Radiopharmaceutical targeting carbonic anhydrase

Abstract

Provided is a radiopharmaceutical targeting carbonic anhydrase. Specifically, provided is a compound, which is a compound represented by formula I, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula I. The compound can inhibit carbonic anhydrase IX or diagnose and / or treat one or more tumors, cancers or cells expressing carbonic anhydrase IX.

Description

Carbonic anhydrase-targeted radiopharmaceuticals 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] Multiple α-carbonic anhydrases (α-CAs) are distributed throughout most organs and tissues of the human body, with a single CA predominating in some organs and tissues. CAIX / XII are the dominant enzymes in most hypoxic solid tumors, and in the blood, CAIX / XII is one of the major protein components of red blood cells. Tumor-specifically expressed CAIX / XII is a transmembrane protein. CAIX is stably expressed in tumors such as RCC (renal cell carcinoma). It is not expressed in normal renal tissue and is only weakly expressed in some organs and tissues other than the kidney. Therefore, CAIX is a potential excellent target for the diagnosis and treatment of ccRCC (clear cell renal cell carcinoma). CAIX is also overexpressed in many other tumor types, 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, and oral cancer.

[0003] Tumor-overexpressed CAIX catalyzes the hydration of carbon dioxide, converting it to bicarbonate ions and protons, thereby regulating the pH of the cellular environment. Increased acidity in the local cellular microenvironment activates the VEGF signaling pathway, promoting new angiogenesis and playing a crucial role in tumor development and progression. Furthermore, most CA-targeted inhibitors bind to the metal active center of the CAIX extracellular enzyme catalytic domain to block its catalytic activity. The structures of CAIX-specific inhibitors are often based on sulfonamide structures, with ionization, hypoxia-activated structures, glycosylation, and nanoparticle inclusion. Radionuclide labeling of small CAIX inhibitor molecules can be used for tumor treatment and diagnosis.

[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 advanced or metastatic RCC cannot be treated with surgery. 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 treatment drugs for advanced and metastatic RCC, is a challenge that needs to be continued to be faced 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.

[0005] Summary of the Invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

[0007] 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:

[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 Alkynylidene;

[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, Heterocyclic ring optionally substituted by R2, heteroaryl ring optionally substituted by R2, 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 Halogenated alkyl, C1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkylamino; 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 Halogenated alkyl, 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 represented by 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] 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 Alkynylidene;

[0018] 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;

[0019] X is selected from halogen, C 1-4 Alkyl, C2-4 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;

[0020] Z is selected from the group consisting of chelating agent residues;

[0021] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, Heterocyclic ring optionally substituted by R2, heteroaryl ring optionally substituted by R2, 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 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0022] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0023] n is an integer selected from 1 to 6.

[0024] 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.

[0025] 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.

[0026] 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:

[0027] 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;

[0028] 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;

[0029] 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;

[0030] Z is selected from the group consisting of chelating agent residues;

[0031] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, Heterocyclic ring optionally substituted by R2, heteroaryl ring optionally substituted by R2, 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 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0032] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0033] n is selected from an integer between 1 and 6;

[0034] m is selected from integers between 1 and 6.

[0035] 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.

[0036] 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.

[0037] According to an embodiment of the present invention, said Y3 is selected from -NH-C(O)-C optionally substituted by R1 1～10 Alkylene.

[0038] According to an embodiment of the present invention, said Y3 is selected from a bond or -NH-C(O)-C optionally substituted by R1. 1～10 Alkylene.

[0039] 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".

[0040] According to an embodiment of the present invention, the R1 is selected from

[0041] According to an embodiment of the present invention, the R1 is selected from

[0042] According to an embodiment of the present invention, Y3 is selected from

[0043] According to an embodiment of the present invention, the X is selected from carboxyl, phenyl, tolyl or C 1-4 alkyl.

[0044] According to an embodiment of the present invention, the X is selected from carboxyl, phenyl, phenolic hydroxyl, naphthyl, tolyl or C 1-4 alkyl.

[0045] According to an embodiment of the present invention, the 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) glutaric acid (NODAGA), 2-(4,7,10 -tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-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-oxobutanoyl}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).

[0046] According to an embodiment of the present invention, Z is selected from

[0047] According to an embodiment of the present invention, when the Y4 is selected from a bond, the Z is selected from

[0048] According to an embodiment of the present invention, when Y4 is selected from -NR2-, Z is selected from

[0049] 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:

[0050] 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;

[0051] 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;

[0052] R1 is independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, NO2, CN, N3, Heterocyclic ring optionally substituted by R2, heteroaryl ring optionally substituted by R2, 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 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkyl or C 1-4 Halogenated alkylamino; wherein A is selected from an aromatic monocyclic or bicyclic ring, and t is selected from an integer between 1 and 6;

[0053] R2 is selected from H, D, =O, OH, NH2, NO2, CN, N3, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-14 Aryl or C 5-14 heteroaryl;

[0054] 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;

[0055] Z1 is selected from

[0056] m is selected from integers between 1 and 6.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] According to an embodiment of the present invention, Y3 is selected from

[0061] According to an embodiment of the present invention, X is selected from carboxyl or phenyl.

[0062] According to an embodiment of the present invention, when the Y4 is selected from a bond, the Z1 is selected from

[0063] According to an embodiment of the present invention, when Y4 is selected from -NR2-, Z1 is selected from

[0064] In the third aspect of the present invention, the present invention provides a compound, the structure of which is selected from the following:

[0065] In a fourth aspect, 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, second or third aspect with M.

[0066] According to an embodiment of the present invention, the M is selected from at least one of radioactive nuclides or non-radioactive elements.

[0067] According to an embodiment of the present invention, the radioactive nuclide includes at least one of a diagnostic nuclide or a therapeutic nuclide.

[0068] 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.

[0069] 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.

[0070] According to an embodiment of the present invention, the radionuclide is selected from 68 Ga, 18 F. 89 Zr, 99 mTc or 177 Lu.

[0071] According to an embodiment of the present invention, the radionuclide 18 F is through 18 FA1 is complexed.

[0072] According to an embodiment of the present invention, the M is selected from 68 Ga, 18 F or 177 Lu.

[0073] According to an embodiment of the present invention, the compound structure is selected from the following:

[0074] In a fifth aspect, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound of the first, second, third, or fourth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof.

[0075] According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0076] 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.

[0077] In a seventh aspect, the present invention provides a method for imaging tissue expressing carbonic anhydrase IX protein. According to embodiments of the present invention, the method comprises administering to the tissue a compound of the first, second, third, or fourth aspect, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof, or the pharmaceutical composition of the fifth aspect, and imaging the tissue after administration.

[0078] According to an embodiment of the present invention, the imaging is performed by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0079] In the eighth aspect of the present invention, the present invention proposes the use of the compound described in the first, second, third or 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 a reagent and / or drug for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX.

[0080] 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 of 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 of the fifth aspect.

[0081] According to an embodiment of the present invention, the diagnosis modality is selected from optical imaging and / or nuclear imaging.

[0082] According to an embodiment of the present invention, the diagnosis modality is selected from fluorescence imaging, PET imaging and / or SPECT imaging.

[0083] According to an embodiment of the present invention, the treatment is selected from radiotherapy and / or assisted surgery with fluorescent surgical navigation.

[0084] 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. Beneficial effects:

[0085] The carbonic anhydrase-targeted radiopharmaceutical disclosed in the present invention exhibits high affinity for carbonic anhydrase IX, demonstrates good specific targeted uptake, rapid accumulation, and sustained uptake in tissues, tumors, or cells that highly express carbonic anhydrase IX in vivo, and is rapidly cleared from non-target tissues. It also exhibits a high tumor-to-normal tissue uptake ratio, clear imaging boundaries, and excellent safety. It can rapidly detect diseased tissues and maintains tumor tissue retention for a long time, demonstrating therapeutic potential and possessing clinical diagnostic and therapeutic significance.

[0086] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0087] Terms and Definitions

[0088] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0089] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0090] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles 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., more than one component may be contemplated for use or use in implementing the described embodiments.

[0091] 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 forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0092] Definitions of standard chemical terms can be found in the references, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4THED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless otherwise defined, the terms used herein in the descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, as well as in the treatment of patients. For example, the manufacturer's instructions for use of the kits can be utilized, or reactions and purifications can be carried out in accordance with methods well known in the art or as described herein. The above techniques and methods can generally be implemented according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0093] In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with 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 with one or more substituents selected from a specified group, the substituents may be the same or different at each substitutable position.

[0094] The term "unsubstituted" means that the designated group bears no substituents.

[0095] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, such as the compounds of the general formula 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 the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.

[0096] In addition, it should be noted that, unless otherwise explicitly stated, the description methods used in the present invention such as "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They 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.

[0097] 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 from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, Indicates the attachment site of a group.

[0098] The section headings used herein are for organizational purposes only and should not be construed 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, manuals, and papers, are incorporated herein by reference in their entirety.

[0099] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0100] When the numerical ranges described in the specification and claims of this application are understood as “integers”, they should be understood as recording the two endpoints of the range and each integer within 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 within the range and each decimal within 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 the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0101] As used herein, the term "halogen" alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

[0102] The term "alkyl" when used alone or as part of another substituent group 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, hydroxy, 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.

[0103] The term "alkylene" when used alone or as part of another substituent is understood to mean a straight-chain or branched saturated, unsaturated or partially saturated divalent hydrocarbon radical. For example, "C 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.

[0104] The term "alkenyl" when used alone or as part of another substituent refers to a linear or branched monovalent hydrocarbon radical of two to forty carbon atoms (e.g., C2-C6 alkenyl, for example, C2-C4 alkenyl) having at least one carbon-carbon sp2 double bond, and includes groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples of alkenyl groups include, but are not limited to, vinyl and allyl.

[0105] When alone or as part of other substituents, the term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical 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 groups include, but are not limited to, ethynyl and propynyl.

[0106] The term "alkoxy" when used alone or as part of another substituent refers to the group -OR Q , where R Q is an "alkyl" group as defined above.

[0107] When used alone or as part of another substituent, the term "heteroaryl 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 can be a carbon group or a heteroatom group (i.e., it can be C-attached or N-attached, as long as it is possible). When one of the rings is a non-aromatic ring, the group can be attached through the aromatic ring or through the non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring," "heteroaryl," or "heteroaromatic ring group."

[0108] The term "bicyclic," when used alone or as part of another substituent, refers to a group having two linked 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 aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic rings (e.g., tetralin).

[0109] The term "naphthyl" when used alone or as part of another substituent is

[0110] The "chelating group" mentioned in the present disclosure for the compound of 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.

[0111] In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0112] In this 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, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0113] 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.

[0114] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, 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 centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for 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.

[0115] When bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62:114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0116] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties 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.

[0117] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0118] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0119] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0120] In this application, "pharmaceutically acceptable carrier" includes but is not limited to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, 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.

[0121] 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 enhance the handling properties of pharmaceutical formulations, specifically by increasing flowability and / or adhesion, making the formulation more suitable for direct compression.

[0122] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes 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.

[0123] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0124] The term "patient" refers to any animal, preferably a mammal, that is about to be or has been administered a 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.

[0125] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "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

[0126] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments with reference to the following drawings, in which:

[0127] FIG1 is an LCMS spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0128] FIG2 is a HPLC spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0129] FIG3 is a nuclear magnetic spectrum of the NYM045 molecule according to an embodiment of the present invention;

[0130] FIG4 is an LCMS spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0131] FIG5 is a HPLC spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0132] FIG6 is an NMR spectrum of the NYM046 molecule according to an embodiment of the present invention;

[0133] FIG7 is an LCMS spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0134] FIG8 is a HPLC spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0135] FIG9 is an NMR spectrum of the NYM047 molecule according to an embodiment of the present invention;

[0136] FIG10 is an LCMS spectrum of the NYM048 molecule according to an embodiment of the present invention;

[0137] FIG11 is a HPLC spectrum of NYM048 molecules according to an embodiment of the present invention;

[0138] FIG12 is an NMR spectrum of NYM048 molecules according to an embodiment of the present invention;

[0139] FIG13 is an LCMS spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0140] FIG14 is a HPLC spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0141] FIG15 is an NMR spectrum of the NYM049 molecule according to an embodiment of the present invention;

[0142] FIG16 is an LCMS spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0143] FIG17 is a HPLC spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0144] FIG18 is an NMR spectrum of the NYM050 molecule according to an embodiment of the present invention;

[0145] FIG. 19 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM045 molecules;

[0146] FIG. 20 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM046 molecules;

[0147] FIG. 21 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM047 molecules;

[0148] FIG. 22 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM048 molecules;

[0149] FIG. 23 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM049 molecules;

[0150] FIG. 24 is a block diagram of an embodiment of the present invention. 68Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM050 molecules;

[0151] FIG. 25 is a block diagram of an embodiment of the present invention. 68 Radioactive thin layer chromatography scanning purity analysis results of Ga-NYM074 molecules;

[0152] FIG. 26 is a block diagram of an embodiment of the present invention. 18 Radioactive thin layer chromatography scanning purity analysis results of F-NYM070 molecule;

[0153] FIG. 27 is a block diagram of an embodiment of the present invention. 18 Radioactive thin layer chromatography scanning purity analysis results of F-NYM071 molecule;

[0154] FIG. 28 is a block diagram of an embodiment of the present invention. 177 Radioactive thin layer chromatography scanning purity analysis results of Lu-NYM073 molecules;

[0155] FIG. 29 is a block diagram of an embodiment of the present invention. 177 Radioactive thin layer chromatography scanning purity analysis results of Lu-NYM074 molecule;

[0156] FIG30 is a block diagram of an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM045 / 046 / 047 in OS-RC-2 tumor-bearing mouse model;

[0157] FIG. 31 is a diagram illustrating an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM048 / 049 / 050 in OS-RC-2 tumor-bearing mouse model;

[0158] FIG. 32 is a block diagram of an embodiment of the present invention. 68 The uptake values ​​of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 in different organs and sites, as well as the uptake ratio between tumors and non-target organs;

[0159] FIG. 33 is a diagram of different time periods according to an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM045 in OS-RC-2 tumor-bearing mouse model;

[0160] FIG. 34 is a diagram of different time periods according to an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM046 in OS-RC-2 tumor-bearing mouse model;

[0161] FIG. 35 is a diagram of different time periods according to an embodiment of the present invention. 68PET / CT imaging results of Ga-NYM047 in OS-RC-2 tumor-bearing mouse model;

[0162] FIG. 36 is a diagram of different time periods according to an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM048 in OS-RC-2 tumor-bearing mouse model;

[0163] FIG. 37 is a diagram of different time periods according to an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM049 in OS-RC-2 tumor-bearing mouse model;

[0164] FIG. 38 is a diagram of different time periods according to an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM050 in OS-RC-2 tumor-bearing mouse model;

[0165] FIG. 39 is a block diagram of an embodiment of the present invention. 68 The uptake of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 in the tumor site changes over time;

[0166] FIG40 is a block diagram of an embodiment of the present invention. 68 PET / CT scans of Ga-NYM074 in mice;

[0167] FIG. 41 is a block diagram of an embodiment of the present invention. 68 The uptake values ​​of Ga-NYM074 drug in different tissues of mice;

[0168] FIG. 42 is a block diagram of an embodiment of the present invention. 68 The ratio of Ga-NYM074 drug in mouse tumors to muscle, and in tumors to heart;

[0169] FIG. 43 is a block diagram of an embodiment of the present invention. 68 PET / CT imaging results of Ga-NYM050 in OS-RC-2 tumor-bearing mouse model;

[0170] FIG. 44 is a block diagram of an embodiment of the present invention. 68 Scanning image of the competitive inhibition experiment of Ga-NYM050 in the OS-RC-2 tumor-bearing mouse model;

[0171] FIG. 45 is a block diagram of an embodiment of the present invention. 68 Uptake values ​​of Ga-NYM050 in different organs and parts at different times in OS-RC-2 tumor-bearing mouse model;

[0172] FIG. 46 is a block diagram of an embodiment of the present invention. 68Ga-NYM050 blocking experiment in OS-RC-2 tumor-bearing mouse model with different organs and parts at different times;

[0173] FIG. 47 is a block diagram of an embodiment of the present invention. 177 Lu-NYM073 / 177 SPECT / CT scans of Lu-NYM074 drug in mice;

[0174] FIG48 is a graph showing changes in tumor volume in mice according to an embodiment of the present invention;

[0175] Figure 49 is a graph showing changes in mouse body weight according to an embodiment of the present invention;

[0176] FIG50 is a block diagram of an embodiment of the present invention. 177 Distribution of Lu-NYM074 in mouse tissues in vitro;

[0177] FIG. 51 is a diagram of patient 1 receiving an injection according to an embodiment of the present invention. 18 MIP (maximum intensity projection) image after F-FDG;

[0178] FIG. 52 is a diagram of patient 1 injected with an injection according to an embodiment of the present invention. 68 MIP map after Ga-NYM046;

[0179] FIG. 53 is a diagram of patient 1 receiving an injection according to an embodiment of the present invention. 18 F-FDG and 68 CT and PET / CT cross-sectional images of Ga-NYM046;

[0180] FIG. 54 is a diagram of patient 1 injected with an injection according to an embodiment of the present invention. 18 F-FDG and 68 SUVmax and SUVmean plots after Ga-NYM046.

[0181] FIG. 55 is a diagram of patient 2 injected with an injection according to an embodiment of the present invention. 18 MIP images after F-FDG;

[0182] FIG. 56 is a diagram of patient 2 injected with an injection according to an embodiment of the present invention. 68 MIP map after Ga-NYM046;

[0183] FIG. 57 is a diagram of patient 2 injected with an injection according to an embodiment of the present invention. 18 F-FDG and 68 CT and PET / CT cross-sectional images of Ga-NYM046;

[0184] FIG. 58 is a diagram of patient 2 injected with an injection according to an embodiment of the present invention. 18 F-FDG and 68SUVmax and SUVmean plots after Ga-NYM046;

[0185] FIG59 is an LCMS spectrum of the NYM070 molecule according to an embodiment of the present invention;

[0186] FIG60 is a HPLC spectrum of the NYM070 molecule according to an embodiment of the present invention;

[0187] FIG61 is an LCMS spectrum of the NYM071 molecule according to an embodiment of the present invention;

[0188] FIG62 is a HPLC spectrum of the NYM071 molecule according to an embodiment of the present invention;

[0189] FIG63 is an LCMS spectrum of the NYM073 molecule according to an embodiment of the present invention;

[0190] FIG64 is a HPLC spectrum of NYM073 molecules according to an embodiment of the present invention;

[0191] FIG65 is an LCMS spectrum of the NYM074 molecule according to an embodiment of the present invention;

[0192] FIG. 66 is a HPLC spectrum of the NYM074 molecule according to an embodiment of the present invention. DETAILED DESCRIPTION

[0193] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and are not to be construed as limiting the present invention. Where specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in this field or the product specifications are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be obtained commercially.

[0194] Example 1: Preparation of the compound

[0195] 1. Synthesis steps of Int 1:

[0196] Compound 2 (3.00 g, 1.00 eq) and pyridine (2.63 g, 2.00 eq) were dissolved in DMF (30.0 mL). 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 mixture was concentrated in vacuo and the residue was washed with 45.0% ethanol.

[0197] The mixture was diluted with 45.0 mL of water and 45.0 mL of saturated NaHCO 3 and filtered to give compound 4 (5.00 g).

[0198] 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 adjusted to pH 4 with 1N HCl. The solution was filtered and washed with water to yield Compound Int 1 (2.00 g, 6.22 mmol, 95.9% purity).

[0199] 2. Synthesis steps of NYM045

[0200] Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0201] 1) Resin Hanging: Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-Asp-OALL (Fmoc-L-aspartic acid alpha-allyl ester) (0.50 mmol, 1.00 eq) into a reaction column. DCM (30.0 mL) and DIEA (2.00 mmol, 4.00 eq) were then added to the column. After nitrogen bubbling at 20°C for 2.00 h, MeOH (1.00 mL) was added and nitrogen bubbling continued for 30 min. The mixture was then discarded until no more liquid remained. DMF was added for washing and discarded.

[0202] 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.

[0203] 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. DIEA (3.00 mmol, 6.00 eq) was then added. The reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0204] 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.

[0205] 5) Reductive Amination: Dissolve benzaldehyde (0.60 mmol, 1.20 eq) and trimethyl orthoformate (3.00 mmol, 6.00 eq) in THF (20.0 mL). Add acetic acid (0.01 mmol, 0.02 eq) and incubate at 20°C under nitrogen for 0.50 h. Dissolve sodium triacetoxyborohydride (3.00 mmol, 6.00 eq) in methanol (1.00 mL) and slowly add dropwise to the reaction column. Incubate at 20°C under nitrogen for 1.00 h. Wash the resin with DMF.

[0206] 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. DIC (0.60 mmol, 1.20 eq) was then added and the reaction was stirred with nitrogen at 20°C for 12.0 h. The resin was washed with DMF.

[0207] 7) Deprotection: DCM (30.0 mL) was added to the reaction column and aerated with nitrogen. PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were then added sequentially and aerated with nitrogen for 15.0 min. This step was repeated three times. The resin was washed with DMF and dried.

[0208] 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. DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were then added to the resin. The reaction was stirred at 20°C with nitrogen for 2.00 h. The resin was heated with DMF.

[0209] 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.

[0210] 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. DIC (0.75 mmol, 1.50 eq) was then added. The reaction was stirred with nitrogen at 20°C for 2 h. The resin was washed with DMF.

[0211] Peptide cleavage and purification:

[0212] The resin was shrunk with MeOH (30.0 mL) and drained until no liquid flowed out. The resin was then poured out and dried for standby use. At room temperature, the dried resin was added to 20.0 mL of cutting solution (92.5% TFA, 2.5% TIS, 2.5% H O and 2.5% 3-MPR) and shaken for 2 h. After filtration, the filtrate was added to ice-cold isopropyl ether (100 mL) and centrifuged, then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain the crude peptide.

[0213] NYM045 (15.0 mg, purity 97.52%) was obtained directly by reverse phase preparation (A: H2O containing 0.075% TFA, B: ACN acetonitrile).

[0214] LCMS:MS:[M+H] + =1069.7 (as shown in Figure 1)

[0215] HPLC: Purity: 97.52% (as shown in Figure 2)

[0216] 1 H NMR: 400 MHz, DMSO-d6 (as shown in Figure 3)

[0217] 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).

[0218] 3. Synthesis steps of NYM046

[0219] Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0220] 1) Resin Hanging: Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-Asp-OALL (0.50 mmol, 1.00 eq) into a reaction column. DCM (30.0 mL) and DIEA (2.00 mmol, 4.00 eq) were then added to the column. After nitrogen bubbling at 20°C for 2.00 h, MeOH (1.00 mL) was added and nitrogen bubbling continued for 30 min. The mixture was then drained until no more liquid remained. DMF was added for washing and the mixture was drained until no more liquid remained.

[0221] 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.

[0222] 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. DIEA (3.00 mmol, 6.00 eq) was then added. The reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DM.

[0223] 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.

[0224] 5) Protecting group: DIEA (3.00 mmol, 6.00 eq) was dissolved in THF (20.0 mL) and added to the reaction column under nitrogen agitation. NsCl (1.50 mmol, 3.00 eq) was then dissolved in THF (10.0 mL) and slowly added dropwise to the reaction column. The reaction was stirred at 20°C under nitrogen agitation for 1.00 h.

[0225] 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 stirred with nitrogen for 5 min. DEAD (2.50 mmol, 5.00 eq) was then slowly added dropwise to the reaction column and the reaction was stirred with nitrogen at 20°C for 12.0 h.

[0226] 7) Deprotection: Dissolve sodium thiophenolate (1.25 mmol, 2.50 eq) in DMF (30.0 mL) and add to the resin under nitrogen aeration for 1 h. Wash the resin with DMF and drain.

[0227] 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. DIC (0.60 mmol, 1.20 eq) was then added and the reaction was stirred with nitrogen at 20°C for 12.0 h. The resin was washed with DMF.

[0228] 9) Deprotection: DCM (30.0 mL) was added to the reaction column and aerated with nitrogen. PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were then added sequentially and aerated with nitrogen for 15.0 min. This step was repeated three times. The resin was washed with DMF and dried.

[0229] 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. DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were then added to the resin. The reaction was stirred at 20°C with nitrogen for 2.00 h. The resin was washed with DMF.

[0230] 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.

[0231] 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. DIC (0.75 mmol, 1.50 eq) was then added. The reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

[0232] Peptide cleavage and purification:

[0233] The resin was shrunk with MeOH (30.0 mL) for 3 min each, drained, and dried until no liquid flowed out. The resin was then poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of a cutting solution (92.5% TFA, 2.5% TIS, 2.5% H2O, and 2.5% 3-MPR) and shaken on a shaking table for 2 h. After filtration, the filtrate was added to ice-cold isopropyl ether and centrifuged, then washed with isopropyl ether (100 mL). The crude peptide was dried under vacuum for 2 hours.

[0234] NYM046 (15.0 mg, purity 95.74%) was obtained directly by reverse phase preparation (A: water containing 0.075% TFA, B: ACN acetonitrile).

[0235] LCMS:MS:[M / 2+H] + =1119.5 (as shown in Figure 4)

[0236] HPLC: Rt=7.72 min, purity: 95.74% (as shown in Figure 5)

[0237] 1 H NMR: 400 MHz, DMSO-d6 (as shown in Figure 6)

[0238] 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).

[0239] 4. Synthesis steps of NYM047

[0240] Step 1:

[0241] To a solution of compound 1b (5.00 g, 1.00 eq) in DMF (50.0 mL) at 20°C were slowly added 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). The reaction mixture was stirred at 20°C for 2 hours. Compound 3b (3.10 g, 90.5% purity) was obtained by purification.

[0242] Step 2:

[0243] 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. The mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 4b.

[0244] Step 3:

[0245] To a solution of compound 4b (2.06 g, 1.20 eq) in DMF (20.0 mL) at 20°C were slowly added 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). The reaction mixture was stirred at 20°C for 12 hours. Compound 6b (2.40 g, 100% purity) was obtained by purification.

[0246] Step 4:

[0247] Compound 6b (2.00 g, 1.00 eq) was dissolved in methanol (40.0 mL), and wet palladium on carbon (200 mg, 10% purity, 8.68 e-2 eq) was added. The reaction was stirred at 20°C under H2 (15.0 Psi) for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 7b.

[0248] Step 5:

[0249] To a solution of compound 7b (393 mg, 1.00 eq) in DMF (4.00 mL) at 20°C were slowly added 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). The reaction mixture was stirred at 20°C for 12 hours. Compound 9b (360 mg) was obtained by purification.

[0250] Step 6:

[0251] Compound 9b (360 mg, 1.00 eq) was dissolved in methanol (8.00 mL), and wet palladium on carbon (36.0 mg, 10% purity, 9.62 e-2 eq) was added. The reaction was stirred at 20°C under H2 (15.0 Psi) for 5 hours. The reaction solution was concentrated under reduced pressure to yield compound 10b.

[0252] Step 7:

[0253] To a solution of compound 10b (78.8 mg, 1.00 eq) in DMF (3.00 mL) was slowly added Int 1 (250 mg, 1.10 eq), BOP (113 mg, 1.00 eq), and DIEA (133 μL, 3.00 eq) at 20°C. The reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was then purified by reverse phase hydrochloric acid to afford compound 11b (180 mg).

[0254] Step 8:

[0255] To compound 11b (180 mg, 1.00 eq) was added TFA / TIS / H2O (V:V = 95%:2.5%:2.5, 2.00 mL) at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was then purified by reverse phase (hydrochloric acid) to afford NYM047 (12.0 mg, 96.0% purity).

[0256] LCMS:MS:[M] + =1011.4 (as shown in Figure 7)

[0257] HPLC: Rt=13.1 min, purity: 96.0% (as shown in Figure 8)

[0258] 1 H NMR: 400 MHz, D2O (as shown in Figure 9)

[0259] 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).

[0260] 5. Synthesis steps of NYM048

[0261] Step 1:

[0262] To a solution of compound 7b (70.9 mg, 1.00 eq) in DMF (2.00 mL) was slowly added Int 1 (200 mg, 1.10 eq), BOP (101 mg, 1.00 eq), and DIEA (120 μL, 3.00 eq) at 20°C. The reaction mixture was stirred at 20°C for 2 hours. Compound 12b (280 mg) was obtained by purification.

[0263] Step 2:

[0264] To compound 12b (100 mg, 1.00 eq) was added TFA / TIS / H2O (V:V = 95%:2.5%:2.5, 2.00 mL) at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was then purified by reverse phase (hydrochloric acid) to afford NYM048 (12.0 mg, 13.0 μmol, 99.0% purity).

[0265] LCMS:MS:[M] + =912.3 (as shown in Figure 10)

[0266] HPLC: Rt = 6.17 min, purity: 99.0% (as shown in Figure 11)

[0267] 1 H NMR: 400 MHz, D2O (as shown in Figure 12)

[0268] 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).

[0269] 6. Synthesis steps of NYM049

[0270] Step 1:

[0271] To a solution of LiAlH4 (139 mL, 3.96 eq) in THF was slowly added dropwise compound 1c (22.0 g, 1.00 eq) dissolved in THF (200 mL) at 0°C. The reaction was stirred at 40°C for 0.5 h. H2O (13.2 mL), 15% NaOH (13.2 mL), and H2O (40.0 mL) were then slowly added dropwise at 0°C under N2 bubbling to quench the reaction. Compound 2c (11.5 g, 91.0% purity) was obtained.

[0272] Step 2:

[0273] To a solution of compound 2c (11.5 g, 1.00 eq) in DCM (250 mL) were added TsCl (48.0 g, 4.00 eq) and TEA (26.2 mL, 3.00 eq), and the reaction mixture was stirred at 25°C for 12 hours. Compound 3c (23.0 g, 93.3% purity) was obtained after purification.

[0274] Step 3:

[0275] To a stirred solution of compound 3c (13.0 g, 1.00 eq) in DMSO (140 mL) at 25°C was added KCN (8.43 g, 5.07 eq), heated to 80°C, and stirred for 3.5 hours to afford compound 4c (4.70 g, 87.7% purity).

[0276] Step 4:

[0277] 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 bubbled through the solution at 0°C for 0.25 h, and the reaction mixture was then stirred at 80°C for 10 h. The mixture was concentrated in vacuo to afford compound 5c (10.1 g, 40.3 mmol).

[0278] Step 5:

[0279] Compound 5c (4.00 g, 1.00 eq) was dissolved in a mixture of THF (60.0 mL) and H2O (60.0 mL). LiOH·H2O (670 mg, 1.00 eq) was added and stirred at 0°C for 1 hour. Compound 6c (1.30 g, 93.3% purity) was obtained after purification.

[0280] Step 6:

[0281] Compound 6c (0.90 g, 3.55 mmol, 1.00 eq) was added to a mixture of DCM (16 mL) and DMF (0.16 mL). (COCl)2 (902 mg, 2.00 eq) was added at 0°C. The mixture was stirred at 25°C for 0.5 h and concentrated in vacuo. The residue was dissolved in DCM (16.0 mL). This 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. Purification afforded compound 7c (1.20 g).

[0282] Step 7:

[0283] Compound 7c (1.10 g, 1.00 eq) was dissolved in a mixture of H2O (12.0 mL) and THF (12.0 mL), and then LiOH·H2O (278 mg, 2.40 eq) was added. The mixture was stirred at 25°C for 1 h. Purification afforded Int 2 (1.00 g, 96.2% purity).

[0284] Step 8:

[0285] Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0286] 1) Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-Asp-OALL (0.50 mmol, 1.00 eq) into a reaction column. DCM (30.0 mL) and DIEA (2.00 mmol, 4.00 eq) were then added to the column. After nitrogen bubbling at 20°C for 2.00 h, MeOH (1.00 mL) was added and nitrogen bubbling continued for 30 min. The mixture was then drained until no more liquid remained. DMF was added for washing and the mixture was drained until no more liquid remained.

[0287] 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.

[0288] 3) Deprotection: DCM (30.0 mL) was added to the reaction column and aerated with nitrogen. PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were then added sequentially and aerated with nitrogen for 15.0 min. This step was repeated three times. The resin was washed with DMF and dried.

[0289] 4) Condensation: Alloc-Cl (1.00 mmol, 2.00 eq) was dissolved in DMF (30.0 mL) and added to the resin. DIEA (2.00 mmol, 4.00 eq) was then added. The reaction was stirred with nitrogen at 20°C for 20.0 min. This step was repeated twice. The resin was washed with DMF.

[0290] 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. DMF (30.0 mL) was then added dropwise, followed by DIEA (3.00 mmol, 6.00 eq). The reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0291] 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.

[0292] 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. DIEA (3.00 mmol, 6.00 eq) was then added. The reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0293] 8) Deprotection: DCM (30.0 mL) was added to the reaction column and aerated with nitrogen. PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were then added sequentially and aerated with nitrogen for 15.0 min. This step was repeated three times. The resin was washed with DMF and dried.

[0294] 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) and added to the resin. DIEA (3.00 mmol, 6.00 eq) was then added and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0295] 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.

[0296] 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. DIC (0.75 mmol, 1.50 eq) was then added and the reaction was stirred with nitrogen at 20°C for 30.0 min. The resin was washed with DMF.

[0297] Peptide cleavage and purification:

[0298] The resin was shrunk with MeOH (30.0 mL) and 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 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 filtration, the filtrate was added to ice-cold isopropyl ether (100 mL) and centrifuged, then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain the crude peptide.

[0299] 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).

[0300] LCMS:MS:[M+H] + =1055.6 (as shown in Figure 13)

[0301] HPLC: Rt=10.2 min, purity: 95.42% (as shown in FIG14 )

[0302] 1 H NMR: 400 MHz, D2O. (as shown in Figure 15)

[0303] 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).

[0304] 7. Synthesis steps of NYM050

[0305] Step 1:

[0306] NaNO2 (7.77 g, 112 mmol, 2.00 eq) dissolved in H2O (15.0 mL) was 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), and HBr (28.4 g, 140 mmol, 19.1 mL, 40% purity, 2.50 eq) in H2O (300 mL) at 0°C. The reaction mixture was stirred at 20°C for 12 h. Purification afforded compound 1d-1 (3.30 g, 100% purity).

[0307] Step 2:

[0308] 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 the mixture was stirred at 25°C for 12 h. Compound 2d-1 (4.75 g, 98.7% purity) was obtained after purification.

[0309] Step 3:

[0310] 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, followed by compound 2d-1 (700 mg, 1.00 eq). The mixture was stirred at 50°C for 12 h. Purification afforded compound 3d-1 (1.00 g, 98.1% purity).

[0311] Step 4:

[0312] Compound 3d-1 (700 mg, 1.00 eq) was added to a mixture of THF (7.00 mL) and deionized water (0.05 mL). Pd / C (70.0 mg, 10% purity, 0.10 eq) was added under nitrogen. The suspension was degassed and replaced with hydrogen. The reaction mixture was stirred at 35°C under H2 (15 psi) for 12 h. The suspension was filtered, and the filtrate was removed under reduced pressure to yield compound Int 3 (500 mg, 84.6% purity).

[0313] Step 5:

[0314] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

[0315] 1) Resin Hanging: Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.50 mmol / g) and Fmoc-Asp-OALL (0.50 mmol, 1.00 eq) into a reaction column. DCM (30.0 mL) and DIEA (2.00 mmol, 4.00 eq) were then added to the column. After nitrogen bubbling at 20°C for 2.00 h, MeOH (1.00 mL) was added and nitrogen bubbling continued for 30 min. The mixture was then drained until no more liquid remained. DMF was added for washing and the mixture was drained until no more liquid remained.

[0316] 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.

[0317] 3) Condensation: Fmoc-Apa-OH (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were added to the resin, followed by DMF (30.0 mL), and then DIEA (3.00 mmol, 6.00 eq) was added dropwise. The reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

[0318] 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.

[0319] 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. DIC (0.75 mmol, 1.50 eq) was then added and the reaction was stirred with nitrogen at 20°C for 3.00 h. The resin was washed with DMF.

[0320] 6) Deprotection: DCM (30.0 mL) was added to the reaction column and aerated with nitrogen. PhSiH3 (5.00 mmol, 10.0 eq) and Pd(PPh3)4 (0.05 mmol, 0.10 eq) were then added sequentially and aerated with nitrogen for 15.0 min. This step was repeated three times. The resin was washed with DMF and dried.

[0321] 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. DIC (0.75 mmol, 1.50 eq) was then added and the reaction was stirred with nitrogen at 20°C for 8.00 h. The resin was washed with DMF.

[0322] Peptide cleavage and purification:

[0323] 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 the crude peptide.

[0324] 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%).

[0325] LCMS:MS:[M+H] + =1042.6 (as shown in Figure 16)

[0326] HPLC: Rt=8.04 min, purity: 98.17% (as shown in Figure 17)

[0327] 1 H NMR: 400 MHz, D2O. (as shown in Figure 18)

[0328] 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).

[0329] 8. Synthesis steps of NYM070

[0330] Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry

[0331] 1) Weigh 0.50 mmol of 2-CTC resin (degree of substitution Sub = 0.70 mmol / g) and Fmoc-Asp-OAll (0.50 mmol, 1.00 eq) into a reaction column. Add 30.0 mL of DCM, then dropwise add DIEA (2.00 mmol, 4.00 eq). Adjust the nitrogen atmosphere to ensure uniform resin expansion. After reacting at 20°C for 2 hours, add MeOH (0.80 mL) dropwise to the reaction column. Purge the reaction column with nitrogen for 30 minutes, then drain the column until no more liquid remains. Wash with DMF and drain the column until no more liquid remains.

[0332] 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.

[0333] 3) Amino Acid Coupling: Fmoc-5-aminovaleric acid (1.50 mmol, 3.00 eq) and HBTU (1.425 mmol, 2.85 eq) were weighed into the above resin. 25.0 mL of DMF was added, followed by the dropwise addition of DIEA (3.00 mmol, 6.00 eq) into the reaction column. A nitrogen atmosphere was maintained to ensure uniform resin swelling. The reaction was allowed to proceed at 20°C for 50 minutes. The reaction solution was then aspirated, washed with DMF, and discarded until no more liquid remained.

[0334] 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.

[0335] 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) to the THF solvent, adjusting the nitrogen atmosphere to ensure uniform resin swelling. React for one hour, then remove the reaction solution, wash with DMF, and drain until no more liquid flows out.

[0336] 6) After washing the resin with DMF, add 25.0 mL of THF, followed by triphenylphosphine (2.50 mmol, 5.00 eq) and 2-naphthol (1.00 mmol, 2.00 eq). Allow to react for 5 min. Then, slowly add DEAD (2.50 mmol, 5.00 eq) dropwise to the reaction mixture, adjusting the nitrogen atmosphere to ensure uniform resin swelling. After one hour of reaction, remove the reaction mixture, add DMF (30.0 mL) for washing, and drain until no more liquid remains.

[0337] 7) NS removal: Add 30.0 mL of DMF and sodium thiophenolate (1.00 mmol, 2.00 eq), adjust the nitrogen atmosphere to make the resin evenly bulge, and react for one hour.

[0338] 8) Amino Acid Coupling: Int 1 (1.50 mmol, 3.00 eq) and HOAt (1.50 mmol, 3.00 eq) were weighed and added to the above resin. 25.0 mL of DMF was added, followed by dropwise addition of DIC (1.50 mmol, 3.00 eq) to the reaction column. A nitrogen atmosphere was maintained to ensure uniform resin swelling. The reaction was allowed to proceed at 20°C for 50 minutes. The reaction solution was then aspirated, washed with DMF (30.0 mL), and discarded until no more liquid remained.

[0339] 9) Deallylation: The resin was washed with DMF 3 times and DCM 3 times. An appropriate amount of DCM was added and nitrogen was introduced. 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 and washed with DMF (30.0 mL). The mixture was discharged until no liquid flowed out.

[0340] 10) Amino Acid Coupling: Weigh N-Fmoc-1,4-butanediamine hydrochloride (1.50 mmol, 3.00 eq) and HOAt (1.50 mmol, 3.00 eq) into the above resin. Add 25.0 mL of DMF, then dropwise add DIC (1.50 mmol, 3.00 eq) to the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin swelling. React at 20°C for 50 minutes, then remove the reaction solution, add DMF (30.0 mL) for washing, and drain until no more liquid remains.

[0341] 11) Amino Acid Coupling: Weigh NOTA(tBu)2-OH (1.50 mmol, 3.00 eq) and HOAt (1.50 mmol, 3.00 eq) into the above resin. Add 25.0 mL of DMF, then dropwise add DIC (1.50 mmol, 3.00 eq) to the reaction column. Adjust the nitrogen atmosphere to ensure uniform resin swelling. Incubate at 20°C for 50 minutes. Drain the reaction solution, wash with DMF (30.0 mL), and drain until no more liquid remains.

[0342] 12) Shrink the resin with MeOH (30.0 mL) and drain until no more liquid flows out. Blow dry the resin with nitrogen and set aside.

[0343] Peptide cleavage and purification:

[0344] The dried resin was added to a prepared cutting solution (90% TFA / 2.5% H2O / 5% TIS / 2.5% 3-Mpr) at room temperature and ultrasonically cut for 2.5 hours. The mixture was filtered, and the filtrate was added to ice-cold isopropyl ether for sedimentation and centrifugation, followed by washing with isopropyl ether. The crude peptide NYM070 (500 mg) was obtained by drying under vacuum for 2 hours.

[0345] The crude peptide was purified by preparative HPLC to obtain the final product NYM070 (14.0 mg, purity 96.6%).

[0346] LCMS: MS observed: [M+H]+=1018.4 (as shown in FIG59 )

[0347] HPLC: Purity: 96.6% (as shown in Figure 60)

[0348] 9. Synthesis steps of NYM071

[0349] Step 1:

[0350] Compound 2a_1 (1.38 g, 1.10 eq) was added to a solution of compound 2a_1 (2.00 g, 1.00 eq), HATU (3.81 g, 1.50 eq), and DIEA (3.49 mL, 3.00 eq) in DMF (20 mL). The reaction mixture was incubated at 25°C for 1 h. Compound 3a_1 (3.00 g) was obtained after purification.

[0351] Step 2:

[0352] Compound 3a_1 (1.00 g, 1.00 eq) was dissolved in trifluoroacetic acid (5 mL), and the reaction mixture was reacted at 20°C for 0.5 hours. The reaction mixture was then dried to give compound 4a_1 (700 mg).

[0353] Step 3:

[0354] Compound 4a_1 (640.1 mg, 1.20 eq) was added to a solution of 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) in DMF (10 mL). The mixture was reacted at 25°C for 12 h. Compound 6a_1 (780 mg, 97.7% purity) was obtained after purification.

[0355] Step 4:

[0356] To a solution of compound 6a_1 (380 mg, 1.00 eq) in methanol (4 mL) was added wet palladium on carbon (100 mg, 10% purity), and the reaction mixture was reacted at 20°C for 3 h under a 15 psi hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to obtain compound 7a_1 (270 mg).

[0357] Step 5:

[0358] Compound 7a_1 (158.04 mg, 1.10 eq) was added to a solution of compound Int 1 (70 mg, 1.00 eq), BOP (150.6 mg, 1.50 eq), and DIEA (118.6 μL, 3.00 eq) in DMF (10 mL). The reaction mixture was incubated at 25°C for 1 h. Compound 8a_1 (100 mg) was obtained after purification.

[0359] Step 6:

[0360] A mixture 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). The reaction mixture was incubated at 25°C for 1.5 h. The reaction mixture was concentrated in vacuo to yield the crude product. The crude product was purified to yield NYM071 (15.0 mg, 99.7% purity).

[0361] LCMS: MS: [M+H] + = 811.3 (as shown in FIG61 )

[0362] HPLC: Purity: 99.7% (as shown in Figure 62)

[0363] 10. Synthesis steps of NYM073

[0364] Step 1:

[0365] 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. After purification, compound 2c-1 (990 mg) was obtained.

[0366] Step 2:

[0367] Compound 2c-1 (990 mg, 1.00 eq) was dissolved in a mixture of tetrahydrofuran (10.0 mL) and water (0.04 mL). Pd / C (99.0 mg, 10.0% purity, 7.30 e-2 eq) was added under a nitrogen atmosphere. The reaction was continued at 25°C under a hydrogen atmosphere (15.0 psi) for 16 hours. The reaction mixture was filtered over celite and dried by rotary evaporation to yield compound 3c-1 (810 mg).

[0368] Step 3:

[0369] Compound 4c-1 (231 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), and 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. The reaction was stirred at 25°C for 1 hour. Compound 5c-1 (120 mg) was obtained after purification.

[0370] Step 4:

[0371] Compound 5c-1 (120 mg, 1.00 eq) was dissolved in a mixture of tetrahydrofuran (1.20 mL) and water (0.04 mL). Pd / C (12.0 mg, 10.0% purity, 9.36 e-2 eq) was added under a nitrogen atmosphere. The reaction was continued at 25°C under a hydrogen atmosphere (15.0 psi) for 3 hours. The reaction solution was filtered over celite and dried by rotary evaporation to afford compound 6c-1 (102 mg).

[0372] Step 5:

[0373] Int 1 (40.1 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (1.00 mL), and compound 6c-1 (102 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (52.3 mg, 1.00 eq), and N,N-diisopropylethylamine (61.8 μL, 3.00 eq) were added. The reaction was stirred at 25°C for 1 hour. Purification afforded compound 7c-1 (58.0 mg).

[0374] Step 6:

[0375] 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, 99.7% purity, TFA) was obtained after purification.

[0376] LCMS: MS: [M+H] + = 928.3. (as shown in FIG63 )

[0377] HPLC: Purity: 99.7% (as shown in Figure 64)

[0378] 11. Synthesis steps of NYM074

[0379] Step 1:

[0380] Compound 1d (217 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), and 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. The reaction was stirred at 25°C for 1 hour. Compound 2d (120 mg) was obtained after purification.

[0381] Step 2:

[0382] Compound 2d (120 mg, 1.00 eq) was dissolved in a mixture of tetrahydrofuran (1.20 mL) and water (0.04 mL). Pd / C (12.0 mg, 10.0% purity, 9.15 e-2 eq) was added under a nitrogen atmosphere. The reaction was continued at 25°C under a hydrogen atmosphere (15.0 psi) for 4 hours. The reaction solution was filtered over celite and dried by rotary evaporation to afford compound 3d (103 mg).

[0383] Step 3:

[0384] Int 1 (41.5 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (3.00 mL), and compound 6c (103 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphonium salt (54.2 mg, 1.00 eq), and N,N-diisopropylethylamine (64.0 μL, 3.00 eq) were added. The reaction was stirred at 25°C for 1 hour. Compound 4d (100 mg) was obtained after purification.

[0385] Step 4:

[0386] Compound 4d (100 mg, 1.00 eq) was dissolved in a mixture 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, 99.9% purity, TFA) was obtained after purification.

[0387] LCMS: MS: [M+H] + = 962.3. (as shown in FIG65 )

[0388] HPLC: Purity: 99.9% (as shown in Figure 66)

[0389] Example 2: Compound labeling process

[0390] 1. Nuclides 68 Ga marking process:

[0391] The compound prepared in Example 1 was 68 Ga was used to label the target product. 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074, the specific process is as follows:

[0392] 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.

[0393] b. Neutralization reaction liquid: 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).

[0394] c. Chelation reaction: Add 60 μg / 60 μl of NYM045 / 046 / 047 / 048 / 049 / 050 / 074 precursor solution (sterile water for injection) to the neutralized solution, shake well, and incubate at 70-80°C for 10 minutes. After the reaction is complete, remove the reaction bottle and cool it down.

[0395] d. Purification: Prepare a disposable Sep-Pak C-18 cartridge and pre-activate it with 10 mL of anhydrous ethanol and 20 mL of sterile water for injection. Use a 10 mL sterile syringe to pre-fill with 5 mL of sterile water for injection, then draw up 5 mL of the reaction solution. Connect the syringe to the C-18 cartridge and push the syringe through the cartridge. The target product will be adsorbed onto the cartridge. Rinse the cartridge with 20 mL of sterile water for injection. Finally, rinse the cartridge with 1.2 mL of 70% anhydrous ethanol and elute the target product into a transfer flask.

[0396] 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. 68 Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074 sterile injection.

[0397] Determination by Radio-iTLC method 68 The radiochemical purity (RCP) of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 / 074 sterile injection products is >90%. The results are shown in Figures 19 to 25. 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%.

[0398] 2. Nuclides 18 F marking process:

[0399] Collection Accelerator contains 18The 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. Then 3 mL of the diluted reaction solution and 7 mL of sterile water for injection were extracted, mixed and loaded onto the activated C18 column. Repeat three times until the loading was completed. The C18 column was rinsed with 10 mL of sterile water for injection. After repeating twice, it was eluted with 1.5 mL of 70% ethanol solution. The eluate was collected in a product bottle and sent for sample detection. Determined by Radio-iTLC method. 18 The radiochemical purity (RCP) of the F-NYM070 / 071 sterile injection products were 98.6% and 99.92%, respectively. The results are shown in Figures 26 and 27.

[0400] 3. Nuclides 177 Lu's marking process:

[0401] 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 177 LuCl3 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 membrane, collected in a vacuum bottle, and sampled for detection. 177 The radiochemical purity (RCP) of the Lu-NYM073 / 074 sterile injection products were 100% and 99.19%, respectively. The results are shown in Figures 28 and 29.

[0402] Example 3: SPR affinity testing of compounds

[0403] The affinity of NYM045 / 046 / 047 / 048 / 049 / 050 compounds for CAIX was determined using the Biacore 8K protein interaction system. Benzothiazine, which has a strong affinity for CAIX, was used as a positive control.

[0404] CAIX (purchased from ACROBiosystems Inc., 0.5 mg / mL) was coupled to a CM5 chip surface. The analyte was diluted in running buffer (HBS-EP buffer) (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% (v / v) Surfactant P20 (Tween 20), 5% DMSO, pH 7.4). A series of different concentrations of the analyte solution were diluted in DMSO (a dilution ratio of 2:2). The affinity of the analyte for CAIX was measured. The affinity of the analyte NYM045 / 046 / 047 / 048 / 049 / 050 / 070 / 071 / 073 / 074 for CAIX was expressed as the equilibrium dissociation constant (KD / Ka), where Kd represents the dissociation constant and Ka represents the association constant. A smaller KD value indicates a higher affinity for the compound. The test results are shown in Table 1 below. The results show that among the tested compounds, NYM046, NYM048, NYM049, NYM050, NYM070, NYM071, NYM073, and NYM074 showed low nanomolar affinity for CA9 and strong affinity for CA9.

[0405] Table 1

[0406] Example 4: PET / CT scanning tissue distribution and targeting experiment of target product in OS-RC-2 model mice

[0407] 1. Mouse model: Experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was based on the OS-RC-2 subcutaneous heterotopic transplant tumor model established in BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0408] The experimental steps are as follows:

[0409] Twenty-four mice were selected and divided into six groups (Groups 045, 046, 047, 048, 049, and 050), with four mice in each group. Each mouse in each group was administered 80-120 μCi of the corresponding drug. One hour after administration, the mice underwent MicroPET / CT scanning (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.). Scanned images were reconstructed using the device software and analyzed.

[0410] The experimental results of tumor drug uptake are shown in Figures 30, 31 and 32 (the arrows indicate the tumor uptake sites), where 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 drug was observed at the tumor site 1 hour after drug injection. In addition, the experimental results of drug uptake in various tissues are shown in Figure 32. 68 Ga-NYM045, 68 Ga-NYM049, 68 Ga-NYM050 intake is low, and the 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 The uptake of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 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 using as an imaging agent to diagnose tumor diseases.

[0411] 2. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant tumor model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0412] The experimental steps are as follows:

[0413] 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 dynamic MicroPET / CT scanning 30 minutes after administration of 60-120 μCi of Ga-NYM045 / 046 / 047 / 048 / 049 / 050 drugs, and static scanning was performed 1 hour, 2 hours, and 3 hours after administration. Scanned images were obtained after reconstruction by the equipment software. The scanned images are shown in Figures 33 to 38 and analyzed.

[0414] As shown in Figure 33, 68 One hour after administration, Ga-NYM045 showed high radioactive uptake in the tumor, while in other normal tissues 68Ga-NYM045 drug can be rapidly excreted through the kidneys; as shown in Figure 34, 68 One hour after the administration of Ga-NYM046, it was found that its radioactive uptake in the tumor was obvious and maintained at a high level for 3 hours without a significant downward trend. 68 Ga-NYM046 drug can be taken up in tumors or metastases for a long time; as shown in Figure 36, 68 One hour after administration, Ga-NYM048 was found to be significantly taken up in tumors. The uptake value did not change significantly until 3 hours, with no significant increase or decrease trend. However, the uptake in other organs gradually decreased. 68 Ga-NYM048 drug can be rapidly excreted through the kidneys; as shown in Figure 37, 68 One hour after administration, Ga-NYM049 was found to be significantly uptaken in the tumor. Uptake did not change significantly until 3 hours, with no significant increase or decrease trend. However, uptake in other normal tissues gradually decreased. As shown in FIG38 , 68 One hour after administration, Ga-NYM050 was found to be clearly visible in the tumor. The uptake value did not change much until 3 hours, with no obvious increase or decrease trend. However, the uptake in other organs gradually decreased, and the uptake in normal tissues was 68 Ga-NYM050 is rapidly excreted by the kidneys.

[0415] The changes in tumor radioactive uptake are shown in Figure 39. 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.

[0416] 3. Mouse model: Experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was based on the OS-RC-2 subcutaneous heterotopic transplant tumor model established in BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0417] The experimental steps are as follows:

[0418] Two mice were selected and each mouse was given 68Ga-NYM074 80 μCi, the animals were subjected to dynamic scanning with MicroPET / CT (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) 1 hour after administration, and static scanning was performed 2 hours after administration. Scanned images were obtained after reconstruction by the equipment software and analyzed.

[0419] The experimental results of tumor drug uptake are shown in Figure 40 (the arrows indicate the tumor uptake site), where 68 Ga-NYM074 rapidly accumulates at the tumor site, and imaging shows a high tumor-to-background uptake ratio one hour after drug injection, with significant drug uptake observed in the tumor. High uptake was maintained at the tumor site two hours after administration.

[0420] The experimental results of drug uptake in various tissues are shown in Figures 41 and 42, where the data 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 increases over time, and it has potential value as an imaging agent in the diagnosis of tumor diseases.

[0421] Example 5: 68 Ga-NYM050 OS-RC-2 model competitive inhibition experiment

[0422] 1. Experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was based on the OS-RC-2 subcutaneous heterotopic transplant tumor model established in BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0423] The experimental steps are as follows:

[0424] The experiment was divided into two parts: one baseline experiment and one blocking experiment.

[0425] 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. Scanned images were obtained after reconstruction by the equipment software and analyzed. The experimental results are shown in Figures 43 and 45.

[0426] 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 mass of Ga-NYM050 drug; injected 1 hour after NYM050 68Ga-NYM050 80 μCi was administered, and MicroPET / CT scans were performed 0.5 h, 1 h, 2 h, and 3 h after administration. Scanned images were obtained after reconstruction using the device software and analyzed. The experimental results are shown in Figures 44 and 46.

[0427] It can be seen that in the baseline experiment, the drug alone 68 After 1 hour of Ga-NYM050, it was found that its imaging at the tumor was clear 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's 68 The uptake of Ga-NYM050 confirmed 68 Ga-NYM050 can specifically recognize tumors.

[0428] Example 6: 177 Lu-NYM073 / 177 Lu-NYM074 SPECT / CT scanning experiment on OS-RC-2 model

[0429] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant tumor model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0430] Experimental steps:

[0431] One animal model mouse was selected. Each animal was given 177 Lu-NYM073 / 177 The Lu-NYM074 drug was administered at a dose of 300 μCi, and SPECT / CT scans of the 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.

[0432] As can be seen from Figure 47, 177 Four hours after administration, Lu-NYM073 was enriched in the tumor (arrows in the figure), and the uptake in normal tissues gradually decreased. 177 Six hours after administration, Lu-NYM074 was enriched in the tumor (arrows in the figure), and organ uptake in normal tissues gradually decreased. Until 120 hours later, the target product was still taken up in the tumor. This shows that this target product has a long retention time in the tumor, which is beneficial for the treatment of clinical tumor diseases, with reduced uptake in non-target organs and rapid clearance.

[0433] Example 7: Efficacy experiment of target product in model mice

[0434] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant tumor model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0435] Experimental steps:

[0436] Fifteen mice were randomly selected from the animal model and divided into three groups, each with 5 mice, namely the normal saline group, the single-dose group, and the 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, via tail vein injection. Mouse body weight and tumor volume were measured before the experiment and every three days after administration. Tumor volume was calculated using the following formula: 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.

[0437] 33 and 40 days after administration, the TGI values ​​for the single-dose group were 33.4% and 24.8%, respectively, while those for the multiple-dose group were 76.2% and 72.9%, respectively. As shown in Figure 48 , compared to the saline group, the single-dose and multiple-dose groups demonstrated significant antitumor activity, significantly controlling tumor growth. Tumor growth was slower in the multiple-dose group, demonstrating dose-dependence. Across the three experimental groups, there was little difference in the weight change trends of the mice between groups, as shown in Figure 49 , demonstrating the drug's excellent antitumor efficacy and safety.

[0438] Example 8: In vitro tissue distribution experiment of target product OS-RC-2 model

[0439] Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant tumor model was established based on BALB / c nude mice. This model is a mouse model constructed with human renal cancer cells.

[0440] Experimental steps:

[0441] Six mice were selected for this animal model. Each animal was given 177 Lu-NYM074 drug 100μCi, and 3 rats were dissected 4h and 48h after administration, and 15 tissues and organs including brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonads, skeletal muscle, spleen, stomach, fat, and tumor were collected and the gamma radiation count was detected.

[0442] As can be seen from Figure 50, 177 Lu-NYM074 was enriched in the tumor 4 hours after administration. Radioactivity uptake was high in the kidneys, lungs, stomach, and brown fat (brown fat in the scapula), while uptake in other normal tissues was low.

[0443] 4 hours after administration, 177 Lu-NYM074 drug has high uptake in tumors and low uptake in the heart. After 48 hours of administration, uptake in other normal tissues decreases rapidly, but it is still high in tumors. 177 Lu-NYM074 has clinical therapeutic potential.

[0444] Example 9: 68 Ga-NYM046 clinical research SPET / CT imaging experiment

[0445] 1. Brief information of patient 1: Patient 5, male, 59 years old, weighing 52 kg. Patient 5 underwent a left renal mass biopsy, 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, with multiple metastases in the lungs and lumbar spine. He was subsequently treated with immunotherapy. He was enrolled in a clinical trial of CAIX tracer. The patient was injected 18 1.5 hours after administration of 7.5 mCi of F-FDG, whole-body PET / CT imaging was performed. Two days later, the patient was injected 68 Whole-body PET / CT imaging was performed 1 hour after administration of 4.08 mCi of Ga-NYM046.

[0446] The imaging results are shown in Figures 51 to 54. It can be seen that the tumor and lesion areas 68 Ga-NYM046 has high radioactive uptake and a clear interface. 18 F-FDG, 68 Ga-NYM046 has a higher uptake value in 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.

[0447] 2. Brief information of patient 2: Enhanced CT scan of patient 2 showed: male, 76 years old, weighing 75 kg. 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 bones accompanied by soft tissue mass formation. Multiple solid nodules in both lungs; multiple nodules in both adrenal glands. A 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 68One hour after the administration of 4.83 mCi of Ga-NYM046, whole-body PET / CT imaging was performed. Six days later, patient 2 was injected 18 Whole-body PET / CT imaging was performed 1 hour after administration of 9.8 mCi of F-FDG.

[0448] The imaging results are shown in Figures 55 to 58. 68 Ga-NYM046 has high radioactive uptake and a clear interface. 18 F-FDG, 68 Ga-NYM046 has a higher uptake value in 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 in other non-target organs, and clearer imaging at the tumor site.

[0449] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0450] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify 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 Alkyne; 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 is selected from an integer between 1 and 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-triazonon-1-yl)pentanedioic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazononan ... 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-[acetyl (hydroxy) amino] pentyl}-N-[5-({4-[(5-aminopentyl) (hydroxy) amino]-4-oxobutyryl} amino) pentyl]-N-hydroxysuccinamide, diethylenetriamine pentaacetic acid, trans-cyclohexyl-diethylenetriamine pentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, isobutyl ...hydroxysuccinamide, diethylenetriamine pentaacetic acid, trans-cyclohexyl-diethylenetriamine pentaacetic acid, thiocyanatobenzyl-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 is selected from an integer between 1 and 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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