20°C for 3.00 h. The resin was washed with DMF.

[0355] 6) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

[0356] 7) Condensation: Int 3 (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq), and the reaction was stirred with nitrogen at 20°C for 8.00 h. The resin was washed with DMF.

[0357] Peptide cleavage and purification:

[0358] The dried resin was added to 10 mL of a prepared cutting solution (composed of 90% TFA, 2.5% H2O, 2.5% TIS and 5% 3-Mpr), heated and ultrasonicated for 2 h, and dried to obtain a crude peptide.

[0359] The crude peptide was purified by reverse phase preparative HPLC (A: H2O containing 0.075% TFA, B: MeOH:ACN = 1:1) to give the final product NYM050 (20.0 mg, purity 98.17%).

[0360] LCMS:MS:[M+H] + =1042.6( Fig.16 (shown)

[0361] HPLC: Rt = 8.04 min, purity: 98.17% ( Fig.17 (shown)

[0362] 1 H NMR: 400 MHz, D2O.( Fig.18 (shown)

[0363] δ:12.98(s,1H),8.31-8.18(m,2H),7.88-7.85(m,1H),7.26-7.15(m,5H),4.50(m,1H),3.81(m, 3H),3.60(m,3H),3.18-2.99(m,21H),2.67-2.56(m,7H),2.11-2.09(m,4H),1.66-1.32(m,8H).

[0364] 8. Synthesis steps of NYM070

[0365]

[0366] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry

[0367] 1) Weigh 0.50mmol of 2-CTC resin (Substitution = 0.70mmol / g) and Fmoc-Asp-OAll (0.50mmol, 1.00eq) into a reaction column, add 30.0mL of DCM, then drop DIEA (2.00mmol, 4.00eq), and adjust the nitrogen to make the resin evenly bulge. After reacting at 20°C for 2 hours, drop MeOH (0.80mL) into the reaction column, blow nitrogen for 30 minutes, and drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

[0368] 2) Deprotection: 20% piperidine / DMF (V:V) (50.0 mL) was added to the resin and stirred with nitrogen for 15 minutes. The resin was washed with DMF and dried.

[0369] 3) Coupling of amino acids: Weigh Fmoc-5-aminopentanoic acid (1.50 mmol, 3.00 eq) and HBTU (1.425 mmol, 2.85 eq) into the above resin, add 25.0 mL of DMF, then drop DIEA (3.00 mmol, 6.00 eq) into the reaction column, adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF for washing, and drain until no liquid flows out.

[0370] 4) Deprotection: 20% piperidine / DMF (V:V) (50.0 mL) was added to the resin and stirred with nitrogen for 15 minutes. The resin was washed with DMF and dried.

[0371] 5) After washing the resin with DMF, add 25.0 mL of THF, first add DIEA (2.00 mmol, 4.00 eq), then slowly add NsCl (1.00 mmol, 2.00 eq) into the THF solvent, and adjust the nitrogen to make the resin swell evenly. React for one hour, remove the reaction liquid, add DMF for washing, and drain until no liquid flows out.

[0372] 6) After washing the resin with DMF, add 25.0 mL of THF, first add triphenylphosphine (2.50 mmol, 5.00 eq), 2-naphthol (1.00 mmol, 2.00 eq), react for 5 min, then slowly add DEAD (2.50 mmol, 5.00 eq) dropwise into the reaction solution, and adjust the nitrogen to make the resin swell evenly. After reacting for one hour, remove the reaction solution, add DMF (30.0 mL) for washing, and drain until no liquid flows out.

[0373] 7) NS removal: Add 30.0 mL of DMF and sodium thiophenolate (1.00 mmol, 2.00 eq), adjust the nitrogen gas to make the resin swell evenly, and react for one hour.

[0374] 8) Coupling of amino acids: Int 1 (1.50 mmol, 3.00 eq) and HOAt (1.50 mmol, 3.00 eq) were weighed into the above resin, 25.0 mL of DMF was added, and DIC (1.50 mmol, 3.00 eq) was added dropwise to the reaction column, and nitrogen was adjusted to make the resin swell evenly. After reacting at 20°C for 50 minutes, the reaction liquid was removed, and DMF (30.0 mL) was added for washing, and the waste was discharged until no liquid flowed out.

[0375] 9) Deallylation: The resin was washed with DMF 3 times and DCM 3 times, an appropriate amount of DCM was added and nitrogen was bubbled in, PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.100 eq) were added in sequence and reacted for 15 minutes, the reaction liquid was removed, DMF (30.0 mL) was added for washing, and the mixture was discharged until no liquid flowed out.

[0376] 10) Coupling of amino acids: Weigh N-Fmoc-1,4-butanediamine hydrochloride (1.50mmol, 3.00eq) and HOAt (1.50mmol, 3.00eq) into the above resin, add 25.0mL of DMF, then drop DIC (1.50mmol, 3.00eq) into the reaction column, and adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF (30.0mL) for washing, and drain until no liquid flows out;

[0377] 11) Coupling of amino acids: Weigh NOTA(tBu)2-OH (1.50mmol, 3.00eq) and HOAt (1.50mmol, 3.00eq) into the above resin, add 25.0mL of DMF, then drop DIC (1.50mmol, 3.00eq) into the reaction column, adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF (30.0mL) for washing, and drain until no liquid flows out;

[0378] 12) Use MeOH (30.0 mL) to shrink the resin and drain until no liquid flows out. Use nitrogen to blow dry the resin and set aside.

[0379] Peptide cleavage and purification:

[0380] At room temperature, the dried resin was added to the prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr) and ultrasonically cut for 2.5 hours. Filtered, the filtrate was added to ice isopropyl ether for sedimentation centrifugation, and then washed with isopropyl ether. Drying under vacuum for 2 hours gave the crude peptide NYM070 (500 mg).

[0381] The crude peptide was purified by preparative HPLC to obtain the final product NYM070 (14.0 mg, purity 96.6%).

[0382] LCMS:MS observed:[M+H]+=1018.4( Fig.59 (shown)

[0383] HPLC: Purity: 96.6% ( Fig.60 (shown)

[0384] 9. Synthesis steps of NYM071

[0385] Step 1:

[0386]

[0387] Compound 2a_1 (1.38 g, 1.10 eq) was added to a DMF (20 mL) solution containing compound 2a_1 (2.00 g, 1.00 eq), HATU (3.81 g, 1.50 eq) and DIEA (3.49 mL, 3.00 eq), and the reaction mixture was reacted at 25°C for 1 h. Compound 3a_1 (3.00 g) was obtained after purification.

[0388] Step 2:

[0389]

[0390] Compound 3a_1 (1.00 g, 1.00 eq) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was reacted at 20° C. for 0.5 hours. The reaction solution was spin-dried to obtain compound 4a_1 (700 mg).

[0391] Step 3:

[0392]

[0393] Compound 4a_1 (640.1 mg, 1.20 eq) was added to a DMF (10 mL) solution containing compound 5a_1 (600 mg, 1.00 eq), HOBt (292.6 mg, 1.50 eq), EDCI (415.2 mg, 1.50 eq) and DIEA (754.5 μL, 3.00 eq), and the mixture was reacted at 25° C. for 12 h. Compound 6a_1 (780 mg, purified 97.7%) was obtained by purification.

[0394] Step 4:

[0395]

[0396] Wet palladium carbon (100 mg, purity 10%) was added to a solution of compound 6a_1 (380 mg, 1.00 eq) in methanol (4 mL), and the reaction solution was reacted at 20° C. for 3 h under a 15 psi hydrogen atmosphere. The reaction solution was filtered through celite and concentrated to obtain compound 7a_1 (270 mg).

[0397] Step 5:

[0398]

[0399] Compound 7a_1 (158.04 mg, 1.10 eq) was added to a DMF (10 mL) solution containing compound Int 1 (70 mg, 1.00 eq), BOP (150.6 mg, 1.50 eq) and DIEA (118.6 μL, 3.00 eq), and the reaction mixture was reacted at 25° C. for 1 h. Compound 8a_1 (100 mg) was obtained after purification.

[0400] Step 6:

[0401]

[0402] A mixed solution of trifluoroacetic acid (5 mL), triisopropylsilane (0.13 mL) and water (0.13 mL) was added to compound 8a_1 (100 mg, 1.00 eq), and the reaction solution was reacted at 25°C for 1.5 h. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified to obtain NYM071 (15.0 mg, purity: 99.7%).

[0403] LCMS: MS: [M+H]+ = 811.3 (as Fig.61 (shown)

[0404] HPLC: Purity: 99.7% (as Fig.62 (shown)

[0405] 10. Synthesis steps of NYM073

[0406] Step 1:

[0407]

[0408] Compound 1c-1 (1.00 g, 1.00 eq) was dissolved in N,N-dimethylformamide (10.0 mL), and compound 2a (451 mg, 1.00 eq), O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (796 mg, 1.20 eq) and N,N-diisopropylethylamine (912 μL, 3.00 eq) were added thereto. The reaction was stirred at 25°C for 1 hour, and compound 2c-1 (990 mg) was obtained after purification.

[0409] Step 2:

[0410]

[0411] Compound 2c-1 (990 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (10.0 mL) and water (0.04 mL), and Pd / C (99.0 mg, purity: 10.0%, 7.30 e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 16 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The mixture was dried under rotary evaporation to obtain compound 3c-1 (810 mg).

[0412] Step 3:

[0413]

[0414] Compound 4c-1 (231 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), 1-hydroxybenzotriazole (126 mg, 1.50 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 1.50 eq), N,N-diisopropylethylamine (325 μL, 3.00 eq) and compound 3c-1 (400 mg, 1.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 5c-1 (120 mg) was obtained after purification.

[0415] Step 4:

[0416]

[0417] Compound 5c-1 (120 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (1.20 mL) and water (0.04 mL), and Pd / C (12.0 mg, purity: 10.0%, 9.36e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 3 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The mixture was dried under rotary evaporation to obtain compound 6c-1 (102 mg).

[0418] Step 5:

[0419]

[0420] Int 1 (40.1 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (1.00 mL), compound 6c-1 (102 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphine salt (52.3 mg, 1.00 eq) and N,N-diisopropylethylamine (61.8 μL, 3.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 7c-1 (58.0 mg) was obtained after purification.

[0421] Step 6:

[0422]

[0423] Compound 7c-1 (58.0 mg, 1.00 eq) was dissolved in trifluoroacetic acid (0.57 mL, 152 eq), triisopropylsilane (15.00 μL, 1.00 eq) and water (0.015 mL). The reaction was stirred at 25°C for 3 hours. NYM073 (11.0 mg, purity 99.7%, TFA) was obtained after purification.

[0424] LCMS: MS: [M+H] + = 928.3. (as Fig.63 (shown)

[0425] HPLC: Purity: 99.7% (as Fig.64 (shown)

[0426] 11. Synthesis steps of NYM074

[0427] Step 1:

[0428]

[0429] Compound 1d (217 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), 1-hydroxybenzotriazole (126 mg, 1.50 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 1.50 eq), N,N-diisopropylethylamine (325 μL, 3.00 eq) and compound 3c-1 (400 mg, 1.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 2d (120 mg) was obtained after purification.

[0430] Step 2:

[0431]

[0432] Compound 2d (120 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (1.20 mL) and water (0.04 mL), and Pd / C (12.0 mg, purity: 10.0%, 9.15e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 4 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The compound 3d (103 mg) was obtained by rotary drying under rotary evaporation.

[0433] Step 3:

[0434]

[0435] Int 1 (41.5 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (3.00 mL), compound 6c (103 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphine salt (54.2 mg, 1.00 eq) and N,N-diisopropylethylamine (64.0 μL, 3.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 4d (100 mg) was obtained after purification.

[0436] Step 4:

[0437]

[0438] Compound 4d (100 mg, 1.00 eq) was dissolved in a mixed solution of trifluoroacetic acid (0.950 mL, 144 eq), triisopropylsilane (0.025 mL, 1.00 eq) and water (0.025 mL). The mixture was stirred at 25°C for 3 hours. NYM074 (12.0 mg, purity 99.9%, TFA) was obtained after purification.

[0439] LCMS: MS: [M+H] + = 962.3. (as Fig.65 (shown)

[0440] HPLC: Purity: 99.9% (as Fig.66 (shown)

[0441] Example 2: Labeling process of compounds

[0442] 1. Nuclide 68 Ga marking process:

[0443] The compound prepared in Example 1 was treated with 68 Ga was used to label the target product. 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074, the specific process is as follows:

[0444] a. Elute the germanium gallium generator: Use a 10ml syringe to extract 5ml of 0.1M HCl solution, connect the syringe to the generator inlet, slowly push the syringe to elute the germanium gallium generator, and collect the effluent to obtain 68 5ml of GaCl3 hydrochloric acid solution.

[0445] b. Neutralization reaction solution: 68 To the hydrochloric acid solution of GaCl3 was added 4.0 ml of 0.15 M acetic acid / sodium acetate solution (pH 7.2).

[0446] c. Chelation reaction: Add 60 μg / 60 μl of NYM045 / 046 / 047 / 048 / 049 / 050 / 074 precursor solution (sterile water for injection) to the neutralization solution, shake well and place at 70-80°C for reaction for 10 min. After the reaction is completed, take out the reaction bottle and cool it down.

[0447] d. Purification: Take a disposable Sep-Pak C-18 column and activate it with 10mL anhydrous ethanol and 20mL sterile water for injection. Take a 10mL sterile syringe, draw 5mL of sterile water for injection in advance, and then draw 5mL of reaction solution, then connect the C-18 column to push the liquid in the syringe through the C-18 column, the target product is adsorbed on the C-18 column, then draw 20mL of sterile water for injection to rinse the C-18 column, and finally use 1.2mL 70% anhydrous ethanol solution to elute the C-18, and elute the target product into the transfer bottle.

[0448] e. Filtration sterilization: Use a syringe to draw in 3.8 mL of normal saline, inject the normal saline into the transfer bottle and mix well, draw out all the product solution (crude product) in the transfer bottle, filter it through a 0.22 μm sterile filter membrane into a 10 mL sealed sterile vial to obtain the target product sterile injection solution, i.e. 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074 sterile injection solution.

[0449] Determination by Radio-iTLC method 68 The radiochemical purity (RCP) of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074 sterile injection products is >90%. Figures 19 to 25 As shown, 68 The RCP of Ga-NYM045 is 95.55%; 68 The RCP of Ga-NYM046 is 97.53%; 68 The RCP of Ga-NYM047 is 98.77%; 68 The RCP of Ga-NYM048 is 98.64%; 68 The RCP of Ga-NYM049 is 98.71%; 68 The RCP of Ga-NYM050 is 95.45%; 68 The RCP of Ga-NYM074 is 99.96%.

[0450] 2. Nuclide 18 F marking process:

[0451] Collection Accelerator contains 18 The solution of F was purified by QMA column and eluted with 0.3 mL of normal saline. 3.6 mL of DMSO, 100 μL of aqueous solution (1 mg / mL) containing the precursor (NYM070 / NYM071), 27 μL of aluminum chloride aqueous solution (2 mM) and QMA eluent were added to the reaction bottle. After the reaction bottle was capped, it was placed at 80°C for 15 minutes. After the reaction was completed, it was cooled to room temperature. 6 mL of sterile water for injection was added to the reaction bottle to dilute the reaction solution, and then 3 mL of the diluted reaction solution and 7 mL of sterile water for injection were extracted. After mixing, it was passed through the activated C18 column for column loading. Repeat three times until the column loading was completed. Rinse the C18 column with 10 mL of sterile water for injection. After repeating twice, elute with 1.5 mL of 70% ethanol solution. Collect the eluate in the product bottle and send it for sample testing. Determined by Radio-iTLC method 18 The radiochemical purity (RCP) of F-NYM070 / 071 sterile injection products were 98.6% and 99.92%, respectively. Figures 26-27 shown.

[0452] 3. Nuclide 177 Lu's marking process:

[0453] Add 0.5 mL of sodium acetate / acetic acid buffer solution (pH = 7.2) to the reaction bottle, add 60 μL of NYM073 / NYM074 precursor aqueous solution (containing 60 μg), mix thoroughly, and then add 0.5 mL 177LuCl3 0.05M hydrochloric acid solution, the reaction solution was reacted at 80℃ for 10min, the reaction was terminated, the reaction solution was filtered through a sterile filter membrane, collected in a vacuum bottle, and sampled for detection. Determination by Radio-iTLC method 177 The radiochemical purity (RCP) of the Lu-NYM073 / 074 sterile injection products were 100% and 99.19%, respectively. Figures 28-29 shown.

[0454] Example 3: SPR affinity test of compounds

[0455] The affinity of NYM045 / 046 / 047 / 048 / 049 / 050 compounds to CAIX was determined using the Biacore 8K protein interaction system. Benzothiazine was used as a positive control, which has a strong affinity for CAIX protein.

[0456] CAIX (purchased from ACROBiosystems Inc, 0.5 mg / mL) was coupled to the surface of the CM5 chip, and the sample molecules were diluted with running buffer (HBS-EP buffer) (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% (v / v) Surfactant P20 (Tween20)), 5% DMSO, pH 7.4). The sample was diluted with a series of different concentrations of the sample solution in equal proportion by DMSO solvent (dilution ratio: 2), and the sample was injected and the affinity of the sample to CAIX was measured. The affinity of the sample NYM045 / 046 / 047 / 048 / 049 / 050 / 070 / 071 / 073 / 074 to CAIX is represented by the equilibrium dissociation constant KD (Kd / Ka) value, where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity of the compound to the protein. The test results are shown in Table 1 below. It was found that among the tested compounds, NYM046, NYM048, NYM049, NYM050, NYM070, NYM071, NYM073, and NYM074 showed low nanomolar affinity for CA9 and had a strong affinity for CA9.

[0457] Table 1

[0458] Molecules to be tested KD(nM) NYM045 8.82±1.07 NYM046 4.98±0.50 NYM047 15.5±2.52 NYM048 3.20±0.31 NYM049 4.14±0.14 NYM050 4.36±0.47 NYM070 2.78±0.45 NYM071 2.09±0.21 NYM073 6.87±0.18 NYM074 0.65±0.02

[0459] Example 4: PET / CT scanning tissue distribution and targeting experiment of target product in OS-RC-2 model mice

[0460] 1. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB / c nude mice, which is a mouse model constructed with human renal cancer cells.

[0461] The experimental steps are as follows:

[0462] 24 mice were selected and divided into 6 groups, namely 045, 046, 047, 048, 049, and 050, with 4 mice in each group. Each mouse in each group was given 80-120 μCi of the corresponding drug, and the mice were scanned by MicroPET / CT (SNPC-303 SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) 1 hour after administration. The scanned images were obtained after reconstruction by the equipment software, and the scanned images were analyzed.

[0463] The experimental results of tumor drug uptake are as follows Fig.30 , Fig.31 and Fig.32 As shown (the arrow indicates the tumor uptake), 68 Ga-NYM045, 68 Ga-NYM046, 68 Ga-NYM048, 68 Ga-NYM049, 68 The uptake of Ga-NYM050 drug was high at the tumor site, and significant uptake of the drug was observed at the tumor site 1 hour after injection. Fig.32 As shown, the kidney 68 Ga-NYM045, 68 Ga-NYM049, 68 Ga-NYM050 intake is low, liver 68 Ga-NYM049, 68 Ga-NYM050 has a low uptake; NYM046, 68 Ga-NYM048 uptake is low; lung 68 Ga-NYM045, 68 Ga-NYM046, 68 Ga-NYM048, brain and muscle 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 uptake is very low. The data results of the ratio of tumor tissue uptake to non-target organ uptake (target-to-substance ratio) show that 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 has a high tumor-to-muscle uptake ratio and has potential value in being used as an imaging agent to diagnose tumor diseases.

[0464] 2. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0465] The experimental steps are as follows:

[0466] The mouse models were randomly selected and divided into 6 groups, namely group 045 (4 mice), group 046 (3 mice), group 047 (4 mice), group 048 (3 mice), group 049 (4 mice), and group 050 (4 mice). Each group of mice was given the above 68 The animals were subjected to a 30-minute MicroPET / CT dynamic scan after administration of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 drug at 60-120 μCi. Static scans were performed at 1, 2, and 3 hours after administration. Scan images were obtained after reconstruction by the device software. The scan images are shown in the attached figure. Figures 33-38 As shown, the scanned image is analyzed.

[0467] As attached Fig.33 As shown, 68 One hour after administration, Ga-NYM045 showed high radioactivity uptake in the tumor, but not in other normal tissues. 68 Ga-NYM045 drug is rapidly excreted through the kidneys; Fig.34 As shown, 68 One hour after administration of Ga-NYM046, it was found that the radioactive uptake of the drug was obvious in the tumor and maintained at a high level for 3 hours without a significant downward trend. 68 Ga-NYM046 drug can be absorbed for a long time in tumors or metastases; Fig.36 As shown, 68 One hour after administration of Ga-NYM048, it was found that its uptake in the tumor was obvious. Until 3 hours, the uptake value did not change significantly, with no obvious increase or decrease trend. In other organs, the uptake gradually decreased, and in normal tissues, the uptake 68 Ga-NYM048 drug can be rapidly excreted through the kidneys; Fig.37 As shown, 68 One hour after administration of Ga-NYM049, it was found that its uptake in the tumor was obvious, and the uptake value did not change significantly until 3 hours, with no obvious increase or decrease trend, while the uptake in other normal tissues gradually decreased; as shown in the attached Fig.38 As shown, 68 One hour after administration of Ga-NYM050, it was found that its uptake value in the tumor was obvious. Until 3 hours, the uptake value did not change much, with no obvious increase or decrease trend. However, the uptake in other organs gradually decreased, and the uptake in normal tissues was 68Ga-NYM050 is rapidly excreted by the kidneys.

[0468] Changes in tumor radioactivity uptake are shown in the attached Fig.39 As shown, 68 Ga-NYM046, 68 Ga-NYM048, 68 Ga-NYM049, 68 One hour after administration, Ga-NYM050 drug can be rapidly enriched in the tumor and has high uptake at the tumor location; the high uptake can be maintained for 3 hours, while the uptake in other non-target organs gradually decreases.

[0469] 3. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB / c nude mice, which is a mouse model constructed with human renal cancer cells.

[0470] The experimental steps are as follows:

[0471] Two mice were selected and each mouse was given 68 Ga-NYM07480μCi, the animals were subjected to dynamic scanning with MicroPET / CT (SNPC-303 SuperNova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) 1h after administration, and static scanning was performed 2h after administration. The scanned images were reconstructed by the equipment software and analyzed.

[0472] The experimental results of tumor drug uptake are shown in the attached Fig.40 As shown (the arrow indicates the tumor uptake), 68 Ga-NYM074 can quickly accumulate at the tumor site, and 1 hour after drug injection, the tumor-background uptake ratio is high, and significant drug uptake can be seen at the tumor. 2 hours after administration, the tumor still maintains high uptake.

[0473] The experimental results of drug uptake by various tissues are shown in the attached Fig.41 and 42 As shown, the data results of the ratio of tumor tissue uptake to non-target organ uptake show that 68 The ratio of Ga-NYM074 uptake in tumors to muscle in mice gradually increased over time, and it has potential value as an imaging agent in the diagnosis of tumor diseases.

[0474] Embodiment 5: 68 Ga-NYM050OS-RC-2 model competitive inhibition experiment

[0475] 1. Experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB / c nude mice, which is a mouse model constructed with human renal cancer cells.

[0476] The experimental steps are as follows:

[0477] The experiment was divided into two parts: one baseline experiment and one blocking experiment.

[0478] Four mice were selected for the baseline experiment, and each mouse was given 68 Ga-NYM050 drug 80Ci, mice were scanned by MicroPET / CT at 0.5h, 1h, and 2h after administration, and the scanned images were obtained after reconstruction by the equipment software. The scanned images were analyzed and the experimental results are shown in the attached Fig.43 , 45 shown.

[0479] On the second day of the baseline experiment, the blocking experiment used the same animals as the baseline experiment. Each mouse was first given NYM050 at an injection dose of 68 40 times the weight of Ga-NYM050 drug; injected 1 hour after NYM050 68 Ga-NYM050 80μCi, and MicroPET / CT scans were performed at 0.5h, 1h, 2h, and 3h after administration. Scanned images were obtained after reconstruction by the equipment software and analyzed. The experimental results are shown in the attached Fig.44 , 46 shown.

[0480] It can be seen that in the baseline experiment, the drug alone 68 After 1 hour of Ga-NYM050, it was found that it had clear imaging at the tumor site and there was no obvious downward trend within 2 hours; in the blocking experiment, the addition of NYM050 in advance could significantly block the tumor 68 The uptake of Ga-NYM050 confirmed 68 Ga-NYM050 is able to specifically recognize tumors.

[0481] Embodiment 6: 177 Lu-NYM073 / 177 Lu-NYM074 SPECT / CT scanning experiment in OS-RC-2 model

[0482] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0483] Experimental steps:

[0484] One animal model mouse was selected. Each animal was given 177 Lu-NYM073 / 177 The drug Lu-NYM074 was administered at 300 μCi, and SPECT / CT scans of small animals were performed at 4 h, 24 h, 48 h, 96 h, and 120 h after administration to obtain scanned images, which were then analyzed.

[0485] By the attached Fig.47 It can be seen that 177 Lu-NYM073 was enriched in the tumor (arrow in the figure) 4 hours after administration, and the uptake in normal tissues gradually decreased. 177 Lu-NYM074 was enriched in the tumor (arrow in the figure) 6 hours after administration, and the organ uptake in normal tissues gradually decreased; until 120 hours later, the target product was still taken up in the tumor, which shows that the retention time of this target product in the tumor is long, which is beneficial to the treatment of clinical tumor diseases, and the uptake of non-target organs is reduced and cleared quickly.

[0486] Example 7: Experimental study on the efficacy of the target product in model mice

[0487] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0488] Experimental steps:

[0489] Fifteen mice were randomly selected and divided into three groups, each with five mice, namely, saline group, single-dose group, and multiple-dose group. 177 Lu-NYM074 drug 2mCi, each mouse was given once, by tail vein injection; multiple groups were given to each animal 177 Lu-NYM074 was administered twice, 2 mCi each time, seven days apart, by tail vein injection; the weight and tumor volume of mice were measured before the experiment, and every three days after administration. The long and short diameters of the tumor were measured to calculate the tumor volume, and the calculation formula is as follows: tumor volume (TV) = a × b 2 / 2 (a is the long diameter, b is the short diameter), and the tumor growth inhibition rate TGI was calculated.

[0490] 33 days and 40 days after administration, the TGI values ​​of the single-dose group were 33.4% and 24.8%, respectively, and the TGI values ​​of the multiple-dose group were 76.2% and 72.9%, respectively. Fig.48It can be seen that compared with the saline group, the single and multiple groups showed significant anti-tumor activity and could significantly control tumor growth. The tumor growth in the multiple groups was slower, showing the dependence of tumor on drug dose. In the three groups of experiments, the weight change trend of mice was slightly different between groups, as shown in the attached Fig.49 As shown, it can be seen that this drug has good anti-tumor efficacy and good safety.

[0491] Example 8: In vitro tissue distribution experiment of target product OS-RC-2 model

[0492] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0493] Experimental steps:

[0494] Six mice were selected for this animal model. Each animal was given 177 Lu-NYM074 drug 100μCi, and 3 rats were dissected at 4h and 48h after administration, and 15 tissues and organs including brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonad, skeletal muscle, spleen, stomach, fat, and tumor were obtained, and the gamma radiation count was detected.

[0495] By the attached Fig.50 visible, 177 Lu-NYM074 was enriched in the tumor 4 hours after administration. Except for the kidney, lung, stomach, and brown fat (brown fat at the scapula), the radioactive uptake in other normal tissues was low.

[0496] 4 hours after administration, 177 Lu-NYM074 drug uptake was high in the tumor and low in the heart. After 48 hours of administration, uptake in other normal tissues decreased rapidly, but it was still high in the tumor. 177 Lu-NYM074 has clinical therapeutic potential.

[0497] Embodiment 9: 68 Ga-NYM046 Clinical SPET / CT Imaging Experiment

[0498] 1. Brief information of patient 1: Patient 5, male, 59 years old, weighing 52 kg. The patient underwent a puncture biopsy of the left renal mass, and pathology showed a malignant tumor with necrosis, tending to clear cell carcinoma. Enhanced CT showed a mass in the upper pole of the left kidney, accompanied by multiple metastases in the lungs and lumbar spine. He was then treated with immunotherapy. He was enrolled in a clinical trial of CAIX tracer research. The patient was injected 18Whole-body PET / CT tomography was performed 1.5 hours after 7.5 mCi of F-FDG. After an interval of 2 days, the patient was injected 68 Whole-body PET / CT tomography was performed 1 hour after administration of 4.08 mCi of Ga-NYM046.

[0499] The imaging results are as attached. Figures 51-54 As shown, it can be seen in the tumor and lesion area 68 Ga-NYM046 has high radioactivity uptake and a clear interface. 18 F-FDG, 68 Ga-NYM046 has a higher uptake value for tumors and their metastases, and 68 Ga-NYM046 has a higher tumor and metastasis detection rate, can detect smaller metastases, has higher tumor uptake, a higher ratio of tumor uptake to other non-target organ uptake, and clearer imaging at the tumor site.

[0500] 2. Brief information of patient 2: Enhanced CT of patient 2 showed: male, 76 years old, weight 75kg. The patient had a mass in the lower pole of the left kidney, local nodular thickening of the left anterior renal fascia; bone destruction of the right pubic bone and sacroiliac bone accompanied by soft tissue mass formation. Multiple solid nodules in both lungs; multiple nodular foci in bilateral adrenal glands. Renal puncture biopsy was performed, and pathology showed: (left kidney tumor) clear cell renal cell carcinoma. The patient was enrolled in a clinical trial of CAIX tracer research. The patient was injected 68 Whole-body PET / CT tomography was performed 1 hour after the administration of 4.83 mCi of Ga-NYM046. After an interval of 6 days, patient 2 was injected 18 Whole-body PET / CT imaging was performed 1 hour after administration of 9.8 mCi of F-FDG.

[0501] The imaging results are as attached. Figures 55-58 As shown, it can be seen in the tumor and lesion area 68 Ga-NYM046 has high radioactivity uptake and a clear interface. 18 F-FDG, 68 Ga-NYM046 has a higher uptake value for tumors and their metastases, and 68 Ga-NYM046 has a higher detection rate for tumors and metastases, a higher ability to detect primary and metastatic lesions, can detect smaller metastases, has higher tumor uptake at primary and metastatic lesions, a higher ratio of tumor uptake to uptake by other non-target organs, and clearer imaging at the tumor.

[0502] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0503] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound of formula I or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula I: in, Y1 and Y2 are independently selected from C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkyleneoxy, C optionally substituted by R1 1～10 Alkylene-C(O)-NH-C 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkylene, -NH-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 2～10 Alkenylene or C optionally substituted by R1 2～10 Alkynylidene; Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy; X is selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C 5-10 heteroaryl; Z is selected from the group consisting of chelating agent residues; R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6; R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 Heteroaryl.

2. The compound according to claim 1, characterized in that It is a compound represented by formula II or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula II: n is an integer selected from 1 to 6.

3. The compound according to claim 1, characterized in that It is a compound represented by formula III or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula III: Y4 is selected from -NR2-, -NR2-(C=O)-, -NR2-(C=S)-, (CH2) p -(C=O)-NR2-, -(C=O)-NR2-, -(C=S)-NR2- or a bond, p An integer selected from 1 to 4; n is selected from an integer between 1 and 6; m is selected from an integer between 1 and 6; R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 Heteroaryl.

4. The compound according to any one of claims 1 to 3, characterized in that The Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene; Optionally, the R1 is selected from Optionally, the R1 is selected from Optionally, Y3 is selected from 5. The compound according to any one of claims 1 to 3, characterized in that The X is selected from carboxyl, phenyl, phenolic hydroxyl, naphthyl, tolyl or C 1-4 alkyl; Optionally, Z is derived 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-triazononan-1-yl)pentanedioic acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid, 1,4,7-triazacyclononanephosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid], 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid, N'-{5-[ethyl Acyl (hydroxy) amino] pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy) amino]-4-oxobutanoyl} amino) pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, p-isothiocyanatobenzyl-DTPA, 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA, 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA, 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA, R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid or 6-hydrazinopyridine-3-carboxylic acid; Optionally, Z is selected from 6. A compound, which is a compound of formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of formula IV: in, Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1 1～10 Alkylene, C optionally substituted by R1 1～10 Alkylene, -C(O)-NH-C optionally substituted by R1 1～10 Alkylene, -C(O)-C optionally substituted by R1 1～10 Alkyleneoxy; Y4 is selected from -NR2-, -NR2-(C=O)-, -NR2-(C=S)-, (CH2) p -(C=O)-NR2-, -(C=O)-NR2-, -(C=S)-NR2- or a bond, p An integer selected from 1 to 4; R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, A heterocyclic ring optionally substituted by R2, a heteroaromatic ring optionally substituted by R2, a C optionally substituted by R2 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Haloalkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6; R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-14 Aryl or C 5-14 metaheteroaryl; X is selected from halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, carboxyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclic group, C 6-10 Aryl or C 5-10 metaheteroaryl; Z1 is selected from m is selected from an integer between 1 and 6.

7. The compound according to claim 6, characterized in that The Y3 is selected from Optionally, said X is selected from carboxyl or phenyl.

8. A compound, the structure of which is selected from the following:

9. A compound, characterized in that The compound is formed by complexing the compound according to any one of claims 1 to 8 with M; Optionally, the 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 a diagnostic nuclide or a therapeutic nuclide; Optionally, the diagnostic nuclide 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 or 86 Y; Optionally, the therapeutic nuclide is selected from 177 Lu, 161 Tb, 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, 225 Ac or 227 Th; Optionally, the radionuclide is selected from 68 Ga, 18 F. 89 Zr, 99 mTc or 177 Lu; Optionally, the radionuclide 18 F is through 18 FAl complexation; Preferably, the M is selected from 68 Ga, 18 F or 177 Lu.

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

11. Use of the compound according to any one of claims 1 to 9, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 10 for inhibiting carbonic anhydrase IX.

12. A method for imaging tissue expressing carbonic anhydrase IX protein, characterized in that: The method comprises administering to the tissue the compound according to any one of claims 1 to 9, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 10, and imaging the tissue after administration of the drug.

13. The method according to claim 12, characterized in that The imaging is performed by positron emission tomography or single photon emission computed tomography.

14. Use of a compound according to any one of claims 1 to 9, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition according to claim 10 in the preparation of an agent and / or a drug for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX.

15. The use according to claim 14, characterized in that The diagnosis form is selected from optical imaging and / or nuclear imaging; Optionally, the diagnostic modality is selected from PET imaging and / or SPECT imaging; Optionally, the treatment is selected from radiotherapy and / or assisted surgery with fluorescent surgical navigation.

16. The use according to claim 14, characterized in that The tumors expressing carbonic anhydrase IX include: renal cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma or oral cancer.

17. A method for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX, characterized in that: include: Administering the compound of any one of claims 1 to 9, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of claim 10 to a subject.

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