WO2025044924A1

WO2025044924A1 - Radiopharmaceutical targeting carbonic anhydrase

Info

Publication number: WO2025044924A1
Application number: PCT/CN2024/114181
Authority: WO
Inventors: 方鹏; 虞善友; 颜成龙; 伍维思; 杨思; 于德峰
Original assignee: Norroy Bioscience Co Ltd
Current assignee: Norroy Bioscience Co Ltd
Priority date: 2023-08-25
Filing date: 2024-08-23
Publication date: 2025-03-06
Anticipated expiration: 2026-02-25
Also published as: CN119504733A

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

本发明涉及医药技术领域，具体地，本发明涉及靶向碳酸酐酶放射性药物。The present invention relates to the field of medical technology, and in particular to a carbonic anhydrase-targeted radiopharmaceutical.

Background Art

在人体多数器官组织中分布有多种α-碳酸酐酶类(α-CAs)，部分器官组织中以一种CA占主导。在大多数缺氧性实体瘤中主导者为CAIX/XII，在血液中CAI/II是红细胞主要的蛋白质成分之一。肿瘤特异性表达的CAIX/XII是一种跨膜蛋白类型。CAIX在RCC(肾细胞癌)等肿瘤中稳定表达，CAIX在正常肾组织不表达，在除肾组织以外的器官组织中也仅部分微弱表达。因此，CAIX是一个针对ccRCC(肾透明细胞癌)诊断和治疗的潜在优良靶点。CAIX也在许多其他类型肿瘤中过表达，如肺癌、结直肠癌、胃癌、胰腺癌、黑色素瘤、乳腺癌、宫颈癌、膀胱癌、卵巢癌、脑癌、头颈部癌、星形细胞瘤、口腔癌等。There are many types of α-carbonic anhydrases (α-CAs) distributed in most organs and tissues of the human body, and one type of CA is dominant in some organs and tissues. In most hypoxic solid tumors, CAIX/XII is the dominant one, and in the blood, CAI/II is one of the main protein components of red blood cells. Tumor-specifically expressed CAIX/XII is a type of transmembrane protein. CAIX is stably expressed in tumors such as RCC (renal cell carcinoma). CAIX is not expressed in normal kidney tissue, and is only partially and weakly expressed in organs and tissues other than kidney tissue. Therefore, CAIX is a potential excellent target for the diagnosis and treatment of ccRCC (renal clear cell carcinoma). CAIX is also overexpressed in many other types of tumors, such as lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, oral cancer, etc.

肿瘤过表达的CAIX能够催化二氧化碳的水化反应，使二氧化碳生成碳酸氢根离子和质子，调节细胞环境酸碱度。细胞局部微环境的酸性增强能激活VEGF信号通路，促进新的血管生成，对肿瘤发生发展有重要作用。此外，大多数CA靶向性抑制剂都结合于CAIX胞外酶催化结构域的金属活性中心，以阻断其催化活性。CAIX特异性抑制剂的结构多为在磺胺类结构基础上，进行离子化、缺氧激活结构化、糖基化及纳米粒包合等。而对CAIX抑制剂小分子用核素进行的标记，可用于肿瘤的治疗和诊断。Tumor-overexpressed CAIX can catalyze the hydration reaction of carbon dioxide, converting carbon dioxide into bicarbonate ions and protons, and regulating the pH of the cell environment. The increased acidity of the local microenvironment of the cell can activate the VEGF signaling pathway, promote new angiogenesis, and play an important role in the occurrence and development of tumors. In addition, most CA-targeted inhibitors bind to the metal active center of the CAIX extracellular enzyme catalytic domain to block its catalytic activity. The structure of CAIX-specific inhibitors is mostly based on the sulfonamide structure, with ionization, hypoxia-activated structuring, glycosylation, and nanoparticle inclusion. The labeling of CAIX inhibitor small molecules with nuclides can be used for the treatment and diagnosis of tumors.

目前RCC的有效治疗手段是手术切除，但手术的局限性在于术后5年复发率为30％(或约50％)，而晚期或转移性RCC则无法进行手术。已转移的RCC的经典有效药物为高剂量白介素2，但是其只能在7-10％的患者中产生持续的完全反应。因此对于高复发风险的患者，开发更灵敏更准确的早期诊断策略，以及针对晚期和转移性RCC的有效的全身治疗药物，是一个需要继续面对和解决的挑战。开发更好的CAIX靶向药物、具有高亲和力和特异性的CAIX抑制剂用于肿瘤的治疗，具有重要的科研价值和广阔的应用前景。Currently, the effective treatment for RCC is surgical resection, but the limitation of surgery is that the recurrence rate is 30% (or about 50%) 5 years after surgery, and surgery is not possible for advanced or metastatic RCC. The classic effective drug for metastatic RCC is high-dose interleukin 2, but it can only produce a sustained complete response in 7-10% of patients. Therefore, for patients with a high risk of recurrence, the development of more sensitive and accurate early diagnosis strategies, as well as effective systemic therapeutic drugs for advanced and metastatic RCC, is a challenge that needs to be continued and resolved. The development of better CAIX targeted drugs and CAIX inhibitors with high affinity and specificity for the treatment of tumors has important scientific research value and broad application prospects.

发明内容Summary of the invention

本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。The present invention aims to solve at least one of the technical problems existing in the prior art to at least a certain extent.

在本发明的第一方面，本发明提出了一种化合物，其为式I所示化合物或式I所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
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:

其中，Y₁、Y₂分别独立地选自任选被R₁取代的C_1～10亚烷基、任选被R₁取代的C_1～10亚烷氧基、任选被R₁取代的C_1～10亚烷基-C(O)-NH-C_1～10亚烷基、任选被R₁取代的-C(O)-C_1～10亚烷基、任选被R₁取代的-NH-C_1～10亚烷基、任选被R₁取代的C_2～10亚烯基或任选被R₁取代的C_2～10亚炔基；wherein Y ₁ and Y ₂ are independently selected from C _1-10 alkylene optionally substituted by R ₁ , C _1-10 alkyleneoxy optionally substituted by R ₁ , C _{1-10 alkylene-C(O)-NH-C 1-10} _alkylene optionally substituted by R ₁ , -C(O)-C 1-10 alkylene optionally substituted by R ₁ , -NH-C _1-10 alkylene optionally substituted by R ₁ , C _2-10 alkenylene optionally substituted by R ₁ , or _C _2-10 alkynylene optionally substituted by R ₁ ;

Y₃选自键或任选被R₁取代的-NH-C(O)-C_1～10亚烷基、任选被R₁取代的C_1～10亚烷基、任选被R₁取代的-C(O)-NH-C_1～10亚烷基、任选被R₁取代的-C(O)-C_1～10亚烷氧基；Y ₃ is selected from a bond or -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ , C _1-10 alkylene optionally substituted by R ₁ , -C(O)-NH-C _1-10 alkylene optionally substituted by R ₁ , -C(O)-C _1-10 alkyleneoxy optionally substituted by R ₁ ;

X选自卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4烷氧基、羧基、C_3-10环烷基、C_3-10杂环基、C_6-10芳基或C_5-10杂芳基；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 heterocyclyl, C _6-10 aryl or C _5-10 heteroaryl;

Z选自螯合剂残基； Z is selected from the group consisting of chelating agent residues;

R₁各独立地选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN、N₃、任选被R₂取代的杂环、任选被R₂取代的杂芳环、任选被R₂取代C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4烷氧基、C_1-4烷基氨基、C_1-4卤代烷基、C_1-4卤代烷氧基、C_1-4羟基烷基或C_1-4卤代烷基氨基；其中，A选自芳香族单环或双环，t选自1～6之间的整数；R ₁ is independently selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , Heterocyclic ring optionally substituted by _R2 , heteroaromatic ring optionally substituted by _R2 , _C1-4 alkyl, C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _C1-4 alkylamino, _C1-4 haloalkyl, _C1-4 haloalkoxy, _C1-4 hydroxyalkyl or _C1-4 haloalkylamino optionally substituted by _R2 ; wherein A is selected from an aromatic monocyclic or _bicyclic ring, and t is selected from an integer between 1 and 6;

R₂选自H、D、＝O、OH、NH₂、NO₂、CN、N₃、卤素、C_1-6烷基、C_1-6卤代烷基、C_6-14芳基或C_5-14杂芳基。R ₂ is selected from H, D, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _6-14 aryl or C _5-14 heteroaryl.

根据本发明的实施例，式I所示化合物的X选自羧基、苯基、甲苯基、卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基或C_1-4烷氧基。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.

根据本发明的实施例，式I所示化合物的R₂选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN或N₃。According to an embodiment of the present invention, R ₂ of the compound represented by Formula I is selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN or N ₃ .

根据本发明的实施例，所述化合物为式II所示化合物或式II所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
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:

其中，Y₁选自任选被R₁取代的C_1～10亚烷基、任选被R₁取代的C_1～10亚烷氧基、任选被R₁取代的C_1～10亚烷基-C(O)-NH-C_1～10亚烷基、任选被R₁取代的-C(O)-C_1～10亚烷基、任选被R₁取代的-NH-C_1～10亚烷基、任选被R₁取代的C_2～10亚烯基或任选被R₁取代的C_2～10亚炔基；wherein Y ₁ is selected from C _1-10 alkylene optionally substituted by R ₁ , C 1-10 alkyleneoxy optionally substituted by R ₁ , C _1-10 alkylene-C(O)-NH-C _1-10 alkylene optionally substituted by R ₁ , -C(O)-C _1-10 alkylene optionally substituted by R ₁ , -NH-C _1-10 alkylene optionally substituted by R ₁ , C _2-10 alkenylene optionally substituted by R ₁ _{, or C 2-10} _alkynylene optionally substituted by R ₁ ;

Z选自螯合剂残基；Z is selected from the group consisting of chelating agent residues;

R₂选自H、D、＝O、OH、NH₂、NO₂、CN、N₃、卤素、C_1-6烷基、C_1-6卤代烷基、C_6-14芳基或C_5-14杂芳基；R ₂ is selected from H, D, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _6-14 aryl or C _5-14 heteroaryl;

n选自1～6之间的整数。n is an integer selected from 1 to 6.

根据本发明的实施例，式II所示化合物的X选自羧基、苯基、甲苯基、卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基或C_1-4烷氧基。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.

根据本发明的实施例，式II所示化合物的R₂选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN或N₃。According to an embodiment of the present invention, R ₂ of the compound represented by Formula II is selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN or N ₃ .

根据本发明的实施例，所述化合物为式III所示化合物或式III所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
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:

其中，Y₄选自-NR₂-、-NR₂-(C＝O)-、-NR₂-(C＝S)-、(CH₂)_p-(C＝O)-NR₂-、-(C＝O)-NR₂-、-(C＝S)-NR₂-或键，p选自1～4之间的整数；wherein Y ₄ is selected from -NR ₂ -, -NR ₂ -(C=O)-, -NR ₂ -(C=S)-, (CH ₂ ) _p -(C=O)-NR ₂ -, -(C=O)-NR ₂ -, -(C=S)-NR ₂ - or a bond, and p is selected from an integer between 1 and 4;

R₁各独立地选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN、N₃、任选被R₂取代的杂环、任选被R₂取代的杂芳环、任选被R₂取代的C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4烷氧基、C_1-4烷基氨基、C_1-4卤代烷基、C_1-4卤代烷氧基、C_1-4羟基烷基或C_1-4卤代烷基氨基；其中，A选自芳香族单环或双环，t选自1～6之间的整数；R ₁ is independently selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , Heterocyclic ring optionally substituted by _R2 , heteroaromatic ring optionally substituted by _R2 , _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C1-4 alkoxy, C1-4 alkylamino, _C1-4 haloalkyl, _C1-4 haloalkoxy, _C1-4 hydroxyalkyl or _C1-4 _{haloalkylamino} optionally substituted by _R2 ; wherein A is selected from an aromatic monocyclic or _bicyclic ring, and t is selected from an integer between 1 and 6;

n选自1～6之间的整数；n is selected from an integer between 1 and 6;

m选自1～6之间的整数。m is an integer selected from 1 to 6.

根据本发明的实施例，式III所示化合物的X选自羧基、苯基、甲苯基、卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基或C_1-4烷氧基。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.

根据本发明的实施例，式III所示化合物的R₂选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN或N₃。According to an embodiment of the present invention, R ₂ of the compound represented by formula III is selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN or N ₃ .

根据本发明的实施例，所述Y₃选自任选被R₁取代的-NH-C(O)-C_1～10亚烷基。According to an embodiment of the present invention, Y ₃ is selected from -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ .

根据本发明的实施例，所述Y₃选自键或任选被R₁取代的-NH-C(O)-C_1～10亚烷基。According to an embodiment of the present invention, Y ₃ is selected from a bond or -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ .

需要说明的是，所述R₁可以取代“-NH-C(O)-C_1～10亚烷基”中“-NH-”的“H”，也可取代“-C_1～10亚烷基”中任意“-CH₂”的“H”。It should be noted that the R ₁ may replace the "H" of "-NH-" in "-NH-C(O)-C _1-10 alkylene", and may also replace the "H" of any "-CH ₂ " in "-C _1-10 alkylene".

根据本发明的实施例，所述R₁选自 According to an embodiment of the present invention, the R ₁ is selected from

根据本发明的实施例，所述Y₃选自
According to an embodiment of the present invention, the _Y3 is selected from

根据本发明的实施例，所述X选自羧基、苯基、甲苯基或C_1-4烷基。According to an embodiment of the present invention, X is selected from carboxyl, phenyl, tolyl or C _1-4 alkyl.

根据本发明的实施例，所述X选自羧基、苯基、酚羟基、萘基、甲苯基或C_1-4烷基。According to an embodiment of the present invention, X is selected from carboxyl, phenyl, phenolic hydroxyl, naphthyl, tolyl or C _1-4 alkyl.

根据本发明的实施例，所述Z衍生自1，4，7，10-四氮杂环十二烷-N，N'，N"，N"，四乙酸(DOTA)、N，N"-双【2-羟基-5-(羧乙基)苄基】乙二胺-N，N"-二乙酸(HBED-CC)、1，4，7-三氮杂环壬烷-1，4，7-三乙酸(NOTA)、2-(4，7-双(羧甲基)-1，4，7-三偶氮壬-1-基)戊二酸(NODAGA)、2-(4，7，10-三(羧甲基)-1，4，7，10-四氮杂环十二烷-1-基)戊二酸(DOTAGA)、1，4，7-三氮杂环壬烷次膦酸(TRAP)、1，4，7-三氮杂环壬烷-1-【甲基(2-羧乙基)次膦酸】-4，7-双【甲基(2-羟甲基)次膦酸】(NOPO)、3，6，9，15-四氮杂双环【9.3.1】十五-1(15)，11，13-三烯-3，6，9-三乙酸(PCTA)、N'-{5-【乙酰基(羟基)氨基】戊基}-N-【5-({4-【(5-氨基戊基)(羟基)氨基】-4-氧丁酰基}氨基)戊基】-N-羟基琥珀酰胺(DFO)、二乙三胺五乙酸(DTPA)、反式-环己基-二乙三胺五乙酸(CHX-DTPA)、1-氧杂-4，7，10-三氮杂环十二烷-4，7，10-三乙酸(氧-Do3A)、对异氰硫基苄基-DTPA(SCN-Bz-DTPA)、1-(对异氰硫基苄基)-3-甲基-DTPA(1B3M)、2-(对异氰硫基苄基)-4-甲基-DTPA(1M3B)、1-(2)-甲基-4-异氰硫基苄基-DTPA(MX-DTPA)、R)-2-氨基-3-(4-异硫代氰酰基苯基)丙基]-反式-(S,S)-环己烷-1,2-二胺五乙酸(p-SCN-Bn-CHX-A"-DTPA)或6-肼基吡啶-3-羧酸(HYNIC)。According to an embodiment of the present invention, Z is derived from 1,4,7,10-tetraazacyclododecane-N,N',N",N",tetraacetic acid (DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazononan-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10 -tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononanephosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N'- {5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenetriaminepentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxy-Do3A), p-isocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1 -(p-isothiocyanatobenzyl)-3-methyl-DTPA (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), 1-(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA), [R]-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diaminepentaacetic acid (p-SCN-Bn-CHX-A"-DTPA), or 6-hydrazinopyridine-3-carboxylic acid (HYNIC).

根据本发明的实施例，所述Z选自 According to an embodiment of the present invention, Z is selected from

根据本发明的实施例，当所述Y₄选自键时，所述Z选自 According to an embodiment of the present invention, when Y ₄ is selected from a bond, Z is selected from

根据本发明的实施例，当Y₄选自-NR₂-时，Z选自 According to an embodiment of the present invention, when Y ₄ is selected from -NR ₂ -, Z is selected from

在本发明的第二方面，本发明提出了一种化合物，其为式IV所示化合物或式IV所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
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:

其中，Y₄选自-NR₂-、-NR₂-(C＝O)-、-NR₂-(C＝S)-、(CH₂)_p-(C＝O)-NR₂-、-(C＝O)-NR₂-、-(C＝S)-NR₂-或键，p选自1～4之间的整数； wherein Y ₄ is selected from -NR ₂ -, -NR ₂ -(C=O)-, -NR ₂ -(C=S)-, (CH ₂ ) _p -(C=O)-NR ₂ -, -(C=O)-NR ₂ -, -(C=S)-NR ₂ - or a bond, and p is selected from an integer between 1 and 4;

Z₁选自 Z ₁ is selected from

m选自1～6之间的整数。m is selected from an integer between 1 and 6.

根据本发明的实施例，式IV所示化合物的X选自羧基、苯基、酚羟基、萘基、甲苯基、卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基或C_1-4烷氧基。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.

根据本发明的实施例，式IV所示化合物的X选自羧基、苯基、甲苯基、卤素、C_1-4烷基、C_2-4烯基、C_2-4炔基或C_1-4烷氧基。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.

根据本发明的实施例，式IV所示化合物的R₂选自H、D、F、Cl、Br、I、＝O、OH、NH₂、NO₂、CN或N₃。According to an embodiment of the present invention, R ₂ of the compound represented by formula IV is selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN or N ₃ .

根据本发明的实施例，所述X选自羧基或苯基。According to an embodiment of the present invention, the X is selected from a carboxyl group or a phenyl group.

根据本发明的实施例，当所述Y₄选自键时，所述Z₁选自 According to an embodiment of the present invention, when the Y ₄ is selected from a bond, the Z ₁ is selected from

根据本发明的实施例，当Y₄选自-NR₂-时，Z₁选自 According to an embodiment of the present invention, when Y ₄ is selected from -NR ₂ -, Z ₁ is selected from

在本发明的第三方面，本发明提出了一种化合物，其结构选自如下一种：

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

在本发明第四方面，本发明提出了一种化合物。根据本发明的实施例，所述化合物由第一方面、第二方面或第三方面所述的化合物与M络合而成。In the fourth aspect of the present invention, the present invention provides a compound. According to an embodiment of the present invention, the compound is formed by complexing the compound described in the first aspect, the second aspect or the third aspect with M.

根据本发明的实施例，所述M选自放射性核素或非放射性元素的至少之一。According to an embodiment of the present invention, the M is selected from at least one of radioactive nuclides or non-radioactive elements.

根据本发明的实施例，所述放射性核素包括诊断核素或治疗核素的至少之一。According to an embodiment of the present invention, the radioactive nuclide includes at least one of a diagnostic nuclide or a therapeutic nuclide.

根据本发明的实施例，所述诊断核素选自⁶⁸Ga、¹⁸F、^99mTc、⁸⁹Zr、¹²⁴I、⁷⁶Br、⁴³Sc、¹¹¹In、⁴⁵Ti、⁵²Mn、⁵⁹Fe、⁶⁴Cu、^94mTc、⁶⁷Ga、^71/72/74As、^82mRb或⁸⁶Y。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.

根据本发明的实施例，所述治疗核素选自¹⁷⁷Lu、¹⁶¹Tb、⁹⁰Y、¹³¹I、¹⁵³Sm、⁶⁷Cu、⁸⁹Sr、166Ho、¹⁷⁷Yb、⁴⁷Sc、^186/188Re、^212/213Bi、¹⁴⁹Pm、²¹²Pb、²¹¹At、²²³Ra、²²⁵Ac或²²⁷Th。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, 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.

根据本发明的实施例，所述放射性核素选自⁶⁸Ga、¹⁸F、⁸⁹Zr、⁹⁹mTc或¹⁷⁷Lu。According to an embodiment of the present invention, the radioactive nuclide is selected from ⁶⁸ Ga, ¹⁸ F, ⁸⁹ Zr, ⁹⁹ mTc or ¹⁷⁷ Lu.

根据本发明的实施例，所述放射性核素¹⁸F是通过¹⁸FAl进行络合的。According to an embodiment of the present invention, the radionuclide ¹⁸ F is complexed by ¹⁸ FAl.

根据本发明的实施例，所述M选自⁶⁸Ga、¹⁸F或¹⁷⁷Lu。According to an embodiment of the present invention, the M is selected from ⁶⁸ Ga, ¹⁸ F or ¹⁷⁷ Lu.

根据本发明的实施例，所述化合物结构选自如下一种：

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

在本发明的第五方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括：第一方面、第二方面、第三方面或第四方面所述的化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药。In a fifth aspect of the present invention, the present invention provides a pharmaceutical composition. According to an embodiment of the present invention, the pharmaceutical composition comprises: the compound described in the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug.

根据本发明的实施例，所述药物组合物进一步包含药学上可接受的载体或辅料。According to an embodiment of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

在本发明的第六方面，本发明提出了第一方面、第二方面、第三方面或第四方面所述的化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第五方面所述的药物组合物在用于抑制碳酸酐酶IX中的用途。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.

在本发明的第七方面，本发明提出了一种对表达碳酸酐酶IX蛋白的组织进行成像的方法。根据本发明的实施例，所述方法包括向所述组织施用第一方面、第二方面、第三方面或第四方面所述的化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第五方面所述的药物组合物，以及对施药后的所述组织进行成像。In a seventh aspect of the present invention, the present invention provides a method for imaging a tissue expressing carbonic anhydrase IX protein. According to an embodiment of the present invention, the method comprises administering to the tissue the compound of the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition of the fifth aspect, and imaging the tissue after administration.

根据本发明的实施例，所述成像是通过正电子发射断层扫描(PET)或单光子发射计算机断层成像术(SPECT)进行的。According to an embodiment of the present invention, the imaging is performed by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

在本发明的第八方面，本发明提出了第一方面、第二方面、第三方面或第四方面所述的化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第五方面所述的药物组合物在制备用于诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症或细胞的试剂和/或药物中的用途。In the eighth aspect of the present invention, the present invention proposes the use of the compound described in the first aspect, the second aspect, the third aspect or the fourth aspect, or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition described in the fifth aspect in the preparation of reagents and/or drugs for diagnosing and/or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX.

在本发明第八方面，本发明提供一种抑制碳酸酐酶IX，或诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症或细胞的方法，包括步骤：给需要的对象施用本发明第一方面、第二方面、第三方面或第四方面所述的化合物，或其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，或第五方面所述的药物组合物。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.

根据本发明的实施例，所述诊断的形式选自光学成像和/或核素成像。According to an embodiment of the present invention, the diagnosis modality is selected from optical imaging and/or nuclear imaging.

根据本发明的实施例，所述诊断的形式选自荧光显像、PET成像和/或SPECT成像。 According to an embodiment of the present invention, the diagnosis modality is selected from fluorescence imaging, PET imaging and/or SPECT imaging.

根据本发明的实施例，所述治疗选自放射性治疗和/或辅助手术开展荧光手术导航。According to an embodiment of the present invention, the treatment is selected from radiotherapy and/or assisted surgery with fluorescent surgical navigation.

根据本发明的实施例，所述表达碳酸酐酶CAIX的肿瘤包括：肾癌、肺癌、结直肠癌、胃癌、胰腺癌、黑色素瘤、乳腺癌、宫颈癌、膀胱癌、卵巢癌、脑癌、头颈部癌、星形细胞瘤或口腔癌。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:

本发明公开的靶向靶向碳酸酐酶放射性药物，其表现出对碳酸酐酶IX的高亲和力，在生物体内高表达碳酸酐酶IX的组织、肿瘤或细胞内表现出良好的特异性靶向摄取，快速富集，且维持较长时间的摄取，且在非靶组织中快速清除，肿瘤与正常组织的摄取比率高，显像边界清晰，且安全性好。可快速的检出病变的组织，同时肿瘤组织滞留时间久，显示出治疗的潜在可能性，具有临床诊断和治疗意义。The targeted carbonic anhydrase radiopharmaceutical disclosed in the present invention has a high affinity for carbonic anhydrase IX, and exhibits good specific targeted uptake, rapid enrichment, and long-term uptake maintenance in tissues, tumors or cells that highly express carbonic anhydrase IX in vivo, and is rapidly cleared in non-target tissues, with a high uptake ratio of tumors to normal tissues, clear imaging boundaries, and good safety. The diseased tissue can be quickly detected, and the tumor tissue retention time is long, showing the potential possibility of treatment, and has clinical diagnosis and treatment significance.

本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

术语和定义Terms and Definitions

除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The group definitions and compound structures after such combinations and combinations shall fall within the scope of the description of this application.

除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。Unless otherwise defined, all technical terms used herein have the same meaning as those commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. If there are multiple definitions of a term herein, the definition in this chapter shall prevail.

除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular form used in this specification and claims includes the plural form of the referred thing. It should also be noted that unless otherwise stated, the "or" and "or" used mean "and/or". In addition, the term "including" and other forms, such as "including", "containing" and "containing" are not restrictive.

可在参考文献(包括Carey and Sundberg" ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,NewYork)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。Definitions of standard chemical terms may be found in the literature, 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 employed. Unless specific definitions are provided, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and drugs and medicinal chemistry are known in the art. Standard techniques may be used in chemical syntheses, chemical analyses, drug preparation, formulation and delivery, and treatment of patients. For example, the manufacturer's instructions for the use of the kit may be used, or the reactions and purifications may be carried out in a manner known in the art or as described in the present invention. The above techniques and methods may generally be carried out in accordance with conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable structural moieties and compounds.

一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个被取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代时，那么取代基可以相同或不同地在各个可取代的位置取代。In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specified substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted by one or more substituents selected from a specified group, then the substituents may be the same or different at each substitutable position.

术语“未取代的”，表示指定基团不带有取代基。The term "unsubstituted" means that the designated group bears no substituents.

如本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者如实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted", indicates that one or more hydrogen atoms in a given structure are replaced with a specific substituent. Unless otherwise indicated, an optionally substituted group may have a substituent substituted at each substitutable position of the group. When more than one position in a given structural formula can be selected from a specific group If the moiety is substituted by one or more substituents, the substituents may be the same or different at each position.

另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH₂O等同于OCH₂。如本文所用，表示基团的连接位点。When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH ₂ O is equivalent to OCH ₂ . As used herein, Indicates the attachment site of a group.

本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are only for the purpose of organizing the article and should not be interpreted as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals and papers, are incorporated herein by reference in their entirety.

除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically stated.

本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。当该数值范围被理解为“数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数以及该范围内的每一个小数。例如，“1～10的数”应当被理解为不仅记载了1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。The numerical ranges recorded in the specification and claims of this application, when the numerical range is understood as an "integer", should be understood as recording the two endpoints of the range and each integer in the range. For example, "an integer from 1 to 6" should be understood as recording each integer of 0, 1, 2, 3, 4, 5 and 6. When the numerical range is understood as a "number", it should be understood as recording the two endpoints of the range and each integer in the range and each decimal in the range. For example, "a number from 1 to 10" should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘；优选氟或氯。As used herein, the term "halogen" alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.

在单独或作为其他取代基一部分时，术语“烷基”，表示1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代，取代基包括但不限于，氘、氨基、羟基、氰基、F、Cl、Br、I、巯基、硝基、氧代(＝O)等等。烷基的实例包括，但并不限于，甲基(Me，-CH₃)、乙基(Et，-CH₂CH₃)、正丙基(n-Pr，-CH₂CH₂CH₃)、异丙基(i-Pr，-CH(CH₃)₂)、正丁基(n-Bu，-CH₂CH₂CH₂CH₃)、异丁基(i-Bu，-CH₂CH(CH₃)₂)、仲丁基(s-Bu，-CH(CH₃)CH₂CH₃)、叔丁基(t-Bu，-C(CH₃)₃)、正戊基(-CH₂CH₂CH₂CH₂CH₃)、2-戊基(-CH(CH₃)CH₂CH₂CH₃)、3-戊基(-CH(CH₂CH₃)₂)等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。The term "alkyl", when used alone or as part of other substituents, refers to a saturated linear or branched monovalent hydrocarbon group of 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted with one or more substituents described herein, including but not limited to deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), and the like. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

在单独或作为其他取代基一部分时，术语“亚烷基”应理解为表示直链或含支链的饱和、不饱和或部分饱和的二价烃基。例如“C_1-10亚烷基”或“C_1-C₁₀亚烷基”表示具有1-10个碳原子的直链或含支链的二价烃基，包括但不限于亚甲基、亚乙基、亚丙基、1-甲基亚丙基、亚丁基。When used alone or as part of other substituents, the term "alkylene" should be understood to mean a straight chain or branched saturated, unsaturated or partially saturated divalent hydrocarbon group. For example, "C _1-10 alkylene" or "C _1- C ₁₀ alkylene" means a straight chain or branched divalent hydrocarbon group having 1 to 10 carbon atoms, including but not limited to methylene, ethylene, propylene, 1-methylpropylene, and butylene.

在单独或作为其他取代基一部分时，术语“烯基”是指具有至少一个碳-碳sp2双键的二到四十个碳原子的直链或支链的一价烃基(例如C₂-C₆烯基，又例如C₂-C₄烯基)，并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。烯基的实例包括但不限于乙烯基和烯丙基。When alone or as part of other substituents, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to forty carbon atoms having at least one carbon-carbon sp2 double bond (e.g., _C2 - _C6 alkenyl, for example, _C2 - _C4 alkenyl), 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.

在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳sp三键的二到四十个碳原子的直链或支链的单价烃基(例如C₂-C₆炔基，又例如C₂-C₄炔基)。炔基的实例包括但不限于乙炔基和丙炔基。The term "alkynyl" 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 alkynyl, for example, _C2 - _C4 alkynyl) with at least one carbon-carbon sp triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.

在单独或作为其他取代基一部分时，术语“烷氧基”是指基团-O-R^Q，其中，R^Q为如上文所定义的“烷基”。The term "alkoxy" by itself or as part of another substituent refers to the group ^-ORQ , wherein ^RQ is an "alkyl" as defined above.

在单独或作为其他取代基一部分时，术语“杂芳环”是指单环或多环碳环，其中至少一个环原子为独立地选自氧、硫和氮的杂原子，其余的环原子为C，其中至少一个环是芳香环。该基团可为碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。当其中一个环是非芳香环时，该基团可通过芳香环连接，也可通过非芳香环连接。杂芳基的实例包括但不限于：咪唑基、吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、N-甲基吡咯基和四氢喹啉。术语“杂芳环”可以和术语“杂芳香环”、“杂芳基”或“杂芳环基”交换使用。When alone or as part of other substituents, the term "heteroaromatic ring" refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring. The group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible). When one of the rings is a non-aromatic ring, the group may be connected through an aromatic ring or through a non-aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline. The term "heteroaromatic ring" may be used interchangeably with the terms "heteroaromatic ring", "heteroaryl" or "heteroaromatic cyclyl".

在单独或作为其他取代基一部分时，术语“双环”指具有两个连接环的基团。双环可以为碳环(所有环原子为碳原子)或杂环(除了碳原子之外，环原子包括例如1、2或3个杂原子，例如N、O或S)。这两个环都可以是脂肪族的(例如萘烷和降冰片烷)，或可以是芳香族(例如萘)，或脂肪族和芳香族的组合(例如四氢化萘)。 The term "bicyclic" when used alone or as part of another substituent refers to a group having two connected rings. The bicyclic ring can be a carbocyclic ring (all ring atoms are carbon atoms) or a heterocyclic ring (in addition to carbon atoms, the ring atoms include, for example, 1, 2 or 3 heteroatoms, such as N, O or S). Both rings can be aliphatic (e.g., decalin and norbornane), or can be aromatic (e.g., naphthalene), or a combination of aliphatic and aromatic (e.g., tetralin).

在单独或作为其他取代基一部分时，术语“萘基”结构为 The term "naphthyl" when used alone or as part of another substituent is

本公开针对通式(I)的化合物提及的“螯合基团”是指衍生自螯合剂的分子片段。例如螯合基团是衍生自1,4,7,10-四氮杂环十二烷-N,N',N,N'-四乙酸(DOTA)的分子片段其可以是通过DOTA的一个羧基与其他基团连接成键，例如酰胺键而引入到通式(I)的化合物中。The "chelating group" mentioned in the present disclosure for the compound of general formula (I) refers to a molecular fragment derived from a chelating agent. For example, the chelating group is a molecular fragment derived from 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA) It can be introduced into the compound of general formula (I) by connecting one carboxyl group of DOTA to other groups through a bond, such as an amide bond.

在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。In the present application, "optional" or "optionally" means that the event or situation described later may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, "optionally substituted aryl" means that aryl is substituted or unsubstituted, and the description includes both substituted aryl and unsubstituted aryl.

在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。In the present application, the term "salt" or "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。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.

依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。Depending on the choice of starting materials and methods, the compounds of the invention may exist in the form of one of the possible isomers or a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。When the bonds to the chiral carbon in the formula of the present invention are depicted as straight lines, it should be understood that both the (R) and (S) configurations of the chiral carbon and the enantiomerically pure compounds and mixtures thereof produced therefrom are included within the scope of the general formula. The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge-shaped bond and a dashed bond.

术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。The term "solvate" means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。The term "prodrug" refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/ 或粘着性使制剂更适于直接压缩。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 characteristics of a pharmaceutical formulation by increasing fluidity and/or Or adhesive properties make the formulation more suitable for direct compression.

术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

术语“预防”是指获得或发生疾病或障碍的风险降低。The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为优。The term "patient" refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.

术语“治疗有效量”是指在给予患者时，足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，可由本领域技术人员根据需要进行调整。The term "therapeutically effective amount" refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient."Therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：The above and/or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

图1是根据本发明实施例的NYM045分子的LCMS谱图；FIG1 is an LCMS spectrum of NYM045 molecules according to an embodiment of the present invention;

图2是根据本发明实施例的NYM045分子的HPLC谱图；FIG. 2 is a HPLC spectrum of the NYM045 molecule according to an embodiment of the present invention;

图3是根据本发明实施例的NYM045分子的核磁谱图；FIG3 is a nuclear magnetic resonance spectrum of the NYM045 molecule according to an embodiment of the present invention;

图4是根据本发明实施例的NYM046分子的LCMS谱图；FIG4 is an LCMS spectrum of NYM046 molecules according to an embodiment of the present invention;

图5是根据本发明实施例的NYM046分子的HPLC谱图；FIG5 is a HPLC spectrum of NYM046 molecules according to an embodiment of the present invention;

图6是根据本发明实施例的NYM046分子的核磁谱图；FIG6 is a nuclear magnetic resonance spectrum of the NYM046 molecule according to an embodiment of the present invention;

图7是根据本发明实施例的NYM047分子的LCMS谱图；FIG. 7 is an LCMS spectrum of NYM047 molecules according to an embodiment of the present invention;

图8是根据本发明实施例的NYM047分子的HPLC谱图；FIG8 is a HPLC spectrum of NYM047 molecules according to an embodiment of the present invention;

图9是根据本发明实施例的NYM047分子的核磁谱图；FIG9 is a nuclear magnetic resonance spectrum of the NYM047 molecule according to an embodiment of the present invention;

图10是根据本发明实施例的NYM048分子的LCMS谱图；FIG10 is an LCMS spectrum of NYM048 molecules according to an embodiment of the present invention;

图11是根据本发明实施例的NYM048分子的HPLC谱图；FIG11 is a HPLC spectrum of NYM048 molecules according to an embodiment of the present invention;

图12是根据本发明实施例的NYM048分子的核磁谱图；FIG12 is a nuclear magnetic resonance spectrum of NYM048 molecule according to an embodiment of the present invention;

图13是根据本发明实施例的NYM049分子的LCMS谱图；FIG13 is an LCMS spectrum of NYM049 molecules according to an embodiment of the present invention;

图14是根据本发明实施例的NYM049分子的HPLC谱图；FIG. 14 is a HPLC spectrum of NYM049 molecules according to an embodiment of the present invention;

图15是根据本发明实施例的NYM049分子的核磁谱图；FIG15 is a nuclear magnetic resonance spectrum of NYM049 molecule according to an embodiment of the present invention;

图16是根据本发明实施例的NYM050分子的LCMS谱图；FIG16 is an LCMS spectrum of NYM050 molecules according to an embodiment of the present invention;

图17是根据本发明实施例的NYM050分子的HPLC谱图；FIG. 17 is a HPLC spectrum of NYM050 molecules according to an embodiment of the present invention;

图18是根据本发明实施例的NYM050分子的核磁谱图；FIG18 is an NMR spectrum of NYM050 molecule according to an embodiment of the present invention;

图19是根据本发明实施例的⁶⁸Ga-NYM045分子的放射性薄层色谱扫描纯度分析结果图；FIG19 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM045 molecules according to an embodiment of the present invention;

图20是根据本发明实施例的⁶⁸Ga-NYM046分子的放射性薄层色谱扫描纯度分析结果图；FIG20 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM046 molecules according to an embodiment of the present invention;

图21是根据本发明实施例的⁶⁸Ga-NYM047分子的放射性薄层色谱扫描纯度分析结果图；FIG21 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM047 molecules according to an embodiment of the present invention;

图22是根据本发明实施例的⁶⁸Ga-NYM048分子的放射性薄层色谱扫描纯度分析结果图；FIG22 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM048 molecules according to an embodiment of the present invention;

图23是根据本发明实施例的⁶⁸Ga-NYM049分子的放射性薄层色谱扫描纯度分析结果图；FIG23 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM049 molecules according to an embodiment of the present invention;

图24是根据本发明实施例的⁶⁸Ga-NYM050分子的放射性薄层色谱扫描纯度分析结果图；FIG24 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM050 molecules according to an embodiment of the present invention;

图25是根据本发明实施例的⁶⁸Ga-NYM074分子的放射性薄层色谱扫描纯度分析结果图；FIG25 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ⁶⁸ Ga-NYM074 molecules according to an embodiment of the present invention;

图26是根据本发明实施例的¹⁸F-NYM070分子的放射性薄层色谱扫描纯度分析结果图；FIG. 26 is a graph showing the results of radioactive thin layer chromatography scanning purity analysis of ¹⁸ F-NYM070 molecules according to an embodiment of the present invention;

图27是根据本发明实施例的¹⁸F-NYM071分子的放射性薄层色谱扫描纯度分析结果图；FIG27 is a graph showing the results of radioactive thin layer chromatography scanning purity analysis of ¹⁸ F-NYM071 molecules according to an embodiment of the present invention;

图28是根据本发明实施例的¹⁷⁷Lu-NYM073分子的放射性薄层色谱扫描纯度分析结果图；FIG28 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of ¹⁷⁷ Lu-NYM073 molecules according to an embodiment of the present invention;

图29是根据本发明实施例的¹⁷⁷Lu-NYM074分子的放射性薄层色谱扫描纯度分析结果图；FIG29 is a graph showing the radioactive thin layer chromatography scanning purity analysis result of the ¹⁷⁷ Lu-NYM074 molecule according to an embodiment of the present invention;

图30是根据本发明实施例的⁶⁸Ga-NYM045/046/047在OS-RC-2荷瘤鼠模型上的PET/CT显像结果图； FIG30 is a diagram showing the PET/CT imaging results of ⁶⁸ Ga-NYM045/046/047 on an OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention;

图31是根据本发明实施例的图⁶⁸Ga-NYM048/049/050在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG31 is a PET/CT imaging result of Ga-NYM048/049/050 in an OS-RC-2 tumor-bearing mouse model according to an ^embodiment of the present invention;

图32是根据本发明实施例的⁶⁸Ga-NYM045/046/047/048/049/050在不同器官、部位中的摄取值以及肿瘤与非靶器官的摄取值比率；FIG32 shows the uptake values of ⁶⁸ Ga-NYM045/046/047/048/049/050 in different organs and parts and the uptake value ratio of tumor to non-target organs according to an embodiment of the present invention;

图33是根据本发明实施例的不同时间段的⁶⁸Ga-NYM045在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG33 is a PET/CT imaging result of ⁶⁸ Ga-NYM045 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图34是根据本发明实施例的不同时间段的⁶⁸Ga-NYM046在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG. 34 is a PET/CT imaging result of ⁶⁸ Ga-NYM046 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图35是根据本发明实施例的不同时间段的⁶⁸Ga-NYM047在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG. 35 is a PET/CT imaging result of ⁶⁸ Ga-NYM047 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图36是根据本发明实施例的不同时间段的⁶⁸Ga-NYM048在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG36 is a PET/CT imaging result of ⁶⁸ Ga-NYM048 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图37是根据本发明实施例的不同时间段的⁶⁸Ga-NYM049在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG37 is a PET/CT imaging result of ⁶⁸ Ga-NYM049 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图38是根据本发明实施例的不同时间段的⁶⁸Ga-NYM050在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG38 is a PET/CT imaging result of ⁶⁸ Ga-NYM050 in OS-RC-2 tumor-bearing mouse model at different time periods according to an embodiment of the present invention;

图39是根据本发明实施例的⁶⁸Ga-NYM045/046/047/048/049/050在肿瘤部位的摄取量随时间的变化图；FIG39 is a graph showing changes in the uptake of ⁶⁸ Ga-NYM045/046/047/048/049/050 at the tumor site over time according to an embodiment of the present invention;

图40是根据本发明实施例的⁶⁸Ga-NYM074药物在小鼠体内的PET/CT扫描图；FIG40 is a PET/CT scan of the ⁶⁸ Ga-NYM074 drug in mice according to an embodiment of the present invention;

图41是根据本发明实施例的⁶⁸Ga-NYM074药物在小鼠体内的不同组织摄取值；FIG41 is a graph showing the uptake values of different tissues of ⁶⁸ Ga-NYM074 drug in mice according to an embodiment of the present invention;

图42是根据本发明实施例的⁶⁸Ga-NYM074药物在小鼠肿瘤与肌肉中的比例、以及肿瘤和心脏中的比例；FIG42 shows the ratio of ⁶⁸ Ga-NYM074 drug in mouse tumor to muscle, and the ratio in tumor to heart according to an embodiment of the present invention;

图43是根据本发明实施例的⁶⁸Ga-NYM050在OS-RC-2荷瘤鼠模型上的PET/CT显像结果；FIG43 is a PET/CT imaging result of ⁶⁸ Ga-NYM050 in an OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention;

图44是根据本发明实施例的⁶⁸Ga-NYM050在OS-RC-2荷瘤鼠模型上的竞争抑制实验扫描图；FIG44 is a scanning diagram of a competitive inhibition experiment of ⁶⁸ Ga-NYM050 in an OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention;

图45是根据本发明实施例的⁶⁸Ga-NYM050在OS-RC-2荷瘤鼠模型上不同时间不同器官、部位中的摄取值；FIG45 shows the uptake values of ⁶⁸ Ga-NYM050 in different organs and parts at different times in an OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention;

图46是根据本发明实施例的⁶⁸Ga-NYM050阻断实验OS-RC-2荷瘤鼠模型上不同时间不同器官、部位中的摄取值；FIG46 shows the uptake values in different organs and parts at different times in the ⁶⁸ Ga-NYM050 blocking experiment in the OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention;

图47是根据本发明实施例的¹⁷⁷Lu-NYM073/¹⁷⁷Lu-NYM074药物在小鼠体内的SPECT/CT扫描图；FIG47 is a SPECT/CT scan of ¹⁷⁷ Lu-NYM073/ ¹⁷⁷ Lu-NYM074 drugs in mice according to an embodiment of the present invention;

图48是根据本发明实施例的小鼠的肿瘤体积变化图；FIG48 is a graph showing changes in tumor volume in mice according to an embodiment of the present invention;

图49是根据本发明实施例的小鼠体重变化图；Figure 49 is a graph showing changes in mouse body weight according to an embodiment of the present invention;

图50是根据本发明实施例的¹⁷⁷Lu-NYM074在小鼠的离体组织分布图；FIG50 is a diagram showing the in vitro tissue distribution of ¹⁷⁷ Lu-NYM074 in mice according to an embodiment of the present invention;

图51是根据本发明实施例的患者1注射¹⁸F-FDG后的MIP(最大密度投影)图；FIG51 is a MIP (maximum intensity projection) image of patient 1 after injection of ¹⁸ F-FDG according to an embodiment of the present invention;

图52是根据本发明实施例的患者1注射⁶⁸Ga-NYM046后的MIP图；FIG52 is a MIP image of patient 1 after injection of ⁶⁸ Ga-NYM046 according to an embodiment of the present invention;

图53是根据本发明实施例的患者1注射¹⁸F-FDG与⁶⁸Ga-NYM046的CT和PET/CT截面显像图；FIG53 is a CT and PET/CT cross-sectional image of patient 1 injected with ¹⁸ F-FDG and ⁶⁸ Ga-NYM046 according to an embodiment of the present invention;

图54是根据本发明实施例的患者1注射¹⁸F-FDG与⁶⁸Ga-NYM046后的SUVmax以及SUVmean图。54 is a graph of SUVmax and SUVmean of patient 1 after injection of ¹⁸ F-FDG and ⁶⁸ Ga-NYM046 according to an embodiment of the present invention.

图55是根据本发明实施例的患者2注射¹⁸F-FDG后的MIP图；FIG55 is a MIP image of patient 2 after injection of ¹⁸ F-FDG according to an embodiment of the present invention;

图56是根据本发明实施例的患者2注射⁶⁸Ga-NYM046后的MIP图；FIG56 is a MIP image of patient 2 after injection of ⁶⁸ Ga-NYM046 according to an embodiment of the present invention;

图57是根据本发明实施例的患者2注射¹⁸F-FDG与⁶⁸Ga-NYM046的CT和PET/CT截面显像图；FIG57 is a CT and PET/CT cross-sectional image of patient 2 injected with ¹⁸ F-FDG and ⁶⁸ Ga-NYM046 according to an embodiment of the present invention;

图58是根据本发明实施例的患者2注射¹⁸F-FDG与⁶⁸Ga-NYM046后的SUVmax以及SUVmean图；FIG58 is a graph of SUVmax and SUVmean after injection of ¹⁸ F-FDG and ⁶⁸ Ga-NYM046 in patient 2 according to an embodiment of the present invention;

图59是根据本发明实施例的NYM070分子的LCMS谱图；FIG. 59 is an LCMS spectrum of NYM070 molecules according to an embodiment of the present invention;

图60是根据本发明实施例的NYM070分子的HPLC谱图；FIG60 is a HPLC spectrum of NYM070 molecules according to an embodiment of the present invention;

图61是根据本发明实施例的NYM071分子的LCMS谱图；FIG61 is an LCMS spectrum of NYM071 molecules according to an embodiment of the present invention;

图62是根据本发明实施例的NYM071分子的HPLC谱图；FIG62 is a HPLC spectrum of NYM071 molecules according to an embodiment of the present invention;

图63是根据本发明实施例的NYM073分子的LCMS谱图；FIG63 is an LCMS spectrum of NYM073 molecules according to an embodiment of the present invention;

图64是根据本发明实施例的NYM073分子的HPLC谱图； FIG64 is a HPLC spectrum of NYM073 molecules according to an embodiment of the present invention;

图65是根据本发明实施例的NYM074分子的LCMS谱图；FIG65 is an LCMS spectrum of NYM074 molecules according to an embodiment of the present invention;

图66是根据本发明实施例的NYM074分子的HPLC谱图。FIG. 66 is a HPLC spectrum of the NYM074 molecule according to an embodiment of the present invention.

DETAILED DESCRIPTION

下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

实施例1：化合物的制备过程Example 1: Preparation of the compound

1.Int 1的合成步骤：
1. Synthesis steps of Int 1:

将化合物2(3.00g,1.00eq)和吡啶(2.63g,2.00eq)溶于DMF(30.0mL)中，在0℃往其中加入溶有化合物4a(2.97g,1.00eq)的DCM(20.0mL)。反应在25℃下搅拌14小时。反应液真空浓缩，残渣用45.0Compound 2 (3.00 g, 1.00 eq) and pyridine (2.63 g, 2.00 eq) were dissolved in DMF (30.0 mL), and compound 4a (2.97 g, 1.00 eq) in DCM (20.0 mL) was added at 0°C. The reaction was stirred at 25°C for 14 hours. The reaction solution was concentrated in vacuo, and the residue was washed with 45.0

mL水和45.0mL饱和NaHCO₃稀释，过滤后得到化合物4(5.00g)。
mL of water and 45.0 mL of saturated NaHCO ₃ were diluted and filtered to obtain compound 4 (5.00 g).

将化合物4(5.00g,1.00eq)和NaOH(3.45g,5.76eq)溶于H₂O(70.0mL)中。反应在60℃下搅拌1小时。将反应液冷却并用1N HCl调节pH为4，过滤后水洗得到化合物Int 1(2.00g,6.22mmol,纯度为95.9％)。Compound 4 (5.00 g, 1.00 eq) and NaOH (3.45 g, 5.76 eq) were dissolved in H ₂ O (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, filtered and washed with water to obtain compound Int 1 (2.00 g, 6.22 mmol, purity 95.9%).

2.NYM045的合成步骤
2. Synthesis steps of NYM045

多肽合成：该肽是用标准的Fmoc化学方法合成的。Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

1)挂树脂：称取0.50mmol 2-CTC树脂(取代度Sub＝0.50mmol/g)，Fmoc-Asp-OALL(Fmoc-L-天冬氨酸alpha-烯丙酯)(0.50mmol,1.00eq)加在反应柱中，再加入DCM(30.0mL)和DIEA(2.00mmol,4.00eq)到反应柱。在20℃下氮气鼓气2.00h后，加入MeOH(1.00mL)继续氮气鼓气30min，排废，直至没有液体流出。加入DMF洗涤，排废。1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol/g), Fmoc-Asp-OALL (Fmoc-L-aspartic acid alpha-allyl ester) (0.50mmol, 1.00eq) and add it to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen blowing for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen blowing for 30min, and drain until no liquid flows out. Add DMF for washing and drain.

2)脱保护：将20％哌啶/DMF(V:V)(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

3)缩合：将Fmoc-Apa-OH(Fmoc-5-氨基戊酸-OH，1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)溶在DMF(30.0mL)加入到树脂中，再加入DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。3) Condensation: Fmoc-Apa-OH (Fmoc-5-aminopentanoic acid-OH, 1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

4)脱保护：将20％哌啶/DMF(V:V)(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

5)还原胺化：将苯甲醛(0.60mmol,1.20eq)和原甲酸三甲酯(3.00mmol,6.00eq)溶解在THF(20.0mL)中，再加入醋酸(0.01mmol,0.02eq)，反应在20℃氮气鼓动0.50h，将三乙酰氧基硼氢化钠(3.00mmol,6.00eq)溶解在甲醇(1.00mL)中，缓慢滴加到反应柱中，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。5) Reductive amination: Benzaldehyde (0.60mmol, 1.20eq) and trimethyl orthoformate (3.00mmol, 6.00eq) were dissolved in THF (20.0mL), and acetic acid (0.01mmol, 0.02eq) was added. The reaction was stirred with nitrogen at 20℃ for 0.50h. Sodium triacetoxyborohydride (3.00mmol, 6.00eq) was dissolved in methanol (1.00mL), and slowly added dropwise to the reaction column. The reaction was stirred with nitrogen at 20℃ for 1.00h. The resin was washed with DMF.

6)缩合：将Int 1(0.60mmol,1.20eq)和HOAt(0.60mmol,1.20eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.60mmol,1.20eq)，反应在20℃氮气鼓动12.0h。树脂用DMF洗涤。 6) Condensation: Int 1 (0.60 mmol, 1.20 eq) and HOAt (0.60 mmol, 1.20 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.60 mmol, 1.20 eq), and the reaction was stirred with nitrogen at 20°C for 12.0 h. The resin was washed with DMF.

7)脱保护：在反应柱中加入DCM(30.0mL)氮气鼓动，再先后加入PhSiH₃(5.00mmol,10.0eq)和Pd(PPh₃)₄(0.05mmol,0.10eq)氮气鼓动15.0min，重复该步骤三次。树脂用DMF洗涤，抽干。7) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

8)缩合：将N-Fmoc-1,4-丁二胺盐酸盐(0.75mmol,1.50eq)和DIEA(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(1.50mmol,3.00eq)和HOAt(0.75mmol,1.50eq)到树脂中，反应在20℃氮气鼓动2.00h。树脂用DMF。8) Condensation: N-Fmoc-1,4-butanediamine hydrochloride (0.75 mmol, 1.50 eq) and DIEA (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were added to the resin, and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was treated with DMF.

9)脱保护：将20％哌啶(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

10)缩合：将DOTA(tBu*3)(三叔丁基1,4,7,10-四氮杂环十二烷-四乙酸，0.75mmol,1.50eq)和HOAt(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.75mmol,1.50eq)，反应在20℃氮气鼓动2.00h。树脂用DMF洗涤。10) Condensation: DOTA(tBu*3) (tri-tert-butyl 1,4,7,10-tetraazacyclododecane-tetraacetic acid, 0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (0.75 mmol, 1.50 eq) was added. The reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

多肽切割和纯化:Peptide cleavage and purification:

用MeOH(30.0mL)收缩树脂，排废，直至没有液体流出，将树脂倒出干燥，备用。在室温下，将干燥后的树脂加入到配好的20.0mL切割液(由92.5％TFA、2.5％TIS、2.5％H₂O和2.5％3-MPR组成)中，震荡2h。过滤后将滤液加入冰的异丙醚(100mL)中进行沉降离心，再用异丙醚洗涤。在真空下干燥2小时得到粗肽。The resin was shrunk with MeOH (30.0 mL) and was drained until no liquid flowed out. The resin was poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of the prepared cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H ₂ O and 2.5% 3-MPR) and shaken for 2 hours. After filtration, the filtrate was added to ice isopropyl ether (100 mL) for sedimentation centrifugation and then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain the crude peptide.

直接用反相制备(A:含有0.075％TFA的H₂O,B:ACN乙腈)得到NYM045(15.0mg,纯度为97.52％)。NYM045 (15.0 mg, purity: 97.52%) was obtained directly by reverse phase preparation (A: H ₂ O containing 0.075% TFA, B: ACN acetonitrile).

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

HPLC:纯度:97.52％(图2所示)HPLC: Purity: 97.52% (as shown in Figure 2)

¹H NMR:400MHz,DMSO-d6(图3所示) ¹ H NMR: 400 MHz, DMSO-d6 (as shown in Figure 3)

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).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).

3.NYM046的合成步骤
3. Synthesis steps of NYM046

1)挂树脂：称取0.50mmol 2-CTC树脂(取代度Sub＝0.50mmol/g)，Fmoc-Asp-OALL(0.50mmol,1.00eq)加在反应柱中，再加入DCM(30.0mL)和DIEA(2.00mmol,4.00eq)到反应柱。在20℃下氮气鼓气体2.00h后，加入MeOH(1.00mL)继续氮气鼓气30min，排废，直至没有液体流出。加入DMF洗涤，排废，直至没有液体流出。1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol/g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add it to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

3)缩合：将Fmoc-Apa-OH(Fmoc-5-氨基戊酸-OH，1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)溶在DMF(30.0mL)加入到树脂中，再加入DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DM洗涤。3) Condensation: Fmoc-Apa-OH (Fmoc-5-aminopentanoic acid-OH, 1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DM.

5)保护基:将DIEA(3.00mmol,6.00eq)溶解在THF(20.0mL)中，加入反应柱中氮气鼓动，再将NsCl(1.50mmol,3.00eq)溶解在THF(10.0mL)中，缓慢滴入反应柱，反应在20℃氮气鼓动1.00h。5) Protecting group: DIEA (3.00 mmol, 6.00 eq) was dissolved in THF (20.0 mL), added to the reaction column and agitated with nitrogen. Then, NsCl (1.50 mmol, 3.00 eq) was dissolved in THF (10.0 mL), slowly dripped into the reaction column, and the reaction was agitated with nitrogen at 20 °C for 1.00 h.

6)Mitsunobu反应(光延反应)：将PPh₃(2.50mmol,5.00eq)溶解在THF(30.0mL)中，加入2-萘甲醇(1.00mmol,2.00eq)加入树脂中氮气鼓动5min，再向反应柱中缓慢滴加DEAD(2.50mmol,5.00eq)，反应在20℃氮气鼓动12.0h。 6) Mitsunobu reaction: PPh ₃ (2.50 mmol, 5.00 eq) was dissolved in THF (30.0 mL), 2-naphthalene methanol (1.00 mmol, 2.00 eq) was added to the resin and nitrogen was agitated for 5 min, DEAD (2.50 mmol, 5.00 eq) was slowly added dropwise to the reaction column, and the reaction was agitated with nitrogen at 20° C. for 12.0 h.

7)脱保护：将苯硫酚钠(1.25mmol,2.50eq)溶解在DMF(30.0mL)中，加入树脂中氮气鼓动1h。树脂用DMF洗涤，抽干。7) Deprotection: Sodium thiophenolate (1.25 mmol, 2.50 eq) was dissolved in DMF (30.0 mL), added to the resin and stirred with nitrogen for 1 h. The resin was washed with DMF and dried.

8)缩合：将Int 1(0.60mmol,1.20eq)和HOAt(0.60mmol,1.20eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.60mmol,1.20eq)，反应在20℃氮气鼓动12.0h。树脂用DMF洗涤。8) Condensation: Int 1 (0.60 mmol, 1.20 eq) and HOAt (0.60 mmol, 1.20 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.60 mmol, 1.20 eq). The reaction was stirred with nitrogen at 20 °C for 12.0 h. The resin was washed with DMF.

9)脱保护：在反应柱中加入DCM(30.0mL)氮气鼓动，再先后加入PhSiH₃(5.00mmol,10.0eq)和Pd(PPh₃)₄(0.05mmol,0.10eq)氮气鼓动15.0min，重复该步骤三次。树脂用DMF洗涤，抽干。9) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

10)缩合：将N-Fmoc-1,4-丁二胺盐酸盐(0.75mmol,1.50eq)和DIEA(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(1.50mmol,3.00eq)和HOAt(0.75mmol,1.50eq)到树脂中，反应在20℃氮气鼓动2.00h。树脂用DMF洗涤。10) Condensation: N-Fmoc-1,4-butanediamine hydrochloride (0.75 mmol, 1.50 eq) and DIEA (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, and then DIC (1.50 mmol, 3.00 eq) and HOAt (0.75 mmol, 1.50 eq) were added to the resin, and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

11)脱保护：将20％哌啶(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

12)缩合：将DOTA(tBu*3)(0.75mmol,1.50eq)和HOAt(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.75mmol,1.50eq)，反应在20℃氮气鼓动2.00h。树脂用DMF洗涤。12) Condensation: DOTA(tBu*3) (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq), and the reaction was stirred with nitrogen at 20°C for 2.00 h. The resin was washed with DMF.

多肽切割和纯化:Peptide cleavage and purification:

用MeOH(30.0mL)收缩树脂，每次3min，排废，直至没有液体流出，将树脂倒出干燥，备用。在室温下，将干燥后的树脂加入到配好的20.0mL切割液(由92.5％TFA、2.5％TIS、2.5％H₂O和2.5％3-MPR组成)中，在摇床上震荡2h。过滤后将滤液加入冰的异丙醚中进行沉降离心，再用异丙醚(100mL)洗涤。在真空下干燥2小时得到粗肽。The resin was shrunk with MeOH (30.0 mL) for 3 min each time, and the waste was discharged until no liquid flowed out. The resin was poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of the prepared cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H ₂ O and 2.5% 3-MPR) and shaken on a shaker for 2 h. After filtration, the filtrate was added to ice isopropyl ether for sedimentation centrifugation, and then washed with isopropyl ether (100 mL). Dry under vacuum for 2 hours to obtain the crude peptide.

直接用反相制备(A:含有0.075％TFA得水，B:ACN乙腈)得到NYM046(15.0mg,纯度为95.74％)。NYM046 (15.0 mg, purity 95.74%) was obtained directly by reverse phase preparation (A: water containing 0.075% TFA, B: ACN acetonitrile).

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

HPLC:Rt＝7.72min,纯度:95.74％(图5所示)HPLC: Rt = 7.72 min, purity: 95.74% (as shown in Figure 5)

¹H NMR:400MHz,DMSO-d6(图6所示) ¹ H NMR: 400 MHz, DMSO-d6 (as shown in Figure 6)

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).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).

4.NYM047的合成步骤4. Synthesis steps of NYM047

步骤一：
Step 1:

在20℃下，往溶有化合物1b(5.00g,1.00eq)的DMF(50.0mL)溶液中缓慢加入HOBt(3.39g,1.50eq)，DIEA(8.73mL,3.00eq),EDCI(4.80g,1.50eq)和化合物2b(3.30g,1.05eq)。反应液于20℃下搅拌2小时。纯化得到化合物3b(3.10g,纯度为90.5％)。At 20°C, HOBt (3.39 g, 1.50 eq), DIEA (8.73 mL, 3.00 eq), EDCI (4.80 g, 1.50 eq) and compound 2b (3.30 g, 1.05 eq) were slowly added to a solution of compound 1b (5.00 g, 1.00 eq) in DMF (50.0 mL). The reaction solution was stirred at 20°C for 2 hours. Compound 3b (3.10 g, purity 90.5%) was obtained by purification.

步骤二：
Step 2:

将化合物3b(2.00g,1.00eq)溶在DCM(10.0mL)中，往其中加入TFA(9.06mL,31.6eq)。反应20℃下搅拌1小时。将反应液减压浓缩得到化合物4b。Compound 3b (2.00 g, 1.00 eq) was dissolved in DCM (10.0 mL), and TFA (9.06 mL, 31.6 eq) was added thereto. The mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 4b.

步骤三：
Step 3:

在20℃下，往溶有化合物4b(2.06g,1.20eq)的DMF(20.0mL)溶液中缓慢加入HOBt(719mg,1.50eq),DIEA(3.09mL,5.00eq),EDCI(1.02g,1.50eq)和化合物5b(2.03g,1.00eq)。反应液于20℃下搅拌12小时。纯化得到化合物6b(2.40g,纯度为100％)。At 20°C, HOBt (719 mg, 1.50 eq), DIEA (3.09 mL, 5.00 eq), EDCI (1.02 g, 1.50 eq) and compound 5b (2.03 g, 1.00 eq) were slowly added to a solution of compound 4b (2.06 g, 1.20 eq) in DMF (20.0 mL). The reaction solution was stirred at 20°C for 12 hours. Compound 6b (2.40 g, purity 100%) was obtained by purification.

步骤四：
Step 4:

将化合物6b(2.00g,1.00eq)溶在甲醇(40.0mL)中，往其中加入湿钯碳(200mg,纯度为10％,8.68e-2eq)。反应在20℃、H₂(15.0Psi)下搅拌12小时。将反应液减压浓缩得到化合物7b。Compound 6b (2.00 g, 1.00 eq) was dissolved in methanol (40.0 mL), and wet palladium carbon (200 mg, purity 10%, 8.68e-2 eq) was added. The reaction was stirred at 20° C. and H ₂ (15.0 Psi) for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 7b.

步骤五：
Step 5:

在20℃下，往溶有化合物7b(393mg,1.00eq)的DMF(4.00mL)溶液中缓慢加入HOBt(100mg,1.50eq),DIEA(259μL,3.00eq),EDCI(143mg,1.50eq)和化合物8b(131mg,1.05eq)。反应液于20℃下搅拌12小时。纯化得到化合物9b(360mg)。At 20°C, HOBt (100 mg, 1.50 eq), DIEA (259 μL, 3.00 eq), EDCI (143 mg, 1.50 eq) and compound 8b (131 mg, 1.05 eq) were slowly added to a solution of compound 7b (393 mg, 1.00 eq) in DMF (4.00 mL). The reaction solution was stirred at 20°C for 12 hours. Compound 9b (360 mg) was obtained by purification.

步骤六：
Step 6:

将化合物9b(360mg,1.00eq)溶在甲醇(8.00mL)中，往其中加入湿钯碳(36.0mg,纯度为10％,9.62e-2eq)。反应在20℃、H₂(15.0Psi)下搅拌5小时。将反应液减压浓缩得到化合物10b。Compound 9b (360 mg, 1.00 eq) was dissolved in methanol (8.00 mL), and wet palladium carbon (36.0 mg, purity 10%, 9.62e-2 eq) was added thereto. The reaction was stirred at 20°C and H ₂ (15.0 Psi) for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 10b.

步骤七：
Step 7:

在20℃下，往溶有化合物10b(78.8mg,1.00eq)的DMF(3.00mL)溶液中缓慢加入Int 1(250mg,1.10eq),BOP(113mg,1.00eq),DIEA(133μL,3.00eq)。反应液于20℃下搅拌1小时。反应液用反相(盐酸)制备得到化合物11b(180mg)。At 20°C, slowly add Int 1 (250 mg, 1.10 eq), BOP (113 mg, 1.00 eq), and DIEA (133 μL, 3.00 eq) to a solution of compound 10b (78.8 mg, 1.00 eq) in DMF (3.00 mL). The reaction solution was stirred at 20°C for 1 hour. The reaction solution was prepared by reverse phase (hydrochloric acid) to obtain compound 11b (180 mg).

步骤八：
Step 8:

在20℃下，往化合物11b(180mg,1.00eq)中加入TFA/TIS/H₂O(V:V＝95％:2.5％:2.5,2.00mL)。反应液于20℃下搅拌12小时。反应液用反相(盐酸)制备得到NYM047(12.0mg,纯度为96.0％)。At 20°C, TFA/TIS/H ₂ O (V:V=95%:2.5%:2.5, 2.00 mL) was added to compound 11b (180 mg, 1.00 eq). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was prepared with reverse phase (hydrochloric acid) to obtain NYM047 (12.0 mg, purity 96.0%).

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

HPLC:Rt＝13.1min,纯度:96.0％(图8所示)HPLC: Rt = 13.1 min, purity: 96.0% (as shown in Figure 8)

¹H NMR:400MHz,D₂O(图9所示) ¹ H NMR: 400 MHz, D ₂ O (as shown in Figure 9)

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).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).

5.NYM048的合成步骤5. Synthesis steps of NYM048

步骤一：
Step 1:

在20℃下，往溶有化合物7b(70.9mg,1.00eq)的DMF(2.00mL)溶液中缓慢加入Int 1(200mg,1.10eq),BOP(101mg,1.00eq),DIEA(120μL,3.00eq)。反应液于20℃下搅拌2小时。纯化得到化合物12b(280mg)。At 20°C, Int 1 (200 mg, 1.10 eq), BOP (101 mg, 1.00 eq), and DIEA (120 μL, 3.00 eq) were slowly added to a solution of compound 7b (70.9 mg, 1.00 eq) in DMF (2.00 mL). The reaction solution was stirred at 20°C for 2 hours. Compound 12b (280 mg) was obtained by purification.

步骤二：
Step 2:

在20℃下，往化合物12b(100mg,1.00eq)中加入TFA/TIS/H₂O(V：V＝95％:2.5％:2.5,2.00mL)。反应液于20℃下搅拌12小时。反应液用反相(盐酸)制备得到NYM048(12.0mg,13.0μmol，纯度为99.0％)。At 20°C, TFA/TIS/H ₂ O (V:V=95%:2.5%:2.5, 2.00 mL) was added to compound 12b (100 mg, 1.00 eq). The reaction solution was stirred at 20°C for 12 hours. The reaction solution was used for reverse phase (hydrochloric acid) to prepare NYM048 (12.0 mg, 13.0 μmol, purity 99.0%).

LCMS:MS:[M]⁺＝912.3(图10所示)LCMS:MS: [M] ⁺ = 912.3 (as shown in FIG10 )

HPLC:Rt＝6.17min,纯度:99.0％(图11所示)HPLC: Rt = 6.17 min, purity: 99.0% (as shown in Figure 11)

¹H NMR:400MHz,D₂O(图12所示) ¹ H NMR: 400 MHz, D ₂ O (as shown in Figure 12)

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).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).

6.NYM049的合成步骤6. Synthesis steps of NYM049

步骤一：
Step 1:

在0℃下，往LiAlH₄(139mL,3.96eq)的THF溶液中缓慢滴加THF(200mL)溶解的化合物1c(22.0g,1.00eq)，反应液在40℃下搅拌0.5小时。在0℃下,N₂鼓气，向反应液中依次缓慢滴加H₂O(13.2mL),15％NaOH(13.2mL)溶液和H₂O(40.0mL)来淬灭反应,纯化得到化合物2c(11.5g,纯度为91.0％)。At 0°C, compound 1c (22.0 g, 1.00 eq) dissolved in THF (200 mL) was slowly added dropwise to a THF solution of LiAlH ₄ (139 mL, 3.96 eq), and the reaction solution was stirred at 40°C for 0.5 hours. At 0°C, with N ₂ blowing, H ₂ O (13.2 mL), 15% NaOH (13.2 mL) solution and H ₂ O (40.0 mL) were slowly added dropwise to the reaction solution in sequence to quench the reaction, and compound 2c (11.5 g, purity 91.0%) was obtained by purification.

步骤二：
Step 2:

向溶解有化合物2c(11.5g,1.00eq)的DCM(250mL)溶液中加入TsCl(48.0g,4.00eq)和TEA(26.2mL,3.00eq)，反应液在25℃下搅拌12小时。纯化得到化合物3c(23.0g,纯度为93.3％)。TsCl (48.0 g, 4.00 eq) and TEA (26.2 mL, 3.00 eq) were added to a solution of compound 2c (11.5 g, 1.00 eq) in DCM (250 mL), and the reaction solution was stirred at 25° C. for 12 hours. Compound 3c (23.0 g, purity 93.3%) was obtained by purification.

步骤三：
Step 3:

在25℃下向搅拌中的溶有化合物3c(13.0g,1.00eq)的DMSO(140mL)加入KCN(8.43g,5.07eq)，并加热到80℃，继续搅拌3.5小时。纯化得到化合物4c(4.70g,纯度为87.7％)。KCN (8.43 g, 5.07 eq) was added to a stirred solution of compound 3c (13.0 g, 1.00 eq) in DMSO (140 mL) at 25°C, and the mixture was heated to 80°C and stirred for 3.5 hours to obtain compound 4c (4.70 g, purity 87.7%).

步骤四：
Step 4:

化合物4c(7.60g,1.00eq)溶于MeOH(140mL)的溶液中，HCl气体(12.0M,114mL,33.2eq)通入此溶液内，在0℃下通入0.25小时，然后在80℃下搅拌反应混合物10h。将混合物真空浓缩得到化合物5c(10.1g,40.3mmol)。Compound 4c (7.60 g, 1.00 eq) was dissolved in MeOH (140 mL), HCl gas (12.0 M, 114 mL, 33.2 eq) was passed into the solution at 0°C for 0.25 hours, and then the reaction mixture was stirred at 80°C for 10 hours. The mixture was concentrated in vacuo to obtain compound 5c (10.1 g, 40.3 mmol).

步骤五：
Step 5:

将化合物5c(4.00g,1.00eq)溶在THF(60.0mL)和H₂O(60.0mL)的混合溶液中，加入LiOH·H₂O(670mg,1.00eq)，在0℃下搅拌1小时。纯化得到化合物6c(1.30g,纯度为93.3％)。Compound 5c (4.00 g, 1.00 eq) was dissolved in a mixed solution of THF (60.0 mL) and H ₂ O (60.0 mL), LiOH·H ₂ O (670 mg, 1.00 eq) was added, and the mixture was stirred at 0° C. for 1 hour. Compound 6c (1.30 g, purity: 93.3%) was obtained by purification.

步骤六：
Step 6:

将化合物6c(0.90g,3.55mmol,1.00eq)加入到DCM(16mL)和DMF(0.16mL)的混合溶液中，在0℃条件下加入(COCl)₂(902mg,2.00eq)，在25℃条件下搅拌0.5h，真空浓缩，将残留物溶于DCM(16.0mL)中。然后将该溶液加入到溶有化合物2a(704mg,1.10eq)和Py(573μL,2.00eq)的DMF(16.0mL)溶液中，在0℃下搅拌8h。纯化得到化合物7c(1.20g)。Compound 6c (0.90 g, 3.55 mmol, 1.00 eq) was added to a mixed solution of DCM (16 mL) and DMF (0.16 mL), (COCl) ₂ (902 mg, 2.00 eq) was added at 0°C, stirred at 25°C for 0.5 h, concentrated in vacuo, and the residue was dissolved in DCM (16.0 mL). The solution was then added to a solution of compound 2a (704 mg, 1.10 eq) and Py (573 μL, 2.00 eq) in DMF (16.0 mL), and stirred at 0°C for 8 h. Compound 7c (1.20 g) was obtained after purification.

步骤七：
Step 7:

将化合物7c(1.10g,1.00eq)溶在H₂O(12.0mL)和THF(12.0mL)的混合溶液中，然后加入LiOH·H₂O(278mg,2.40eq)，在25℃下搅拌1h。纯化得到Int 2(1.00g,纯度为96.2％)。Compound 7c (1.10 g, 1.00 eq) was dissolved in a mixed solution of H ₂ O (12.0 mL) and THF (12.0 mL), and then LiOH·H ₂ O (278 mg, 2.40 eq) was added and stirred at 25° C. for 1 h. Int 2 (1.00 g, purity: 96.2%) was obtained after purification.

步骤八：
Step 8:

1)称取0.50mmol 2-CTC树脂(取代度Sub＝0.50mmol/g)，Fmoc-Asp-OALL(0.50mmol,1.00eq)加在反应柱中，再加入DCM(30.0mL)和DIEA(2.00mmol,4.00eq)到反应柱。在20℃下氮气鼓气体2.00h后，加入MeOH(1.00mL)继续氮气鼓气体30min，排废，直至没有液体流出。加入DMF洗涤，排废，直至没有液体流出。1) Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol/g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

3)脱保护：在反应柱中加入DCM(30.0mL)氮气鼓动，再先后加入PhSiH₃(5.00mmol,10.0eq)和Pd(PPh₃)₄(0.05mmol,0.10eq)氮气鼓动15.0min，重复该步骤三次。树脂用DMF洗涤，抽干。3) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

4)缩合：将Alloc-Cl(1.00mmol,2.00eq)溶在DMF(30.0mL)加入到树脂中，再加入DIEA(2.00mmol,4.00eq)，反应在20℃氮气鼓动20.0min，重复该步骤两次。树脂用DMF洗涤。4) Condensation: Alloc-Cl (1.00 mmol, 2.00 eq) was dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (2.00 mmol, 4.00 eq), and the reaction was stirred with nitrogen at 20°C for 20.0 min, and this step was repeated twice. The resin was washed with DMF.

5)缩合：将N-Fmoc-1,4-diaminobutane HCl(N-Fmoc-1,4-丁二胺盐酸盐)(1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)加入树脂中，加入DMF(30.0mL)后，再滴加DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。5) Condensation: N-Fmoc-1,4-diaminobutane HCl (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were added to the resin, and DMF (30.0 mL) was added, followed by dropwise addition of DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

6)脱保护：将20％哌啶(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

7)缩合：将DOTA(tBu*3)(1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)溶在DMF(30.0mL)加入到树脂中，再加入DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。7) Condensation: DOTA(tBu*3) (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIEA (3.00 mmol, 6.00 eq), and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

8)脱保护：在反应柱中加入DCM(30.0mL)氮气鼓动，再先后加入PhSiH₃(5.00mmol,10.0eq)和Pd(PPh₃)₄(0.05mmol,0.10eq)氮气鼓动15.0min，重复该步骤三次。树脂用DMF洗涤，抽干。8) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

9)缩合：将Fmoc-Apa-OH(1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)溶在DMF(30.0mL)，加入到树脂中，再加入DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。9) Condensation: Fmoc-Apa-OH (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were dissolved in DMF (30.0 mL), added to the resin, and then DIEA (3.00 mmol, 6.00 eq) was added, and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

10)脱保护：将20％哌啶(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

11)缩合：将Int 2(0.75mmol,1.50eq)和HOAt(0.73mmol,1.45eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.75mmol,1.50eq)，反应在20℃氮气鼓动30.0min。树脂用DMF洗涤。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.

多肽切割和纯化:Peptide cleavage and purification:

用MeOH(30.0mL)收缩树脂，排废，直至没有液体流出，将树脂倒出干燥，备用。在室温下，将干燥后的树脂加入到配好的20.0mL切割液(由92.5％TFA、2.5％TIS、2.5％H₂O和2.5％3-MPR组成)中，在摇床上震荡2h。过滤后将滤液加入冰的异丙醚(100mL)中进行沉降离心，再用异丙醚洗涤。在真空下干燥2小时得到粗肽。 The resin was shrunk with MeOH (30.0 mL) and was drained until no liquid flowed out. The resin was poured out and dried for later use. At room temperature, the dried resin was added to 20.0 mL of the prepared cutting solution (composed of 92.5% TFA, 2.5% TIS, 2.5% H ₂ O and 2.5% 3-MPR) and shaken on a shaker for 2 h. After filtration, the filtrate was added to ice isopropyl ether (100 mL) for sedimentation centrifugation and then washed with isopropyl ether. Dry under vacuum for 2 hours to obtain the crude peptide.

直接用反相制备(A:含0.075％TFA的H₂O,B:ACN乙腈)得到化合物NYM049(15.0mg,12.8μmol,纯度为95.42％)。The compound NYM049 (15.0 mg, 12.8 μmol, purity: 95.42%) was obtained directly by reverse phase preparation (A: H ₂ O containing 0.075% TFA, B: ACN acetonitrile).

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

HPLC:Rt＝10.2min,纯度:95.42％(图14所示)HPLC: Rt = 10.2 min, purity: 95.42% (as shown in Figure 14)

¹H NMR:400MHz,D₂O.(图15所示) ¹ H NMR: 400 MHz, D ₂ O. (as shown in FIG. 15 )

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).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).

7.NYM050的合成步骤7. Synthesis steps of NYM050

步骤一：
Step 1:

将NaNO₂(7.77g,112mmol,2.00eq)溶于H₂O(15.0mL)中滴入到化合物2b(15.0g,56.3mmol,1.00eq)、KBr(24.8g,208mmol,9.02mL,3.7eq)、HBr(28.4g,140mmol,19.1mL,纯度为40％，2.50eq)的H₂O(300mL)中，加料温度为0℃。反应液在20℃下搅拌12h。纯化得到化合物1d-1(3.30g,纯度为100％)。NaNO ₂ (7.77 g, 112 mmol, 2.00 eq) was dissolved in H ₂ O (15.0 mL) and added dropwise to compound 2b (15.0 g, 56.3 mmol, 1.00 eq), KBr (24.8 g, 208 mmol, 9.02 mL, 3.7 eq), HBr (28.4 g, 140 mmol, 19.1 mL, purity 40%, 2.50 eq) in H ₂ O (300 mL) at 0°C. The reaction solution was stirred at 20°C for 12 h. Compound 1d-1 (3.30 g, purity 100%) was obtained after purification.

步骤二：
Step 2:

在DCM(55.0mL)中加入化合物1d-1(5.30g,1.00eq)然后加入O-叔丁基-N,N'-二异丙基异脲(6.43g,2.00eq)，在25℃下搅拌12h。纯化得到化合物2d-1(4.75g,纯度为98.7％)。Compound 1d-1 (5.30 g, 1.00 eq) and then O-tert-butyl-N,N'-diisopropylisourea (6.43 g, 2.00 eq) were added to DCM (55.0 mL), and stirred at 25° C. for 12 h. Compound 2d-1 (4.75 g, purity 98.7%) was obtained by purification.

步骤三：
Step 3:

将化合物2d-2(1.05g,1.50eq)和K₂CO₃(375mg,2.00eq)加入DMF(10.0mL)溶液中，然后加入化合物2d-1(700mg,1.00eq)。然后在50℃下搅拌12h。纯化得到化合物3d-1(1.00g,纯度为98.1％)。Compound 2d-2 (1.05 g, 1.50 eq) and K ₂ CO ₃ (375 mg, 2.00 eq) were added to a DMF (10.0 mL) solution, and then compound 2d-1 (700 mg, 1.00 eq) was added. The mixture was stirred at 50° C. for 12 h. Compound 3d-1 (1.00 g, purity 98.1%) was obtained by purification.

步骤四：
Step 4:

将化合物3d-1(700mg,1.00eq)加入到THF(7.00mL)和去离子水(0.05mL)的混合溶液中，在氮气保护下加入Pd/C(70.0mg,纯度为10％，0.10eq)。对悬浮液进行脱气和氢气置换。将反应液在H₂(15psi)和35℃下搅拌12h。对悬浮液进行过滤，减压滤出滤液，得到化合物Int 3(500mg,纯度为84.6％)。Compound 3d-1 (700 mg, 1.00 eq) was added to a mixed solution of THF (7.00 mL) and deionized water (0.05 mL), and Pd/C (70.0 mg, 10% purity, 0.10 eq) was added under nitrogen protection. The suspension was degassed and replaced with hydrogen. The reaction solution was stirred at H ₂ (15 psi) and 35° C. for 12 h. The suspension was filtered, and the filtrate was filtered out under reduced pressure to obtain compound Int 3 (500 mg, purity 84.6%).

步骤五：
Step 5:

多肽合成：该肽是用标准的Fmoc化学方法合成的.Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry.

1)挂树脂:称取0.50mmol 2-CTC树脂(取代度Sub＝0.50mmol/g)，Fmoc-Asp-OALL(0.50mmol,1.00eq)加在反应柱中，再加入DCM(30.0mL)和DIEA(2.00mmol,4.00eq)到反应柱。在20℃下氮气鼓气体2.00h后，加入MeOH(1.00mL)继续氮气鼓气体30min，排废，直至没有液体流出。加入DMF洗涤，排废，直至没有液体流出。1) Resin hanging: Weigh 0.50mmol 2-CTC resin (substitution degree Sub = 0.50mmol/g), Fmoc-Asp-OALL (0.50mmol, 1.00eq) and add them to the reaction column, then add DCM (30.0mL) and DIEA (2.00mmol, 4.00eq) to the reaction column. After nitrogen bubbling for 2.00h at 20℃, add MeOH (1.00mL) and continue nitrogen bubbling for 30min, drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

3)缩合：将Fmoc-Apa-OH(1.50mmol,3.00eq)和HBTU(1.43mmol,2.85eq)加入树脂中，加入DMF(30.0mL)，再滴加DIEA(3.00mmol,6.00eq)，反应在20℃氮气鼓动1.00h。树脂用DMF洗涤。3) Condensation: Fmoc-Apa-OH (1.50 mmol, 3.00 eq) and HBTU (1.43 mmol, 2.85 eq) were added to the resin, DMF (30.0 mL) was added, and DIEA (3.00 mmol, 6.00 eq) was added dropwise, and the reaction was stirred with nitrogen at 20°C for 1.00 h. The resin was washed with DMF.

4)脱保护：将20％哌啶(30.0mL)加入树脂中氮气鼓动30min。树脂用DMF洗涤，抽干。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.

5)缩合：Int 2(0.75mmol,1.50eq)和HOAt(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.75mmol,1.50eq)，反应在20℃氮气鼓动3.00h。树脂用DMF洗涤。5) Condensation: Int 2 (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq). The reaction was stirred with nitrogen at 20 °C for 3.00 h. The resin was washed with DMF.

6)脱保护：在反应柱中加入DCM(30.0mL)氮气鼓动，再先后加入PhSiH₃(5.00mmol,10.0eq)和Pd(PPh₃)₄(0.05mmol,0.10eq)氮气鼓动15.0min，重复该步骤三次。树脂用DMF洗涤，抽干。6) Deprotection: DCM (30.0 mL) was added to the reaction column and nitrogen was agitated, then PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.10 eq) were added successively and nitrogen was agitated for 15.0 min, and this step was repeated three times. The resin was washed with DMF and dried.

7)缩合：Int 3(0.75mmol,1.50eq)和HOAt(0.75mmol,1.50eq)溶在DMF(30.0mL)加入到树脂中，再加入DIC(0.75mmol,1.50eq)，反应在20℃氮气鼓动8.00h。树脂用DMF洗涤。7) Condensation: Int 3 (0.75 mmol, 1.50 eq) and HOAt (0.75 mmol, 1.50 eq) were dissolved in DMF (30.0 mL) and added to the resin, followed by DIC (0.75 mmol, 1.50 eq). The reaction was stirred with nitrogen at 20 °C for 8.00 h. The resin was washed with DMF.

多肽切割与纯化:Peptide cleavage and purification:

将干燥后的树脂加入到配好的10mL切割液(由90％TFA、2.5％％H₂O、2.5％TIS和5％3-Mpr组成)中，加热超声2h。干燥得到粗肽。The dried resin was added to 10 mL of a prepared cutting solution (composed of 90% TFA, 2.5% H ₂ O, 2.5% TIS and 5% 3-Mpr), heated and ultrasonicated for 2 h, and dried to obtain a crude peptide.

粗肽通过反相制备HPLC(A:含0.075％TFA的H₂O,B:MeOH:ACN＝1:1)得到终产物NYM050(20.0mg,纯度为98.17％)。The crude peptide was purified by reverse phase preparative HPLC (A: H ₂ O containing 0.075% TFA, B: MeOH: ACN = 1:1) to obtain the final product NYM050 (20.0 mg, purity 98.17%).

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

HPLC:Rt＝8.04min,纯度:98.17％(图17所示)HPLC: Rt = 8.04 min, purity: 98.17% (as shown in Figure 17)

¹H NMR:400MHz,D₂O.(图18所示) ¹ H NMR: 400 MHz, D ₂ O. (shown in FIG. 18 )

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). 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).

8.NYM070的合成步骤
8. Synthesis steps of NYM070

多肽合成：该肽是用标准的Fmoc化学方法合成的Peptide synthesis: The peptide was synthesized using standard Fmoc chemistry

1)称取0.50mmol的2-CTC resin(取代度Sub＝0.70mmol/g)和Fmoc-Asp-OAll(0.50mmol,1.00eq)到反应柱中，加入30.0mL的DCM后滴加DIEA(2.00mmol,4.00eq)，调节好氮气使树脂均匀鼓起。在20℃下反应2小时后，向反应柱中滴加MeOH(0.80mL)，鼓氮气30分钟后，排废，直至没有液体流出。加入DMF洗涤，排废，直至没有液体流出。1) Weigh 0.50mmol of 2-CTC resin (substitution degree Sub = 0.70mmol/g) and Fmoc-Asp-OAll (0.50mmol, 1.00eq) into the reaction column, add 30.0mL of DCM and then drop DIEA (2.00mmol, 4.00eq), adjust the nitrogen to make the resin swell evenly. After reacting at 20℃ for 2 hours, drop MeOH (0.80mL) into the reaction column, blow nitrogen for 30 minutes, and drain until no liquid flows out. Add DMF for washing and drain until no liquid flows out.

2)脱保护：将20％哌啶/DMF(V:V)(50.0mL)加入树脂中氮气鼓动15分钟。树脂用DMF洗涤，抽干。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.

3)氨基酸的偶联：称取Fmoc-5-氨基戊酸(1.50mmol,3.00eq)，和HBTU(1.425mmol,2.85eq)到上述树脂中，加入25.0mL的DMF后滴加DIEA(3.00mmol,6.00eq)至反应柱中，调节好氮气使树脂均匀鼓起。在20℃下反应50分钟后。抽掉反应液，加入DMF洗涤，排废，直至没有液体流出。3) Coupling of amino acids: Weigh Fmoc-5-aminopentanoic acid (1.50 mmol, 3.00 eq) and HBTU (1.425 mmol, 2.85 eq) into the above resin, add 25.0 mL of DMF, then drop DIEA (3.00 mmol, 6.00 eq) into the reaction column, adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF for washing, and drain until no liquid flows out.

4)脱保护：将20％哌啶/DMF(V:V)(50.0mL)加入树脂中氮气鼓动15分钟。树脂用DMF洗涤，抽干。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.

5)用DMF将树脂洗涤干净后，加入25.0mL的THF，先加DIEA(2.00mmol,4.00eq)，然后将NsCl(1.00mmol,2.00eq)慢慢加入THF溶剂中，调节好氮气使树脂均匀鼓起。反应一个小时，抽掉反应液，加入DMF洗涤，排废，直至没有液体流出。5) After washing the resin with DMF, add 25.0 mL of THF, first add DIEA (2.00 mmol, 4.00 eq), then slowly add NsCl (1.00 mmol, 2.00 eq) into the THF solvent, and adjust the nitrogen to make the resin swell evenly. React for one hour, remove the reaction liquid, add DMF for washing, and drain until no liquid flows out.

6)用DMF将树脂洗涤干净后，加入25.0mL的THF，先加三苯基膦(2.50mmol,5.00eq)，2-萘醇(1.00mmol,2.00eq)，反应5min，然后DEAD(2.50mmol,5.00eq)慢慢滴加入反应液中，调节好氮气使树脂均匀鼓起。反应一个小时后，抽掉反应液，加入DMF(30.0mL)洗涤，排废，直至没有液体流出。6) After washing the resin with DMF, add 25.0 mL of THF, first add triphenylphosphine (2.50 mmol, 5.00 eq), 2-naphthol (1.00 mmol, 2.00 eq), react for 5 min, then slowly add DEAD (2.50 mmol, 5.00 eq) dropwise into the reaction solution, and adjust the nitrogen to make the resin swell evenly. After reacting for one hour, remove the reaction solution, add DMF (30.0 mL) for washing, and drain until no liquid flows out.

7)脱NS：加入30.0mL的DMF，加入苯硫酚钠(1.00mmol,2.00eq)，调节好氮气使树脂均匀鼓起，反应一个小时。7) NS removal: Add 30.0 mL of DMF and sodium thiophenolate (1.00 mmol, 2.00 eq), adjust the nitrogen gas to make the resin swell evenly, and react for one hour.

8)氨基酸的偶联：称取Int 1(1.50mmol,3.00eq)，和HOAt(1.50mmol,3.00eq)到上述树脂中，加入25.0mL的DMF后滴加DIC(1.50mmol,3.00eq)至反应柱中，调节好氮气使树脂均匀鼓起。在20℃下反应50分钟后。抽掉反应液，加入DMF(30.0mL)洗涤，排废，直至没有液体流出。8) Coupling of amino acids: Int 1 (1.50 mmol, 3.00 eq) and HOAt (1.50 mmol, 3.00 eq) were weighed into the above resin, 25.0 mL of DMF was added, and DIC (1.50 mmol, 3.00 eq) was added dropwise to the reaction column. The nitrogen was adjusted to make the resin swell evenly. After reacting at 20°C for 50 minutes, the reaction liquid was removed, and DMF (30.0 mL) was added for washing and discharged until no liquid flowed out.

9)脱烯丙基：将树脂用DMF洗3次，DCM洗3次,加入适量DCM并鼓入氮气，顺序加入PhSiH₃(5.00mmol，10.0eq)，Pd(PPh₃)₄(0.05mmol，0.100eq)反应15分钟，抽掉反应液，加入DMF(30.0mL)洗涤，排废，直至没有液体流出。9) Deallylation: The resin was washed with DMF 3 times and DCM 3 times, an appropriate amount of DCM was added and nitrogen was bubbled in, PhSiH ₃ (5.00 mmol, 10.0 eq) and Pd(PPh ₃ ) ₄ (0.05 mmol, 0.100 eq) were added in sequence and reacted for 15 minutes, the reaction liquid was removed, DMF (30.0 mL) was added for washing, and the mixture was discharged until no liquid flowed out.

10)氨基酸的偶联：称取N-Fmoc-1,4-丁二胺盐酸盐(1.50mmol,3.00eq)，和HOAt(1.50mmol,3.00eq)到上述树脂中，加入25.0mL的DMF后滴加DIC(1.50mmol,3.00eq)至反应柱中，调节好氮气使树脂均匀鼓起。在20℃下反应50分钟后抽掉反应液，加入DMF(30.0mL)洗涤，排废，直至没有液体流出；10) Coupling of amino acids: Weigh N-Fmoc-1,4-butanediamine hydrochloride (1.50mmol, 3.00eq) and HOAt (1.50mmol, 3.00eq) into the above resin, add 25.0mL of DMF, then drop DIC (1.50mmol, 3.00eq) into the reaction column, and adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF (30.0mL) for washing, and drain until no liquid flows out;

11)氨基酸的偶联：称取NOTA(tBu)2-OH(1.50mmol,3.00eq)，和HOAt(1.50mmol,3.00eq)到上述树脂中，加入25.0mL的DMF后滴加DIC(1.50mmol,3.00eq)至反应柱中，调节好氮气使树脂均匀鼓起。在20℃下反应50分钟后。抽掉反应液，加入DMF(30.0mL)洗涤，排废，直至没有液体流出；11) Coupling of amino acids: Weigh NOTA(tBu)2-OH (1.50mmol, 3.00eq) and HOAt (1.50mmol, 3.00eq) into the above resin, add 25.0mL of DMF, then drop DIC (1.50mmol, 3.00eq) into the reaction column, adjust the nitrogen to make the resin swell evenly. After reacting at 20°C for 50 minutes, remove the reaction liquid, add DMF (30.0mL) for washing, and drain until no liquid flows out;

12)用MeOH(30.0mL)收缩树脂，排废，直至没有液体流出，用氮气将树脂吹干，备用。12) Use MeOH (30.0 mL) to shrink the resin and drain until no liquid flows out. Use nitrogen to blow dry the resin and set aside.

多肽切割和纯化: Peptide cleavage and purification:

在室温下，将干燥后的树脂加入到配好的切割液(90％TFA/2.5％H₂O/5％TIS/2.5％3-Mpr)中，超声切割2.5小时。过滤，将滤液加入到冰异丙醚中进行沉降离心，再用异丙醚洗涤。在真空下干燥2小时得到粗肽NYM070(500mg)。At room temperature, the dried resin was added to the prepared cutting solution (90% TFA/2.5% _H2O /5% TIS/2.5% 3-Mpr) and ultrasonically cut for 2.5 hours. Filtered, the filtrate was added to ice isopropyl ether for sedimentation centrifugation, and then washed with isopropyl ether. Drying under vacuum for 2 hours gave crude peptide NYM070 (500 mg).

粗肽通过制备型高效液相色谱仪纯化得到最终产品NYM070(14.0mg,纯度为96.6％)。The crude peptide was purified by preparative HPLC to obtain the final product NYM070 (14.0 mg, purity 96.6%).

LCMS:MS observed:[M+H]+＝1018.4(图59所示)LCMS: MS observed: [M+H]+＝1018.4 (as shown in Figure 59)

HPLC:纯度:96.6％(图60所示)HPLC: Purity: 96.6% (as shown in Figure 60)

9.NYM071的合成步骤9. Synthesis steps of NYM071

步骤一：
Step 1:

向溶有化合物2a_1(2.00g,1.00eq),HATU(3.81g,1.50eq)以及DIEA(3.49mL,3.00eq)的DMF(20mL)溶液中加入化合物2a_1(1.38g,1.10eq),反应液在25℃下反应1h。纯化得到化合物3a_1(3.00g)。Compound 2a_1 (1.38 g, 1.10 eq) was added to a DMF (20 mL) solution containing compound 2a_1 (2.00 g, 1.00 eq), HATU (3.81 g, 1.50 eq) and DIEA (3.49 mL, 3.00 eq), and the reaction mixture was reacted at 25°C for 1 h. Compound 3a_1 (3.00 g) was obtained after purification.

步骤二：
Step 2:

化合物3a_1(1.00g,1.00eq)溶于三氟乙酸(5mL)，反应液在20℃下反应0.5小时。反应液旋干后得到化合物4a_1(700mg)。Compound 3a_1 (1.00 g, 1.00 eq) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was reacted at 20° C. for 0.5 hours. The reaction solution was spin-dried to obtain compound 4a_1 (700 mg).

步骤三：
Step 3:

向溶有化合物5a_1(600mg,1.00eq),HOBt(292.6mg,1.50eq),EDCI(415.2mg,1.50eq)以及DIEA(754.5μL,3.00eq)的DMF(10mL)溶液中加入化合物4a_1(640.1mg,1.20eq),在25℃下反应12h。纯化得到化合物6a_1(780mg,纯化97.7％)。Compound 4a_1 (640.1 mg, 1.20 eq) was added to a DMF (10 mL) solution containing compound 5a_1 (600 mg, 1.00 eq), HOBt (292.6 mg, 1.50 eq), EDCI (415.2 mg, 1.50 eq) and DIEA (754.5 μL, 3.00 eq), and the mixture was reacted at 25° C. for 12 h. Compound 6a_1 (780 mg, purified 97.7%) was obtained by purification.

步骤四：
Step 4:

向溶有化合物6a_1(380mg,1.00eq)的甲醇(4mL)溶液中加入湿钯碳(100mg,纯度10％)，反应液在15psi氢气氛围下，20℃反应3h。反应液经硅藻土过滤后，浓缩得到化合物7a_1(270mg)。Wet palladium carbon (100 mg, purity 10%) was added to a solution of compound 6a_1 (380 mg, 1.00 eq) in methanol (4 mL), and the reaction solution was reacted at 20° C. for 3 h under a 15 psi hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth and concentrated to obtain compound 7a_1 (270 mg).

步骤五：
Step 5:

向溶有化合物Int 1(70mg,1.00eq),BOP(150.6mg,1.50eq)以及DIEA(118.6μL,3.00eq)的DMF(10mL)溶液中加入化合物7a_1(158.04mg,1.10eq),反应液在25℃下反应1h。纯化得到化合物8a_1(100mg)。Compound 7a_1 (158.04 mg, 1.10 eq) was added to a DMF (10 mL) solution containing compound Int 1 (70 mg, 1.00 eq), BOP (150.6 mg, 1.50 eq) and DIEA (118.6 μL, 3.00 eq), and the reaction mixture was reacted at 25°C for 1 h. Compound 8a_1 (100 mg) was obtained after purification.

步骤六：
Step 6:

向化合物8a_1(100mg,1.00eq)中加入配有三氟乙酸(5mL),三异丙基硅烷(0.13mL)以及水(0.13mL)的混合溶液,反应液在25℃下反应1.5h。反应液真空浓缩得到粗品。粗品纯化得到NYM071(15.0mg,纯度为：99.7％)。A mixed solution of trifluoroacetic acid (5 mL), triisopropylsilane (0.13 mL) and water (0.13 mL) was added to compound 8a_1 (100 mg, 1.00 eq), and the reaction solution was reacted at 25°C for 1.5 h. The reaction solution was concentrated in vacuo to obtain a crude product. The crude product was purified to obtain NYM071 (15.0 mg, purity: 99.7%).

LCMS:MS：[M+H]+＝811.3(如图61所示)LCMS: MS: [M+H]+=811.3 (as shown in FIG61 )

HPLC:纯度:99.7％(如图62所示)HPLC: Purity: 99.7% (as shown in Figure 62)

10.NYM073的合成步骤10. Synthesis steps of NYM073

步骤一：
Step 1:

将化合物1c-1(1.00g,1.00eq)溶于N,N-二甲基甲酰胺(10.0mL)中，往其中加入化合物2a(451mg,1.00eq)，O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(796mg,1.20eq)和N,N-二异丙基乙胺(912μL,3.00eq)，反应在25℃下搅拌1小时，纯化后得到化合物2c-1(990mg)。Compound 1c-1 (1.00 g, 1.00 eq) was dissolved in N,N-dimethylformamide (10.0 mL), and compound 2a (451 mg, 1.00 eq), O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (796 mg, 1.20 eq) and N,N-diisopropylethylamine (912 μL, 3.00 eq) were added thereto. The reaction was stirred at 25°C for 1 hour, and compound 2c-1 (990 mg) was obtained after purification.

步骤二：
Step 2:

将化合物2c-1(990mg,1.00eq)溶于四氢呋喃(10.0mL)和水(0.04mL)的混合溶液里，在氮气氛围下加入Pd/C(99.0mg,纯度为：10.0％,7.30e-2eq)。反应在氢气(15.0Psi)氛围下25℃反应16小时。反应液在硅藻土下过滤。在旋蒸下旋干得到化合物3c-1(810mg)。Compound 2c-1 (990 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (10.0 mL) and water (0.04 mL), and Pd/C (99.0 mg, purity: 10.0%, 7.30 e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 16 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The compound 3c-1 (810 mg) was obtained by rotary drying under rotary evaporation.

步骤三：
Step 3:

将化合物4c-1(231mg,1.00eq)溶在N,N-二甲基甲酰胺(4.00mL)中，往其中加入1-羟基苯并三唑(126mg,1.50eq)，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(178mg,1.50eq)，N,N-二异丙基乙胺(325μL,3.00eq)和化合物3c-1(400mg,1.00eq)，反应在25℃搅拌1小时。纯化得到化合物5c-1(120mg)。Compound 4c-1 (231 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), 1-hydroxybenzotriazole (126 mg, 1.50 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 1.50 eq), N,N-diisopropylethylamine (325 μL, 3.00 eq) and compound 3c-1 (400 mg, 1.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 5c-1 (120 mg) was obtained after purification.

步骤四：
Step 4:

将化合物5c-1(120mg,1.00eq)溶于四氢呋喃(1.20mL)和水(0.04mL)的混合溶液，在氮气氛围下加入Pd/C(12.0mg,纯度为：10.0％,9.36e-2eq)。反应在氢气(15.0Psi)氛围下25℃反应3小时。反应液在硅藻土下过滤。在旋蒸下旋干得到化合物6c-1(102mg)。Compound 5c-1 (120 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (1.20 mL) and water (0.04 mL), and Pd/C (12.0 mg, purity: 10.0%, 9.36e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 3 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The mixture was dried under rotary evaporation to obtain compound 6c-1 (102 mg).

步骤五：
Step 5:

将Int 1(40.1mg,1.10eq)溶于N,N-二甲基甲酰胺(1.00mL)中，往其中加入化合物6c-1(102mg,1.00eq)，苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(52.3mg,1.00eq)和N,N-二异丙基乙胺(61.8μL,3.00eq)，反应在25℃下搅拌1小时。纯化得到化合物7c-1(58.0mg)。Int 1 (40.1 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (1.00 mL), compound 6c-1 (102 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphine salt (52.3 mg, 1.00 eq) and N,N-diisopropylethylamine (61.8 μL, 3.00 eq) were added thereto, and the reaction was stirred at 25 °C for 1 hour. Compound 7c-1 (58.0 mg) was obtained after purification.

步骤六：
Step 6:

将化合物7c-1(58.0mg,1.00eq)溶于三氟乙酸(0.57mL,152eq)，三异丙基硅烷(15.00μL,1.00eq)和水(0.015mL)。反应25℃下搅拌3小时。纯化得到NYM073(11.0mg,纯度为99.7％,TFA)。Compound 7c-1 (58.0 mg, 1.00 eq) was dissolved in trifluoroacetic acid (0.57 mL, 152 eq), triisopropylsilane (15.00 μL, 1.00 eq) and water (0.015 mL). The reaction was stirred at 25°C for 3 hours. NYM073 (11.0 mg, purity 99.7%, TFA) was obtained after purification.

LCMS:MS:[M+H]+＝928.3.(如图63所示)LCMS: MS: [M+H]+ = 928.3. (as shown in FIG63)

HPLC:纯度：99.7％(如图64所示)HPLC: Purity: 99.7% (as shown in Figure 64)

11.NYM074的合成步骤11. Synthesis steps of NYM074

步骤一：
Step 1:

将化合物1d(217mg,1.00eq)溶在N,N-二甲基甲酰胺(4.00mL)中，往其中加入1-羟基苯并三唑(126mg,1.50eq)，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(178mg,1.50eq)，N,N-二异丙基乙胺(325μL,3.00eq)和化合物3c-1(400mg,1.00eq)，反应在25℃搅拌1小时。纯化得到化合物2d(120mg)。Compound 1d (217 mg, 1.00 eq) was dissolved in N,N-dimethylformamide (4.00 mL), 1-hydroxybenzotriazole (126 mg, 1.50 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (178 mg, 1.50 eq), N,N-diisopropylethylamine (325 μL, 3.00 eq) and compound 3c-1 (400 mg, 1.00 eq) were added thereto, and the reaction was stirred at 25° C. for 1 hour. Compound 2d (120 mg) was obtained after purification.

步骤二：
Step 2:

将化合物2d(120mg,1.00eq)溶于四氢呋喃(1.20mL)和水(0.04mL)的混合溶液，在氮气氛围下加入Pd/C(12.0mg,纯度为：10.0％,9.15e-2eq)。反应在氢气(15.0Psi)氛围下25℃反应4小时。反应液在硅藻土下过滤。在旋蒸下旋干得到化合物3d(103mg)。Compound 2d (120 mg, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (1.20 mL) and water (0.04 mL), and Pd/C (12.0 mg, purity: 10.0%, 9.15e-2 eq) was added under a nitrogen atmosphere. The reaction was carried out at 25°C for 4 hours under a hydrogen (15.0 Psi) atmosphere. The reaction solution was filtered under diatomaceous earth. The compound 3d (103 mg) was obtained by rotary drying under rotary evaporation.

步骤三：
Step 3:

将Int 1(41.5mg,1.10eq)溶于N,N-二甲基甲酰胺(3.00mL)中，往其中加入化合物6c(103mg,1.00eq)，苯并三唑-1-氧代-三(二甲氨基磷)六氟磷盐(54.2mg,1.00eq)和N,N-二异丙基乙胺(64.0μL,3.00eq)，反应在25℃下搅拌1小时。纯化得到化合物4d(100mg)。Int 1 (41.5 mg, 1.10 eq) was dissolved in N,N-dimethylformamide (3.00 mL), compound 6c (103 mg, 1.00 eq), benzotriazole-1-oxo-tris(dimethylaminophosphine)hexafluorophosphine salt (54.2 mg, 1.00 eq) and N,N-diisopropylethylamine (64.0 μL, 3.00 eq) were added thereto, and the reaction was stirred at 25°C for 1 hour. Compound 4d (100 mg) was obtained after purification.

步骤四：
Step 4:

将化合物4d(100mg,1.00eq)溶于三氟乙酸(0.950mL,144eq)，三异丙基硅烷(0.025mL,1.00eq)和水(0.025mL)的混合溶液。反应25℃下搅拌3小时。纯化得到NYM074(12.0mg,纯度为99.9％,TFA)。Compound 4d (100 mg, 1.00 eq) was dissolved in a mixed solution of trifluoroacetic acid (0.950 mL, 144 eq), triisopropylsilane (0.025 mL, 1.00 eq) and water (0.025 mL). The mixture was stirred at 25°C for 3 hours. NYM074 (12.0 mg, purity 99.9%, TFA) was obtained after purification.

LCMS:MS:[M+H]+＝962.3.(如图65所示)LCMS: MS: [M+H]+ = 962.3. (as shown in FIG. 65 )

HPLC:纯度:99.9％(如图66所示)HPLC: Purity: 99.9% (as shown in Figure 66)

实施例2：化合物的标记过程Example 2: Labeling process of compounds

1、核素⁶⁸Ga的标记工艺：1. Labeling process of nuclide ⁶⁸ Ga:

将实施例1制备得到的化合物使用核素⁶⁸Ga进行标记，得到目标产物⁶⁸Ga-NYM045/046/047/048/049/050/074，具体过程如下所示：The compound prepared in Example 1 was labeled with radionuclide ⁶⁸ Ga to obtain the target product ⁶⁸ Ga-NYM045/046/047/048/049/050/074. The specific process is as follows:

a.淋洗锗镓发生器：使用10ml注射器抽取5ml 0.1M HCl溶液，注射器连接发生器进口，缓慢推动注射器淋洗锗镓发生器，收集流出液得⁶⁸GaCl₃的盐酸溶液5ml。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 5ml of ⁶⁸ GaCl ₃ hydrochloric acid solution.

b.中和反应液：向⁶⁸GaCl₃的盐酸溶液加入4.0ml 0.15M醋酸/醋酸钠溶液(pH 7.2)。b. Neutralize the reaction solution: Add 4.0 ml of 0.15 M acetic acid/sodium acetate solution (pH 7.2) to the ⁶⁸ GaCl ₃ hydrochloric acid solution.

c.螯合反应：向中和液中加入60μg/60μl的NYM045/046/047/048/049/050/074前体溶液(灭菌注射用水)，摇匀后置于70～80℃下反应10min。反应结束后取出反应瓶降温。c. Chelation reaction: Add 60 μg/60 μl of NYM045/046/047/048/049/050/074 precursor solution (sterile water for injection) to the neutralization solution, shake well and place at 70-80°C for reaction for 10 minutes. After the reaction is completed, take out the reaction bottle and cool it down.

d.纯化：取一根一次性Sep-Pak C-18小柱，预先使用10mL无水乙醇、20mL灭菌注射用水活化该小柱。取一支10mL无菌注射器，预先吸入5mL灭菌注射用水后再吸取5mL反应液，然后连接C-18小柱推动注射器内液体流经C-18小柱，目标产物被吸附在C-18小柱上，然后再吸取20mL灭菌注射用水冲洗C-18小柱，最后使用1.2mL 70％无水乙醇溶液淋洗C-18，将目标产物洗脱至中转瓶内。d. Purification: Take a disposable Sep-Pak C-18 column and activate it with 10 mL of anhydrous ethanol and 20 mL of sterile water for injection. Take a 10 mL sterile syringe, draw 5 mL of sterile water for injection in advance, and then draw 5 mL of reaction solution. Then connect the C-18 column to push the liquid in the syringe through the C-18 column. The target product is adsorbed on the C-18 column, and then draw 20 mL of sterile water for injection to rinse the C-18 column. Finally, use 1.2 mL of 70% anhydrous ethanol solution to rinse the C-18 column and elute the target product into the transfer bottle.

e.过滤除菌：使用注射器吸入3.8mL生理盐水，将生理盐水注入中转瓶中混匀，吸取出中转瓶内所有产品溶液(粗品)，经0.22μm无菌滤膜过滤至10mL封闭的无菌西林瓶中，即得目标产物无菌注射液，即⁶⁸Ga-NYM045/046/047/048/049/050/074无菌注射液。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 through a 0.22 μm sterile filter membrane into a 10 mL sealed sterile vial to obtain the target product sterile injection, i.e., ⁶⁸ Ga-NYM045/046/047/048/049/050/074 sterile injection.

经Radio-iTLC方法测定⁶⁸Ga-NYM045/046/047/048/049/050/074无菌注射液产品的放射化学纯度(RCP)均>90％。结果如图19～25所示，⁶⁸Ga-NYM045的RCP为95.55％；⁶⁸Ga-NYM046的RCP为97.53％；⁶⁸Ga-NYM047的RCP为98.77％；⁶⁸Ga-NYM048的RCP为98.64％；⁶⁸Ga-NYM049的RCP为98.71％； ⁶⁸Ga-NYM050的RCP为95.45％；⁶⁸Ga-NYM074的RCP为99.96％。The radiochemical purity (RCP) of the sterile injection products of ⁶⁸ Ga-NYM045/046/047/048/049/050/074 was determined by Radio-iTLC method and was >90%. The results are shown in Figures 19 to 25. The RCP of ⁶⁸ Ga-NYM045 is 95.55%; The RCP of ⁶⁸ Ga-NYM046 is 97.53%; The RCP of ⁶⁸ Ga-NYM047 is 98.77%; The RCP of ⁶⁸ Ga-NYM048 is 98.64%; The RCP of ⁶⁸ Ga-NYM049 is 98.71%; The RCP of ⁶⁸ Ga-NYM050 is 95.45%; the RCP of ⁶⁸ Ga-NYM074 is 99.96%.

2、核素¹⁸F的标记工艺：2. Labeling process of nuclide ¹⁸ F:

收集加速器含有¹⁸F的溶液，通过QMA柱纯化，用0.3mL生理盐水进行淋洗。将3.6mLDMSO、100μL含有前体(NYM070/NYM071)的水溶液(1mg/mL)、27μL氯化铝水溶液(2mM)和QMA淋洗液加入反应瓶。将反应瓶封盖后，置于80℃下反应15min，反应结束后冷却至室温，在反应瓶中加入6mL无菌注射用水稀释反应液，然后抽取3mL稀释后的反应液和7mL无菌注射用水，混合后通过活化好的C18柱进行上柱，重复三次直至上柱完成后,用10mL无菌注射用水冲洗C18柱,重复两次后用1.5mL 70％乙醇溶液进行洗脱，用产品瓶收集洗脱液并送样检测。经Radio-iTLC方法测定¹⁸F-NYM070/071无菌注射液产品的放射化学纯度(RCP)分别为98.6％、99.92％，结果如图26～27所示。Collect the solution containing ¹⁸ F from the accelerator, purify it through a QMA column, and elute it with 0.3 mL of normal saline. Add 3.6 mL of DMSO, 100 μL of an aqueous solution (1 mg/mL) containing the precursor (NYM070/NYM071), 27 μL of an aqueous solution of aluminum chloride (2 mM), and a QMA eluent to the reaction bottle. After the reaction bottle is capped, place it at 80 ° C for 15 minutes. After the reaction is completed, cool it to room temperature, add 6 mL of sterile water for injection to dilute the reaction solution in the reaction bottle, then extract 3 mL of the diluted reaction solution and 7 mL of sterile water for injection, mix them, and pass them through the activated C18 column for column loading. Repeat three times until the column loading is completed. Rinse the C18 column with 10 mL of sterile water for injection, repeat twice, and elute with 1.5 mL of 70% ethanol solution. Collect the eluate with a product bottle and send it for sample testing. The radiochemical purity (RCP) of ^{the 18} F-NYM070/071 sterile injection products was determined by Radio-iTLC method to be 98.6% and 99.92%, respectively. The results are shown in FIGS. 26-27 .

3、核素¹⁷⁷Lu的标记工艺：3. Labeling process of nuclide ¹⁷⁷ Lu:

在反应瓶中加入0.5mL醋酸钠/醋酸缓冲溶液(pH＝7.2)，加入NYM073/NYM074前体水溶液60μL(含60μg)，充分混合后后加入0.5mL¹⁷⁷LuCl₃的0.05M盐酸溶液，反应液在80℃下反应10min，终止反应，将反应液过无菌滤膜后，收集在真空瓶中，并取样检测。经Radio-iTLC方法测定¹⁷⁷Lu-NYM073/074无菌注射液产品的放射化学纯度(RCP)分别为100％、99.19％，结果如图28～29所示。Add 0.5mL sodium acetate/acetic acid buffer solution (pH=7.2) to the reaction bottle, add 60μL of NYM073/NYM074 precursor aqueous solution (containing 60μg), add 0.5mL ¹⁷⁷ LuCl ₃ 0.05M hydrochloric acid solution after thorough mixing, react the reaction solution at 80°C for 10min, terminate the reaction, filter the reaction solution through a sterile filter membrane, collect it in a vacuum bottle, and take samples for testing. The radiochemical purity (RCP) of the ¹⁷⁷ Lu-NYM073/074 sterile injection product was determined by Radio-iTLC method to be 100% and 99.19%, respectively, as shown in Figures 28-29.

实施例3：化合物的SPR亲和力测试Example 3: SPR affinity test of compounds

利用Biacore 8K蛋白互作系统测定了NYM045/046/047/048/049/050化合物对CAIX的亲和力。苯并噻嗪作为阳性对照，其对CAIX蛋白有很强的亲和力。The affinity of NYM045/046/047/048/049/050 compounds to CAIX was determined using the Biacore 8K protein interaction system. Benzothiazine was used as a positive control, which has a strong affinity for CAIX protein.

将CAIX(购于ACROBiosystems Inc，0.5mg/mL)偶联到CM5芯片表面，用运行缓冲液(HBS-EP缓冲液)(10mM HEPES,150mM NaCl,3mM EDTA,0.05％(v/v)Surfactant P20(Tween 20)),5％DMSO,pH 7.4)稀释待测样分子，待测样由DMSO溶剂等比例稀释一系列不同浓度待测样溶液(稀释比例为：2)，进样并测量待测样与CAIX的亲和力。待测样NYM045/046/047/048/049/050/070/071/073/074与CAIX的亲和力由平衡解离常数KD(Kd/Ka)值表示，其中Kd为解离常数，Ka为结合常数，KD值越小，表明化合物与蛋白的亲和力越高。测试结果如下表1所示，结果发现在测试的化合物中，NYM046、NYM048、NYM049、NYM050、NYM070、NYM071、NYM073、NYM074显示出了对CA9的低纳摩尔亲和性，对CA9的亲和力较强。CAIX (purchased from ACROBiosystems Inc, 0.5 mg/mL) was coupled to the surface of a CM5 chip, and the test molecule was diluted with 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 test sample solutions with different concentrations were diluted in equal proportions with DMSO solvent (dilution ratio: 2), and the sample was injected and the affinity of the test sample to CAIX was measured. The affinity of the test samples NYM045/046/047/048/049/050/070/071/073/074 to CAIX is represented by the equilibrium dissociation constant KD (Kd/Ka) value, where Kd is the dissociation constant and Ka is the binding constant. The smaller the KD value, the higher the affinity of the compound to the protein. The test results are shown in Table 1 below. It was found that among the tested compounds, NYM046, NYM048, NYM049, NYM050, NYM070, NYM071, NYM073, and NYM074 showed low nanomolar affinity for CA9 and strong affinity for CA9.

表1
Table 1

实施例4：目标产物在OS-RC-2模型鼠上的PET/CT扫描组织分布及靶向性实验Example 4: PET/CT scanning tissue distribution and targeting experiment of target product in OS-RC-2 model mice

1、小鼠模型：实验小鼠购自上海润诺生物科技有限公司，小鼠模型是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。1. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB/c nude mice, which is a mouse model constructed with human renal cancer cells.

实验步骤如下：The experimental steps are as follows:

选取该小鼠模型24只，分为6组，分别为045、046、047、048、049、050组，每组4只小鼠。分别给予每组每只小鼠对应的药物80-120μCi，于给药后1h对小鼠进行MicroPET/CT(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)扫描，经设备软件重建后获得扫描图像，对扫描图像进行分析。24 mice were selected and divided into 6 groups, namely 045, 046, 047, 048, 049, and 050, with 4 mice in each group. Each mouse in each group was given 80-120μCi of the corresponding drug, and the mice were scanned by MicroPET/CT (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) 1 hour after administration. The scanned images were obtained after reconstruction by the equipment software and analyzed.

肿瘤摄取药物的实验结果如图30、图31和图32所示(箭头处为肿瘤摄取处)，其中⁶⁸Ga-NYM045、 ⁶⁸Ga-NYM046、⁶⁸Ga-NYM048、⁶⁸Ga-NYM049、⁶⁸Ga-NYM050药物在肿瘤位置处摄取高，且注射药物1小时后，肿瘤处药物可见显著摄取。此外，各组织摄取药物的实验结果如图32所示，肾脏处⁶⁸Ga-NYM045、⁶⁸Ga-NYM049、⁶⁸Ga-NYM050摄取较少，肝脏处⁶⁸Ga-NYM049、⁶⁸Ga-NYM050摄取较少；心脏处NYM046、⁶⁸Ga-NYM048摄取较少；肺部⁶⁸Ga-NYM045、⁶⁸Ga-NYM046、⁶⁸Ga-NYM048，脑和肌肉对于⁶⁸Ga-NYM045/046/047/048/049/050摄取均很少。其中肿瘤组织摄取与非靶器官摄取比率(靶本比)数据结果可知，⁶⁸Ga-NYM045/046/047/048/049/050肿瘤与肌肉摄取比高，在用作显像剂诊断肿瘤疾病方面具有潜在价值。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 Ga-NYM050 drugs were highly absorbed at the tumor site, and significant drug uptake was observed at the tumor site 1 hour after drug injection. In addition, the experimental results of drug uptake in each tissue are shown in FIG32 , ⁶⁸ Ga-NYM045, ⁶⁸ Ga-NYM049, ⁶⁸ Ga-NYM050 were less absorbed in the kidney, ⁶⁸ Ga-NYM049, ⁶⁸ Ga-NYM050 were less absorbed in the liver; NYM046, ⁶⁸ Ga-NYM048 were less absorbed in the heart; ⁶⁸ Ga-NYM045, ⁶⁸ Ga-NYM046, ⁶⁸ Ga-NYM048 were less absorbed in the lungs, brain and muscle for ⁶⁸ Ga-NYM045/046/047/048/049/050. The data results of the ratio of tumor tissue uptake to non-target organ uptake (target-to-muscle ratio) show that ⁶⁸ Ga-NYM045/046/047/048/049/050 has a high tumor-to-muscle uptake ratio, and has potential value in being used as an imaging agent to diagnose tumor diseases.

2、小鼠模型：实验小鼠购自上海润诺生物科技有限公司，是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。2. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB/c nude mice. This model is a mouse model constructed with human renal cancer cells.

实验步骤如下：The experimental steps are as follows:

随机选取小鼠模型，分为6组，分别为045组(4只)、046组(3只)、047组(4只)、048组(3只)、049组(4只)、050组(4只)。每组小鼠分别给予上述⁶⁸Ga-NYM045/046/047/048/049/050药物60-120μCi，将动物于给药后进行30min MicroPET/CT动态扫描，给药后1h、2h、3h进行静态扫描，经设备软件重建后获得扫描图像，扫描图像如附图33～38所示，对扫描图像进行分析。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 ⁶⁸ Ga-NYM045/046/047/048/049/050 drugs at 60-120 μCi, and the animals were subjected to 30-min MicroPET/CT dynamic scanning after administration, and static scanning was performed 1 h, 2 h, and 3 h after administration. Scanned images were obtained after reconstruction by the equipment software, and the scanned images are shown in Figures 33 to 38, and the scanned images were analyzed.

如附图33所示，⁶⁸Ga-NYM045药物在给药1h后，在肿瘤处有放射性高摄取，而在其它正常组织处的⁶⁸Ga-NYM045药物可快速经过肾脏排泄；如附图34所示，⁶⁸Ga-NYM046药物在给药1h后，发现其在肿瘤处放射性摄取明显，并维持3个小时的高摄取，且无明显下降趋势，可见⁶⁸Ga-NYM046药物在肿瘤或转移灶处可维持较长时间摄取；如附图36所示，⁶⁸Ga-NYM048药物在给药1h后，发现其在肿瘤处摄取明显，直至3h时摄取值变化不明显，无明显增高或下降趋势，而在其它器官中则摄取逐渐下降，在正常组织处的⁶⁸Ga-NYM048药物可快速经过肾脏排出；如附图37所示，⁶⁸Ga-NYM049药物在给药1h后，发现其在肿瘤处摄取明显，直至3h时摄取值变化不明显，无明显增高或下降趋势，而在其它正常组织处摄取逐渐下降；如附图38所示，⁶⁸Ga-NYM050药物在给药1h后，发现其在肿瘤处显像明显，直至3h时摄取值都变化不大，无明显增高或下降趋势，而在其它器官中摄取逐渐下降，在正常组织处的⁶⁸Ga-NYM050药物可快速通过肾脏排泄。As shown in FIG33, 1 hour after administration of ⁶⁸ Ga-NYM045 drug, high radioactive uptake was found in the tumor, while ⁶⁸ Ga-NYM045 drug in other normal tissues could be rapidly excreted through the kidneys; as shown in FIG34, 1 hour after administration of ⁶⁸ Ga-NYM046 drug, obvious radioactive uptake was found in the tumor, and high uptake was maintained for 3 hours, with no obvious downward trend, indicating that ⁶⁸ Ga-NYM046 drug could be maintained for a long time in tumor or metastasis; as shown in FIG36, 1 hour after administration of ⁶⁸ Ga-NYM048 drug, obvious uptake was found in the tumor, and uptake value did not change significantly until 3 hours, with no obvious increase or decrease trend, while uptake in other organs gradually decreased, and ⁶⁸ Ga-NYM048 drug in normal tissues could be rapidly excreted through the kidneys; as shown in FIG37, ⁶⁸ One hour after the administration of Ga-NYM049 drug, it was found that its uptake was obvious in the tumor, and the uptake value did not change significantly until 3 hours, with no obvious increase or decrease trend, while the uptake in other normal tissues gradually decreased; as shown in Figure 38, one hour after the administration of ⁶⁸ Ga-NYM050 drug, it was found that its imaging was obvious in the tumor, and the uptake value did not change much until 3 hours, with no obvious increase or decrease trend, while the uptake in other organs gradually decreased, and the ⁶⁸ Ga-NYM050 drug in normal tissues can be quickly excreted through the kidneys.

肿瘤放射性摄取变化如附图39所示，⁶⁸Ga-NYM046、⁶⁸Ga-NYM048、⁶⁸Ga-NYM049、⁶⁸Ga-NYM050药物在给药一小时后，可快速富集在肿瘤处，且在肿瘤位置处摄取高；并可维持3小时的高摄取，而在其它非靶器官中的摄取则逐渐下降。The changes in tumor radioactive uptake are shown in FIG39 . One hour after administration, ⁶⁸ Ga-NYM046, ⁶⁸ Ga-NYM048, ⁶⁸ Ga-NYM049, and ⁶⁸ Ga-NYM050 drugs can be rapidly enriched in the tumor and have high uptake at the tumor location; and the high uptake can be maintained for 3 hours, while the uptake in other non-target organs gradually decreases.

3、小鼠模型：实验小鼠购自上海润诺生物科技有限公司，小鼠模型是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。3. Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB/c nude mice, which is a mouse model constructed with human renal cancer cells.

实验步骤如下：The experimental steps are as follows:

选取该小鼠模型2只，分别给予每只小鼠⁶⁸Ga-NYM074 80μCi，将动物于给药后进行1h MicroPET/CT(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)动态扫描，给药后2h进行静态扫描经设备软件重建后获得扫描图像，对扫描图像进行分析。Two mice of this mouse model were selected and each mouse was given 80 μCi of ⁶⁸ Ga-NYM074. The animals were subjected to dynamic scanning with MicroPET/CT (SNPC-303 Super Nova, Pingsheng Medical Technology (Kunshan) Co., Ltd.) 1 h after administration and static scanning was performed 2 h after administration. The scanned images were obtained after reconstruction by the equipment software and analyzed.

肿瘤摄取药物的实验结果如附图40所示(箭头处为肿瘤摄取处)，其中⁶⁸Ga-NYM074药物可快速在肿瘤位置处聚集，且注射药物1小时后，显像可见肿瘤-背景摄取比值高，肿瘤处药物可见显著摄取。给药后2小时，肿瘤处依旧保持高摄取。The experimental results of tumor drug uptake are shown in Figure 40 (the arrows indicate the tumor uptake sites), where ⁶⁸ Ga-NYM074 drugs can quickly accumulate at the tumor site, and 1 hour after drug injection, the tumor-background uptake ratio is high, and the drug can be significantly uptaken at the tumor. 2 hours after administration, the tumor still maintains high uptake.

各组织摄取药物的实验结果如附图41和42所示，其中肿瘤组织摄取与非靶器官摄取比率数据结果可知，⁶⁸Ga-NYM074在小鼠体内摄取肿瘤与肌肉摄取比随着时间逐渐增高，用作显像剂诊断肿瘤疾病中具有潜在价值。The experimental results of drug uptake in various tissues are shown in Figures 41 and 42. The data of the ratio of tumor tissue uptake to non-target organ uptake show that the ratio of tumor uptake to muscle uptake of ⁶⁸ Ga-NYM074 in mice gradually increases over time, and it has potential value in diagnosing tumor diseases as an imaging agent.

实施例5：⁶⁸Ga-NYM050 OS-RC-2模型竞争抑制实验Example 5: ⁶⁸ Ga-NYM050 OS-RC-2 model competitive inhibition experiment

1、实验小鼠购自上海润诺生物科技有限公司，小鼠模型是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。1. Experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The mouse model was an OS-RC-2 tumor subcutaneous heterotopic transplant model established based on BALB/c nude mice, which is a mouse model constructed with human renal cancer cells.

实验步骤如下：The experimental steps are as follows:

实验分两次，一次为基线实验，一次为阻断实验。The experiment was divided into two parts: one baseline experiment and one blocking experiment.

基线实验选取该小鼠模型4只，给予每只小鼠⁶⁸Ga-NYM050药物80Ci，小鼠于给药后0.5h、1h、 2h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，对扫描图像进行分析，实验结果如附图43、45所示。Four mice were selected for the baseline experiment. Each mouse was given 80 Ci of ⁶⁸ Ga-NYM050. The mice were MicroPET/CT scanning was performed for 2 hours, and the scanned image was obtained after reconstruction by the equipment software. The scanned image was analyzed, and the experimental results are shown in Figures 43 and 45.

基线实验第二天，阻断实验采用同基线实验相同的动物，先给予每只小鼠NYM050药物，注射剂量为注射⁶⁸Ga-NYM050药物质量的40倍；在给NYM050药后1h注射⁶⁸Ga-NYM050 80μCi，并于给药后0.5h、1h、2h、3h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，对扫描图像进行分析。实验结果如附图44、46所示。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, and the injection dose was 40 times the mass of the injected ⁶⁸ Ga-NYM050 drug; ⁶⁸ Ga-NYM050 80μCi was injected 1h after NYM050 administration, and MicroPET/CT scans were performed 0.5h, 1h, 2h, and 3h after administration. The scanned images were obtained after reconstruction by the equipment software and analyzed. The experimental results are shown in Figures 44 and 46.

可见在基线实验中，单独给药⁶⁸Ga-NYM0501h后，发现其在肿瘤处显像清晰，且2小时内无明显下降趋势；而在阻断实验中，预先加入NYM050后可以明显阻断肿瘤对⁶⁸Ga-NYM050的摄取，从而证实⁶⁸Ga-NYM050能够特异性识别肿瘤。It can be seen that in the baseline experiment, after 1 hour of single administration of ⁶⁸ Ga-NYM050, it was found that it had clear imaging at the tumor site and there was no obvious downward trend within 2 hours; in the blocking experiment, the pre-addition of NYM050 can significantly block the tumor's uptake of ⁶⁸ Ga-NYM050, thus confirming that ⁶⁸ Ga-NYM050 can specifically identify tumors.

实施例6：¹⁷⁷Lu-NYM073/¹⁷⁷Lu-NYM074在OS-RC-2模型SPECT/CT扫描实验Example 6: ¹⁷⁷ Lu-NYM073/ ¹⁷⁷ Lu-NYM074 SPECT/CT Scanning Experiment in OS-RC-2 Model

小鼠模型：实验小鼠购自上海润诺生物科技有限公司，是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。Mouse model: The experimental mice were purchased from Shanghai Runnuo Biotechnology Co., Ltd. The OS-RC-2 tumor subcutaneous heterotopic transplant model was established based on BALB/c nude mice. This model is a mouse model constructed with human renal cancer cells.

实验步骤：Experimental steps:

选取该动物模型小鼠1只。分别为每只动物给予¹⁷⁷Lu-NYM073/¹⁷⁷Lu-NYM074药物300μCi，并于给药后4h、24h、48h、96h、120h进行小动物SPECT/CT扫描，获得扫描图像，对扫描图像进行分析。One animal model mouse was selected. Each animal was given 300 μCi of ¹⁷⁷ Lu-NYM073/ ¹⁷⁷ Lu-NYM074 drugs, and small animal SPECT/CT scans were performed at 4h, 24h, 48h, 96h, and 120h after administration to obtain scanned images, which were analyzed.

由附图47可以看出，¹⁷⁷Lu-NYM073在给药4小时后，富集在肿瘤处(图中箭头处)，正常组织处器官摄取逐渐减少，¹⁷⁷Lu-NYM074在给药6小时后，富集在肿瘤处(图中箭头处)，正常组织处器官摄取逐渐减少；直到120小时后，目标产物在肿瘤处仍保持摄取，可见此目标产物在肿瘤的滞留时间久，有利于临床肿瘤疾病的治疗，非靶器官摄取减少且清除快。As can be seen from Figure 47, ¹⁷⁷ Lu-NYM073 is enriched in the tumor (arrow in the figure) 4 hours after administration, and the organ uptake in normal tissues gradually decreases. ¹⁷⁷ Lu-NYM074 is enriched in the tumor (arrow in the figure) 6 hours after administration, and the organ uptake in normal tissues gradually decreases. Until 120 hours later, the target product is still taken up in the tumor, which shows that the target product has a long retention time in the tumor, which is beneficial to the treatment of clinical tumor diseases, and the uptake of non-target organs is reduced and cleared quickly.

实施例7：目标产物在模型鼠的疗效实验Example 7: Experimental study on the efficacy of the target product in model mice

实验步骤：Experimental steps:

随机选取该动物模型15只小鼠，分成3组，每组5只小鼠，分别为生理盐水组、单次组、多次组。单次组分别为每只动物给予¹⁷⁷Lu-NYM074药物2mCi，每只小鼠给药一次，尾静脉注射；多次组分别为每只动物给予¹⁷⁷Lu-NYM074药物两次，每次给药2mCi，两次给药间隔七天，尾静脉注射；实验开始前测量小鼠体重和瘤体积，给药后每隔三天测量一次体重和瘤体积。测量肿瘤的长径和短径用于计算肿瘤体积大小，计算公式如下：肿瘤体积(tumor volume，TV)＝a×b²/2(a为长径、b为短径)，并计算肿瘤生长抑制率TGI。Fifteen mice of the animal model were randomly selected and divided into three groups, with 5 mice in each group, namely, saline group, single group, and multiple group. In the single group, each animal was given 2mCi of ¹⁷⁷ Lu-NYM074 drug once, and each mouse was given the drug by tail vein injection; in the multiple group, each animal was given ¹⁷⁷ Lu-NYM074 drug twice, 2mCi each time, and the interval between the two administrations was seven days, and the tail vein injection; the weight and tumor volume of the mice were measured before the experiment, and the weight and tumor volume were measured every three days after the administration. The long and short diameters of the tumor were measured to calculate the tumor volume, and the calculation formula was as follows: tumor volume (TV) = a×b ² /2 (a is the long diameter, b is the short diameter), and the tumor growth inhibition rate TGI was calculated.

给药后33天、40天，单次组TGI值分别为33.4％、24.8％，多次组的TGI值分别为76.2％、72.9％。由附图48可看出，相较于生理盐水组，单次组和多次组显示出了明显的抗肿瘤活性，能明显的控制肿瘤的生长，且多次组的肿瘤生长更慢，显示出了肿瘤对药物剂量的依赖性。三组实验中，小鼠的体重变化趋势组间差异小，如附图49所示，可见此药物的抗肿瘤疗效好且安全性好。33 days and 40 days after administration, the TGI values of the single group were 33.4% and 24.8%, respectively, and the TGI values of the multiple groups were 76.2% and 72.9%, respectively. As shown in Figure 48, compared with the saline group, the single group and the multiple groups showed obvious anti-tumor activity, which could significantly control the growth of tumors, and the tumor growth of the multiple groups was slower, showing the dependence of tumors on drug dosage. In the three groups of experiments, the weight change trend of mice was slightly different between groups, as shown in Figure 49, which shows that this drug has good anti-tumor efficacy and good safety.

实施例8：目标产物OS-RC-2模型离体组织分布实验Example 8: In vitro tissue distribution experiment of target product OS-RC-2 model

实验步骤：Experimental steps:

选取该动物模型6只小鼠。分别为每只动物给予¹⁷⁷Lu-NYM074药物100μCi，并于给药后4h、48h各解剖3只，取脑、甲状腺、心脏、肾脏、大肠、小肠、肝脏、肺脏、胰腺、性腺、骨骼肌、脾脏、胃、脂肪、肿瘤共15个组织器官，并检测γ放射计数。Six mice were selected for this animal model. Each animal was given ¹⁷⁷ Lu-NYM074 at 100 μCi, and three mice were dissected at 4h and 48h after administration, and 15 tissues and organs including brain, thyroid, heart, kidney, large intestine, small intestine, liver, lung, pancreas, gonad, skeletal muscle, spleen, stomach, fat, and tumor were taken and the gamma radiation count was detected.

由附图50可见，¹⁷⁷Lu-NYM074在给药4小时后富集在肿瘤处，除肾脏、肺脏、胃、棕色脂肪(肩胛骨处的棕色脂肪)处放射性摄取较高，其他正常组织摄取低；As shown in FIG. 50 , ¹⁷⁷ Lu-NYM074 was enriched in the tumor 4 hours after administration. Except for the kidney, lung, stomach, and brown fat (brown fat at the scapula), which had high radioactive uptake, other normal tissues had low uptake.

在给药后4小时，¹⁷⁷Lu-NYM074药物在肿瘤处高摄取，在心脏处摄取低，给药48小时后，其他正常组织摄取快速下降，在肿瘤处仍有高摄取，可见¹⁷⁷Lu-NYM074具有临床治疗潜力。 Four hours after administration, ¹⁷⁷ Lu-NYM074 drug uptake was high in the tumor and low in the heart. After 48 hours of administration, uptake in other normal tissues decreased rapidly, but it was still high in the tumor. This shows that ¹⁷⁷ Lu-NYM074 has clinical therapeutic potential.

实施例9：⁶⁸Ga-NYM046的科研临床SPET/CT显像实验Example 9: ⁶⁸ Ga-NYM046 Clinical SPET/CT Imaging Experiment

1.患者1简单信息：患者5，男性，59岁、体重52kg。患者经左肾肿块穿刺活检术，病理提示恶性肿瘤伴坏死，倾向透明细胞癌，增强CT显示左肾上极占位，伴肺部及腰椎多发转移，后进行免疫药物治疗。入组进行CAIX示踪剂科研临床试验。对患者注射¹⁸F-FDG药物7.5mCi后1.5h后进行全身PET/CT断层显像，间隔2日后，对患者注射⁶⁸Ga-NYM046药物4.08mCi后1h后进行全身PET/CT断层显像。1. Brief information of patient 1: Patient 5, male, 59 years old, weighing 52kg. The patient underwent a puncture biopsy of the left renal mass, and pathology showed malignant tumor with necrosis, tending to clear cell carcinoma. Enhanced CT showed a mass in the upper pole of the left kidney, accompanied by multiple metastases in the lungs and lumbar spine, and then received immunotherapy. The patient was enrolled in a clinical trial of CAIX tracer research. The patient was injected with ¹⁸ F-FDG drug 7.5mCi and underwent whole-body PET/CT tomography 1.5h later. After an interval of 2 days, the patient was injected with ⁶⁸ Ga-NYM046 drug 4.08mCi and underwent whole-body PET/CT tomography 1h later.

显像结果如附图51～54所示，可以看见在肿瘤及病变区⁶⁸Ga-NYM046有放射性高摄取，且界面清晰，相比较¹⁸F-FDG，⁶⁸Ga-NYM046对于肿瘤及其转移灶的摄取值更高，且⁶⁸Ga-NYM046有更高的肿瘤以及转移灶检出率，可检出较小的转移灶，具有更高的肿瘤摄取，肿瘤摄取与其他非靶器官摄取比率更高，肿瘤处显像更清晰。The imaging results are shown in Figures 51 to 54. It can be seen that ⁶⁸ Ga-NYM046 has high radioactive uptake in the tumor and lesion area, and the interface is clear. Compared with ¹⁸ F-FDG, ⁶⁸ Ga-NYM046 has a higher uptake value for tumors and their metastases, and ⁶⁸ Ga-NYM046 has a higher tumor and metastasis detection rate, can detect smaller metastases, has higher tumor uptake, and a higher ratio of tumor uptake to other non-target organ uptake, and the imaging of the tumor is clearer.

2.患者2简单信息：患者2增强CT显示：男性，76岁、体重75kg。患者左肾下极占位，左肾前筋膜局部结节样增厚；右侧耻骨、骶髂骨骨质破坏伴软组织肿块形成。两肺多发实性性结节；双侧肾上腺多发结节灶。行肾穿刺活检，病理显示：(左肾肿瘤)透明细胞性肾细胞癌。入组进行CAIX示踪剂科研临床试验。对患者注射⁶⁸Ga-NYM046药物4.83mCi后1h后进行全身PET/CT断层显像，间隔6日后，对患者2注射¹⁸F-FDG药物9.8mCi后1h后进行全身PET/CT断层显像。2. Brief information of patient 2: Enhanced CT of patient 2 showed: male, 76 years old, weight 75kg. The patient had a mass in the lower pole of the left kidney, local nodular thickening of the left anterior renal fascia; bone destruction of the right pubic bone and sacroiliac bone accompanied by soft tissue mass formation. Multiple solid nodules in both lungs; multiple nodular foci in bilateral adrenal glands. Renal puncture biopsy was performed, and pathology showed: (left kidney tumor) clear cell renal cell carcinoma. The patient was enrolled in the CAIX tracer research clinical trial. The patient was injected with 4.83mCi of ^68Ga -NYM046 drug and underwent whole-body PET/CT tomography 1 hour later. After an interval of 6 days, patient 2 was injected with 9.8mCi of ^18F -FDG drug and underwent whole-body PET/CT tomography 1 hour later.

显像结果如附图55～58所示，可以看见在肿瘤及病变区⁶⁸Ga-NYM046有放射性高摄取，且界面清晰，相比较¹⁸F-FDG，⁶⁸Ga-NYM046对于肿瘤及其转移灶的摄取值更高，且⁶⁸Ga-NYM046有更高的肿瘤以及转移灶检出率，对于原发灶和转移灶的检出能力更高，可检出较小的转移灶，原发灶和转移灶处具有更高的肿瘤摄取，肿瘤摄取与其他非靶器官摄取比率更高，肿瘤处现显像更清晰。The imaging results are shown in Figures 55 to 58. It can be seen that ⁶⁸ Ga-NYM046 has high radioactive uptake in tumors and lesions, and the interface is clear. Compared with ¹⁸ F-FDG, ⁶⁸ Ga-NYM046 has a higher uptake value for tumors and their metastases, and ⁶⁸ Ga-NYM046 has a higher tumor and metastasis detection rate, a higher detection ability for primary lesions and metastases, and can detect smaller metastases. Primary lesions and metastases have higher tumor uptake, and the ratio of tumor uptake to other non-target organ uptake is higher, and the tumor is now imaged more clearly.

在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。 Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

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:

wherein Y ₁ and Y ₂ are independently selected from C _1-10 alkylene optionally substituted by R ₁ , C _1-10 alkyleneoxy optionally substituted by R ₁ , C _{1-10 alkylene-C(O)-NH-C 1-10} _alkylene optionally substituted by R ₁ , -C(O)-C 1-10 alkylene optionally substituted by R ₁ , -NH-C _1-10 alkylene optionally substituted by R ₁ , C _2-10 alkenylene optionally substituted by R ₁ , or _C _2-10 alkynylene optionally substituted by R ₁ ;

Y ₃ is selected from a bond or -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ , C _1-10 alkylene optionally substituted by R ₁ , -C(O)-NH-C _1-10 alkylene optionally substituted by R ₁ , -C(O)-C _1-10 alkyleneoxy optionally substituted by R ₁ ;

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 heterocyclyl, C _6-10 aryl or C _5-10 heteroaryl;

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

R ₁ is independently selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , Heterocyclic ring optionally substituted by _R2 , heteroaromatic ring optionally substituted by _R2 , _C1-4 alkyl, C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _C1-4 alkylamino, _C1-4 haloalkyl, _C1-4 haloalkoxy, _C1-4 hydroxyalkyl or _C1-4 haloalkylamino optionally substituted by _R2 ; wherein A is selected from an aromatic monocyclic or _bicyclic ring, and t is selected from an integer between 1 and 6;

R ₂ is selected from H, D, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _6-14 aryl or C _5-14 heteroaryl.

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.

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:

Y ₄ is selected from -NR ₂ -, -NR ₂ -(C=O)-, -NR ₂ -(C=S)-, (CH ₂ ) _p -(C=O)-NR ₂ -, -(C=O)-NR ₂ -, -(C=S)-NR ₂ - or a bond, and 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;

The compound according to any one of claims 1 to 3, characterized in that Y ₃ is selected from a bond or -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ ;

Optionally, the R ₁ is selected from

Optionally, the _Y3 is selected from

The compound according to any one of claims 1 to 3, characterized in that 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, 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

A compound, which is a compound represented by formula IV or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula IV:

wherein Y ₃ is selected from a bond or -NH-C(O)-C _1-10 alkylene optionally substituted by R ₁ , C _1-10 alkylene optionally substituted by R ₁ , -C(O)-NH-C _1-10 alkylene optionally substituted by R _1, -C(O)-C _1-10 alkyleneoxy optionally substituted by R ₁ ;

R ₁ is independently selected from H, D, F, Cl, Br, I, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , Heterocyclic ring optionally substituted by _R2 , heteroaromatic ring optionally substituted by _R2 , _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C1-4 alkoxy, C1-4 alkylamino, _C1-4 haloalkyl, _C1-4 haloalkoxy, _C1-4 hydroxyalkyl or _C1-4 _{haloalkylamino} optionally substituted by _R2 ; wherein A is selected from an aromatic monocyclic or _bicyclic ring, and t is selected from an integer between 1 and 6;

R ₂ is selected from H, D, =O, OH, NH ₂ , NO ₂ , CN, N ₃ , halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _6-14 aryl or C _5-14 membered heteroaryl;

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 membered heterocyclyl, C _6-10 aryl or C _5-10 membered heteroaryl;

Z ₁ is selected from

m is selected from an integer between 1 and 6.

The compound according to claim 6, characterized in that Y ₃ is selected from

Optionally, said X is selected from carboxyl or phenyl.

A compound whose structure is selected from the following:

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 complexed by ¹⁸ FAl;

Preferably, the M is selected from ⁶⁸ Ga, ¹⁸ F or ¹⁷⁷ Lu.

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.

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.

A method for imaging a tissue expressing carbonic anhydrase IX protein, comprising administering to the tissue 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,

and imaging the tissue after administration of the drug.

The method of claim 12, wherein the imaging is performed by positron emission tomography or single photon emission computed tomography.

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 drug for diagnosing and/or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX.

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.

The use according to claim 14, characterized in that the tumor expressing carbonic anhydrase IX 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.

A method for diagnosing and/or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX, comprising: administering to a subject 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.