Cyclic peptide compound and use thereof

Abstract

Provided are a cyclic peptide compound or a pharmaceutically acceptable salt thereof, and the use thereof. The cyclic peptide compound has the characteristics of simple preparation, good stability, high tumor uptake, long retention time or strong CXCR4 competitive binding ability, and is suitable for clinical development and application.

Description

A cyclic peptide compound and its application

[0001] This application claims priority to Chinese patent application 2025101191625, filed on January 24, 2025, and Chinese patent application 2026100575389, filed on January 15, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a cyclic peptide compound and its applications. Background Technology

[0003] Radiodiagnostic drugs are a class of drugs used in medical imaging. They contain radioactive isotopes and can be imaged using rays produced by radioactive decay (such as gamma rays). They are commonly used to diagnose various diseases, such as cancer, heart disease, and brain disorders. Radiodiagnostic drugs play an important role in the field of molecular imaging, especially in positron emission tomography (PET) and single-photon emission computed tomography (SPECT).

[0004] Currently, the most widely used PET diagnostic reagent internationally is [ 18 FDG (fluorodeoxyglucose) is primarily used for the diagnosis of tumors, heart disease, and brain disorders. However, despite [ 18 FDG is widely used as a radiotracer in PET imaging, but its low specificity for various diseases leads to high background signal in imaging diagnosis, increasing the risk of misdiagnosis and missed diagnosis. This is particularly pronounced in the diagnosis of certain tumors and inflammatory diseases. Therefore, developing novel radiotargeted drugs against specific biological targets is crucial for improving the accuracy of disease diagnosis and treatment monitoring.

[0005] Primary aldosteronism (PA) is an endocrine disorder characterized by hyperaldosteronism and hyporeninemia, and is one of the main causes of secondary hypertension. PA may be caused by adrenocortical adenoma (APA) or bilateral adrenal hyperplasia. Accurate diagnosis and localization are crucial for treatment options (such as surgery or drug therapy). Currently, the classification and diagnosis of primary aldosteronism mainly rely on adrenal imaging and adrenal vein sampling (AVS) to determine the location and function of the lesion. AVS is considered the "gold standard" for primary aldosteronism classification, which can determine whether there is unilateral dominant secretion, with a sensitivity of 95% and a specificity of 100% in identifying the dominant secretion side. However, AVS is an invasive examination, expensive, requires hospitalization, is difficult to perform, and carries risks of catheterization failure and postoperative complications, making it difficult to implement on a large scale in hospitals at all levels.

[0006] Hematologic malignancies (or blood system malignancies) refer to a class of cancers originating from the hematopoietic, immune, or lymphatic systems, mainly including leukemia, lymphoma, and multiple myeloma. Current diagnostic methods primarily include bone marrow aspiration, tissue biopsy, and imaging examinations. For diseases such as leukemia and multiple myeloma, bone marrow aspiration and biopsy can directly observe the morphology and proportion of cells in the bone marrow; imaging examinations such as CT and PET-CT can be used to assess the extent (staging) of the lesion and the effectiveness of treatment. Current treatment methods for hematologic malignancies mainly include chemotherapy, targeted therapy, immunotherapy, hematopoietic stem cell transplantation, and radiotherapy. The trend is shifting from single-method chemotherapy to a diversified approach encompassing targeted therapy, immunotherapy, and transplantation. The most significant problems with current treatment methods are toxic side effects and drug resistance / relapse. For example, chemotherapy is highly toxic, indiscriminately killing cells and damaging normal cells, and easily leads to multidrug resistance, resulting in treatment failure or relapse. Immunotherapy may trigger an excessive immune response, is not effective for everyone, and is ineffective or causes relapse in some patients; it is also extremely costly, complex to prepare, and expensive. Therefore, the future treatment of hematologic malignancies requires the development of more precise and efficient new targeted drugs, the exploration of combination therapy strategies to overcome drug resistance, the reduction of the toxicity of existing therapies, and ultimately the achievement of precision medicine.

[0007] Chemokine receptor CXCR4 (CXC chemokine receptor type 4) is a seven-transmembrane G protein-coupled receptor involved in various biological processes, including HIV infection, hematopoietic stem cell migration and homing, and tumor cell growth, metastasis, angiogenesis, and epithelial-mesenchymal transition. CXCR4 is elevated in various diseases, such as HIV infection, cancer, and inflammatory diseases. Therefore, CXCR4 holds significant potential as a diagnostic and therapeutic target.

[0008] Recent studies have revealed that CXCR4 has become a highly promising molecular target for the precision diagnosis and treatment of hematologic malignancies and some solid tumors. CXCR4 is abnormally expressed in various cancer types, including hematologic malignancies, thyroid cancer, breast cancer, and lung cancer, with a particularly prominent presence in hematologic malignancies. It is widely and highly expressed in various tumor types such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, and lymphoma. Its expression level is also closely related to tumor invasiveness, microenvironment dependence, drug resistance, and poor prognosis. Therefore, conjugating high-affinity CXCR4 targeting ligands with diagnostic or therapeutic radionuclides holds promise for achieving precise visual identification and efficient internal radiation killing of CXCR4-positive hematologic malignancies and some solid tumor lesions.

[0009] Meanwhile, CXCR4 is significantly overexpressed in functional aldosterone-producing tumors, but extremely underexpressed in normal adrenal cortex or non-functional adenomas. This differential expression pattern makes CXCR4 an ideal target for PA-specific imaging.

[0010] Several CXCR4-targeted therapies are already on the market, including Mozobil (Plerixafor) and APHEXDA (motixafortide), both indicated for use in conjunction with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells from patients with non-Hodgkin's lymphoma and multiple myeloma into the peripheral blood for collection and subsequent autologous transplantation. Another small molecule drug, Mavorixafor (Xolremdi), was also approved by the FDA in April 2024 for the treatment of WHIM syndrome. In addition, there has been some progress in the research of CXCR4-targeted radiodiagnostic drugs. Currently, there has been some progress in the international research of radiodiagnostic drugs targeting CXCR4. For example, [68Ga]Ga-Pentixafor, a CXCR4-targeted PET imaging agent, has shown superior imaging capabilities compared to [18F]FDG in several clinical studies. [68Ga]Ga-Pentixafor has shown promising imaging potential, particularly in differentiating between different subtypes of primary aldosteronism (PA). Furthermore, several radiolabeled CXCR4 antagonists are under development, such as […]. 64 Cu]Cu-AMD3100, etc.

[0011] To date, no radiodiagnostic drugs targeting CXCR4 have been approved for marketing, either domestically or internationally. Domestic clinical trials are primarily based on Pentixafor, and no novel CXCR4 radiodiagnostic drugs with independent intellectual property rights have entered clinical research. Therefore, the development of radiodiagnostic drugs targeting CXCR4 in China still holds enormous potential and market space.

[0012] Currently, the development of novel F-18 and Ga-68-labeled radiodiagnostic drugs targeting CXCR4 and Lu-177-labeled radiotherapeutic drugs targeting CXCR4 has attracted widespread attention. However, CXCR4 target binding generally suffers from weak target binding activity and low biological tissue distribution. Therefore, further optimization of their CXCR4 target binding activity and improvement of their biological tissue distribution are needed to enhance imaging quality. Based on the advantages of fluorine-18 over gallium-68, this drug may be easier to use for the diagnosis of primary aldosteronism than [68Ga]Ga-Pentixafor, and can cover more hospital terminals. In addition, in the application scenarios of hematologic malignancies and tumors, existing radiopharmaceutical diagnostic / therapeutic technologies still face problems such as insufficient ligand stability, low tumor uptake efficiency, and high non-specific accumulation in normal tissues (especially the spleen and liver), which limit their diagnostic sensitivity and therapeutic safety. Due to the potential pharmaceutical applications of the CXCR4 target, there is a need to develop novel, highly selective CXCR4 cyclic peptide ligands, and to modify the cyclic peptides to obtain favorable pharmacological properties, such as good in vivo metabolic stability and PK / PD properties, to meet the diagnostic and therapeutic needs of various disease scenarios, including hematologic malignancies and pulmonary arthritis (PA). Developing radiotherapeutic drugs targeting the CXCR4 receptor is an effective therapeutic strategy. Summary of the Invention

[0013] The purpose of this invention is to solve the problems existing in the current technical field, such as low affinity of compounds for CXCR4, short residence time at the target site, or low uptake at the lesion site. This invention provides a cyclic polypeptide compound and its application. The cyclic polypeptide compound has one or more advantages such as simple preparation, good stability, high tumor uptake, long retention and strong competitive binding ability to CXCR4, and is suitable for clinical development and application.

[0014] The present invention provides a cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof;

[0015] Ring [X] 1a -Tyr-Lys(iPr)-DArg-2Nal-X 6a -X 7a ]-L 1a -L 2a -D; (SEQ ID NO:1)

[0016] (I)

[0017] in,

[0018] a) The ring of the cyclic peptide compound of formula (I) is passed through X 1a α-amino and X 7a The side chain carboxyl groups are linked by amide bonds; or

[0019] b) The ring of the cyclic peptide compound of formula (I) is passed through X 1a The side chain amino and X 7a The side chain carboxyl groups are linked together by amide bonds;

[0020] X 1a For example, DAsn, DGLN, Asn, Asp, DAsp, (Ac)Dap, (NH2CO)Dap, or DAla;

[0021] X 6a For Gly or DAla;

[0022] X 7a For DGlu or DAsp;

[0023] L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2);

[0024] L 2a For the connector key, Cya, Asp, or Gly;

[0025] D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide;

[0026] Ring [X] 1b -X 2b -Lys(iPr)-DArg-2Nal-X 6b -DCys]-L 1b -L 2b -D; (SEQ ID NO:2)

[0027] (II)

[0028] in,

[0029] The ring of the cyclic peptide compound of formula (II) is circulated through X 1b The side chain thiol groups of and DCys are linked by disulfide bonds;

[0030] X 1b It is (NH2CO)Cys, (NH2CO)DCys, (hexanoyl)Cys, or (Ac)Cys;

[0031] X 2b It is Tyr or Tyr(PO3H2);

[0032] X 6b For Gly or DAla;

[0033] L 1bThe NH2, OH, Dab(NH2), Dab(OH), Orn(NH2), EDA, Cya, or Lys(Me)OH are used.

[0034] L 2b For connection key, Cya, Asp, Gly, or EDA;

[0035] D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide;

[0036] Ring [(DL) 1c -L 2c )X 1c -Tyr-Lys(iPr)-DArg-2Nal-X 6c -DCys]-L 3c -L 4c (SEQ ID NO:3)

[0037] (III)

[0038] in,

[0039] The ring of the cyclic peptide compound of formula (III) is circumferentially X-linked. 1c The side chain thiol groups of and DCys are linked by disulfide bonds;

[0040] X 1c is DCys, Cys, (hexanoyl)Cys or (Ac)Cys;

[0041] X 6c For Gly or DAla;

[0042] L 1c For the connector key, Cya, (Phospho)Ser, or Asp;

[0043] L 2c It can be SAA, Gly, PEG2 or PEG;

[0044] L 3c For the connection key, Lys(iPr) or Cya;

[0045] L 4c It can be NH2 or OH;

[0046] D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide;

[0047] Ring [(D-Cya-Gly)X 1d -Tyr-Lys(iPr)-DArg-2Nal-X 6d -X 7d]-L 1d -NH2;(SEQ ID NO:4)

[0048] (IV)

[0049] in,

[0050] The ring of the cyclic peptide compound of formula (IV) is circumferentially X-linked. 1d The side chain amino and X 7d The side chain carboxyl groups are linked together by amide bonds;

[0051] X 1d For DAsp, DDap, or Dap;

[0052] X 6d For Gly or DAla;

[0053] X 7d For DDap or DAsp;

[0054] L 1d For connection keys or Lys(iPr);

[0055] D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide.

[0056] In one particular scheme, D is a metal chelating group.

[0057] In one scheme, D is a combination of a metal chelating group and a radioactive nuclide.

[0058] In one embodiment, the metal chelating group may be NOA, DOTA, TETA, PCTA, DTPA, HBED-CC, NODAGA, DOTAGA, TRAP, NOPO, DFO, DTPA, HEBD-CC, or H4-OCTOPA, preferably NOA or DOTA.

[0059] In one embodiment, the radionuclide is a therapeutic radionuclide or a diagnostic radionuclide; the therapeutic radionuclide is preferably a radionuclide capable of emitting alpha, beta, or gamma rays, and more preferably a radionuclide capable of emitting alpha or beta rays.

[0060] In one embodiment, the radionuclide is an element of Ga, Lu, F, Cu, Zr, Y, Sc, Sr, Ra, Sm, Ac, Bi, or Pb, preferably Ga, Lu, or F.

[0061] In one particular scheme, the radionuclide is 68 Ga、 177 Lu、 18 F, Al 18 F,64 Cu、 89 Zr、 90 Y、 44 Sc、 99 Sr、 223 Ra、 153 Sm、 225 Ac、 213 Bior 212 Pb, preferably 68 Ga、 177 Lu、 18 F or Al 18 F.

[0062] In one particular scheme, the 177 Lu can be a carrier 177 Lu or non-carrier 177 Lu.

[0063] In one embodiment, the radionuclide exists in ionic form, with the ion having a monovalent, divalent, trivalent, or tetravalent valence.

[0064] In one embodiment, the ion of the radionuclide is... 68 Ga 3+ , 177 Lu 3+ Al 18 F 2+ , 64 Cu 2+ , 89 Zr、 90 Y 3+ , 44 Sc 3+ , 99 Sr 2+ , 223 Ra 2+ , 213 Bi 3+ , 153 Sm 3+ , 225 Ac 3+ or 212 Pb 2+ Preferred 68 Ga 3+ , 177 Lu 3+ Or Al 18 F 2+ .

[0065] In one embodiment, D is a combination of a metal chelating group and a radionuclide, wherein the combination of the metal chelating group and the radionuclide is any of the following combinations:

[0066] (1) 68Ga combined with Nota or Dota;

[0067] (2) 177 Lu can be combined with Nota or Dota;

[0068] (3)Al 18 F is a combination with Nota or Dota.

[0069] In one embodiment, in the cyclic peptide compound of formula (I), when the ring of the cyclic peptide compound of formula (I) passes through X... 1a α-amino and X 7a When the side chain carboxyl groups are linked by amide bonds, X 1a and X 7a The following groups are included: DAsn / DGlu, DGLN / DGlu, Asn / DGlu, Asp / DGlu, DAsp / DGlu, DAla / DAsp, or DAla / DGlu.

[0070] In one embodiment, in the cyclic peptide compound of formula (I), when the ring of the cyclic peptide compound of formula (I) passes through X... 1a The side chain amino and X 7a When the side chain carboxyl groups are linked by amide bonds, X 1a and X 7a It belongs to the following group: (Ac)Dap / DAsp or (NH2CO)Dap / DAsp, preferably (NH2CO)Dap / DAsp.

[0071] In one embodiment, in the cyclic peptide compound of formula (IV), X... 1d and X 7d The following groups are allowed: DDap / DAsp, DAsp / DDap, or Dap / DAsp.

[0072] In one embodiment, in the cyclic peptide compound of formula (I), X 1a With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6a X 6a With X 7a They are linked by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively.

[0073] In one embodiment, in the cyclic peptide compound of formula (I), X 7a With L 1a Through X 7a α-carboxyl group and L 1a The α-amino group forms an amide bond.

[0074] In one embodiment, in the cyclic peptide compound of formula (I), when L2a When not a connection key, L 1a With L 2a Through L 1a The side chain amino and L 2a The α-carboxyl groups are linked together by amide bonds.

[0075] In one embodiment, in the cyclic peptide compound of formula (I), when L 2a When not a connection key, D and L 2a Through the carboxyl group of D and L 2a The α-amino group forms an amide bond.

[0076] In one embodiment, in the cyclic peptide compound of formula (II), X 1b With X 2b X 2b Lys(iPr), Lys(iPr) and DArg, DArg and 2Nal, 2Nal and X 6b X 6b DCys and DCys are connected by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively.

[0077] In one embodiment, in the cyclic peptide compound of formula (II), DCys and L 1b Through the α-carboxyl group and L of DCys 1b The α-amino group forms an amide bond.

[0078] In one embodiment, in the cyclic peptide compound of formula (II), when L 2b When not a connection key, L 1b With L 2b Through L 1b The side chain amino and L 2b The α-carboxyl groups are linked together by amide bonds.

[0079] In one embodiment, in the cyclic peptide compound of formula (II), when L 2b When not a connection key, D and L 2b Through the carboxyl group of D and L 2b The α-amino group forms an amide bond.

[0080] In one embodiment, in the cyclic peptide compound of formula (III), X 1c With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6c X 6c DCys and DCys are connected by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively.

[0081] In one embodiment, in the cyclic peptide compound of formula (III), X 1c With L2c Through X 1c α-carboxyl group and L 2c The amino groups are linked together by amide bonds.

[0082] In one embodiment, in the cyclic peptide compound of formula (III), when L 1c When not a connection key, L 2c With L 1c Through L 2c amino and L 1c The carboxyl groups are linked together by amide bonds.

[0083] In one embodiment, in the cyclic peptide compound of formula (III), when L 1c When not a connection key, D and L 1c Through the carboxyl group of D and L 1c The amino groups are linked together by amide bonds.

[0084] In one embodiment, in the cyclic peptide compound of formula (III), when L 3c When not a linker, DCys is linked by the α-carboxyl group and the L- group. 3c The α-amino group in the mixture forms an amide bond.

[0085] In one embodiment, in the cyclic peptide compound of formula (III), when L 3c When not a connection key, L 3c Through α-carboxyl group and L 4c Connected.

[0086] In one embodiment, in the cyclic peptide compound of formula (IV), Cya is combined with Gly, and Gly is combined with X. 1d X 1d With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6d X 6d With X 7d They are linked by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively.

[0087] In one embodiment, X in the cyclic peptide compound of formula (IV) 7d Through α-carboxyl group and L 1d Connected.

[0088] In one embodiment, in the cyclic peptide compound of formula (IV), when L 1d When not a connection key, L 1d They are linked by an α-carboxyl group and NH2.

[0089] In one embodiment, the cyclic peptide compound of formula (I) wherein the ring of the cyclic peptide compound of formula (I) is connected by X 1a α-amino and X7a The side chain carboxyl groups are linked together by amide bonds;

[0090] X 1a For DAsn, DGLN, Asn, Asp, DAsp, or DAla;

[0091] X 6a For Gly or DAla;

[0092] X 7a For DGlu or DAsp;

[0093] L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2);

[0094] L 2a For the connector key, Cya, Asp, or Gly;

[0095] The definition of D is as described above.

[0096] In one embodiment, the cyclic peptide compound of formula (I) wherein the ring of the cyclic peptide compound of formula (I) is connected by X 1a α-amino and X 7a The side chain carboxyl groups are linked together by amide bonds;

[0097] X 1a It can be DAsn or Asn;

[0098] X 6a For Gly;

[0099] X 7a For DGlu;

[0100] L 1a It is Lys(NH2) or Lys(OH);

[0101] L 2a For connection key;

[0102] The definition of D is as described above.

[0103] In one embodiment, the cyclic peptide compound of formula (I) wherein the ring of the cyclic peptide compound of formula (I) is connected by X 1a The side chain amino and X 7a The side chain carboxyl groups are linked together by amide bonds;

[0104] X 1a It can be (Ac)Dap or (NH2CO)Dap;

[0105] X 6a For Gly or DAla;

[0106] X7a For DGlu or DAsp;

[0107] L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2);

[0108] L 2a For the connector key, Cya, Asp, or Gly;

[0109] The definition of D is as described above.

[0110] In one embodiment, the cyclic peptide compound of formula (II),

[0111] The ring of the cyclic peptide compound of formula (II) is circulated through X 1b The side chain thiol groups of and DCys are linked by disulfide bonds;

[0112] X 1b It is (NH2CO)Cys;

[0113] X 2b For Tyr;

[0114] X 6b For Gly;

[0115] L 1b It can be Lys(NH2) or Dab(NH2);

[0116] L 2b For connection key or Cya;

[0117] The definition of D is as described above.

[0118] In one embodiment, in the cyclic peptide compound of formula (IV), the ring of the cyclic peptide compound of formula (I) is connected by X. 1a The side chain amino and X 7a The side chain carboxyl groups are linked together by amide bonds;

[0119] X 1a (NH2CO)Dap;

[0120] X 6a For Gly;

[0121] X 7a For DAsp;

[0122] L 1a Lys(NH2);

[0123] L 2a For Cya or Asp;

[0124] The definition of D is as described above.

[0125] In one embodiment, the cyclic peptide compound of formula (II) is as shown in formula (II-A).

[0126] in,

[0127] L 1b It can be Lys(NH2) or Dab(NH2);

[0128] L 2b For connection key or Cya;

[0129] The definition of D is as described above;

[0130] Preferably, D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide; wherein the metal chelating group is NOA or DOTA; and the radionuclide is... 68 Ga、 177 Lu、 18 F or Al 18 F.

[0131] In one embodiment, the cyclic peptide compound of formula (I) is as shown in formula (IA).

[0132] in,

[0133] L 1a It is Lys(NH2) or Lys(OH);

[0134] The carbon atom marked with * indicates that it is either S or R chiral;

[0135] The definition of D is as described above;

[0136] Preferably, D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide; wherein the metal chelating group is NOA or DOTA; and the radionuclide is... 68 Ga、 177 Lu、 18 F or Al 18 F.

[0137] The present invention also provides a cyclic peptide compound or a pharmaceutically acceptable salt thereof, said cyclic peptide compound being any one of the compounds in Tables 1, 2, 3, 4, 6, 7 and 8.

[0138] The present invention also provides a pharmaceutical composition comprising (therapeuticly effective amount) a cyclic peptide compound of formula (I), (II), (III) or (IV) above, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0139] The present invention also provides the use of the above-described cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, the above-described cyclic peptide compound or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition in the preparation of a medicament; wherein the medicament is preferably a medicament for treating or diagnosing CXCR4 receptor-related or mediated diseases.

[0140] In one embodiment, the CXCR4 receptor-related or mediated disease is preferably a tumor.

[0141] The present invention also provides the use of the above-described cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, the above-described cyclic peptide compound or a pharmaceutically acceptable salt thereof, or the above-described pharmaceutical composition in the preparation of a medicament for imaging.

[0142] In one embodiment, the imaging is imaging of tissues expressing CXCR4, preferably tumor tissues expressing CXCR4.

[0143] In one particular scheme, the imaging is tumor imaging.

[0144] In one embodiment, the tumor may be a tumor expressing CXCR4, preferably a hematologic malignancy expressing CXCR4.

[0145] In one scenario, the tumor could be lymphoma, multiple myeloma, or leukemia.

[0146] The present invention provides a cyclic peptide of formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof;

[0147] Ring [X] 1e -Tyr-Lys(iPr)-DArg-2Nal-X 6e -X 7e ]-L 1e -L 2e (SEQ ID NO:5)

[0148] (V)

[0149] X 1e is DAsn, DGLN, Asn, Asp, DAsp, (Ac)Dap, (NH2CO)Dap, DAla, DDap or Dap;

[0150] X 6e For Gly or DAla;

[0151] X 7e For DDap or DAsp;

[0152] L 1eIf it does not exist or Lys(iPr);

[0153] L 2e It is either absent or NH2;

[0154] Ring [X] 1f -X 2f -Lys(iPr)-DArg-2Nal-X 6f -DCys]-L 1f (SEQ ID NO:6)

[0155] (VI)

[0156] X 1f is DCys, Cys, (hexanoyl)Cys, (Ac)Cys, (NH2CO)Cys or (NH2CO)DCys;

[0157] X 2f It is Tyr or Tyr(PO3H2);

[0158] X 6f For Gly or DAla;

[0159] L 1f It is absent, NH2 or OH.

[0160] In one embodiment, the cyclic peptide of formula (V) or formula (VI) is an intermediate of a cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV).

[0161] In one embodiment, the cyclic peptide of formula (V) or formula (VI) is any of the following cyclic peptides:

[0162] Explanation of structural abbreviations:

[0163] Natural amino acids and their D-type amino acid abbreviations:

[0164] Abbreviations for non-natural amino acids:

[0165] Abbreviation for metal chelating groups:

[0166] The term "metal chelating group" refers to a chelating agent that can complex with at least one radionuclide. Examples include NOA, DOTA, TETA, PCTA, DTPA, HBED-CC, NODAGA, DOTAGA, TRAP, NOPO, DFO, DTPA, HEBD-CC, or H4-OCTOPA.

[0167] In the terms "side-chain amino" or "side-chain carboxyl", "side chain" refers to the group other than the amino or carboxyl group that is attached to the α-carbon atom in an amino acid. "Side-chain amino" or "side-chain carboxyl" refers to the amino or carboxyl group on the side chain of an amino acid.

[0168] In the cyclic peptide "ring []" of this invention, the amino acid or amino acid residue within the brackets [] is located within the cyclic structure; the groups outside the brackets [] are located outside the ring. In the cyclic peptide, the connection between the amino acid at position 1 and the amino acid at position 7 mainly takes the following three forms:

[0169] Linkage Method 1: An amide bond is formed between the α-amino group of the amino acid at position 1 and the carboxyl group of the side chain of the amino acid at position 7. For example, in the cyclic peptide compounds of formula (I), cases a) compounds 25, 29, 35, 73-76, 79-81, 83-86, 124-125, 132-133, 144-151, 162-163, 174-206, 223-224 and 233-238.

[0170] Linkage method 2: An amide bond is formed between the side chain amino group of the amino acid at position 1 and the side chain carboxyl group of the amino acid at position 7; for example: cases b) in cyclic peptide compounds of formula (I), cyclic peptide compounds of formula (IV), 65, 94, 96-99, 126-127, 130-131, 134-135, 142-143, 156-161, 166, 168-169 and 225-232.

[0171] Linkage method three: A disulfide bond is formed between the side chain thiol group of the amino acid at position 1 and the side chain thiol group of the amino acid at position 7; for example: cyclic peptide compounds of formula (II), cyclic peptide compounds of formula (III), 28, 40-48, 68, 70-72, 77-78, 87-93, 95, 100-107, 112-123, 128-129, 136-141, 152-155, 164-165, 167, 170-171, 207-222 and 239.

[0172] Connection method four: An amide bond is formed between the carboxyl group on the side chain of the amino acid at position 1 and the amino group on the side chain of the amino acid at position 7. For example, compound 64.

[0173] Unless otherwise specified, amino acids at other sites are linked by amide bonds formed by α-amino and α-carboxyl groups.

[0174] In the compounds of this invention, when there is a conflict between the sequence and the structural formula, the structural formula shall prevail.

[0175] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.

[0176] The term "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the manufacture and dispensing of pharmaceutical products. These are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0177] The term "therapeutic effective dose" refers to the amount of compound or radiation dose administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective doses will vary depending on the compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0178] The term "patient" refers to any animal that has received or is about to receive treatment, preferably a mammal, and most preferably a human. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0179] The term “treatment” refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that triggers the disease; or (3) slowing the development of one or more biological manifestations of a disease.

[0180] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0181] The reagents and raw materials used in this invention are all commercially available.

[0182] The positive and progressive effects of this invention are that the cyclic peptide compounds of this invention have one or more of the following advantages:

[0183] (1) The cyclic peptide compounds of the present invention have strong competitive binding ability to CXCR4;

[0184] (2) High tumor uptake and long retention. Attached Figure Description

[0185] Figure 1 shows the example 10. 68 The distribution of Ga-labeled compounds in mouse tumors and tissues over time;

[0186] Figure 2 shows the example 11. 68 Biodistribution of Ga-labeled compounds in mouse tumors and tissues over time;

[0187] Figure 3 shows the example 12. 68 PET-CT images of Ga-labeled compounds in a tumor-bearing mouse model;

[0188] Figure 4 shows the example 14. 177 Pharmacological effects of Lu-labeled EV-2-179 in Daudi tumor-bearing mouse model;

[0189] Figure 5 shows the example 15. 177 Pharmacological effects of Lu-labeled EV-2-223 in Daudi tumor-bearing mouse model;

[0190] Figure 6 shows the example 16. 177 The pharmacological effects of Lu-labeled compounds in the DMS273 tumor-bearing mouse model. Detailed Implementation

[0191] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0192] Example 1: Compound Synthesis and Preparation

[0193] General compound synthesis and preparation method 1:

[0194] Taking compound EV-2-064 as an example: it is prepared by solid-phase synthesis through the following steps:

[0195] The compound Cyc[(NOTA-Cya-Gly)DAsp-Tyr-Lys(iPr)-DArg-2Nal-Gly-DDap]-NH2 (SEQ ID NO:9) was synthesized using the following steps.

[0196] Step 1: Synthesis

[0197] After swelling and deprotection of the MBHA resin, the amino resin (loading: 0.35 mmol / g, 2 g) was swollen in the reaction column with DMF for ten minutes, followed by three washes with DMF to complete the resin swelling. The Fmoc protecting agent on the amino resin needed to be removed to expose the amino groups. The peptide sequence was then elongated through condensation and coupling with the first protected amino acid, followed by repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 minutes and 20 minutes, respectively. The resin was then washed six times with DMF solution for two minutes each time.

[0198] After Fmoc deprotection, Fmoc-DDap(Dde)-OH (0.3 mmol) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling for 1 h. AcOH (0.5 ml) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the Fmoc-DDap(Dde)-MBHA resin was determined by measuring the content of Fmoc in the deprotected solution at 301 nm absorbance (blank: DMF with 2% DBU added). The degree of substitution was 0.15 mmol / g. The completion of Fmoc-DDap(Dde)-OH coupling was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvent were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time.

[0199] After removing Fmoc, Fmoc-Gly-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-DAsp(Oall)-OH were coupled separately, and the completion of amino acid coupling was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that the coupling was complete. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After the final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum.

[0200] Step 2: Deallylating

[0201] The dried resin was transferred to an in-situ flask, and tetraphenylphosphine (1.5 eq.) and barbituric acid (10 eq.) were added using ultra-dry anhydrous DCM (1 g resin / 15 mL) as solvent. The reaction was carried out under N2 protection for 3 h. After the reaction was completed, the resin was transferred into a reaction column, and Pd(pph3)4 was washed off. A*3, B*3, C*3.

[0202] A: 5% copper reagent (2.5g / 400mL DMF) * 3, 15min each time.

[0203] B: 5% (2mL DIPEA / 400mL DMF) * 3

[0204] C: 5% (5.4g HoBt / 400mL DMF)*3

[0205] Step 3: Cycling of peptide resin

[0206] The peptide resin (3g) was dissolved in 2 volumes of DMF. PyBop (1.5 eq) and DIPEA (2 eq) were added to the reaction column, and the reaction was carried out under N2 bubbling for 1 h. The reaction progress was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that cyclization was complete.

[0207] De-de was removed using 5% hydrazine hydrate DMF solution for 5 min x 3. After Dde removal, Fmoc-Gly-OH, Fmoc-Cya-OH, and NOA were coupled separately, and the coupling completion was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. Then, it was washed twice with DCM solution for two minutes each time and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0208] Step 4: Peptide cleavage

[0209] Freshly prepared lysis buffer (30 mL) (TFA:TIS:H₂O = 90:2.5:2.5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0210] Step 5: Peptide Preparation

[0211] The crude peptides were purified by high performance liquid chromatography.

[0212] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0213] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0214] Flow Rate: 1.0 mL / min

[0215] Gradient:5% B for 3min,5-65% B within 20min.

[0216] The purity of the sample was 95.26% and the yield was 1.7%, determined by high performance liquid chromatography (HPLC) to be 2.5 mg by weight.

[0217] (ESI)m / z=480.0[M+3H] / 3 + 719.4[M+2H] / 2 + .

[0218] General compound synthesis and preparation method 2:

[0219] Taking compound EV-2-048 as an example: it is prepared by solid-phase synthesis through the following steps:

[0220] Compound Cyc[(NOTA-(Phospho)Ser-Gly)DCys-Tyr-Lys(iPr)-DArg-2Nal-Gly-DCys]-NH2 (SEQ ID NO: 10)

[0221] The synthesis was performed using the following steps.

[0222] Synthesis of linear peptides

[0223] Manual synthesis of EV-2-048 linear peptide

[0224] Step 1: Synthesis

[0225] After swelling and deprotection of the MBHA resin, the amino resin (loading: 0.35 mmol / g, 2 g) was swollen in the reaction column with DMF for ten minutes, followed by three washes with DMF to complete the resin swelling. The Fmoc protecting agent on the amino resin needed to be removed to expose the amino groups. The peptide sequence was then elongated through condensation and coupling with the first protected amino acid, followed by repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 minutes and 20 minutes, respectively. The resin was then washed six times with DMF solution for two minutes each time.

[0226] After Fmoc deprotection, Fmoc-DCys(Trt)-OH (0.3 mmol) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling for 1 h. AcOH (0.5 ml) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the Fmoc-DCys(Trt)-MBHA resin was determined by measuring the content of Fmoc in the deprotected solution at 301 nm absorbance (blank: DMF with 2% DBU added). The resin substitution degree was 0.15 mmol / g. The completion of Fmoc-DCys(Trt)-OH coupling was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvent were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time.

[0227] After removing Fmoc, Fmoc-Gly-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-DCys(Trt)-OH, Fmoc-Gly-OH, Fmoc-Ser(HPO3Bzl)-OH, and NOA were coupled separately, and the completion of amino acid coupling was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that the coupling was complete. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After the final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum.

[0228] Step 2: Peptide cleavage

[0229] Freshly prepared lysis buffer (30 mL) (TFA:TIS:H₂O = 90:2.5:2.5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0230] Step 3: Peptide cyclization

[0231] The crude peptide was dissolved in acetonitrile and water (1:3) (1 mg / mL), and the pH was adjusted to 9 with ammonia to oxidize the crude peptide. The reaction was carried out for 10 hours. The reaction results were monitored using LCMS.

[0232] Step 4: Peptide Preparation

[0233] The crude peptides were purified by high performance liquid chromatography.

[0234] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0235] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0236] Flow Rate: 1.0 mL / min

[0237] Gradient:5% B for 3min,5-65% B within 20min.

[0238] The purity of the substance was 92.25% and the yield was 1.49%, determined by high performance liquid chromatography. The weight was 1.93 mg.

[0239] (ESI)m / z=492.4[M+3H] / 3 + 737.9[M+2H] / 2 + .

[0240] General compound synthesis and preparation method 3:

[0241] Taking compound EV-2-104 as an example: it is prepared by solid-state synthesis through the following steps:

[0242] The compound Cyc[(Ac)Cys-Tyr-Lys(iPr)-DArg-2Nal-Gly-DCys]-Lys(OH)-NOTA (SEQ ID NO:11) was synthesized using the following steps.

[0243] Synthesis of linear peptides

[0244] Manual synthesis of linear peptide of EV-2-104

[0245] Preloading of the first amino acid onto dichlororesin: Synthesis began with the loading of the first protected amino acid onto dichlororesin. Dichlororesin (loading: 1.49 mmol / g, 1 g) was swelled in a reaction column with DCM for 30 minutes, followed by washing three times with DCM. Fmoc-Lys(Dde)-OH (0.3 mmol) and DIPEA (6 eq.) were dissolved in 10 mL of DCM and added to the dichlororesin. The reaction was carried out at room temperature for 3 hours under nitrogen protection. Methanol (2 mL) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the Fmoc-Lys(Dde)-CTC resin was determined by measuring the content of Fmoc in the removal solution at 301 nm absorbance (blank: DMF with 2% DBU added). The degree of substitution was 0.19 mmol / g.

[0246] Step 1: Linear peptide synthesis

[0247] After Fmoc deprotection, the peptide sequence was elongated through repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 min and 20 min, respectively. The resin was then washed six times with DMF solution for 2 min each time. Fmoc-DCys(Trt)-OH (2 eq.) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling conditions. The completion of Fmoc-DCys(Trt)-OH coupling was monitored using Kaiser assays. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried, and the resin was washed six times with DMF solution for 2 min each time.

[0248] After removing Fmoc, Fmoc-Gly-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr)-OH, Fmoc-Tyr(PO3HBzl)-OH, and Ac-Cys(Trt)-OH were coupled, respectively. After removing Dde, Nota was coupled. The completion of amino acid coupling was monitored by Kaiser assay; a negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum.

[0249] Step 2: Peptide cleavage

[0250] Freshly prepared lysis buffer (30 mL) (TFA:TIS:H₂O = 90:2.5:2.5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0251] Step 3: Peptide cyclization

[0252] The crude peptide was dissolved in acetonitrile and water (1:3) (1 mg / mL), and the pH was adjusted to 9 with ammonia to oxidize the crude peptide. The reaction was carried out for 10 hours. The reaction results were monitored using LCMS.

[0253] Step 4: Peptide Preparation

[0254] The crude peptides were purified by high performance liquid chromatography.

[0255] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0256] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0257] Flow Rate: 1.0 mL / min

[0258] Gradient:5% B for 3min,5-65% B within 20min.

[0259] The purity of the sample was determined by high performance liquid chromatography to be 94.44% (22.59 mg) and the yield was 29.34%.

[0260] (ESI)m / z=474.8[M+3H] / 3 + 711.5[M+2H] / 2 + 1421.4[M+H] + .

[0261] General compound synthesis and preparation method 4:

[0262] Taking compound EV-2-179 as an example: it is prepared by solid-state synthesis through the following steps:

[0263] The compound Cyc[DAsn-Tyr-Lys(iPr)-DArg-2Nal-Gly-DGlu]-Lys(OH)-DOTA (SEQ ID NO:12) was synthesized using the following steps.

[0264] Synthesis of linear peptides

[0265] Manual synthesis of EV-2-179 linear peptide

[0266] Preloading of the first amino acid onto dichlororesin: Synthesis began with the loading of the first protected amino acid onto dichlororesin. Dichlororesin (loading: 1.49 mmol / g, 1 g) was swelled in a reaction column with DCM for 30 minutes, followed by washing three times with DCM. Fmoc-Lys(Dde)-OH (0.3 mmol) and DIPEA (6 eq.) were dissolved in 10 mL of DCM and added to the dichlororesin. The reaction was carried out at room temperature for 3 hours under nitrogen protection. Methanol (2 mL) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the Fmoc-Lys(Dde)-CTC resin was determined by measuring the content of Fmoc in the removal solution at 301 nm absorbance (blank: DMF with 2% DBU added). The degree of substitution was 0.19 mmol / g.

[0267] Step 1: Linear peptide synthesis

[0268] After Fmoc deprotection, the peptide sequence was elongated through repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 min and 20 min, respectively. The resin was then washed six times with DMF solution for 2 min each time. Fmoc-DGlu(OAll)-OH (2 eq.) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling conditions. The completion of Fmoc-DGlu(OAll)-OH coupling was monitored using Kaiser assays. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried, and the resin was washed six times with DMF solution for 2 min each time.

[0269] After removing Fmoc, Fmoc-Gly-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-DAsn-OH were coupled separately. The completion of amino acid coupling was monitored by Kaiser assay; a negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0270] Step 2: Deallylating

[0271] After cyclization of the peptide resin, it was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum. The dried resin was transferred to an in-situ flask, and tetrakis(triphenylphosphine) (1.5 eq.) and barbituric acid (10 eq.) were added as solvent in ultra-dry anhydrous DCM (1 g resin / 15 mL). The reaction was carried out under N2 protection for 3 h. After the reaction was complete, the resin was transferred into a reaction column, and Pd(pph3)4 was washed off. A*3, B*3, C*3 were then added.

[0272] A: 5% copper reagent (2.5g / 400mL DMF) * 3, 15min each time.

[0273] B: 5% (2mL DIPEA / 400mL DMF) * 3

[0274] C: 5% (5.4g HoBt / 400mL DMF)*3

[0275] Step 3: Cycling of peptide resin

[0276] The peptide resin (3g) was dissolved in 2 volumes of DMF. PyBop (1.5 eq) and DIPEA (2 eq) were added to the reaction column, and the reaction was carried out under N2 bubbling for 1 h. The reaction progress was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that cyclization was complete.

[0277] De-de was removed using 5% hydrazine hydrate DMF solution for 5 min x 3. After D-de removal, the resin was coupled with DOTA. The coupling completion was monitored using a Kaiser assay; a negative result (no blue residue in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. Then, it was washed twice with DCM solution for two minutes each time and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0278] Step 4: Peptide cleavage

[0279] Freshly prepared lysis buffer (30 mL) (TFA:TIS:H₂O = 90:2.5:2.5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0280] Step 5: Peptide Preparation

[0281] The crude peptides were purified by high performance liquid chromatography.

[0282] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0283] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm Flow Rate:1.0mL / min

[0284] Gradient:5% B for 3min,5-65% B within 20min.

[0285] The purity of the sample was 90.92% and the yield was 4.52%, as determined by high performance liquid chromatography (HPLC). The sample weighed 3.0 mg.

[0286] (ESI)m / z=501.4[M+3H] / 3 + 751.5[M+2H] / 2 + 1501.5 [M+H] + .

[0287] The following compounds were synthesized using the general synthesis and preparation method 1 described above, as shown in Table 1.

[0288] Table 1

[0289] The following compounds were synthesized using the general synthesis and preparation method 2 described above, as shown in Table 2.

[0290] Table 2

[0291] The following compounds were synthesized using the general synthesis and preparation method described above, as shown in Table 3.

[0292] Table 3

[0293] The following compounds were synthesized using the general synthesis and preparation method described above, as shown in Table 4.

[0294] Table 4

[0295] Synthesis of Example 1

[0296] Pentixafor corresponds to EV-2-001

[0297] polypeptide sequence:

[0298] Cyc{(D-Tyr)-[D-(NMe)Orn(AMBS-DOTA)]-Arg-(2-Nal)-Gly}(SEQ ID NO:97)

[0299] polypeptide structure:

[0300] Synthesis of linear peptides

[0301] Manual synthesis of EV-2-001 linear peptide

[0302] Step 1: Synthesis

[0303] Dichlororesin: Synthesis began with loading the first protected amino acid onto the dichlororesin. The dichlororesin (loading: 1.49 mmol / g, 1 g) was swelled in a reaction column with DCM for 30 minutes, followed by washing three times with DCM. The first protected amino acid (0.3 mmol) and DIPEA (6 eq.) were dissolved in 10 mL of DCM and added to the dichlororesin. The reaction was carried out at room temperature for 3 hours under nitrogen protection. Methanol (2 mL) was then added to the reaction column for blocking. After 30 minutes, the reaction mixture was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the first protected amino acid in the resin was determined by measuring its content in the Fmoc removal solution at 301 nm absorbance (blank: DMF with 2% DBU added). The resin substitution degree was 0.19 mmol / g.

[0304] After removing the Fmoc, the protecting amino acids in the sequence were sequentially coupled one by one, and the completion of amino acid coupling was monitored using a Kaiser assay. A negative result (no blue residue in the solution or on the resin beads) indicated that coupling was complete. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After the final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum.

[0305] Step 2: Complete Protective Fracturing

[0306] Transfer the dried resin to a round-bottom flask and add 30 mL of fully protective cutting fluid HFIP / DCM = 3:7. The pyrolysis reaction was carried out at room temperature under nitrogen protection for 1 hour. The resin was then filtered and washed twice with a small volume of fully protective cutting fluid. The solution was dried under reduced pressure and then lyophilized for later use.

[0307] Step 3: Peptide cyclization

[0308] The crude peptide was dissolved in DMF (3 mg / mL), and PyBop (1.5 eq) and DIPEA (2 eq) were added to the reaction column. The reaction was carried out under N2 bubbling for 1 h. The reaction progress was monitored by LCMS until cyclization was complete. The DMF was dried under nitrogen to obtain the crude peptide.

[0309] Step 4: Peptide cleavage

[0310] Freshly prepared refrigerated lysis buffer (30 mL) (TFA:TIS:H2O = 90:5:5) was added to the crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0311] Step 5: Peptide preparation and fragment condensation

[0312] The crude peptide was purified by high-performance liquid chromatography (HPLC) to obtain a cyclized polypeptide intermediate. AMBS (1 eq) and 10 mL DMF were added, followed by HATU (1.1 eq) and DIEA (2.5 eq). The reaction was carried out at room temperature for 1 hour. The reaction progress was monitored by LCMS. After the reaction, the crude peptide was deprotected using the lysis method described above. The crude peptide was then purified by HPLC, lyophilized, dissolved in DMF, and then DOTA-OSu (1 eq) and DIEA (1.5 eq) were added. The reaction was carried out at room temperature for 1 hour, and the reaction progress was monitored by LCMS.

[0313] The crude peptides were purified by high performance liquid chromatography.

[0314] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0315] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm Flow Rate:1.0mL / min

[0316] Gradient:5% B for 3min,5-65% B within 20min.

[0317] The purity of 10 mg was determined by high performance liquid chromatography to be 97.27%, with a yield of 2.73%.

[0318] (ESI)m / z=1221.3[M+H]+,611.4[M+2H] / 2+,408.0[M+3H] / 3+

[0319] Synthesis of Example 2

[0320] BL034 corresponds to EV-2-029

[0321] polypeptide sequence:

[0322] Cyc[Lys(Cya-DOTA)-Tyr-Lys(iPr)-DArg-2Nal-DAla-DGlu]-Lys(iPr)-NH2(SEQ ID NO:98)

[0323] polypeptide structure:

[0324] Synthesis of linear peptides

[0325] Manual synthesis of EV-2-029 linear peptide

[0326] Step 1: Synthesis

[0327] After swelling and deprotection of the MBHA resin, the amino resin (loading: 0.35 mmol / g, 2 g) was swollen in the reaction column with DMF for ten minutes, followed by three washes with DMF to complete the resin swelling. The Fmoc protecting agent on the amino resin needed to be removed to expose the amino groups. The peptide sequence was then elongated through condensation and coupling with the first protected amino acid, followed by repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 minutes and 20 minutes, respectively. The resin was then washed six times with DMF solution for two minutes each time.

[0328] After Fmoc deprotection, Fmoc-Lys(iPr)-OH (0.3 mmol) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling for 1 h. AcOH (0.5 ml) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed six times with DMF. The resin was dried under vacuum. The degree of substitution of the Fmoc-Lys(iPr)-MBHA resin was determined by measuring the content of Fmoc in the deprotected solution at 301 nm absorbance (blank: DMF with 2% DBU added). The degree of substitution was 0.15 mmol / g. The completion of Fmoc-Lys(iPr)-OH coupling was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvent were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time.

[0329] After removing Fmoc, Fmoc-DGlu(OAll)-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-Lys(Dde)-OH were coupled separately, and the completion of amino acid coupling was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that the coupling was complete. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After the final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum.

[0330] Step 2: Deallylating

[0331] After cyclization of the peptide resin, it was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. Then, the peptide resin was dried under vacuum. The dried resin was transferred to an in-situ flask, and tetrakis(triphenylphosphine) (1.5 eq.) and barbituric acid (10 eq.) were added as solvent in ultra-dry anhydrous DCM (1 g resin / 15 mL). The reaction was carried out under N2 protection for 3 h. After the reaction was complete, the resin was transferred into a reaction column, and Pd(pph3)4 was washed off. A*3, B*3, C*3 were then added.

[0332] A: 5% copper reagent (2.5g / 400mL DMF) * 3, 15min each time.

[0333] B: 5% (2mL DIPEA / 400mL DMF) * 3

[0334] C: 5% (5.4g HoBt / 400mL DMF)*3

[0335] Step 3: Cycling of peptide resin

[0336] The peptide resin (3g) was dissolved in 2 volumes of DMF. PyBop (1.5 eq) and DIPEA (2 eq) were added to the reaction column, and the reaction was carried out under N2 bubbling for 1 h. The reaction progress was monitored by Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated that cyclization was complete.

[0337] De-de was removed using 5% hydrazine hydrate DMF solution for 5 min x 3. After Dde removal, Fmoc-Cya-OH and DOTA were coupled separately, and the coupling completion was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. Then, it was washed twice with DCM solution for two minutes each time and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0338] Step 4: Peptide cleavage

[0339] Freshly prepared lysis buffer (30 mL) (TFA:TIS:H₂O = 90:2.5:2.5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0340] Step 5: Peptide Preparation

[0341] The crude peptides were purified by high performance liquid chromatography.

[0342] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0343] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm Flow Rate:1.0mL / min

[0344] Gradient:5% B for 3min,5-65% B within 20min.

[0345] The purity of the sample was determined by high performance liquid chromatography to be 97.27% (22.35 mg) and the yield was 12.9%.

[0346] (ESI)m / z=861.6[M+2H] / 2+,574.8[M+3H] / 3+

[0347] Synthesis of Example 3

[0348] LY2510924 corresponds to EV-2-005

[0349] polypeptide sequence:

[0350] Cyc[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]-Lys(iPr)-NH2 (SEQ ID NO:99)

[0351] polypeptide structure:

[0352] Synthesis of linear peptides

[0353] Manual synthesis of EV-2-005 linear peptide

[0354] Step 1: Synthesis

[0355] After swelling and deprotection of the MBHA resin, the amino resin (loading: 0.35 mmol / g, 2 g) was swollen in the reaction column with DMF for ten minutes, followed by three washes with DMF to complete the resin swelling. The Fmoc protecting agent on the amino resin needed to be removed to expose the amino groups. The peptide sequence was then elongated through condensation and coupling with the first protected amino acid, followed by repeated cycles of coupling and Fmoc deprotection until the desired linear peptide was obtained. Fmoc deprotection was performed using 20% ​​piperidine (DMF) solution for 5 minutes and 20 minutes, respectively. The resin was then washed six times with DMF solution for two minutes each time.

[0356] After Fmoc deprotection, Fmoc-Lys(ipr,Boc)-OH (0.3 mmol) and HBTU (2 eq.) were dissolved in DMF, and DIPEA (6 eq.) was added for activation. This solution was then added to the aforementioned peptide resin, and the reaction was carried out under N2 bubbling for 1 h. AcOH (0.5 ml) was then added to the reaction mixture for blocking. After 30 minutes, the reaction solution was dried under vacuum, and the resin was washed 6 times with DMF. The resin was then dried under vacuum. The degree of substitution of the Fmoc-Lys(ipr,Boc)-MBHA resin was determined by measuring the content of Fmoc in the deprotected solution at 301 nm absorbance (blank: DMF with 2% DBU added). The degree of substitution was 0.15 mmol / g. The completion of Fmoc-Lys(ipr,Boc)-OH coupling was monitored using Kaiser assay. A negative result (no blue color in the solution or on the resin beads) indicated successful coupling. Drain the reaction reagents and solvents, and wash the resin six times with DMF solution for two minutes each time.

[0357] After removing Fmoc, Fmoc-DGlu(oall)-OH, Fmoc-Gly-OH, Fmoc-2Nal-OH, Fmoc-DArg(Pbf)-OH, Fmoc-Lys(iPr,Boc)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc-Phe-OH were coupled separately. The completion of amino acid coupling was monitored by Kaiser assay; a negative result (no blue color in the solution or on the resin beads) indicated successful coupling. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. After final Fmoc deprotection, the resin was washed twice with DMF solution for two minutes each time, twice with DCM solution for two minutes each time, and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0358] Step 2: Deallylating

[0359] The dried resin was transferred to a round-bottom flask, and tetrakis(triphenylphosphine) (1.5 eq.) and barbituric acid (10 eq.) were added using ultra-dry anhydrous DCM (1 g resin / 15 mL) as solvent. The reaction was carried out under N2 protection for 3 h. After the reaction was completed, the resin was transferred into a reaction column, and Pd(pph3)4 was washed off. A*3, B*3, C*3.

[0360] A: 5% copper reagent (2.5g / 400mL DMF) * 3, 15min each time.

[0361] B: 5% (2mL DIPEA / 400mL DMF) * 3

[0362] C: 5% (5.4g HoBt / 400mL DMF)*3

[0363] Step 3: Cycling of peptide resin

[0364] The peptide resin (3g) was dissolved in 2 volumes of DMF. PyBop (1.5 eq) and DIPEA (2 eq) were added to the reaction column, and the reaction was carried out under N2 bubbling for 1 hour. The reaction progress was monitored by Kaiser assay; a negative result (no blue color in the solution or on the resin beads) indicated that cyclization was complete. The reaction reagents and solvents were dried under vacuum, and the resin was washed six times with DMF solution for two minutes each time. Then, it was washed twice with DCM solution for two minutes each time and twice with MeOH solution for two minutes each time. The peptide resin was then dried under vacuum.

[0365] Step 4: Peptide cleavage

[0366] Freshly prepared refrigerated lysis buffer (30 mL) (TFA:TIS:H2O = 90:5:5) was added to the dried crude peptide. The lysis reaction was carried out at room temperature under nitrogen protection for 2.5 hours. The resin was then filtered and washed twice with a small volume of TFA. More than ten times the volume of cold methyl tert-butyl ether was added to the TFA solution, and the mixture was thoroughly shaken. The mixture was centrifuged, and the crude peptide was washed twice with methyl tert-butyl ether, centrifuged each time, and then dried under reduced pressure.

[0367] Step 5: Peptide Preparation

[0368] The crude peptides were purified by high performance liquid chromatography.

[0369] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0370] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm Flow Rate:1.0mL / min

[0371] Gradient:5% B for 3min,5-65% B within 20min.

[0372] The purity of the sample was determined by high performance liquid chromatography to be 95.90% (30 mg by weight), with a yield of 8.42%.

[0373] (ESI)m / z=1190.4[M+H]+,595.4[M+2H] / 2+,397.5[M+3H] / 3+

[0374] Analytical methods

[0375] Mobile Phase:A:0.05% TFA in water

[0376] B: 0.05% TFA in ACN

[0377] Gradient: 5% B for 3 minutes.

[0378] 5-65% B within 20 minutes

[0379] Flow Rate: 1.0 mL / min

[0380] Column Temperature: 40℃

[0381] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0382] The HPLC elution times and mass spectra of the above precursor compounds are shown in Table 5.

[0383] Table 5

[0384] Example 2: Compound [ nat F]AlF cold label: Taking EV-2-194 as an example

[0385] polypeptide complex

[0386] 15 mg of EV-2-193 peptide was added to 7000 μL of AlCl3 solution (10 mM, 0.1 M sodium acetate), followed by 300 μL of NaF (10 mg / mL, 0.1 M sodium acetate). The reaction mixture was stirred for 5 min. 7000 μL of anhydrous ethanol was then added to the reaction solution. The reaction was carried out for 90 min at 70 °C. Results were controlled by LC-MS. The crude peptide was purified by high performance liquid chromatography.

[0387] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0388] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0389] Flow Rate: 1.0 mL / min

[0390] Gradient:5% B for 3min,5-65% B within 20min.

[0391] The purity of the sample was determined to be 92.14% by high performance liquid chromatography (HPLC), with a weight of 8.93 mg and a yield of 59.53%.

[0392] (ESI)m / z=532.4[M+3H] / 3 + 798.0[M+2H] / 2 + 1593.8 [M+H] +

[0393] Using the above [natF] The HPLC peak times and mass spectra of compounds obtained by the cold standard synthesis of AlF are shown in Table 6.

[0394] Table 6

[0395] Example 3: Compound nat Ga's cold label: Taking EV-2-035 as an example

[0396] Polypeptide complex Ga

[0397] At the start of the reaction, 7000 μL of aqueous solution (10 mM, 0.1 M sodium acetate, 10 equivalents) was added to the polypeptide (25 mg), and the reaction mixture was stirred for 5 minutes. Then, 3 equivalents of GaCl3 were added to the mixture. The reaction was carried out at 90 °C for 60 minutes. The crude peptide was purified by high performance liquid chromatography.

[0398] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0399] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm Flow Rate:1.0mL / min

[0400] Gradient:5% B for 3min,5-65% B within 20min.

[0401] The purity of the sample was determined to be 97.40% by high performance liquid chromatography (HPLC), with a weight of 12.12 mg and a yield of 6.8%.

[0402] (ESI)m / z=895.2[M+2H] / 2+,597.0[M+3H] / 3+

[0403] Using the above nat The HPLC peak times and mass spectra of compounds obtained by the cold standard synthesis of Ga are shown in Table 7.

[0404] Table 7

[0405] Example 4: Compound nat Lu's cold label: Taking EV-2-239 as an example

[0406] polypeptide complex nat Lu

[0407] 15 mg of the peptide derived from EV-2-170 was added to 3000 μL of sodium acetate aqueous solution (0.1 M sodium acetate), followed by the addition of LuCl3 (3 eq). The reaction mixture was stirred for 5 min. The reaction was carried out for 60 min at 90 °C. Results were controlled by LC-MS. The crude peptide was purified by high performance liquid chromatography.

[0408] Mobile Phase:A:0.05% TFA in Water,B:0.05% TFA in ACN

[0409] Column:XBridge Peptide BEH C18,4.6*150mm,3.5μm

[0410] Flow Rate: 1.0 mL / min

[0411] Gradient:5% B for 3min,5-65% B within 20min.

[0412] The purity of the sample was determined by high performance liquid chromatography to be 95.56% (8 mg by weight) and the yield was 53.33%.

[0413] (ESI)m / z = 606.8[M+3H] / 3 + 909.3[M+2H] / 2 +

[0414] Using the above nat The HPLC peak times and mass spectra of the compounds obtained by the cold standard synthesis method of Lu are shown in Table 8.

[0415] Table 8

[0416] Example 5: Competitive Binding Experiment of Compound CXCR4

[0417] Detection of compounds using I radioligand binding CXCR4 / CHO-K1 cell filtration assay

[0418] (1) Pre-treat MultiScreen with 100 μL of fixation buffer (10% BSA HEPES solution) at 25°C. HTS BV filter plate, filter and clean once after 60 minutes, store at 4℃ for later use;

[0419] (2) Add 70 μL of logarithmic growth phase CXCR4 / CHO-K1 cell suspension to a 96-well plate, with a cell density of 1*10⁻⁶ cells. 5 Cell per well;

[0420] (3) Add 20 μL 125A mixture of I-SDF-1α and SDF-1a was prepared, ensuring a final SDF-1a concentration of 0.26 nM. 125 The final concentration of I-SDF-1α was 0.04 nM, and the final concentration of DMSO was 0.5%.

[0421] (4) Add 10 μL of different concentrations of the compound (initial concentration 2 μM, dilution factor 3 times, a total of 9 concentrations) or AMID3100 diluent to make the final concentration of DMSO 0.5% and the final concentration of BSA 0.2%.

[0422] (5) Mix and incubate the experimental plate at 25℃ and 300rpm for 180min;

[0423] (6) Transfer all liquids to MultiScreen HTS In the BV filter plate, filter and wash 4 times, dry at room temperature for 40 min, and add 120 μL of scintillation solution;

[0424] (7) Use the MicroBeta counter instrument in TopCount mode to read the board using the 125I program and calculate the IC. 50， in, 125 The results of the competitive binding experiments between I-SDF-1α and the compound in CXCR4 are shown in Table 9.

[0425] Table 9 125 The IC50 of the compound was determined by a competitive binding assay between I-SDF-1α and the compound in CXCR4. 50 (nM)

[0426] Example 6: Compound 18 F's heat label

[0427] (1) Dissolve and dilute with 0.5M pH4.0 sodium acetate buffer solution to prepare 3mg / mL.

[0428] (2) Elute 18F through an OMA column and take the part with the highest activity.

[0429] (3) Take a 1.5 mL centrifuge tube as a reaction vessel and add 18F ion solution, 0.1 mL buffer solution, 6 μL 10 mM AlCl3, 0.3 mL acetonitrile and 30 μL precursor solution at one time.

[0430] (4) Reaction temperature 100℃, reaction time 15min, 800rpm.

[0431] (5) After the reaction is completed, the reaction solution is purified by C18 column and the final product is obtained by radiochemical purity identification (radiochemical purity >95%).

[0432] Example 7: Compound 68 Ga's hotspot

[0433] (1) Dissolve and dilute the solution in 0.25M pH4.5 metal-free sodium acetate buffer solution to prepare a solution of 0.1mg / mL.

[0434] (2) Rinse the germanium-gallium generator in stages with 5 mL of 0.1 M HCl and take the part with the highest activity.

[0435] (3) Take a 1.5 mL centrifuge tube as the reaction vessel, calculate the amount of precursor to be added based on the activity, and add 0.3 mL of buffer solution and 0.2 mL of precursor respectively. 68 0.5 mL of Ga ions.

[0436] (4) Reaction temperature 100℃, reaction time 10min, 800rpm.

[0437] (5) After the reaction is completed, the reaction solution is purified by C18 column and the final product is obtained by radiochemical purity identification (radiochemical purity >95%).

[0438] Example 8: Compound 177 Lu's hot label

[0439] (1) Label according to specific activity (1000 mCi / μmol): Take 177 LuCl3 was prepared by adjusting the pH to 4 with 1M sodium acetate and adding the corresponding precursor compound.

[0440] (2) Set the heating mixer to (95°C) for 30 minutes, preheating the mixer to the specified temperature 20 minutes in advance. The final formulation should be a clear solution, prepared and used immediately, and is only for use on the same day.

[0441] Example 9: Mouse model for in vivo biodistribution studies

[0442] (1) Collect Daudi cells in the logarithmic growth phase and resuspend them in serum-free medium;

[0443] (2) Mix the cell suspension with Matrigel gel at a ratio of 1:1 (v / v);

[0444] (3) Using 6-8 week old male Balb / c Nude mice, at a ratio of 5*10 6 Cells / mouse density were subcutaneously inoculated into the right upper limb axilla of mice;

[0445] (4) After 3 weeks of tumor growth, the tumor volume will be approximately 300-600 mm. 3 It is used for in vivo biological distribution studies.

[0446] Example 10:18 Biodistribution of F-labeled compounds in tumor-bearing mice

[0447] Using Daudi tumor-bearing mice, Al was administered via tail vein injection. 18 F radiolabeled compounds (e.g., Al) 18 Radiolabeled EV-2-177, EV-2-046, EV-2-065, EV-2-098, or EV-2-070 were administered to each animal at a volume of 200 μL, with a radioactivity of approximately 200 μCi per animal. Following administration, tumor-bearing mice underwent dynamic Micro-PET / CT scans for 1 hour and static scans for 2 hours. After the scans, the dynamic distribution of the radioactive material in various tissues throughout the body was analyzed. Pmod software was used to delineate sites of interest (such as tumors, kidneys, liver, stomach, heart, lungs, brain, bone marrow (thigh bone), and spleen (spleen only required qualitative analysis, not precise quantification)). The percentage dose rate per unit volume of tissue in each organ was calculated based on the administered dose (%ID / cc).

[0448] Al 18 F radiolabeled compounds (e.g., Al) 18 Two hours after administration of radiolabeled EV-2-177 and EV-2-046, the animals were immediately dissected. After isoflurane anesthesia, blood was collected by enucleation and placed in test tubes. The blood samples were weighed and gamma counts were performed. The mice were then euthanized, and the following tissues and samples were immediately dissected: brain, heart, whole liver, spleen, whole kidney, both kidneys, stomach (without contents), small intestine (without contents), large intestine (without contents), thigh muscles, bones, joints, gonads (testes), tumors, and blood. After weighing, gamma counts were immediately performed. The radioactive uptake %ID / g of each tissue was calculated using the formula: Radioactive uptake %ID / g = Tissue radioactivity count (CPM) / Total systemic radioactivity count (CPM) * 100 / Tissue weight (g).

[0449] Figure 1 shows the tissue uptake values ​​over time in the PET / CT imaging study. Table 10 shows the ex vivo tissue distribution data 2 hours after drug administration. All labeled compounds showed good targeting in tumors. Within 0-120 minutes after drug administration, the uptake values ​​of radioactivity in tumor tissues rose rapidly and then tended to stabilize or slightly decrease. In other tissues such as the kidneys, liver, and heart, the radioactivity concentrations gradually decreased.

[0450] Table 10 Al 18 F-EV-2-177, Al 18 Tissue distribution of F-EV-2-046 2 hours after a single intravenous injection in the Daudi-CDX model

[0451] (Unit: %ID / g)(n=3)

[0452] Example 11: 68 Biodistribution of Ga-labeled compounds in tumor-bearing mice

[0453] Using Daudi tumor-bearing mice, the drug was administered via tail vein injection. 68 Ga radiolabeled compounds (e.g.) 68 Ga-labeled EV-2-001, EV-2-029, EV-2-065, EV-2-124, EV-2-168, EV-2-170, EV-2-175, EV-2-179, or EV-2-223 were administered at a dose of 150-200 μCi / mouse, with two mice per compound. Immediately after administration, PET / CT scans were performed for 1 hour of dynamic scanning and 2 hours of static scanning to examine the dynamic distribution of the radioactive material in various tissues throughout the body, including tumors, kidneys, liver, stomach, heart, lungs, brain, bone marrow (thigh bone), and spleen. PET-CT results showed... 68 After being injected via the tail vein into tumor-bearing mice, Ga-labeled compounds were rapidly distributed to various tissues and organs, including the tumor, and were quickly metabolized by the kidneys. Compared to the reference compound, several radiolabeled compounds showed high enrichment in the tumor and exhibited longer retention times. The results are shown in Figure 2 and Table 11.

[0454] Table 11 68 Tissue quantification results of Daudi-CDX model mice 1 hour after a single intravenous injection of Ga-labeled compounds via PET / CT imaging.

[0455] (Unit: %ID / g)(n=2)

[0456] Example 12: 68 Receptor-specific binding of Ga-labeled compounds in tumors

[0457] (1) Using Daudi (CXCR4 high expression) tumor-bearing mouse model and HCT116 (CXCR4 low expression) tumor-bearing mouse model;

[0458] (2) Daudi (CXCR4 high expression) tumor-bearing mouse models were divided into a baseline imaging group and a blocking imaging group. The baseline imaging group was given... 68 Ga-labeled radioactive compounds were administered at a dose of 150-200 μCi per animal. Appropriate precursors (e.g., EV-2-170 or EV-2-179) were used as the blocker. 68 Ga-labeled radioactive compounds ( 68Ga-EV-2-170 or 68 After mixing, Ga-EV-2-179 was administered via tail vein injection. The dosage of the block drug was 7.5 μg / animal, and the dosage of the radioactive compound was 150-200 μCi / animal.

[0459] (3) HCT116 (CXCR4 low expression) tumor-bearing mouse model was given 68 Ga-labeled radioactive compounds were administered at a dose of 150-200 μCi per animal.

[0460] (4) PET / CT examines the dynamic distribution of radioactive substances in various tissues throughout the body within 1 hour. The key areas of interest include tumors, kidneys, liver, stomach, heart, lungs, brain, bone marrow (thigh bone), and spleen.

[0461] (5) Immediately after completing the 1-hour PET / CT scan, dissect the animals and collect tissues (brain, heart, whole liver, spleen, whole lung, both kidneys, stomach (without contents), small intestine (without contents), large intestine (without contents), thigh muscles, bones, joints, gonads (testes or ovaries), tumors, and blood) from each animal. After weighing, perform gamma counting and calculate the %ID / g distribution of each tissue at 1 hour.

[0462] 68 Figure 3 shows PET-CT images of Ga-labeled molecules in a tumor-bearing mouse model. Compared with a tumor-bearing mouse model with low receptor expression of HCT116, 68 Ga-labeled compounds showed significant tumor uptake in a mouse model of Daudi receptor-overexpressing tumors, and this uptake could be blocked by high doses of the precursor, demonstrating... 68 The uptake of Ga-labeled compounds in tumors is associated with receptor-specific binding.

[0463] Example 13: 177 Biodistribution of Lu-labeled compounds in tumor-bearing mice

[0464] Daudi tumor-bearing mouse model, via tail vein injection 177 Lu-labeled radioactive compounds were administered at a dose of 15 MBq per animal. Animals were dissected 72 hours after administration, and tissues were collected from each animal, including brain, heart, whole liver, gallbladder, spleen, whole lung, both kidneys, stomach (excluding contents), small intestine (excluding contents), large intestine (excluding contents), muscle, femur (excluding bone marrow), joints, gonads (testes or ovaries), tumors, blood, salivary glands, adrenal glands, thyroid gland, bone marrow, and tail. After weighing, gamma counts were performed, and the %ID / g distribution of each tissue at different time points in each group was calculated. 177 The distribution of Lu-labeled compounds in tumor-bearing mice after 72 hours is shown in Table 12 below:

[0465] Table 12177 Distribution of Lu-labeled compound in various tissues of Daudi-CDX model mice 72 hours after a single intravenous injection.

[0466] (Unit: %ID / g)(n=3).

[0467] Example 14: 177 Pharmacological effects of Lu-labeled EV-2-179 in Daudi tumor-bearing mouse model

[0468] The Daudi tumor-bearing mouse model showed an average tumor volume of 150 mm². 3 Animals were randomly divided into two groups based on tumor volume. The Control group was given a single injection of saline via the tail vein. 177 Lu-EV-2-179 40MBq 177 Lu-EV-2-179 20Mbq, continue to observe after administration. Monitor body weight and tumor volume twice a day during the first week of administration, and weigh body weight and tumor volume 2-3 times a week thereafter.

[0469] The experimental results are shown in Figure 4. 177 Lu-labeled EV-2-179 showed significant inhibitory effects on tumor growth with single intravenous injections of 20 MBq and 40 MBq, and could completely inhibit tumor growth.

[0470] Example 15: 177 Pharmacological effects of Lu-labeled EV-2-223 in Daudi tumor-bearing mouse model

[0471] The Daudi tumor-bearing mouse model showed an average tumor volume of 150 mm². 3 Animals were randomly divided into two groups based on tumor volume. The Control group was given a single injection of saline via the tail vein. 177 Lu-pentixather 540μCi, 177 Lu-EV-2-223 540μCi, 177 Lu-EV-2-223 270μCi 177 Lu-EV-2-223 135μCi. Continue to observe after administration. Monitor body weight and tumor volume twice a day during the first week of administration, and then weigh body weight and tumor volume 2-3 times a week thereafter.

[0472] The experimental results are shown in Figure 5 below. 177 A single intravenous injection of Lu-labeled EV-2-223 significantly inhibited tumor growth; a high dose of 540 μCi completely suppressed tumor growth, and it showed superior inhibitory effects compared to the reference compound.

[0473] Example 16: 177 Pharmacological effects of Lu-labeled compounds in DMS273 tumor-bearing mouse model

[0474] Collect DMS273 cells in the logarithmic growth phase, resuspend them in serum-free medium, and mix the cell suspension with Matrigel gel at a 1:1 (v / v) ratio. Then, spray with 5 x 10⁻⁶ cells / ml. 6 Cells / mouse density were subcutaneously inoculated into the right upper limb axilla of 6-8 week old male Balb / c Nude mice. After 3 weeks of tumor growth, the tumor volume was approximately 100-200 mm². 3 Animals were randomly assigned to groups and administered a single injection via the tail vein. 177 Lu-labeled radioactive compounds (e.g.) 177 Lu-labeled EV-2-223 was administered and continued to be monitored. During the first week of administration, body weight and tumor volume were monitored twice a day, and thereafter body weight and tumor volume were measured 2-3 times a week.

[0475] The experimental results are shown in Figure 6 below: Compared with the reference compound, the synthesized labeled compound showed better tumor growth inhibition at the same dose.

Claims

1. A cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof; Ring [X] 1a -Tyr-Lys(iPr)-DArg-2Nal-X 6a -X 7a ]-L 1a -L 2a -D; (SEQ ID NO:1), (I)， in, a) The ring of the cyclic peptide compound of formula (I) is passed through X 1a α-amino and X 7a The side chain carboxyl groups are linked by amide bonds; or b) The ring of the cyclic peptide compound of formula (I) is passed through X 1a The side chain amino and X 7a The side chain carboxyl groups are linked by amide bonds; X 1a For example, DAsn, DGLN, Asn, Asp, DAsp, (Ac)Dap, (NH2CO)Dap, or DAla; X 6a For Gly or DAla; X 7a For DGlu or DAsp; L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2); L 2a For the connector key, Cya, Asp, or Gly; D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide; Ring [X 1b -X 2b -Lys(iPr)-DArg-2Nal-X 6b -DCys]-L 1b -L 2b -D; (SEQ ID NO:2) (II), in, The ring of the cyclic peptide compound of formula (II) is circulated through X 1b The side chain thiol groups of and DCys are linked by disulfide bonds; X 1b It is (NH2CO)Cys, (NH2CO)DCys, (hexanoyl)Cys, or (Ac)Cys; X 2b It is Tyr or Tyr(PO3H2); X 6b For Gly or DAla; L 1b The NH2, OH, Dab(NH2), Dab(OH), Orn(NH2), EDA, Cya, or Lys(Me)OH are used. L 2b For connection key, Cya, Asp, Gly, or EDA; D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide; Cyclo[(D-L 1c -L 2c )X 1c -Tyr-Lys(iPr)-DArg-2Nal-X 6c -DCys]-L 3c -L 4c ;(SEQ ID NO:3), (III), in, The ring of the cyclic peptide compound of formula (III) is circumferentially X-linked. 1c The side chain thiol groups of and DCys are linked by disulfide bonds; X 1c is DCys, Cys, (hexanoyl)Cys or (Ac)Cys; X 6c For Gly or DAla; L 1c For the connector key, Cya, (Phospho)Ser, or Asp; L 2c It can be SAA, Gly, PEG2 or PEG; L 3c For the connection key, Lys(iPr) or Cya; L 4c It can be NH2 or OH; D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radioactive nuclide; Cyclo[(D-Cya-Gly)X 1d -Tyr-Lys(iPr)-DArg-2Nal-X 6d -X 7d -L 1d -NH2; (SEQ ID NO:4), (IV), in, The ring of the cyclic peptide compound of formula (IV) is circumferentially X-linked. 1d The side chain amino and X 7d The side chain carboxyl groups are linked together by amide bonds; X 1d For DAsp, DDap, or Dap; X 6d For Gly or DAla; X 7d For DDap or DAsp; L 1d For connection keys or Lys(iPr); D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide.

2. The cyclic peptide compound of formula (I), (II), (III), or (IV) as claimed in claim 1, characterized in that, The cyclic peptide compounds of formula (I), (II), (III) or (IV) satisfy one or more of the following conditions: (1) D is a metal chelating group; (2) D is a combination of a metal chelating group and a radioactive nuclide; (3) The metal chelating group is NOTA, DOTA, TETA, PCTA, DTPA, HBED-CC, NODAGA, DOTAGA, TRAP, NOPO, DFO, DTPA, HEBD-CC or H4-OCTOPA, preferably NOTA or DOTA; (4) The radionuclide is a therapeutic radionuclide or a diagnostic radionuclide; the therapeutic radionuclide is preferably a radionuclide capable of emitting α-rays, β-rays or γ-rays, and more preferably a radionuclide capable of emitting α-rays or β-rays. (5) The radionuclide is of the element Ga, Lu, F, Cu, Zr, Y, Sc, Sr, Ra, Sm, Ac, Bi or Pb, preferably Ga, Lu or F; (6) The radioactive nuclide is 68 Ga、 177 Lu、 18 F, Al 18 F, 64 Cu、 89 Zr、 90 Y、 44 Sc、 99 Sr、 223 Ra、 153 Sm、 225 Ac、 213 Bior 212 Pb, preferably 68 Ga、 177 Lu、 18 F or Al 18 F; The 177 Lu is preferred as a carrier. 177 Lu or non-carrier 177 Lu; (7) The radionuclides exist in ionic form, and the valence state of the ions is monovalent, divalent, trivalent or tetravalent; The ions of the radionuclides mentioned in (8) are 68 Ga 3+ , 177 Lu 3+ Al 18 F 2+ , 64 Cu 2+ , 89 Zr、 90 Y 3+ , 44 Sc 3+ , 99 Sr 2+ , 223 Ra 2+ , 213 Bi 3+ , 153 Sm 3+ , 225 Ac 3+ or 212 Pb 2+ Preferred 68 Ga 3+ , 177 Lu 3+ Or Al 18 F 2+ .

3. The cyclic peptide compound of formula (I), (II), (III), or (IV) as claimed in claim 1, characterized in that, D is a combination of a metal chelating group and a radioactive nuclide, wherein the combination of the metal chelating group and the radioactive nuclide is any of the following combinations: (1) 68 Ga combined with Nota or Dota; (2) 177 Lu combined with Nota or Dota; (3)Al 18 F is a combination with Nota or Dota.

4. The cyclic peptide compound of formula (I), (II), (III), or (IV) as claimed in claim 1, characterized in that, The cyclic peptide compounds of formula (I), (II), (III) or (IV) satisfy one or more of the following conditions: (1) In the cyclic peptide compound of formula (I), when the ring of the cyclic peptide compound of formula (I) passes through X 1a α-amino and X 7a When the side chain carboxyl groups are linked by amide bonds, X 1a and X 7a For the following groups: DAsn / DGlu, DGLN / DGlu, Asn / DGlu, Asp / DGlu, DAsp / DGlu, DAla / DAsp, or DAla / Dglu; (2) In the cyclic peptide compound of formula (I), when the ring of the cyclic peptide compound of formula (I) passes through X 1a The side chain amino and X 7a When the side chain carboxyl groups are linked by amide bonds, X 1a and X 7a It belongs to the following group: (Ac)Dap / DAsp or (NH2CO)Dap / DAsp, preferably (NH2CO)Dap / DAsp; In the cyclic peptide compound of formula (IV) described in (3), X 1d and X 7d The following groups are allowed: DDap / DAsp, DAsp / DDap, or Dap / DAsp.

5. The cyclic peptide compound of formula (I), (II), (III), or (IV) as claimed in claim 1, characterized in that, The cyclic peptide compounds of formula (I), (II), (III) or (IV) satisfy one or more of the following conditions: (1) In the cyclic peptide compound of formula (I), X 1a With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6a X 6a With X 7a They are linked by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively; (2) In the cyclic peptide compound of formula (I), X 7a With L 1a Through X 7a α-carboxyl group and L 1a The α-amino group forms an amide bond; (3) In the cyclic peptide compound of formula (I), when L 2a When not a connection key, L 1a With L 2a Through L 1a The side chain amino and L 2a The α-carboxyl groups are linked together by amide bonds; (4) In the cyclic peptide compound of formula (I), when L 2a When not a connection key, D and L 2a Through the carboxyl group of D and L 2a The α-amino group forms an amide bond; (5) In the cyclic peptide compound of formula (II), X 1b With X 2b X 2b Lys(iPr), Lys(iPr) and DArg, DArg and 2Nal, 2Nal and X 6b X 6b DCys and DCys are connected by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively. (6) In the cyclic peptide compound of formula (II), DCys and L 1b Through the α-carboxyl group and L of DCys 1b The α-amino group forms an amide bond; (7) In the cyclic peptide compound of formula (II), when L 2b When not a connection key, L 1b With L 2b Through L 1b The side chain amino and L 2b The α-carboxyl groups are linked together by amide bonds; (8) In the cyclic peptide compound of formula (II), when L 2b When not a connection key, D and L 2b Through the carboxyl group of D and L 2b The α-amino group forms an amide bond; (9) In the cyclic peptide compound of formula (III), X 1c With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6c X 6c DCys and DCys are connected by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively. (10) In the cyclic peptide compound of formula (III), X 1c With L 2c Through X 1c α-carboxyl group and L 2c The amino groups are linked together by amide bonds; (11) In the cyclic peptide compound of formula (III), when L 1c When not a connection key, L 2c With L 1c Through L 2c amino and L 1c The carboxyl groups are linked together to form amide bonds; (12) In the cyclic peptide compound of formula (III), when L 1c When not a connection key, D and L 1c Through the carboxyl group of D and L 1c The amino groups are linked together by amide bonds; (13) In the cyclic peptide compound of formula (III), when L 3c When not a linker, DCys is linked by the α-carboxyl group and the L- group. 3c The α-amino group in the amino group forms an amide bond; (14) In the cyclic peptide compound of formula (III), when L 3c When not a connection key, L 3c Through α-carboxyl group and L 4c Connected; (15) In the cyclic peptide compound of formula (IV), Cya and Gly, Gly and X 1d X 1d With Tyr, Tyr with Lys(iPr), Lys(iPr) with DArg, DArg with 2Nal, 2Nal with X 6d X 6d With X 7d They are linked by amide bonds formed by the carboxyl group at the α-position and the amino group at the α-position, respectively; (16) In the cyclic peptide compound of formula (IV), X 7d Through α-carboxyl group and L 1d Connected; In the cyclic peptide compound of formula (IV) described in (17), when L 1d When not a connection key, L 1d They are linked by an α-carboxyl group and NH2.

6. The cyclic peptide compound of formula (I), (II), (III), or (IV) as described in any one of claims 1-5, characterized in that, The cyclic peptide compound of formula (I), formula (II), formula (III) or formula (IV) satisfies one of the following schemes: Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6 and Scheme 7: Option 1: In the cyclic peptide compound of formula (I), the ring of the cyclic peptide compound of formula (I) is permeated by X. 1a α-amino and X 7a The side chain carboxyl groups are linked together by amide bonds; X 1a For DAsn, DGLN, Asn, Asp, DAsp, or DAla; X 6a For Gly or DAla; X 7a For DGlu or DAsp; L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2); L 2a For the connector key, Cya, Asp, or Gly; The definition of D is as described in any one of claims 1-3; Option 2: In the cyclic peptide compound of formula (I), the ring of the cyclic peptide compound of formula (I) is permeated by X. 1a α-amino and X 7a The side chain carboxyl groups are linked together by amide bonds; X 1a It can be DAsn or Asn; X 6a For Gly; X 7a For DGlu; L 1a It is Lys(NH2) or Lys(OH); L 2a For connection key; The definition of D is as described in any one of claims 1-3; Option 3: In the cyclic peptide compound of formula (I), the ring of the cyclic peptide compound of formula (I) is permeated by X. 1a The side chain amino and X 7a The side chain carboxyl groups are linked together by amide bonds; X 1a It can be (Ac)Dap or (NH2CO)Dap; X 6a For Gly or DAla; X 7a For DGlu or DAsp; L 1a It can be Lys(NH2), Lys(OH), Dab(NH2), or Orn(NH2); L 2a For the connector key, Cya, Asp, or Gly; The definition of D is as described in any one of claims 1-3; Option 4: In the cyclic peptide compound of formula (II), the ring of the cyclic peptide compound of formula (II) is connected by X 1b The side chain thiol groups of and DCys are linked by disulfide bonds; X 1b It is (NH2CO)Cys; X 2b For Tyr; X 6b For Gly; L 1b It can be Lys(NH2) or Dab(NH2); L 2b For connection key or Cya; The definition of D is as described in any one of claims 1-3; Option 5: In the cyclic peptide compound of formula (IV), the ring of the cyclic peptide compound of formula (I) is connected by X. 1a The side chain amino and X 7a The side chain carboxyl groups are linked together by amide bonds; X 1a (NH2CO)Dap; X 6a For Gly; X 7a For DAsp; L 1a Lys(NH2); L 2a For Cya or Asp; The definition of D is as described in any one of claims 1-3; Option Six: The cyclic peptide compound of formula (II) is shown in formula (II-A) below. in, L 1b It can be Lys(NH2) or Dab(NH2); L 2b For connection key or Cya; The definition of D is as described in any one of claims 1-3; Preferably, D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide; wherein the metal chelating group is NOA or DOTA; and the radionuclide is... 68 Ga、 177 Lu、 18 F or Al 18 F; Option Seven: The cyclic peptide compound of formula (I) is shown in formula (IA). in, L1a is Lys(NH2) or Lys(OH); The definition of D is as described in any one of claims 1-3; The carbon atom marked with * indicates that it is either S or R chiral; Preferably, D is (1) a metal chelating group; or (2) a combination of a metal chelating group and a radionuclide; wherein the metal chelating group is NOA or DOTA; and the radionuclide is... 68 Ga、 177 Lu、 18 F or Al 18 F.

7. A cyclic peptide compound or a pharmaceutically acceptable salt thereof, characterized in that, The cyclic peptide compound is any of the following compounds: Preferably, the cyclic peptide compound is any of the following compounds: Among them, Ga, Lu and AlF are preferably their radioactive isotopes, for example 68 Ga、 177 Lu or Al 18 F.

8. A pharmaceutical composition comprising a cyclic peptide compound of formula (I), (II), (III) or (IV) as claimed in any one of claims 1-6, or a cyclic peptide compound of formula (II), (III) or a pharmaceutically acceptable salt thereof, or a cyclic peptide compound of claim 7, and at least one pharmaceutically acceptable excipient.

9. The use of a cyclic peptide compound of formula (I), (II), (III) or (IV) as claimed in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, a cyclic peptide compound of claim 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, in the preparation of a medicament; said medicament being a medicament for treating or diagnosing CXCR4 receptor-related or mediated diseases; The CXCR4 receptor-related or mediated diseases are preferably tumors.

10. The use of a cyclic peptide compound of formula (I), (II), (III) or (IV) as claimed in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, a cyclic peptide compound of claim 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 8, in the preparation of a medicament for imaging; The imaging is preferably imaging of tissues expressing CXCR4, and more preferably imaging of tumor tissues expressing CXCR4.

11. The application as described in claim 9 or 10, characterized in that, The tumor may be a tumor expressing CXCR4, preferably a hematologic malignancy expressing CXCR4; Alternatively, the tumor may be lymphoma, multiple myeloma, or leukemia.

12. A cyclic peptide of formula (V) or formula (VI) or a pharmaceutically acceptable salt thereof; Ring [X] 1e -Tyr-Lys(iPr)-DArg-2Nal-X 6e -X 7e ]-L 1e -L 2e ;(SEQ ID NO:5), (V)， X 1e is DAsn, DGLN, Asn, Asp, DAsp, (Ac)Dap, (NH2CO)Dap, DAla, DDap or Dap; X 6e For Gly or DAla; X 7e For DDap or DAsp; L 1e If it does not exist or Lys(iPr); L 2e It is either absent or NH2; Ring[X 1f -X 2f -Lys(iPr)-DArg-2Nal-X 6f -DCys]-L 1f ;(SEQ ID NO:6), (VI), X 1f is DCys, Cys, (hexanoyl)Cys, (Ac)Cys, (NH2CO)Cys or (NH2CO)DCys; X 2f It is Tyr or Tyr(PO3H2); X 6f For Gly or DAla; L 1f It is absent, NH2 or OH; Preferably, the cyclic peptide of formula (V) or formula (VI) is any of the following cyclic peptides:

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