Cyclic peptide compound, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are a cyclic peptide compound, a pharmaceutical composition thereof, and use thereof. Specifically, disclosed in the present invention are compounds represented by formula (A), formula (B), formula (C), and formula (D), pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof. The compound of the present invention not only has good in-vivo distribution after being radiolabeled, but also has relatively high tumor uptake and relatively long tumor retention time, and thus has the potential of serving as a targeted diagnosis and treatment integrated reagent.

Description

Cyclic peptide compounds, pharmaceutical compositions thereof and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 202410472107X, filed on April 17, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to cyclic peptide compounds, pharmaceutical compositions thereof and uses thereof as targeted diagnosis and treatment integrated nuclear drugs. BACKGROUND

[0003] CXC chemokine 4 (CXCR4) is a G protein-coupled receptor with seven transmembrane domains, which is the specific receptor of endogenous chemokine stromal cell-derived factor-1 (CXCL12). It is lowly expressed or not expressed in many normal human tissues (Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol. 2017 Sep; 17(9): 559-572.), but is overexpressed in numerous human tumor cells. Current studies have shown that more than 23 types of cancers are related to chemokine receptor CXCR4, which plays an important role in tumor growth, cell metastasis, and promotion of angiogenesis (Chatterjee, Samit, Babak Behnam Azad, and Sridhar Nimmagadda. "The intricate role of CXCR4 in cancer." Advances in cancer research 124 (2014): 31-82.), and the expression level of CXCR4 on tumor cells is closely related to the severity of the disease. In addition, it is also involved in HIV virus infection (Hernandez, Paolo A., et al. "Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease." Nature genetics 34.1 (2003): 70-74.). These biological functions determine that CXCR4 targeted drugs can be used for the treatment of tumors, hematopoietic stem cell mobilization, HIV and other diseases.

[0004] Nuclear medicine targeted diagnosis and treatment integration is a new technology that combines visual diagnosis and precise treatment. It labels diagnostic and therapeutic radionuclides (such as Ga-68, F-18, etc.) on the same molecule to combine imaging and internal irradiation organically to achieve precise treatment. Ga-68 labeled PSMA-11 and Lu-177 labeled PSMA-617 have achieved good results in clinical prostate cancer as diagnostic and therapeutic agents. This has prompted people to develop new molecules for diagnosis and treatment integration for potential targets, thereby further improving and perfecting the specificity of diagnosis and treatment of various tumors.

[0005] LY2510924 (WO2017 / 176565) is a cyclic peptide composed of 8 amino acids cyclized by amide bond, which is an antagonist of CXCR4 with good affinity and selectivity, and can specifically inhibit the binding of SDF-1 to CXCR4. Due to its good in vivo and in vitro safety, people study it as a precursor compound for radionuclide labeling in order to obtain a CXCR4 diagnosis and treatment integration molecule. However, the Ga-68 labeled molecule is mainly metabolized by the kidney in vivo, and the high accumulation of radioactive elements in the kidney can easily cause radioactive nephrotoxicity, which is not conducive to the diagnosis and treatment integration molecule.

[0006] WO 2022 / 082312 discloses a class of cyclic peptide molecules based on the structural optimization of LY2510924. This class of cyclic peptide molecules with chelating functional groups (DOTA) has high affinity and selectivity for CXCR4, and improves the accumulation of LY25109254 in the kidney. After Ga-68 labeling, this class of molecules shows good in vivo distribution and can be used as a potential diagnostic agent, but after Lu-177 labeling, its uptake in tumors is low, so further optimization is needed as a therapeutic agent. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the defects of the existing technology of CXCR4 high binding affinity compounds, and to provide a novel cyclic peptide compound, its pharmaceutical composition and its application. The naked peptide molecule of the present application has high CXCR4 affinity, and the cyclic peptide molecule combined with the metal chelating agent also has high CXCR4 affinity. The cyclic peptide molecule with metal chelating agent labeled with radioisotope not only has good in vivo distribution, but also has high tumor uptake and long tumor retention time, and has the potential as a diagnosis and treatment integration agent.

[0008] The present application solves the above technical problems by the following scheme.

[0009] The present application provides a compound as shown in formula (A), formula (B), formula (C), formula (D), their pharmaceutically acceptable salts, their solvates or solvates of their pharmaceutically acceptable salts:

[0010] wherein,

[0011] In the compound as shown in formula (A),

[0012] Rx is H;

[0013] or a metal chelating group capable of binding to a radioisotope, which is connected to L 5 by forming an amide bond;

[0014] R 4 is C1-C4 alkyl substituted by one or more R 4-1 ; and / or

[0015] R 4-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 4-1-1 aryl or 5-10 membered heteroaryl substituted by one or more R 10 ; and / or 4-1-1 R

[0016] R 4-1-1 is independently -OH or halogen;

[0017] X 6 is wherein the “#2” end is connected to “and X 6 adjacent” C(=O);

[0018] X 8 is NH;

[0019] R 2 is each independently -H or C1-C4 alkyl;

[0020] m is 0, 1, 2, 3, 4 or 5;

[0021] X 4 , R 8 , X 5 , L 5 , R 7 and X 7 are defined as any of the following cases:

[0022] Case 6:

[0023] X 7 is wherein the “#6” end is connected to L 5is connected to;

[0024] Ring Z is a 3-12 membered nitrogen-containing heterocycle;

[0025] X 4 is a bond or wherein the "a1" end is connected to "and X 4 adjacent "C(=0)";

[0026] n7 is 0, 1, 2, 3, or 4;

[0027] R 8 is independently NH or O;

[0028] X 5 is a bond, wherein the "a2" end is connected to "and X 5 adjacent "C(=0)";

[0029] R 5 is -H or C1-C4 alkyl;

[0030] n 10 is 0, 1, 2, 3, or 4;

[0031] R 6 is -H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R 6-1 ;

[0032] R 6-1 is or -COOH;

[0033] L 5 is a bond, wherein the "g" end is connected to R x ;

[0034] n2, n7, n8, n 10 , n 11 , n 12 , n 18 , and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0035] L a are each independently C1-C4 alkyl substituted with one or more L a-1 ;

[0036] L a-1 is independently -SO3H or -COOH;

[0037] L b is C1-C6 alkylene;

[0038] Ring C is independently a 3-12 membered nitrogen-containing heterocycle;

[0039] Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring;

[0040] Ring E is independently a 5-6 membered nitrogen-containing heterocyclene;

[0041] Ring F is independently a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0042] Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene;

[0043] Ring D and Ring E form a fused ring;

[0044] Ring D and Ring G form a fused ring;

[0045] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0046] R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0047] Case 4:

[0048] L 5 is a bond, where the "g" end is attached to R x ;

[0049] n2, n7, n8, n 10 , n 11 , n 12 , n 18 , and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0050] L a is independently C1-C4 alkyl substituted with one or more L a-1 ;

[0051] L a-1 is independently -SO3H or -COOH;

[0052] L b is C1-C6 alkylene;

[0053] Ring C is independently a 3-12 membered nitrogen-containing heterocycle;

[0054] Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring;

[0055] Ring E is independently a 5-6 membered nitrogen-containing heterocycloalkene;

[0056] Ring F is independently a C3-C 12 carbocyclic or 3-12 membered heterocyclic ring;

[0057] Ring G is independently a C5-C6 cycloalkene or 5-6 membered heterocycloalkene;

[0058] Ring D and Ring E form a fused ring;

[0059] Ring D and Ring G form a fused ring;

[0060] X 7 is -NR 7-11 - or wherein the "a6" end is attached to L 5 ;

[0061] R 7-11 is -H or C1-C4 alkyl;

[0062] Ring Z is a 3-12 membered nitrogen-containing heterocyclic ring;

[0063] X 4 is a bond or wherein the "a1" end is attached to the "C(=O)" adjacent to "and X 4 ;

[0064] n7 is 0, 1, 2, 3, or 4;

[0065] R 8 is independently NH or O;

[0066] X 5 is a bond, wherein the "a2" end is attached to the "C(=O)" adjacent to "and X 5 ;

[0067] R 5 is -H or C1-C4 alkyl;

[0068] n 10 is 0, 1, 2, 3, or 4;

[0069] R 6 is -H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R 6-1 ;

[0070] R 6-1 is or -COOH;

[0071] R 7 is substituted with one or more R 7-1substituted C1-C4alkyl;

[0072] R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl;

[0073] Case 1:

[0074] X 4 is wherein the "a1" end is attached to a "C(=O) adjacent to "and X 4 ;

[0075] n7 is 0, 1, 2, 3, or 4;

[0076] R 8 is independently NH or O;

[0077] X 5 is a bond, wherein the "a2" end is attached to a "C(=O) adjacent to "and X 5 ;

[0078] R 5 is -H or C1-C4alkyl;

[0079] n 10 is 0, 1, 2, 3, or 4;

[0080] R 6 is -H, C1-C4alkyl or C1-C4alkyl substituted with one or more R 6-1 ;

[0081] R 6-1 is or -COOH;

[0082] X 7 is -NR 7-11 - or wherein the "#6" end is attached to L 5 ;

[0083] R 7-11 is -H or C1-C4alkyl;

[0084] Ring Z is a 3-12 membered nitrogen-containing heterocyclic ring;

[0085] L 5 is a bond, wherein the "g" end is attached to R x ;

[0086] n2, n7, n8, n10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5;

[0087] L a each independently is C1-C4 alkyl substituted with one or more L a- 1;

[0088] L a-1 independently is -SO3H or -COOH;

[0089] L b is C1-C6 alkylene;

[0090] Ring C independently is a 3-12 membered nitrogen-containing heterocycle;

[0091] Ring D independently is a phenyl ring or a 5-6 membered heteroaryl ring;

[0092] Ring E independently is a 5-6 membered nitrogen-containing heterocyclene;

[0093] Ring F independently is a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0094] Ring G independently is a C5-C6 cycloalkene or a 5-6 membered heterocyclene;

[0095] Ring D and Ring E form a fused ring;

[0096] Ring D and Ring G form a fused ring;

[0097] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0098] R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0099] Case 2:

[0100] R 8 independently is O;

[0101] X 4 is a bond or wherein the "a1" end is attached to the "C(=O) adjacent to X 4 ;

[0102] n7 is 0, 1, 2, 3, or 4;

[0103] X 5is a bond, wherein the "a2" end is attached to the "and X 5 adjacent C(=0) group;

[0104] R 5 is -H or C1-C4 alkyl;

[0105] n 10 is 0, 1, 2, 3, or 4;

[0106] R 6 is -H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R 6-1 groups;

[0107] R 6-1 is or -COOH;

[0108] X 7 is -NR 7-11 - or wherein the "g" end is attached to Rx; 5 ;

[0109] R 7-11 is -H or C1-C4 alkyl;

[0110] Ring Z is a 3-12 membered nitrogen-containing heterocyclic ring;

[0111] L 5 is a bond, wherein the "g" end is attached to Rx;

[0112] n2, n7, n8, n 10 , n11, n 12 , h18, and n19 are each independently 0, 1, 2, 3, 4, or 5;

[0113] L a is each independently C1-C4 alkyl substituted with one or more L a-1 groups;

[0114] L a-1 is independently -SO3H or -COOH;

[0115] L b is C1-C6 alkylene;

[0116] Ring C is independently a 3-12 membered nitrogen-containing heterocyclic ring;

[0117] Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring;

[0118] Ring E is independently a 5-6 membered nitrogen-containing heterocyclic alkenyl;

[0119] Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring;

[0120] Ring G is independently C5-C6cycloalkenyl or 5-6 membered heterocycloalkenyl;

[0121] Ring D and Ring E form a fused ring;

[0122] Ring D and Ring G form a fused ring;

[0123] R 7 is C1-C4alkyl substituted with one or more R 7-1 ;

[0124] R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0125] Case 3:

[0126] X 5 is a bond, wherein the "a2" end is attached to "C(=O) adjacent to X 5 ;

[0127] R 5 is -H or C1-C4alkyl;

[0128] n 10 is 2, 3, or 4;

[0129] R 6 is C1-C4alkyl substituted with one or more R 6-1 ;

[0130] R 6-1 is or -COOH;

[0131] X 4 is a bond or wherein the "a1" end is attached to "C(=O) adjacent to X 4 ;

[0132] n7 is 0, 1, 2, 3, or 4;

[0133] R 8 is independently NH or O;

[0134] X 7 is -NR 7-11 - or wherein the "#6" end is attached to L 5 ;

[0135] R 7-11 is -H or C1-C4 alkyl;

[0136] Ring Z is a 3-12 membered nitrogen-containing heterocycle;

[0137] L 5 is a bond, where the "g" end is attached to R x ;

[0138] n2, n7, n8, n 10 , n 11 , n 12 , n 18 , and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0139] L a is each independently C1-C4 alkyl substituted with one or more L a- 1;

[0140] L a- 1is independently -SO3H or -COOH;

[0141] L b is C1-C6 alkylene;

[0142] Ring C is independently a 3-12 membered nitrogen-containing heterocycle;

[0143] Ring D is independently a phenyl ring or a 5-6 membered heteroaryl ring;

[0144] Ring E is independently a 5-6 membered nitrogen-containing heterocyclene;

[0145] Ring F is independently a C3-C 12 carbocyclic ring or a 3-12 membered heterocyclic ring;

[0146] Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene;

[0147] Ring D and Ring E form a fused ring;

[0148] Ring D and Ring G form a fused ring;

[0149] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0150] R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12cycloalkyl or 3-12 membered heterocycloalkyl;

[0151] Case 5:

[0152] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0153] R 7-1 is C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl;

[0154] X 4 is a bond or wherein the "a1" end is attached to "C(=0)" adjacent to "and X 4 ;

[0155] n7 is 0, 1, 2, 3, or 4;

[0156] R 8 is independently O or NH;

[0157] X 5 is a bond, wherein the "a2" end is attached to "C(=0)" adjacent to "and X 5 ;

[0158] R 5 is -H or C1-C4 alkyl;

[0159] n 10 is 0, 1, 2, 3, or 4;

[0160] R 6 is -H, C1-C4 alkyl, or C1-C4 alkyl substituted with one or more R 6 -1;

[0161] R 6-1 is or -COOH;

[0162] X 7 is -NR 7-11 - or wherein the "a6" end is attached to L 5 ;

[0163] R 7-11 is -H or C1-C4 alkyl;

[0164] Ring Z is a 3-12 membered nitrogen-containing heterocycle;

[0165] L 5 is a bond, wherein the "g" end is attached to R x ;

[0166] n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0167] L a are each independently C1-C4 alkyl substituted with one or more L a- 1;

[0168] L a- 1is independently -SO3H or -COOH;

[0169] L b is C1-C6 alkylene;

[0170] Ring C is independently a 3-12 membered nitrogen-containing heterocycle;

[0171] Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring;

[0172] Ring E is independently a 5-6 membered nitrogen-containing heterocyclene;

[0173] Ring F is independently a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0174] Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene;

[0175] Ring D and Ring E form a fused ring;

[0176] Ring D and Ring G form a fused ring;

[0177] In the compound of Formula (B),

[0178] R x1 is H;

[0179] or a metal chelating group capable of binding to a radioisotope, which is attached to L 4 by forming an amide bond;

[0180] X 4 is a bond or wherein the "a1" end is attached to the "C(=O)" adjacent to "and X 4 ;

[0181] n7 is 0, 1, 2, 3, or 4;

[0182] R 4 is a C1-C4 alkyl substituted with one or more R4-1 Substituted C1-C4 alkyl;

[0183] R 4-1 C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 4-1-1 Substituted C6-C 10 Aryl or one or more R 4-1-1 substituted 5-10 membered heteroaryl;

[0184] R 4-1-1 are independently -OH or halogen;

[0185] X 6 for The "#2" end and "X 6 Adjacent "C(=O) are connected;

[0186] R 2 Each is independently -H or C1-C4 alkyl;

[0187] X 8 for NH;

[0188] R 7 For one or more R 7-1 Substituted C1-C4 alkyl;

[0189] R 7-1 C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl;

[0190] X 5 For the connection key, The "a2" end is connected to the "X 5 Adjacent "C(=O) are connected;

[0191] R 5 is -H or C1-C4 alkyl;

[0192] n 10 is 0, 1, 2, 3, or 4;

[0193] R 6 is -H, C1-C4 alkyl or is replaced by one or more R 6-1 Substituted C1-C4 alkyl;

[0194] R 6-1 for or -COOH;

[0195] R 3 -H or one or more R 3-1 Substituted C1-C4 alkyl;

[0196] R 3 -1 is C1-C4 alkoxy, C6-C 10 Aryl, -COOH, -SO3H, -C(=O)NH2, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl;

[0197] R a For one or more R a1 Substituted C1-C4 alkyl;

[0198] R a 1 independently or -COOH;

[0199] R b For one or more R b1 Substituted C1-C4 alkyl;

[0200] R b1 C6-C 10 Aryl, 5-10 membered heteroaryl, By one or more R b12 Substituted C6-C 10 Aryl or one or more R b12 substituted 5-10 membered heteroaryl;

[0201] R b11 C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R b11-1 Substituted C6-C 10 Aryl or one or more R b11-

[0202] 1-substituted 5-10 membered heteroaryl;

[0203] R b11-1 are independently halogen;

[0204] R b12 are independently C1-C4 alkyl;

[0205] R 8 is NH or O;

[0206] L 4 for L 4-1 For the connection key, Where "f' end and R x1 connected;

[0207] n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5;

[0208] L a independently is C1-C4 alkyl substituted with one or more L a-1 ;

[0209] L a-1 independently is -SO3H or -COOH;

[0210] L b is C1-C6 alkylene;

[0211] Ring C independently is a 3-12 membered nitrogen-containing heterocycle;

[0212] Ring D independently is a phenyl ring or a 5-6 membered heteroaromatic ring;

[0213] Ring E independently is a 5-6 membered nitrogen-containing heterocyclene;

[0214] Ring F independently is a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0215] Ring G independently is a C5-C6 cycloalkene or a 5-6 membered heterocyclene;

[0216] Ring D and Ring E form a fused ring;

[0217] Ring D and Ring G form a fused ring;

[0218] In the compound of Formula (C),

[0219] X 6 is wherein the “#2” end is attached to the “and X 6 adjacent” C(=O);

[0220] R 2 each independently is -H or C1-C4 alkyl;

[0221] X 8 is NH;

[0222] L 3 is a bond, wherein the “#5” end is attached to R x2 ;

[0223] n2, n7, n8, n10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0224] L a are each independently C1-C4alkyl substituted with one or more L a-1 ;

[0225] L a-1 is independently -SO3H or -COOH;

[0226] L b is C1-C6alkylene;

[0227] Ring C is independently a 3-12 membered nitrogen-containing heterocycle;

[0228] Ring D is independently a phenyl ring or a 5-6 membered heteroaryl ring;

[0229] Ring E is independently a 5-6 membered nitrogen-containing heterocyclene;

[0230] Ring F is independently a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0231] Ring G is independently a C5-C6cycloalkene or a 5-6 membered heterocyclene;

[0232] Ring D and Ring E form a fused ring;

[0233] Ring D and Ring G form a fused ring;

[0234] Rx 2 is H;

[0235] or a metal chelating group capable of binding a radioisotope, which is attached to L3 by forming an amide bond;

[0236] R 4 is C1-C4alkyl substituted with one or more R 4-1 ;

[0237] R 4-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C6-C 4-1-1 aryl substituted with one or more R 10 , or 5-10 membered heteroaryl substituted with one or more R 4-1 ; 1 ;

[0238] R 4-1-1 is independently -OH or halogen;

[0239] R7 C1-C4alkyl substituted with one or more R 7-1 C1-C4alkyl substituted with one or more R

[0240] R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0241] R 8 independently NH or O;

[0242] in a compound of Formula (D):

[0243] R 8 independently NH or O;

[0244] R 7 C1-C4alkyl substituted with one or more R 7-1 C1-C4alkyl substituted with one or more R

[0245] R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0246] X 6 is wherein the “#2” end is attached to the “and X 6 adjacent” C(=O);

[0247] R 2 each independently -H or C1-C4alkyl;

[0248] X 8 is NH;

[0249] R 4 C1-C4alkyl substituted with one or more R 4-1 C1-C4alkyl substituted with one or more R

[0250] R 4-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 4-1-1 cycloalkyl, or 3-12 membered heterocycloalkyl; 10 cycloalkyl, or 3-12 membered heterocycloalkyl; 4-1 membered heteroaryl substituted with one or more R

[0251] R 4-1-1 independently -OH or halogen;

[0252] X 1 , X 2 , and X 3 are defined as any of the following:

[0253] Case 1:

[0254] X 1 is a bond or where the "a" end is attached to X 2 ;

[0255] X 2 is where the "b" end is attached to X 1 and the "c" end is attached to X 3 ;

[0256] n and n1 are each independently 0, 1, 2, 3, 4, or 5;

[0257] L 1 is a linking chain;

[0258] Rx 3 is H;

[0259] or a metal chelating group capable of binding a radioisotope;

[0260] X 3 is where the "d" end is attached to X 2 ;

[0261] Ring A is a C6-C 10 benzene ring or a 5-10 membered heteroaromatic ring;

[0262] Ring B is a C3-C 12 carbocyclic ring or a 3-12 membered heterocyclic ring;

[0263] n4, n5, and n6 are each independently 0, 1, 2, 3, 4, or 5;

[0264] Case 2:

[0265] X 1 is a bond or where the "a" end is attached to X 2 ;

[0266] X 2 is where the "b" end is attached to X 1 and the "c" end is attached to X 3 ;

[0267] n and n1 are each independently 0, 1, 2, 3, 4, or 5;

[0268] X 3 is where the "d" end is attached to X 2 ;

[0269] L 2 is a linking chain;

[0270] R x4 is H;

[0271] or a metal chelating group capable of binding to a radioisotope;

[0272] Case 3:

[0273] X 1 is where the a end is attached to X 2 ;

[0274] X 2 is where the a end is attached to X 3 ;

[0275] L 6 is L 6-1 is a linking chain, where the a end is attached to R x ;

[0276] n2, n7, n8, n 10 , n 11 , n 12 , n 18 , and n 19 are each independently 0, 1, 2, 3, 4, or 5;

[0277] L a is each independently C1-C4alkyl substituted with one or more L a- 1;

[0278] L a-1 is independently -SO3H or -COOH;

[0279] L b is C1-C6alkylene;

[0280] Ring C is independently a 3-12 membered nitrogen-containing heterocyclic ring;

[0281] Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring;

[0282] Ring E is independently a 5-6 membered nitrogen-containing heterocyclic alkene;

[0283] Ring F is independently a C3-C 12 carbocyclic ring or a 3-12 membered heterocyclic ring;

[0284] Ring G is independently a C5-C6cyclic alkene or a 5-6 membered heterocyclic alkene;

[0285] Ring D and ring E form a fused ring;

[0286] Ring D and ring G form a fused ring;

[0287] X 3 is one end of the label "### " is connected with X 2 ;

[0288] L c is

[0289] Ring A1 is a C6-C 10 aromatic ring or a 5-10 membered heteroaromatic ring;

[0290] n 13 and n 14 are each independently 0, 1, 2, 3, 4 or 5;

[0291] Rx 5 is H;

[0292] or a metal chelating group capable of binding a radioisotope, which is connected with L6 by forming an amide bond; Case 4:

[0293] X 1 is -X 1-1 -X 1-2 -***, one end of the label "***" is connected with X 2 ;

[0294] X 1-1 is one end of the label "#1" is connected with X 1-2 ;

[0295] X 1 -2 is

[0296] X 2 is

[0297] n 13 , n 14 , n 15 and n 16 are each independently 0, 1, 2, 3, 4 or 5;

[0298] Ld is a connecting bond, one end of the label "#2" is connected with R x ;

[0299] n2, n7, n8, n 10 , n11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5;

[0300] L a each independently is C1-C4alkyl substituted with one or more L a-1 ;

[0301] L a-1 independently is -SO3H or -COOH;

[0302] L b is C1-C6alkylene;

[0303] Ring C independently is a 3-12 membered nitrogen-containing heterocycle;

[0304] Ring D independently is a phenyl ring or a 5-6 membered heteroaromatic ring;

[0305] Ring E independently is a 5-6 membered nitrogen-containing heterocyclene;

[0306] Ring F independently is a C3-C 12 carbocycle or a 3-12 membered heterocycle;

[0307] Ring G independently is a C5-C6cycloalkene or a 5-6 membered heterocyclene;

[0308] Ring D and Ring E form a fused ring;

[0309] Ring D and Ring G form a fused ring;

[0310] X 3 is -X 3-1 -X 3-2 -*, the end marked with “*” is connected to X 2 ;

[0311] X 3-1 is the end marked with “**” is connected to X 3-2 ;

[0312] X 3-2 is

[0313] R x6 is H;

[0314] or, a metal chelating group capable of binding to a radioisotope, which is connected to Rx 6 by forming an amide bond;

[0315] above,

[0316] the carbon atom marked with “*” is in R configuration, S configuration, or a mixture thereof;

[0317] In each "5-10 membered heteroaryl", the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0318] In each "3-10 membered heterocycloalkyl", the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0319] In each "3-12 membered nitrogen containing heterocycle", the heteroatoms are selected from one or two of N, O and S in addition to N, and the number of heteroatoms is 1, 2 or 3;

[0320] In each "5-6 membered heteroaromatic ring", the heteroatoms are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0321] In each "5-6 membered nitrogen containing heterocycle", the heteroatoms are selected from one or two of N, O and S in addition to N, and the number of heteroatoms is 1, 2 or 3.

[0322] In certain preferred embodiments of the application, certain groups of the compounds according to Formula (A), Formula (B), Formula (C), Formula (D), their pharmaceutically acceptable salts, their solvates or solvates of their pharmaceutically acceptable salts are defined as follows, and the groups not mentioned are as defined in any of the schemes of the application (simply "in a scheme of the application").

[0323] In a scheme of the application, each "Ci-C4alkyl" is independently of the other(s) methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl or t-butyl, for example methyl, ethyl, n-propyl or n-butyl.

[0324] In a scheme of the application, each "C6-C 10 In a scheme of the application, each "aryl" is independently of the other(s) phenyl or naphthyl.

[0325] In a scheme of the application, each "5-10 membered heteroaryl" is independently of the other(s) a 5-6 membered heteroaryl with one or two heteroatoms being N, for example pyridyl, further for example

[0326] In a scheme of the application, each "halogen" is independently of the other(s) F, Cl, Br or I, for example F.

[0327] In a scheme of the application, each "C3-C 12 In a scheme of the application, each "C3-C6cycloalkyl" is independently of the other(s) C3-C6cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0328] In one embodiment of the application, each "3-12 membered heterocycloalkyl" is independently a 3-6 membered heterocycloalkyl having 1 or 2 N heteroatoms, such as piperidinyl or piperazinyl.

[0329] In one embodiment of the application, each "3-12 membered nitrogen containing heterocycle" is independently a 3-6 membered saturated nitrogen containing heterocycle having 1 or 2 N heteroatoms, such as a piperidinyl or piperazinyl ring, further such as

[0330] In one embodiment of the application, each "5-6 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring having 1 or 2 N heteroatoms, such as a pyridine ring.

[0331] In one embodiment of the application, each "5-6 membered nitrogen containing heterocycle" is independently a 5-6 membered nitrogen containing heterocycle having 1 or 2 N heteroatoms, such as

[0332] In one embodiment of the application, each "C5-C6 cycloalkene" is independently a cyclohexene.

[0333] In one embodiment of the application, each "C1-C4 alkoxy" is independently methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, or tert-butoxy, such as methoxy.

[0334] In one embodiment of the application, each "5-10 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring having 1 or 2 N heteroatoms, such as a pyridine ring.

[0335] In one embodiment of the application, each "C3-C 12 "carbocycle" is independently a C3-C 12 saturated carbocycle, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0336] In one embodiment of the application, each "3-12 membered heterocycle" is independently a 3-6 membered saturated heterocycle having 1 or 2 N heteroatoms, such as a piperidinyl or piperazinyl ring, further such as

[0337] In one embodiment of the application, in the compound of formula (A), m is 1, 3, or 4.

[0338] In one embodiment of the application, in the compound of formula (A), in cases 1, 2, 3, 4, and 5, X7is independently -NH- or

[0339] In one embodiment of the present application, the compound of formula (A) is a compound of formula (A-1) wherein X is 7 is

[0340] In one embodiment of the present application, the compound of formula (A) is a compound of formula (A-1) wherein X is 4 is

[0341] In one embodiment of the present application, the compound of formula (A) is a compound of formula (A-1) wherein X is 4 is independently a bond or

[0342] In one embodiment of the present application, the compound of formula (B) is a compound of formula (B-1) wherein X is 4 is a bond or

[0343] In one embodiment of the present application, the compound of formula (A), (B), (C) and (D) is a compound of formula (A-1), (B-1), (C-1) and (D-1) respectively, wherein R 4 is independently -(CH2) a -R 4-1 , a is 1, 2, 3 or 4, R 4 is, for example, -(CH2)-R 4-1 .

[0344] In one embodiment of the present application, the compound of formula (A), (B), (C) and (D) is a compound of formula (A-1), (B-1), (C-1) and (D-1) respectively, wherein R 4-1 is independently phenyl, naphthyl, phenyl substituted with one hydroxy or phenyl substituted with one F, for example for example

[0345] In one embodiment of the present application, the compound of formula (A), (B), (C) and (D) is a compound of formula (A-1), (B-1), (C-1) and (D-1) respectively, wherein R 4 is independently

[0346] In one embodiment of the present application, the compound of formula (C) is a compound of formula (C-1) wherein X is 6 is

[0347] In one embodiment of the present application, the compound of formula (A), (B) and (D) is a compound of formula (A-1), (B-1) and (D-1) respectively, wherein X is 6 is independently

[0348] In one embodiment of the present application, in the compound of formula (A), (B), (C) or (D), R 7 independently is -(CH2) a1 -R 7-1 , a1 is 1, 2, 3 or 4, R 7 is, for example, -(CH2)-R 7-1 .

[0349] In one embodiment of the present application, in the compound of formula (A), in cases 1, 2, 3, 4 and 6, R 7-1 independently is C6-C 10 aryl, 5-6 membered heteroaryl or C5-C6cycloalkyl, for example phenyl, naphthyl, cyclohexyl or pyridyl.

[0350] In one embodiment of the present application, in the compound of formula (A), in case 5, R 7-1 is C5-C6cycloalkyl, for example cyclohexyl.

[0351] In one embodiment of the present application, in the compound of formula (B), (C) or (D), R 7-1 is C6-C 10 aryl, 5-6 membered heteroaryl or C5-C6cycloalkyl, for example phenyl, naphthyl, cyclohexyl or pyridyl.

[0352] In one embodiment of the present application, in the compound of formula (A), in cases 1, 2, 3, 4 and 6, R 7 independently is

[0353] In one embodiment of the present application, in the compound of formula (A), in case 5, R 7 is

[0354] In one embodiment of the present application, in the compound of formula (B), (C) and (D), R 7 independently is

[0355] In one embodiment of the present application, in the compound of formula (A), in cases 1, 2, 4, 5 and 6, X 5 independently is a bond, for example a bond,

[0356] In an embodiment of the present application, in the compound of formula (A), in case 3, X 5 is a bond, for example a bond,

[0357] In an embodiment of the present application, in the compound of formula (B), in case 3, X 5 is a bond, for example a bond,

[0358] In an embodiment of the present application, in the compound of formula (A), in cases 1, 2, 3, 5 and 6, L 5 is independently a bond,

[0359] for example a bond,

[0360] In an embodiment of the present application, in the compound of formula (A), in case 4, L 5 is a bond, for example a bond,

[0361] In an embodiment of the present application, in the compound of formula (B), R 3 is -H or -(CH2) a3 R 3-1 , a3 is 1, 2, 3 or 4, R 3 for example -H,

[0362] In an embodiment of the present application, in the compound of formula (B), L 4 is L 4-1 is a bond, L 4 for example

[0363] In an embodiment of the present application, in the compound of formula (C), L 3is a bond,

[0364] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein X 2 is a bond, wherein the b end is attached to X 1 and the c end is attached to X 3 .

[0365] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein L 1 is a bond, L 1-1 is a bond, for example, wherein the #3 end is attached to R x3 and R x3 is attached to L 1 by forming an amide bond, wherein n2, n7, n8, n 10 , n 11 , n 12 , n 18 , L a , L b , ring C, ring D and ring E are as defined in any embodiment of the present application.

[0366] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein L 1 is a bond, wherein the #3 end is attached to R x3 and R x3 is attached to L 1 by forming an amide bond.

[0367] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein X 3 is a bond,

[0368] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein X 2 is a bond,

[0369] In one embodiment of the present application, the compound of formula (D) is the compound of formula (D-1) wherein L 2 is a bond, for example, wherein the "#4" end is attached to R x4 , said R x4 is attached to L 2 by forming an amide bond, wherein n2, n7, n8, n 10 , n 11 , n 12 , n 18 , L a , L b , ring C, ring D and ring E are defined according to any one of the embodiments of the present invention.

[0370] In one embodiment of the present invention, said compound of formula (D) is in case 2, wherein L 2 is wherein the "#4" end is attached to R x4 , said R x4 is attached to L 2 by forming an amide bond.

[0371] In one embodiment of the present invention, said compound of formula (D) is in case 3, wherein L 6 is for example

[0372] In one embodiment of the present invention, said compound of formula (D) is in case 3, wherein L c is

[0373] In one embodiment of the present invention, said compound of formula (D) is in case 4, wherein X 2 is

[0374] In one embodiment of the present invention, said compound of formula (D) is in case 4, wherein Ld is for example is

[0375] In one embodiment of the present invention, said compound of formula (A) is a compound of formula (A-1):

[0376] In one embodiment of the present invention, said compound of formula (A-1) is in case 1, wherein

[0377] X 4 , R 8 , X 5 , L 5 , R 7 and X 7is defined as Case 6 described in any of the above schemes, and the definitions of the remaining variables are the same as those described in any of the schemes of the present invention.

[0378] In one embodiment of the present invention, in the compound represented by formula (A-1),

[0379] X 7 for Among them, the "#6" end and L 5 connected;

[0380] Ring Z is a 5-6 membered nitrogen-containing saturated heterocyclic ring;

[0381] L 5 for The "g" end is connected to R x connected;

[0382] n10 is 1;

[0383] L a Each independently is one or more L a-1 Substituted C1-C4 alkyl;

[0384] L a-1 independently -SO3H;

[0385] m is 1 or 2;

[0386] R 4 For one or more R 4-1 Substituted C1-C4 alkyl;

[0387] R 4-1 C6-C 10 Aryl or one or more R 4-1-1 Substituted C6-C 10 aryl;

[0388] R 4-1-1 are independently -OH or halogen;

[0389] R 8 is O or NH;

[0390] R 7 For one or more R 7-1 Substituted C1-C4 alkyl;

[0391] R 7-1 C6-C 10 aryl;

[0392] X 5 for

[0393] n7 is 1 or 2;

[0394] X 4 is a bond;

[0395] R x is H;

[0396] or a metal chelating group capable of binding to a radioisotope, which is connected to L 5 by forming an amide bond.

[0397] In one embodiment of the present application, the compound of formula (A-1) is:

[0398] X 4 , R 8 , X 5 , L 5 , R 7 and X7are as defined in any of the above embodiments.

[0399] In one embodiment of the present application, the compound of formula (A-1) is:

[0400] L 5 is wherein the "g" end is connected to R x ;

[0401] n 11 is independently 0 or 1;

[0402] n 12 is independently 1;

[0403] ring C is a 5-6 membered nitrogen-containing saturated heterocyclic ring;

[0404] ring D is a benzene ring;

[0405] ring E is a 5-6 membered nitrogen-containing heterocyclic olefin;

[0406] L a is independently C1-C4 alkyl substituted with one or more L a-1 ;

[0407] L a-1 is -SO3H or -COOH;

[0408] X 7 is NH;

[0409] m is 3 or 4;

[0410] R 4 is C1-C4 alkyl substituted with one or more R 4-1 ;

[0411] R 4-1 is C6-C 10C6-C10aryl or C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl; 10 substituted C6-C10aryl;

[0412] R 4-1-1 independently -OH or halogen;

[0413] R 8 is O or NH;

[0414] R 7 is C1-C4alkyl substituted by one or more R 7-1 substituted C1-C4alkyl;

[0415] R 7-1 is C6-C10aryl; 10 substituted C6-C10aryl;

[0416] X 5 is a bond;

[0417] n7 is 1 or 2;

[0418] X 4 is a bond;

[0419] R x is H;

[0420] or a metal chelating group capable of binding to a radioisotope, which is linked to L 5 by forming an amide bond. In one embodiment of the present application, the compound of formula (B) is a compound of formula (B-1):

[0421] In one embodiment of the present application, the compound of formula (B-1) is a compound of formula (B-1-1):

[0422] X 4 is a bond;

[0423] R 3 is C1-C4alkyl substituted by one or more R 3-1 substituted C1-C4alkyl;

[0424] R 3-1 is -COOH or -SO3H;

[0425] R 4 is C1-C4alkyl substituted by one or more R 4-1 substituted C1-C4alkyl;

[0426] R 4-1 is C6-C10aryl; 10 substituted C6-C10aryl; 4-1-1 substituted C6-C10aryl; 10 substituted C6-C10aryl;

[0427] R 4-1-1 independently -OH or halogen;

[0428] R 8 is NH or O;

[0429] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0430] R 7-1 is C6-C 10 aryl;

[0431] X 5 is wherein the "a2" end is attached to the "C(=O) adjacent to X 5 ;

[0432] R 5 is -H or C1-C4 alkyl;

[0433] n 10 is 1 or 2;

[0434] L 4 is L 4 -1 is

[0435] n11 is 0;

[0436] Ring D is a phenyl ring;

[0437] Ring E is a 5-6 membered nitrogen-containing heterocyclic olefin;

[0438] Ring C is a 5-6 membered nitrogen-containing saturated monocyclic heterocycle or a 9-11 membered nitrogen-containing saturated spirocyclic heterocycle;

[0439] L b is C1-C6 alkylene;

[0440] L a is independently C1-C4 alkyl substituted with one or more L a-1 ;

[0441] L a-1 is independently -SO3H or -COOH;

[0442] R x1 is H;

[0443] or, a metal chelating group capable of binding to a radioisotope, which is attached to L 4 by forming an amide bond.

[0444] In an embodiment of the present application, the compound as shown in formula (C) is a compound as shown in formula (C-1):

[0445] wherein the carbon atom marked with "*" is in R configuration, S configuration or a mixture thereof.

[0446] In an embodiment of the present application, the compound as shown in formula (D) is a compound as shown in formula (D-1):

[0447] In an embodiment of the present application, in the compound as shown in formula (D), in the case 1, -X 2 -X 3 - is:

[0448] In an embodiment of the present application, in the compound as shown in formula (A), formula (B), formula (C) or formula (D), R x , R x1 , R x2 , R x3 , R x4 , R x5 and R x6 are each independently H, preferably

[0449] In an embodiment of the present application, the compound as shown in formula (A) is any one of the following compounds:

[0450] In an embodiment of the present application, the compound as shown in formula (B) is any one of the following compounds:

[0451] In an embodiment of the present application, the compound as shown in formula (C) is any one of the following compounds:

[0452] In an embodiment of the present application, the compound of formula (D) is any one of the following compounds:

[0453] In an embodiment of the present application, the specific compounds of formula (A), (B), (C) and (D) above are replaced by -H.

[0454] The present application also provides a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, characterized in that the compound E is a compound of formula (A), (B), (C) or (D) as described in any of the above embodiments, chelated with a radioisotope.

[0455] In an embodiment of the present application, the radioisotope is 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 165 Er, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 111 In, 47 8c, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 223 Ra, 224 Ra, 227 Th, 64 Cu, 67 Cu, 68 Ga, 177 Lu, 67 Ga, 61 Cu, 99m Tc, 114m In,44 Sc, 86 Y, 89 Zr or 90 Nb, for example 177 Lu or 68 Ga.

[0456] In a certain embodiment of the application, the radioisotope is a therapeutic radioisotope, for example 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 165 Er, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 111 In, 47 Sc, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 223 Ra, 224 Ra, 227 Th or 67 Cu, further for example 177 Lu.

[0457] In a certain embodiment of the application, the radioisotope is a diagnostic radioisotope, for example 68 Ga, 177 Lu, 67 Ga, 61 Cu, 64 Cu, 99m Tc, 114m In, 111 In, 44 Sc, 86 Y, 89 Zr or 90 Nb, for example 68 Ga or 177 Lu.

[0458] The present application also provides a pharmaceutical combination comprising a substance X and a substance Y, wherein the substance X is a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of the above aspects, wherein the compound E comprises a diagnostic radioisotope according to any one of the above aspects; and the substance Y is a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of the above aspects, wherein the compound E comprises a therapeutic radioisotope according to any one of the above aspects.

[0459] The present application also provides a pharmaceutical composition comprising a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of the above aspects, and a pharmaceutically acceptable excipient.

[0460] The present application also provides use of a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of the above aspects in the manufacture of a medicament for diagnosing a disease, wherein the compound E comprises a diagnostic radioisotope according to any one of the above aspects, and the disease is a disease associated with CXCR4; preferably, the disease is a disease positive for CXCR4 expression; more preferably, the disease is a solid tumor, such as fibroblastoma.

[0461] The present application also provides use of a compound E, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of the above aspects in the manufacture of a medicament for treating a disease, wherein the compound E comprises a therapeutic radioisotope according to any one of the above aspects, and the disease is a disease associated with CXCR4; preferably, the disease is a disease positive for CXCR4 expression; more preferably, the disease is a solid tumor, such as fibroblastoma.

[0462] The present application also provides a compound represented by formula (a), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0463] wherein X 6 , "*" and m are defined according to any one of the above aspects;

[0464] X 4 , R 4 , R 8 , X 5 , R 7 and X7 are defined as any one of the following:

[0465] Scenario A:

[0466] X 4 for The "a1" end is connected to the "X 4 Adjacent "C(=O) are connected;

[0467] n7、R 4 、R 8 、X 5 、R 7 and X 7 is defined as in any of the above schemes;

[0468] Scenario B:

[0469] R 4 For one or more R 4-1 Substituted C1-C4 alkyl, R 4-1 For one or more R 4-1-1 Substituted C6-C 10 Aryl or one or more R 4 - 1-1 Substituted 5-10 membered heteroaryl, R 4-1-1 are independently halogen;

[0470] X 4 、R 8 、X 5 、R 7 and X 7 is defined as in any of the above schemes;

[0471] Preferably, R 4 The definitions of the variables in R are the same as those in any of the above schemes. 4 The corresponding variables are defined as follows;

[0472] Scenario C:

[0473] X 5 For the connection key,

[0474] n 10 is 2, 3 or 4;

[0475] R 6 For one or more R 6-1 Substituted C1-C4 alkyl, R 6-1 for or -COOH;

[0476] X 4 、R 4 、R 8 、R 5 、R 7and X 7 are as defined in any of the preceding embodiments;

[0477] Preferably, X 5 are as defined in any of the preceding embodiments for X 5 are as defined in any of the preceding embodiments for the corresponding variables of X

[0478] Case D:

[0479] R 8 is O;

[0480] X 4 , R 4 , X 5 , R 7 and X 7 are as defined in any of the preceding embodiments;

[0481] Case E:

[0482] R 7 is C1-C4 alkyl substituted with one or more R 7-1 ;

[0483] R 7-1 is phenyl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl, or 3-12 membered heterocycloalkyl;

[0484] X 4 , R 4 , R 8 , X 5 and X 7 are as defined in any of the preceding embodiments;

[0485] Preferably, X 7 are as defined in any of the preceding embodiments for X 7 are as defined in any of the preceding embodiments for the corresponding variables of X

[0486] Case F:

[0487] X 7 is wherein the “#6” end is attached to H;

[0488] Ring Z is a 3-12 membered nitrogen-containing heterocyclic ring;

[0489] X 4 , R 4 , R 8 , X 5 and R 7 are as defined in any of the preceding embodiments;

[0490] Preferably, X 7 are as defined in any of the preceding embodiments for X7 The definitions of the respective variables of each pair are described above.

[0491] The present application also provides any one of the following compounds:

[0492] The present application also provides a compound as shown in formula (b), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0493] X 4 , R 4 , X 6 , “*”, X 5 and R 7 are defined as described above in any of the aspects;

[0494] R 3 and R 8 are defined as any of the following:

[0495] Case 1:

[0496] R 3 is -H or C1-C4 alkyl substituted with one or more R 3-1 ;

[0497] R 3 -1 is C1-C4 alkoxy, -COOH, -SO3H, -C(=O)NH2, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl;

[0498] R a is C1-C4 alkyl substituted with one or more R a1 ;

[0499] R a 1 is independently or -COOH;

[0500] R b is C1-C4 alkyl substituted with one or more R b1 ;

[0501] R b1 is C6-C 10 aryl, 5-10 membered heteroaryl, substituted with one or more R b12 C6-C 10 aryl or 5-10 membered heteroaryl substituted with one or more R b12 ;

[0502] R b11 is C6-C 10 aryl, 5-10 membered heteroaryl, C6-C b11-1 aryl or 5-10 membered heteroaryl substituted with one or more R 10 aryl or 5-10 membered heteroaryl substituted with one or more R b11- 1 substituted 5-10 membered heteroaryl;

[0503] R b11-1 independently halogen;

[0504] R b12 independently C1-C4 alkyl;

[0505] R 8 is NH or O;

[0506] R 3 independently halogen; 3 independently halogen;

[0507] R 8 is O;

[0508] R 3 independently halogen.

[0509] The present application also provides any one of the following compounds:

[0510] The present application also provides a compound as shown in formula (d), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0511] wherein the definitions of X 1 , R 7 , R 8 , “*”, X 6 and R 4 are as described in any of the above aspects;

[0512] X 2 and X 3 are as defined in any of the following cases:

[0513] Case i:

[0514] X 2 is wherein b is connected to X 1 and c is connected to X3 is connected to X

[0515] n and n1 are each independently 0, 1, 2, 3, 4, or 5;

[0516] X 3 is connected to X wherein "d" is connected to X 2 is connected to X

[0517] Ring A is a C6-C 10 benzene ring or a 5-10 membered heteroaromatic ring;

[0518] Ring B is a C3-C 12 carbocyclic ring or a 3-12 membered heterocyclic ring;

[0519] n4, n5, and n6 are each independently 0, 1, 2, 3, 4, or 5;

[0520] Preferably, the definitions of the variables in X 2 are the same as the corresponding definitions of the variables in X 2 of any of the above embodiments;

[0521] X 3 are the same as the corresponding definitions of the variables in X 3 of any of the above embodiments;

[0522] Case ii:

[0523] X 2 is connected to X wherein "b" is connected to X 1 and "c" is connected to X 3 ;

[0524] n and n1 are each independently 0, 1, 2, 3, 4, or 5;

[0525] X 3 is connected to X wherein "d" is connected to X 2 ;

[0526] Preferably, the definitions of the variables in X 2 are the same as the corresponding definitions of the variables in X 2 of any of the above embodiments;

[0527] X 3 are the same as the corresponding definitions of the variables in X 3 of any of the above embodiments.

[0528] In one embodiment of the present application, the compound of formula (d) is any one of the following compounds:

[0529] The present application also provides a pharmaceutical composition comprising a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the compound e is a compound of Formula (a), (b), or (d) according to any one of the above aspects.

[0530] The present application also provides use of a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the above aspects in the manufacture of a CXCR4 antagonist or a CXCR4 binding agent.

[0531] The present application also provides use of a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the above aspects in the manufacture of a medicament for the prevention and / or treatment of a disease associated with CXCR4; preferably, the disease is a CXCR4-expressing disease; more preferably, the disease is a solid tumor, such as fibrosarcoma.

[0532] The present application also provides a compound of Formula (II):

[0533] wherein,

[0534] Pg is an amino protecting group;

[0535] m, ring Z, n10, and L a are as defined in any one of the above aspects;

[0536] Rxp is Rxp protected by a protecting group 1 , Rxp 1 is a metal chelating group capable of binding a radioisotope according to any one of the above aspects.

[0537] In one aspect of the present application,

[0538] Pg is an amino protecting group that is removable under acidic conditions, such as Fmoc

[0539] m is 1 or 2;

[0540] ring Z is a 5-6 membered nitrogen-containing saturated heterocyclic ring;

[0541] L a each independently is C1-C4 alkyl substituted with one or more L a-1 ; and

[0542] L a-1 independently is -SO3H;

[0543] R xp For

[0544] Pg 1 is independently C1-C6 alkyl.

[0545] In one embodiment of the present application, the compound of formula (II) is:

[0546] Definitions of terms

[0547] The term "linker" means that the bond is absent, e.g. A-L-B is A-B when L is a linker.

[0548] The term "linker chain" means a linking group as is conventional in the art, unless specifically defined otherwise.

[0549] The term "alkyl" means a straight or branched chain alkyl group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl.

[0550] The term "alkoxy" means the group -O-R X where R X is alkyl as defined above.

[0551] The term "aryl" means a cyclic, aromatic, monovalent hydrocarbon group having the specified number of carbon atoms (e.g., C6to C 10 ) which is monocyclic or polycyclic. Examples of aryl groups include phenyl or naphthyl.

[0552] The term "heteroaryl" means a cyclic, aromatic, monovalent group having the specified number of ring atoms (e.g., 5 to 10 membered), the specified number of heteroatoms (e.g., 1, 2, or 3), and the specified number of types of heteroatoms (e.g., 1, 2, or 3 of N, O, and S). Examples of heteroaryl groups include pyridyl.

[0553] The term "halogen" means F, Cl, Br, I.

[0554] The term "cycloalkyl" means a cyclic, saturated, monovalent hydrocarbon group having the specified number of carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0555] The term "heterocycloalkyl" means a saturated cyclic group having the specified number of ring atoms, the specified number of heteroatoms (e.g., 1, 2, or 3), and the specified number of types of heteroatoms (e.g., 1, 2, or 3 of N, O, and S). Examples of heterocycloalkyl groups include piperidinyl or piperazinyl.

[0556] The term "carbocyclo" refers to a ring having the indicated number of ring atoms, consisting solely of carbon atoms, which is saturated or partially unsaturated.

[0557] The term "heterocyclo" refers to a ring having the indicated number of ring atoms (e.g., 5-15 membered), the indicated number of heteroatoms (e.g., 1, 2, or 3), the indicated kind of heteroatoms (1, 2, or 3 of N, O, and S), which is saturated or partially unsaturated.

[0558] The term "heteroarocyclo" refers to a cyclic aromatic ring having the indicated number of ring atoms, the indicated number of heteroatoms (e.g., 1, 2, or 3), the indicated kind of heteroatoms (1, 2, or 3 of N, O, and S).

[0559] The term "heterocycloalkene" refers to a partially unsaturated ring having the indicated number of ring atoms, the indicated number of heteroatoms (e.g., 1, 2, or 3), the indicated kind of heteroatoms (one or more of N, O, and S), which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds.

[0560] The term "cycloalkene" refers to a partially unsaturated ring having the indicated number of ring atoms, consisting solely of carbon atoms, which has one or more (e.g., 1, 2, or 3) carbon-carbon sp 2 double bonds.

[0561] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application, prepared from a relatively nontoxic, pharmaceutically acceptable acid or base. When a compound of the present application contains a relatively acidic moiety, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. When a compound of the present application contains a relatively basic moiety, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.

[0562] The term "solvate" means a compound formed by a complex of a compound of the present application with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules can be present in ordered or disordered arrangements.

[0563] The terms "pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" are as described above, meaning a compound of the present application formed with: (1) a relatively nontoxic, pharmaceutically acceptable acid or base, and (2) a stoichiometric or non-stoichiometric amount of solvent.

[0564] The term "pharmaceutically acceptable excipient" refers to excipients and additives used in the production of pharmaceutical products and the dispensing of prescriptions, and all substances contained in pharmaceutical preparations other than active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) Volume IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

[0565] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0566] The reagents and raw materials used in the present application are commercially available.

[0567] The positive progress effect of the present application is that the naked peptide molecule of the present application has high CXCR4 affinity, and the cyclic peptide molecule combined with the metal chelating agent also has high CXCR4 affinity. After being labeled with a radioisotope, the cyclic peptide molecule with a metal chelating agent not only has good in vivo distribution, but also has high tumor uptake and long tumor retention time, and has the potential as a diagnosis and treatment integrated reagent. BRIEF DESCRIPTION OF DRAWINGS

[0568] Figure 1 is 68 PET-CT images of Ga-JHL047 in tumor-bearing mice (from left to right, the images are 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 120 min and 180 min) DETAILED DESCRIPTION

[0569] The present application will be further described by way of examples, but the present application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0570] The following abbreviations are used in the following examples:

[0571] The analysis methods involved in the following examples are as follows:

[0572] HPLC-MS Waters 2696-Micromass system: chromatographic column: Shim-pack VP-ODS, (4.6x150mm, 5μm), mobile phase A: H2O (0.1% TFA), mobile phase B: acetonitrile (0.1% TFA). Flow rate: 1.0 mL / min.

[0573] Column temperature: 30℃

[0574] Detection: UV (214.4 nm) and MS (ESI, Positive mode, 110 to 1000 amu).

[0575] Method 1 : 20-30% 15 30 min (20-30% is representative of the concentration of the B phase, 20-30 15 means the B phase is gradient from 20% to 30% in 15 minutes.)

[0576] 20-30% 15 30 min

[0577] Method 2: 15-25% 15 30 min

[0578] 15_25% 15 30 min

[0579] Method 3: 15-20% 15 30 min 15 20% 15 30 min

[0580] Method 4: 15-45% 20 23 min 15 45% 15 30 min

[0581] Method 5: 10-40% 20 23 min 10_40%_15_30 min

[0582] Method 6: 22-25% 15 30 min

[0583] 22_25% 15 30 min

[0584] Method 7: 25 25 30% 15 30 min

[0585] Method 8: 20 25% 15 30 min 20 25% 15 30 min

[0586] Method 9: 25 30% 15 30 min

[0587] Method 10: 10 20% 15 30 min

[0588] The following compounds were prepared using the following preparative HPLC conditions:

[0589] Preparative liquid phase: Shimadzu LC-20AP-SPD40 system, column: Bonnasil-BS C 18 (30 x 250 mm, 5 μm), mobile phase A: H20 (0.1% TFA), mobile phase B: acetonitrile (0.1% TFA), flow rate: 20 mL / min, detection: UV (214.4 nm, 254 nm)

[0590] 1. Synthesis of JHL compounds

[0591] All compounds were synthesized by Fmoc solid phase synthesis method, according to the corresponding reaction sequence, the following general synthetic method illustrates the synthesis of the corresponding cyclic peptide, for cyclic peptides with different sequences only need to add or replace different protected amino acids and use the corresponding synthetic method to prepare.

[0592] General synthesis method 1 : take Cyclo[Ac-Cys(3MeBn)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Cys]Lys(iPr)-PEG6-DOTA (amino acid sequence corresponding to sequence 1) JHL001 molecule synthesis as an example

[0593] Step 1 : synthesis of intermediate 1

[0594] Scale: 0.5 mmol CTC resin (0.77 g) to synthesize the naked peptide on the solid phase according to the following sequence

[0595] After the completion of condensation, wash with MeOH, dry to obtain 1.5 g resin; then cut 10 min with 15 mL cutting solution (1% TFA / DCM), cut 3 times; add DIEA to adjust pH to 7.0 in the filtered cutting solution, spin dry, then freeze-dried to obtain the product 220 mg.

[0596] Step 2: synthesis of intermediate 2

[0597] Dissolve compound 1 (220 mg) and DOTA-NHS (33.93 mg, 1.5 eq.) in a DMF (2 mL) solution, then add to DIEA (7.45 uL, 4.0 eq.), react for 1 h, detect by LCMS, compound 1 is completely consumed and the product is generated. Add the reaction solution to isopropyl ether (10 mL), precipitate the product, dry under N2 gas to obtain the crude product 260 mg.

[0598] Step 3: synthesis of intermediate 3

[0599] Compound 2 (130 mg crude) was added to 2 mL cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) and reacted for 3 h, after which the reaction was added to 10 mL of isopropyl ether to precipitate the product, centrifuged (3000 r, 3 min) and the supernatant was decanted and the solid was blown dry to give the crude product 130 mg.

[0600] Step 4: Synthesis of JHL001

[0601] Compound 3 (130 mg) was added to 50% ACN / H2O (140 mL) and compound 4 was added followed by saturated NH4HCO3 to adjust the pH to 8.0 and reacted for 2 h, LCMS showed product formation and compound 3 was consumed completely, after lyophilization, solid crude 150 mg was obtained, followed by preparative purification and lyophilization to give the product 29.78 mg. Using analytical method 1 : HPLC: 95.27%, RT; 10.031 min, MS: [M+2] 2+ = 967.08.

[0602] The following compounds were prepared using the general synthesis method 1 to synthesize the bare peptide, followed by cyclization and attachment of the corresponding linker and DOTA using the synthesis method described in EP 3 763 726.

[0603] Cyclo[Ac-Cys(tMeBn-AET-AEEPA-DOTA)-Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Cys]Lys(iPr)-NH2(amino acid sequence corresponds to sequence 4) (JHL007)

[0604] General synthesis method 2: example with synthesis of Cyclo[Lys(DOTA)-Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-NH2(amino acid sequence corresponds to sequence 2) (JHL002)

[0605] Step 1 : Synthesis of JHL002

[0606] Scale: 0.5 mmol MBHA resin (0.78 g) the bare peptide synthesis was completed on solid phase following the reaction steps below

[0607] After completion of the condensation, the resin was washed with MeOH and dried under suction to give 1.5 g of resin; this was then cleaved with 15 mL of cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) for 12 h; after filtration, the cleavage solution was added to 80 mL of ice isopropyl ether to precipitate the solid, which was centrifuged (3000 r / 3 min) and the supernatant was decanted and the solid was dried under vacuum to give the crude product (500 mg); 100 mg of the crude product was lyophilized to give 22.64 mg of product. Analytical method 2 was used

[0608] HPLC: 96.38%, RT; 13.769 min, MS: [M+2] 2+ = 853.37

[0609] The following compounds were prepared using the general synthesis method 2:

[0610] Cyclo[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(DOTA)-NH2(amino acid sequence corresponds to sequence 3) (JHL004)

[0611] Cyclo[Lys(Gly-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-CysAcid-D-Glu]-Lys(iPr)-NH2(amino acid sequence corresponds to sequence 5) (JHL009)

[0612] Cyclo[Lys(AEEA-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]-Lys(iPr)-NH2(amino acid sequence corresponds to sequence 6) (JHL010)

[0613] Cyclo[Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-Cha-D-Ala-D-Glu]-Lys(iPr)-NH2(amino acid sequence corresponds to sequence 11) (JHL015)

[0614] Cyclo[Gly-Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Glu]-Lys(iPr)-NH2(amino acid sequence corresponds to sequence 13) (JHL017)

[0615] Cyclo[Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-N-Me-B-Ala-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponds to SEQ ID NO: 17) (JHL021)

[0616] Cyclo[Lys(Gly-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-CysAcid-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponds to SEQ ID NO: 18) (JHL022)

[0617] Cyclo[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 19) (JHL023)

[0618] Cyclo[Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponds to SEQ ID NO: 20) (JHL024)

[0619] Cyclo[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(hhy02-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 25) (JHL029)

[0620] Cyclo[Cha-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 26 (JHL030)

[0621] Cyclo[O-Me-hSer-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 27) (JHL031)

[0622] Cyclo[Arg-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 28) (JHL032)

[0623] Cyclo[Phe-Tyr-Lys(iPr)-D-Cit-2-Nal-Gly-D-Glu]Lys(iPr)Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 29) (JHL033)

[0624] Cyclo[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(hhy02-CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 30) (JHL034)

[0625] Cyclo[Cit-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 31) (JHL035)

[0626] Cyclo[Cit-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(hhy02-CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 37) (JHL041)

[0627] Cyclo[Gly-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(hhy02-CysAcid-DOTA)NH2 (amino acid sequence corresponds to SEQ ID NO: 38) (JHL042)

[0628] Cyclo[Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Glu]Lys(iPr)-NH2 (amino acid sequence corresponds to SEQ ID NO: 42) (JHL046)

[0629] Cyclo[Lys(hhy02-CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-NH2 (amino acid sequence corresponds to SEQ ID NO: 43) (JHL047)

[0630] Cyclo[Lys(hhy02-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-NH2 (amino acid sequence corresponds to SEQ ID NO: 44) (JHL048)

[0631] Cyclo[Lys(DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-NH2 (amino acid sequence corresponds to SEQ ID NO: 45) (JHL049)

[0632] Cyclo[Lys(hhy06-CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-NH2 (amino acid sequence corresponds to SEQ ID NO: 46) (JHL050)

[0633] Cyclo[Glu-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(hhy02-CysAcid-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 48) (JHL052)

[0634] Cyclo[Cit-4-FPhe-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(hhy02-CysAcid-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 49) (JHL053)

[0635] Cyclo[Gln-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys(hhy02-CysAcid-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 50) (JHL054)

[0636] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0637] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0638] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0639] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0640] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0641] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0642] Cyclo[CysAcid-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)-Lys-(hhy02-AVA-DOTA)-NH2 (amino acid sequence corresponds to SEQ ID NO: 53) (JHL056)

[0643] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0644] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0645] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0646] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0647] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0648] Cyclo[Orn(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)NH2 (amino acid sequence corresponding sequence 57) (JHL060)

[0649] JHL061 can also be prepared by the following method:

[0650] Step 1 : Synthesis of compound 2

[0651] Compound 1 (4.3 g, 8.7 mmol) was added to a solution of 4 M HC1 in 1,4-dioxane (20 mL), followed by DIEA (7.45 uL, 4.0 eq), and the mixture was allowed to react at room temperature for 1 h, and the reaction progress was monitored by LCMS. When compound 1 was consumed completely and the product was generated, the reaction mixture was concentrated to give compound 2 (3.2 g, HC1 salt). Compound 2 was used directly in the next step without any purification. ESI-MS (+): m / z 395.1 [M+H] +

[0652] Step 2: Synthesis of compound 4

[0653] Compound 3 (6.48 g, 14.7 mmol) was added to a solution of dry THF (100 mL), followed by NHS (4.06 g, 35.3 mmol) and DCC (7.0 g, 33.8 mmol), and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. When compound 3 was consumed completely and the product was generated, the reaction solution was filtered, and the filtrate was concentrated to give compound 4 (9 g). ESI-MS (+): m / z 657.2 [M+Na] +

[0654] Step 3: Synthesis of compound 5

[0655] Compound 4 (0.32 g, 0.5 mmol) was added to a solution of dry THF (40 mL), followed by compound 2 (0.39 g, 1.0 mmol), and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. When the product was generated, the mixture was filtered, and the filtrate was concentrated to give compound 5 (0.72 g). ESI-MS (+): m / z 1193.0 [M+H] +

[0656] Step 4: Synthesis of compound 6

[0657] Compound 5 (0.72 g, 0.4 mmol) was added to a mixture of formic acid (10 mL) and 30% H2O2 (2 mL), and the mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. When the product was generated, the mixture was purified by flash chromatography and lyophilized to give compound 6 (0.3 g). 1 H NMR (DMSO-d6, 500 MHz)

[0658] 7.90 (d, J = 10.0 Hz, 2H), 7.72 (d, J = 5.0 Hz, 2H), 7.63 (bs, 1H), 7.42 (t, J = 10.0 Hz, 2H), 7.34 (t, J = 5.0 Hz, 2H), 4.32-4.51 (m, 5H), 3.99 (bs, 1H), 3.73 (bs, 1H), 3.10 (bs, 1H), 2.49-2.81 (m, 3H), 1.31-1.78 (m, 5H), 0.88-1.19 (m, 2H), ESI-MS (+): m / z 546.2 [M+H] +

[0659] Step 5: Synthesis of compound 7

[0660] Compound 6 (1.9 g, 3.48 mmol) was added to a solution of DMF (20 mL), followed by DOTA-tBu-NHS (2.79 g, 4.18 mmol) and TEA (5 mL). The reaction was stirred at room temperature for 1 h, and LCMS indicated that the product was formed. Flash purification and lyophilization gave the product compound 7 (1.8 g). 1H NMR (DMSO-d6, 500 MHz), 7.80 (d, J = 10 Hz, 2H), 7.61-7.74 (m, 2H), 7.39 (t, J = 10 Hz, 2H), 7.31 (t, J = 10 Hz, 2H), 4.09-4.50 (m, 6H), 2.51-3.22 (m, 20H), 1.77-2.25 (m, 7H), 1.51-1.76 (m, 4H), 1.23-1.51 (m, 34H). ESI-MS (+): m / z 1100.4 [M+H] + .

[0661] Step 6: Synthesis of JHL061

[0662] Using 0.1 mmol MBHA resin (0.45 g) and Fmoc-based polypeptide synthesis chemistry, JHL061 was synthesized according to the following table of amino acid sequence and reaction conditions.

[0663] After completion of condensation, wash with MeOH, dry under vacuum to get 1 g of resin; cut with 10 mL of cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) for 12 h; after filtration, add the cleavage solution to 50 mL of ice isopropyl ether to precipitate the solid, centrifuge (3000 r / 3 min), pour the supernatant and dry the solid to get the crude product (200 mg), purify by preparative HPLC and lyophilize to get the product 7.27 mg. HPLC: 95.61%, RT: 13.272 min, MS: [M / 2+1] = 868.25.

[0664] General synthesis method 3: take the synthesis of Cyclo-[D-Tyr-D-MeArg-Arg-2-Nal-Lys(DOTA)] JHL011 (amino acid sequence corresponds to sequence 7) as an example

[0665] Step 1: synthesis of compound 1

[0666] Scale: 0.5 mmol CTC resin (0.78 g)

[0667] After completion of condensation, add methanol to shrink and dry the resin, add 20% HFIP / DCM to cut for 30 min / three times, filter out the cleavage solution, and directly proceed to the next step without further post-treatment.

[0668] Step 2: synthesis of compound 2

[0669] Add 6 mL of 0.12 mmol / mL HOAT / HATU to the cleavage solution of the previous step, and then add DIEA to adjust the pH to 8.0, react for 30 min, detect by LCMS that compound 1 is completely consumed, and the LCMS result shows that the product is generated, spin dry, and then purify by flash to get the product 47 mg.

[0670] Step 2: synthesis of JHL011

[0671] Add compound 1 (47.0 mg) to 2 mL of cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O), react for 8 h, then add the reaction solution to 10 mL of isopropyl ether to precipitate the solid, centrifuge (3000 r / 3 min) to pour out the supernatant and dry the solid to get the crude product, purify by preparative HPLC to get the product JHL011 14.99 mg, analytical method 5

[0672] HPLC: 98.37%, RT: 10.501 min

[0673] MS: [M+2] 2+ = 601.70

[0674] The following compounds were prepared using General Synthesis Method 3

[0675] Cyclo-[D-Tyr-D-MeArg-Arg-2-Nal-D-Lys(DOTA)] (amino acid sequence corresponds to Sequence 8) (JHL012)

[0676] Cyclo-[D-Tyr-Arg-Arg-2-Nal-Lys(DOTA)] (amino acid sequence corresponds to Sequence 9) (JHL013)

[0677] Cyclo-[D-Tyr-Arg-Arg-2-Nal-D-Lys(DOTA)] (amino acid sequence corresponds to Sequence 10) (JHL014)

[0678] General Synthesis Method 4: Illustrated by the synthesis of Cyclo-[Lys(Cysacid-Ac)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]-Lys(iPr)-Lys(DOTA)-NH2 (amino acid sequence corresponds to Sequence 12) JHL016

[0679] Step 1: Synthesis of JHL016

[0680] Scale: 0.5 mmol MBHA resin (0.78 g)

[0681] After completion of the condensation the resin was washed with MeOH to dryness (1.5 g resin). The resin was then cleaved with 15 mL cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) for 12 h. The cleavage solution was filtered and the solid was precipitated by addition of 80 mL ice-cold isopropyl ether, centrifuged (3000 r / 3 min), the supernatant was decanted and the solid was blown dry to give the crude product (600 mg). 100 mg of the crude product was purified by preparative HPLC to give 40.07 mg of the product. Using analytical method 5, HPLC: 96.40%, RT; 10.125 min, MS: [M / 2+1] = 947.49

[0682] The following compounds were prepared using General Synthesis Method 4:

[0683] Cyclo[Lys(CysAcid-Ac)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]Lys(iPr)Lys(hhy41-DOTA)NH2(amino acid sequence corresponds to SEQ 21) (JHL025)

[0684] Cyclo[Lys(CysAcid-PBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]Lys(iPr)Lys(DOTA)NH2(amino acid sequence corresponds to SEQ 22) (JHL026)

[0685] Cyclo[Lys(CysAcid-FOBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]Lys(iPr)Lys(DOTA)NH2(amino acid sequence corresponds to SEQ 23) (JHL027)

[0686] Cyclo[Lys(CysAcid-TBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-D-Ala-D-Glu]Lys(iPr)Lys(DOTA)NH2(amino acid sequence corresponds to SEQ 24) (JHL028)

[0687] Cyclo[Lys(CysAcid-Ac)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]Lys(iPr)Lys(hhy41-CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ 36) (JHL040)

[0688] General synthesis method 5: example with synthesis of Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Dap(TGA)]Lys(iPr)-PEG2-DOTA (amino acid sequence corresponds to SEQ 14) (JHL018)

[0689] Step 1: synthesis of compound 1

[0690] Scale: 0.5 mmol CTC resin (0.78 g)

[0691] After completion of condensation, methanol was added to shrink dry the resin, 20% HFIP / DCM was added to cleave for 30 min 三三 After completion of condensation, methanol was added to shrink dry the resin, 20% HFIP / DCM was added to cleave for 30 min

[0692] Step 2: Synthesis of compound 2

[0693] Compound 1 (100 mg) and DOTA-NHS (43.03 mg, 1.5 eq) were added together into 2 mL of DMF solution, followed by the addition of DIEA (37.82 uL, 4.0 eq) and reaction for 1 h. LCMS detection showed that compound 1 was completely consumed and the product was generated. The reaction solution was added to 10 mL of isopropyl ether to precipitate the product. After blowing dry, 120 mg of crude product was obtained.

[0694] Step 3: Synthesis of JHL018

[0695] Compound 2 (120 mg) was added together into 2 mL of cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) and reacted for 3 h. The reaction solution was added to 10 mL of isopropyl ether to precipitate the solid. After centrifugation (3000 r / 3 min) and blowing dry, the crude product was obtained. After preparation purification and lyophilization, 10.08 mg of product was obtained. Using analysis method 1, HPLC: 97.41%, RT; 11.259 min, MS: [M+2] = 813.26 2+

[0696] The following compounds were prepared using general synthesis method 5

[0697] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Lys]Lys(iPr)-PEG2-DOTA (amino acid sequence corresponds to sequence 15) JHL019

[0698] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Dap(TGA)]Lys(iPr)-PEG2-DOTA (amino acid sequence corresponds to sequence 16) JHL020

[0699] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Dap(TGA)]Lys(iPr)-Lys(CysAcid-DOTA)NH2 (amino acid sequence corresponds to sequence 32) JHL036 ​

[0700] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Lys(TGA)]Lys(iPr)-Lys(CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 33) JHL037

[0701] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Dap(TGA)]Lys(iPr)-Lys(CysAcid-CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 34) JHL038

[0702] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-Dap(TGA)]Lys(iPr)-Lys(CysAcid-CysAcid-CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 35) JHL039

[0703] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-4-PyAla-Gly-Dap(TGA)]Lys(iPr)-Lys(CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 40) JHL044

[0704] Cyclo[(CMTMBA)-Tyr-Lys(iPr)-D-Arg-Phe-Gly-Dap(TGA)]Lys(iPr)-Lys(CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 41) JHL045

[0705] General synthesis method 6: synthesis of Cyclo[(hhy41-TGA)-Tyr-Lys(iPr)-D-Arg-Phe-Gly-Cys]Lys(iPr)-Lys(CysAcid-DOTA)NH2(amino acid sequence corresponds to SEQ ID NO: 39) JHL043 as an example

[0706] Step 1: synthesis of compound 1

[0707] Scale: 0.3 mmol CTC resin (0.46 g)

[0708] Note: After completion of condensation, 1.0 g of resin was obtained by MeOH condensation. Then, 10.0 mL of cleavage solution (87.5% TFA / 7.5% DTT / 2.5% TIS / 2.5% H2O) was used to cleave the resin for 4 h. After filtration, the cleavage solution was added to 50 mL of ice isopropyl ether to precipitate the solid, which was centrifuged (3000 r / 3 min) and the supernatant was discarded. The solid was dried to obtain the crude product (500 mg).

[0709] Step 1: Synthesis of JHL043

[0710] Compound 1 (500 mg) was added to 50% ACN / H2O (120 / 120 mL), followed by saturated NH4HCO3to adjust the pH to 8.0. The reaction was allowed to proceed for 2 h, and LCMS indicated the formation of the product and complete consumption of compound 1. After lyophilization, 600 mg of solid crude product was obtained. 200 mg was subjected to preparative purification and lyophilization to obtain 25.38 mg of product. HPLC: 96.08%, RT: 10.903 min, MS: [M+2] = 934.26 using analytical method 2. 2+

[0711] The following compounds were prepared using General Synthesis Method 6

[0712] Cyclo[TGA-Lys(CysAcid-DOTA)-Tyr-Lys(iPr)-D-Arg-Phe-Gly-Cys]Lys(iPr)-NH2(amino acid sequence corresponds to Sequence 47) JHL051. HPLC: 99.61%, RT: 12.630 min, MS: [M+2] = 871.14 using analytical method 2. 2+

[0713] 2. 68 Ga and 177 Lu compound labeling

[0714] a. 68 Ga compound labeling

[0715] (1) 1.18 mg of precursor (JHL compound in 1 above) was weighed and dissolved in DMSO to make a 10 mg / ml precursor stock solution. 10 μL of the precursor stock solution was added to 990 μL of pH 4.5 sodium acetate buffer to make a 0.1 mg / mL precursor solution.

[0716] (2) 68 Ga solution preparation: ​​

[0717] Prepare three centrifuge tubes for use, marked as elution 1, elution 2, and elution 3. Elute the germanium gallium generator with 5 mL of 0.1 M HCl three times, and take the highest activity part for subsequent radiolabeling. Take two centrifuge tubes and add 0.5 mL of pH = 4.5 metal-free sodium acetate buffer, 0.5 mL of HCl, and 1 mL of HCl. 68 Ga solution, measure the radioactivity and record the time, add precursor solution according to the activity, vortex mix for 10 seconds, and heat the reaction at 95℃ and 800 rpm for 15 minutes.

[0718] After activation, add the labeling reaction mixture to the C18 cartridge, rinse dry, and rinse with saline, then with anhydrous ethanol, adding 3 drops to each tube for a total of 10 tubes. The sample with the highest activity is analyzed by radio-HPLC. Samples with a radiochemical purity greater than 90% are released for use in biological experiments.

[0719] b. 177 Lu compound labeling:

[0720] (1) 1 mg of the precursor compound (JHL compound in 1 above) was weighed and dissolved in DMSO to a 10 mg / mL stock solution. A certain amount of the stock solution was taken and dissolved in 0.45 M ascorbic acid buffer (pH 4.5) to a 0.1 mg / mL solution.

[0721] (2) Labeling according to a certain ratio of nuclide: precursor: 2mCi 177 LuCl3 and the amount of precursor calculated based on the real-time specific activity were added to a labeling buffer (0.45 M pH 4.5 ascorbic acid buffer) system to make the total volume of the reaction system 0.15 mL.

[0722] (3) The reaction was carried out at 95°C for 20 minutes on a thermostat. After the reaction was completed, the product was subjected to Radio-HPLC.

[0723] (4) If the Radio-HPLC result reaches 90%, the labeled product is considered qualified.

[0724] (5) Transfer the reaction solution to a vial, wash the reaction tube with 0.15 mL of saline, and add the washing solution to the vial.

[0725] (6) Add 6.7 μL of DTPA solution (0.25 mM) and mix well for later use.

[0726] The final preparation should be a clear solution and should be used immediately upon preparation and only on the same day.

[0727] 3. Cell competition binding assay:

[0728] (1) Accurately weigh a certain amount of compound (JHL compound in the above 1, i.e. compound without radionuclide labeling), add DMSO to dissolve the compound to prepare a 1 mM stock solution for storage, and store the solution at -20°C after dissolution.

[0729] (2) Take HT1080 CXCR4 6# in the logarithmic growth phase (constructed by Suzhou Jinweizhi Biological Technology Co., Ltd.), wash the cells once with PBS, add trypsin containing 0.25% EDTA for digestion, centrifuge at 400g for 5 min, and discard the supernatant.

[0730] (3) Resuspend each cell line with FACS buffer (PBS buffer + 2% FBS) and count the cells. r

[0731] (4) Adjust the cell density to 2×10 6 cells / mL, and inoculate into a U-bottom 96-well plate at 50 VL / well, i.e. 1×10 5 cells / well.

[0732] (5) Prepare 3× test compound using FACS buffer, set up a control well without adding sample, and add 50 μL of the corresponding compound to each well. Mix well, incubate on ice for 15 min.

[0733] (6) Prepare 3× competing fluorescent molecule BL34-cy5 using FACS buffer, set up a blank well without adding fluorescent molecule, and add 50 μL of the corresponding compound to each well. Mix well, incubate on ice for 60 min.

[0734] (7) Wash away the unbound compound with ice-cold FACS buffer, centrifuge at 400g for 5 min, discard the supernatant, and repeat once.

[0735] (8) Resuspend the cells in each well with 50 μL FACS buffer, mix well, add 100 μL 4% PFA solution, and fix at room temperature for 30 min. Detect the fluorescence signal using a flow cytometer.

[0736] (9) Analyze the data using Flowjo software, calculate the mean fluorescence intensity value (MFI), and calculate the inhibition rate of competing binding: inhibition rate (%) = (control group MFI - treatment group MFI) / control group MFI * 100. Use GraphPad Prism 9 software to plot, with sample concentration as the X axis and the inhibition rate (%) of the test compound as the Y axis, and use a four-parameter nonlinear model to fit and calculate the IC 50 value.

[0737] The in vitro cell competition binding activity of the compound is shown in Table 1.

[0738] ​Table 1 In vitro cell competition binding of JHL compounds

[0739] 4. In vitro stability study

[0740] The 68 Ga-JHL052, 68 Ga-JHL061 and 177 Lu-JHL061 were added to saline or human serum, respectively, and incubated in a water bath at 37 °C. The equilibration duration was 0 h, 1 h, 2 h. 200 μL of sample in saline or serum was pipetted each time, 200 μL of precipitant methanol was added, mixed well to precipitate the proteins. Centrifuged at 12000 rpm and the supernatant was collected, diluted with water in a ratio of 1 : 1. Subsequently, the radiolabeled mixture was filtered through a PVDF needle filter and then analyzed on RP-HPLC. The specific analysis results are shown in Table 2 and Table 3 (wherein the data in the table represent the peak on RP-HPLC, which corresponds to the purity of Ga-68 labeled compounds.).

[0741] Table 2 68 Stability of Ga-JHL052 and 68 Ga-JHL061 in human serum and saline

[0742] Table 3 177 Stability of Lu-JHL061 in human serum and saline

[0743] 5. Endocytosis experiment

[0744] HT1080hCXCR4 cells (AZENTA) were cultured in MEM medium (Gibco) supplemented with 10% fetal bovine serum (FBS, Gibco), 2 μg / mL puromycin (Beyotime) and 100 U / mL penicillin-streptomycin (P / S, Gibco) at 37 °C and 5% CO2.

[0745] HT1080hCXCR4 cells (1.5 x 10 5 ) were incubated with 68 Ga-JHL061, 68 Ga-JHL-052 and 68 Ga-Pentixafor (185 kBq / mL), respectively, for 10, 30, 60 and 120 minutes at 37 °C.

[0746] The medium supernatant was collected into a sample tube, the cells were washed twice with ice-cold PBS, and the supernatant and washes were collected into supernatant tube a. The cells were incubated with 0.5 M glycine buffer (100 mM NaCl, pH = 2.8) for 10 minutes to remove all the radiopharmaceutical bound to the cell surface, and the glycine wash was collected into glycine wash tube b. The cells were lysed with 1 M NaOH (0.5 mL), washed twice with 0.5 mL PBS, and the NaOH lysate and PBS washes were collected into cell lysate tube c. Each collection tube was counted for gamma activity (Auto Gamma Counter, PerkinElmer).

[0747] Total uptake (%) = (CPM value of glycine wash tube b + CPM value of cell lysate tube c) / (CPM value of supernatant tube a + CPM value of glycine wash tube b + CPM value of cell lysate tube c) * 100;

[0748] Internalization (%) = (CPM value of cell lysate tube c) / (CPM value of supernatant tube a + CPM value of glycine wash tube b + CPM value of cell lysate tube c) * 100.

[0749] Similarly, cells were incubated with 177 Lu-JHL061, 177 Lu-JHL052 and 177 Lu-Pentixafther (185 kBq / mL) for 0.5, 1, 3, and 6 hours at 37 °C. The wash and cell lysis procedures were the same as for the 68 Ga experiments.

[0750] The results of specific experiments are shown in Tables 4-7.

[0751] Table 4 68 Ga-JHL052 internalization on HT1080 hCXCR4 cells

[0752] Table 5 177 Lu-JHL052 internalization on HT1080 hCXCR4 cells

[0753] Table 6 68 Ga-JHL061 internalization on HT1080 hCXCR4 cells

[0754] Table 7 177 Lu-JHL061 internalization on HT1080 hCXCR4 cells

[0755] 6.68 Imaging of Ga labeled compounds in tumor bearing mice

[0756] 6-8 weeks old (Balb / c Nude) female mice were inoculated subcutaneously in the right shoulder with 2x10 6 HT10808#CXCR4 cells (in 50% matrigel, Corning) were inoculated subcutaneously in the right shoulder of the animals. When tumors reached the desired size for the experiment, the experiment was performed.

[0757] PCT / CT scan

[0758] 1) Turn on the PET / CT according to the operation procedure, open the scanning software, and perform daily calibration;

[0759] 2) Anesthetize the animals, and anesthetize the tumor-bearing mice by isoflurane (animal supplier: Zhejiang Vantoll Lihua Experimental Animal Technology Co., Ltd. Tumor-bearing mice supplier: Jinghe Biomedicine Technology (Shanghai) Co., Ltd. HT10808#CXCR4 is a CXCR4-overexpressing HT1080 cell line)

[0760] 3) After the tumor-bearing mice lost the righting reflex, a certain amount of the above Ga-labeled compound was injected into the tail vein; 68 Ga-labeled compound;

[0761] 4) Perform 1-hr dynamic, 2-hr, and 3-hr static scanning for 10 min after administration;

[0762] 5) During the process, record the animal weight, injection dose, injection time, residual dose, and measure the injection dose time and residual dose time, respectively, according to the record table;

[0763] 6) Circle the uptake of organs such as tumors and muscles of the animals, and perform image processing by PMOD software.

[0764] 68 The distribution of Ga-labeled JHL047 in mouse organs over time is shown in Table 8 and FIG. 1.

[0765] Table 8. 68 Distribution of Ga-labeled compound in mouse organs over time (%ID / g)

[0766] 7. 177 Distribution of Lu-labeled compound in tumor-bearing mice

[0767] 5-7 weeks old Balb / c Nude mice (Zhejiang Vantoll Lihua Experimental Animal Technology Co., Ltd.) were inoculated subcutaneously in the right shoulder with 2x10 6 HT10806#CXCR4 cells (in 50% matrigel, Corning) were inoculated subcutaneously in the right shoulder of the animals. When tumors reached the desired size for the experiment, the experiment was performed. 3The size of the tumor is measured and the animals are randomized into 13 groups according to the tumor size. The animals are weighed and the tumor size is measured. The animals are dosed with the control (saline) and the test compound (JHL-1, JHL-2, JHL-3, JHL-4, JHL-5, JHL-6, JHL-7, JHL-8, JHL-9, JHL-10, JHL-11, JHL-12, JHL-13) at a dose of 0.1 mg / kg. The animals are observed for general health and appearance twice a week for 4 weeks. The animals are weighed and the tumor size is measured twice a week for 4 weeks. The results show that the JHL compounds are effective in inhibiting the growth of CXCR4 positive tumors in animal models. 177 The Lu radiolabeled compound is injected into the tail vein of the mice (about 3.7 MBq / mouse). The animals are euthanized using carbon dioxide inhalation at 4 hours post-dosing. The blood and organs (liver, kidney, muscle tumor) are collected after euthanasia.

[0768] The blood is collected through inferior vena cava and immediately quantified 100 μL into designated centrifuge tubes (weighed). The organs are washed twice with deionized water and dried, and then put into pre-weighed test tubes, weighed again, and the sample weight is calculated. All blood samples and tissue samples are measured for radioactivity counts using a gamma counter. 177 The in vivo distribution of Lu-labeled JHL compound at 4 hours in tumor-bearing mice is shown in Table 9 and Table 10.

[0769] Table 9 177 The in vivo distribution of Lu-labeled JHL compound at 4 hours in tumor-bearing mice is shown in Table 9 and Table 10.

[0770] Table 10 177 The in vivo distribution of Lu-labeled JHL compound at 4 hours in tumor-bearing mice is shown in Table 9 and Table 10.

[0771] 8. -177 Treatment experiment of Lu-labeled compound

[0772] The 6-8 weeks old (Balb / c Nude) female mice are inoculated with 2 x 106 cells of HT1080 # CXCR4 (50% matrigel, Corning) subcutaneously in the right scapular region of the animals. When the tumor grows to the required size, the animals are randomly assigned to 13 experimental groups according to the tumor volume, 4 animals per group. The animal body weight and tumor size are measured, and the animals are dosed according to the control (saline) and groups 1-12 on the same day. The general health and appearance of the animals are observed twice a week for 1 week after the start of the experiment, and the animal body weight and tumor size are measured. Any abnormal observation is recorded in the original data during the entire study period. The results show that the JHL compound labeled with Lu-177 can effectively inhibit the growth of CXCR4 positive tumors in animal models, and the inhibitory effect is significantly better than that of the reference compound BL34, and the animal body weight does not change significantly during the experiment.

[0773] 9. Cell competition binding experiment of the compound shown in formula (a), (b) and (d)

[0774] The cell competition binding experiment of the compound represented by formula (a), (b) and (d) was operated as described above in the experiment operation of "3. Cell competition binding experiment". The experimental results showed that the compound represented by formula (a), (b) and (d) had good binding activity to CXCR4.

[0775] Although the specific embodiments of the present application are described above, those skilled in the art should understand that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the protection scope of the present application is defined by the appended claims.

Claims

1. A compound as shown in Formula (A), Formula (B), Formula (C), Formula (D), their pharmaceutically acceptable salts, their solvates, or solvates of their pharmaceutically acceptable salts: wherein in the compound of formula (A), R x is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 5 by forming an amide bond; R 4 For one or more R 4-1 Substituted C1-C4 alkyl; R 4-1 C6-C 10 Aryl, 5-10 membered heteroaryl, substituted by one or more R 4-1-1 Substituted C6-C 10 Aryl or one or more R 4-1-1 substituted 5-10 membered heteroaryl; R 4-1-1 independently -OH or halogen; X 6 for wherein the "#2" end is attached to "and X 6 adjacent to a "C(=O) group; X 8 is NH; R 2 each independently -H or C1-C4alkyl; m is 0, 1, 2, 3, 4, or 5; X 4 , R 8 , X 5 , L 5 , R 7 and X 7 are defined as any one of the following: Case 6: X 7 for wherein the "#6" end is connected to L 5 ; Ring Z is a 3-12 membered nitrogen-containing heterocycle; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 8 independently NH or O; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) group; R 5 -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted by one or more R R 6-1 For or -COOH; L 5 for a bond, wherein "g" is connected to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted with one or more L L a-1 independently -SO3H or -COOH; L b Ci-C6-alkylene is C1-C6-alkylene as defined above; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; R 7 substituted by one or more R 7-1 C1-C4alkyl; R 7-1 is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; Case 4: L 5 for a bond, wherein "g" is connected to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5; L a independently substituted C1-C4alkyl; or a-1 substituted C1-C4alkyl; or L a-1 independently -SO3H or -COOH; L b R is C1-C6alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; X 7 -NR 7-11 - or wherein the "#6" end is connected to L 5 ; R 7-11 is -H or C1-C4alkyl; Ring Z is a 3-12 membered nitrogen-containing heterocycle; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 8 independently NH or O; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) group; R 5 is -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted by one or more R R 6-1 for or -COOH; R 7 substituted by one or more R 7-1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; Case 1: X 4 for wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 8 independently NH or O; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) group; R 5 is -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted C1-C4 alkyl; R 6-1 for or -COOH; X 7 -NR 7-11 - or wherein the "#6" end is connected to L 5 ; R 7-11 is -H or C1-C4alkyl; Ring Z is a 3-12 membered nitrogen-containing heterocycle; L 5 for a bond, wherein "g" is connected to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted C1-C4alkyl; L a-1 independently -SO3H or -COOH; L b R is C1-C6alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C6-C12aryl, 5-10 membered heteroaryl, C3-C12cycloalkyl, or 3-12 membered 10 heterocycloalkyl; each R7is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 3-6 membered 12 heterocycloalk Case 2: R 8 independently O; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) R 5 -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted by one or more R R 6-1 for or -COOH; X 7 -NR 7-11 - or wherein the "#6" end is connected to L 5 ; R 7-11 is -H or C1-C4alkyl; Ring Z is a 3-12 membered nitrogen-containing heterocycle; L 5 for a bond, wherein "g" is attached to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5; L a Each independently is one or more L a-1 Substituted C1-C4 alkyl; L a-1 independently -SO3H or -COOH; L b R is C1-C6alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; Case 3: X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to the "C(=O) R 5 is -H or C1-C4alkyl; n 10 is 2, 3 or 4; R 6 substituted by one or more R 6-1 C1-C4alkyl; R 6-1 for or -COOH; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 8 independently NH or O; X 7 -NR 7-11 - or wherein the "#6" end is connected to L 5 ; R 7-11 -H or C1-C4alkyl; Ring Z is a 3-12 membered nitrogen-containing heterocycle; L 5 for a bond, wherein "g" is connected to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted with one or more L L a-1 independently -SO3H or -COOH; L b R is C1-C6alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl; Case 5: R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 8 independently O or NH; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to the "C(=O) R 5 -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted by one or more R R 6-1 For or -COOH; X 7 -NR 7-11 - or wherein the "#6" end is connected to L 5 ; R 7-11 -H or C1-C4alkyl; Ring Z is a 3-12 membered nitrogen-containing heterocycle; L 5 for a bond, wherein "g" is attached to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a Each independently is one or more L a-1 Substituted C1-C4 alkyl; L a-1 independently -SO3H or -COOH; L b Ci-C6-alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; in the compound of formula (B), R x1 is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 4 by forming an amide bond; X 4 is a bond or wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7 is 0, 1, 2, 3, or 4; R 4 For one or more R 4-1 Substituted C1-C4 alkyl; R 4-1 C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, R 4-1-1 independently -OH or halogen; X 6 for wherein the "#2" end is attached to "and X 6 adjacent to a "C(=O) group; R 2 each independently -H or C1-C4alkyl; X 8 is NH; R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl; X 5 for a bond, wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) R 5 -H or C1-C4alkyl; n 10 is 0, 1, 2, 3, or 4; R 6 -H, C1-C4 alkyl or C1-C4 alkyl substituted by one or more R 6-1 substituted by one or more R R 6-1 for or -COOH; R 3 -H or C1-C4alkyl substituted by one or more R 3-1 substituted by one or more R R 3-1 C1-C4alkoxy, C6-C10aryl, -COOH, -SO3H, -C(=O)NH2, 10 C1-C4alkoxy, C6-C10aryl, -COOH, -SO3H, -C(=O)NH2, C3-C 12 Cycloalkyl or 3-12 membered heterocycloalkyl; R a For one or more R a1 Substituted C1-C4 alkyl; R a1 independently or -COOH; R b For one or more R b1 Substituted C1-C4 alkyl; R b1 C6-C10aryl, 5-10 membered heteroaryl, 10 C6-C10aryl, 5-10 membered heteroaryl, By one or more R b12 Substituted C6-C 10 Aryl or one or more R b12 substituted 5-10 membered heteroaryl; R b11 C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R b11-1 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R b11- 1 substituted C6-C10aryl, 5-10 membered R b11-1 independently halogen; R b12 independently C1-C4alkyl; R 8 is NH or O; L 4 for L 4-1 for a bond, wherein "f' end is connected to R x1 ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5; L a Independently for one or more L a-1 Substituted C1-C4 alkyl; L a-1 independently -SO3H or -COOH; L b Ci-C6-alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently a C5-C6 cycloalkene or a 5-6 membered heterocyclene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; in the compound of formula (C), X 6 for wherein the "#2" end is attached to "and X 6 adjacent to a "C(=O) group; R 2 each independently -H or C1-C4alkyl; X 8 is NH; L 3 for a bond, wherein the "#5" end is connected to R x2 ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 are each independently 0, 1, 2, 3, 4, or 5; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted with one or more L L a-1 independently -SO3H or -COOH; L b Ci-C6-alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocyclene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently C5-C6cycloalkene or 5-6 membered heterocycloalkene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; R x2 is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 3 by forming an amide bond; R 4 substituted by one or more R 4-1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R 4-1 C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, R 4-1-1 independently -OH or halogen; R 7 substituted by one or more R 7-1 C1-C4alkyl; R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; R 8 independently NH or O; In the compound of formula (D): R 8 independently NH or O; R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; X 6 for wherein the "#2" end is attached to "and X 6 adjacent to a "C(=O) group; R 2 each independently -H or C1-C4alkyl; X 8 is NH; R 4 substituted by one or more R 4-1 C1-C4alkyl; R 4-1 C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 4-1-1 substituted C6-C10aryl, R 4-1-1 independently -OH or halogen; X 1 , X 2 and X 3 are defined as any one of the following: Case 1: X 1 is a bond or wherein the "a" end is attached to X 2 ; X 2 for wherein the b end is connected to X 1 and the c end is connected to X 3 ​ n and n1 are each independently 0, 1, 2, 3, 4, or 5; L 1 to connect a chain; R x3 is H; or a metal chelating group capable of binding to a radioisotope; X 3 for wherein the "d" end is attached to X 2 ; Ring A is a C6-C10 aryl or 5-10 membered heteroaryl ring; 10 a phenyl ring or a 5-10 membered heteroaryl ring; Ring B is C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; n4, n5, and n6 are each independently 0, 1, 2, 3, 4, or 5; Case 2: X 1 is a bond or wherein the "a" end is connected to X 2 ; X 2 for wherein the b end is connected to X 1 and the c end is connected to X 3 ​ n and n1 are each independently 0, 1, 2, 3, 4, or 5; X 3 for wherein d is connected to X 2 ; L 2 to connect a chain; R x4 is H; or a metal chelating group capable of binding to a radioisotope; Case 3: X 1 for wherein a is connected to X 2 ; X 2 for The end marked "#" is connected to X 3 ; L 6 for L 6-1 for a bond, one end of the label "##" is connected to R x ; n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a each independently is substituted C1-C4alkyl substituted with one or more L a-1 substituted C1-C4alkyl; L a-1 independently -SO3H or -COOH; L b Ci-C6-alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocycloalkene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently C5-C6cycloalkene or 5-6 membered heterocycloalkene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; X 3 for one end of the label "###" is connected to X 2 in connection with L c for Cycloalkyl A1is C3-C10 10 C6-C10aryl or 5-10 membered heteroaryl; n 13 and n 14 each independently is 0, 1, 2, 3, 4, or 5; R x5 is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 6 by forming an amide bond; Case 4: X 1 for -X 1-1 -X 1-2 - *** , labeled "***" is connected to X 2 ; X 1-1 for Label "#1" is connected to X 1-2 at one end; X 1-2 for X 2 for n 13 , n 14 , n 15 and n 16 are each independently 0, 1, 2, 3, 4 or 5; L d for a bond, the end marked "#2" is connected to R x R n2, n7, n8, n 10 , n 11 , n 12 , n 18 and n 19 each independently is 0, 1, 2, 3, 4, or 5; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted with one or more L L a-1 independently -SO3H or -COOH; L b R is C1-C6alkylene; Ring C is independently a 3-12 membered nitrogen-containing heterocycle; Ring D is independently a phenyl ring or a 5-6 membered heteroaromatic ring; Ring E is independently a 5-6 membered nitrogen-containing heterocycloalkene; Ring F is independently C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; Ring G is independently C5-C6cycloalkene or 5-6 membered heterocycloalkene; Ring D and Ring E form a fused ring; Ring D and Ring G form a fused ring; X 3 for -X 3-1 -X 3-2 - * , the end marked "*" is connected with X 2 ; X 3-1 for Label "**" at D end of X 3-2 connected; X 3-2 for R x6 is H; or a metal chelating group capable of binding to a radioisotope, which is linked to R x6 by forming an amide bond; Above, the carbon atom marked "*" is in the R configuration, the S configuration, or a mixture thereof; in each "5-10 membered heteroaryl", the heteroatoms are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; in each "3-10 membered heterocycloalkyl", the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3; in each "3-12 membered nitrogen-containing heterocycle", the heteroatoms are selected from one or both of N, O, and S, and the number of heteroatoms is 1, 2, or 3; in each "5-6 membered heteroaromatic ring", the heteroatoms are selected from one, two, or three of N, O, and S, and the number of heteroatoms is 1, 2, or 3; in each "5-6 membered nitrogen-containing heterocycloalkene", the heteroatoms are selected from one or both of N, O, and S, and the number of heteroatoms is 1, 2, or 3.

2. The compound as shown in formula (A), formula (B), formula (C), formula (D), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, one or more of the following conditions are met: (1) each "C1-C4alkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, or t-butyl, for example methyl, ethyl, n-propyl, or n-butyl; (2) each "C6-CiO aryl" is phenyl or naphthyl; 10 each "aryl" is independently phenyl or naphthyl; (3) each "5-10 membered heteroaryl" is independently a 5-6 membered heteroaryl having 1 or 2 heteroatoms which are N, for example pyridyl, further for example (4) each "halogen" is independently F, Cl, Br, or I, for example F; (5) each "C3-C6cycloalkyl" is independently a C3-C6cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; 12 each "cycloalkyl" is independently a C3-C6cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (6) each "3-12 membered heterocycloalkyl" is independently a 3-6 membered heterocycloalkyl group having one or two heteroatoms that are N, for example piperidinyl or piperazinyl; (7) each "3-12 membered nitrogen-containing heterocycle" is independently a 3-6 membered nitrogen-containing saturated heterocycle having 1 or 2 heteroatoms which are N, for example a piperidine or piperazine ring, further for example (8) each "5-6 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring having one or two heteroatoms that are N, for example a pyridine ring; (9) each "5-6 membered nitrogen-containing heterocyclic olefin" is independently a 5-6 membered nitrogen-containing heterocyclic olefin having 1 or 2 heteroatoms of which each is N, for example (10) each "C5-C6cycloalkene" is independently cyclohexene; (11) each "C1-C4alkoxy" is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, or t-butoxy, for example methoxy; (12) each "5-10 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring having 1 or 2 heteroatoms which are N, for example a pyridine ring; (13) each "C3-C6cycloalkyl" is independently a saturated carbocyclic ring of from 3 to 6 carbon atoms; 12 each "carbocyclic" is independently C3-C6carbocyclic; 12 saturated carbocyclic rings, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane; (14) each "3-12 membered heterocycle" is independently a 3-6 membered saturated heterocycle with 1 or 2 heteroatoms being N, for example a piperidine or piperazine ring, further for example 3. The compound as claimed in claim 1 or 2, which is represented by formula (A), formula (B), formula (C), formula (D), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are satisfied: (1) in the compound of formula (A), m is 1, 3 or 4; (2) In the above-mentioned compounds of formula (A), in the above-mentioned cases 1, 2, 3, 4 and 5, X 7 independently -NH- or (3) In the compound represented by formula (A), in the case 6, X 7 is (4) In the compound represented by formula (A), in the case 1, X 4 is (5) In the compounds of formula (A), in cases 2, 3, 4, 5 and 6, X 4 independently a bond or (6) the compound represented by formula (B) is a compound in which X 4 is a bond or (7) In the compounds of formula (A), (B), (C), and (D) described above, R 4 independently -(CH2) a -R 4-1 , a is 1, 2, 3, or 4, R 4 for example -(CH2)-R 4-1 ; (8) In the compounds of formula (A), (B), (C), and (D) described above, R 4-1 independently phenyl, naphthyl, phenyl substituted with one hydroxy, or phenyl substituted with one F, for example For example (9) In the compound represented by formula (C), X 6 is (10) In the compounds of formula (A), (B) and (D) described above, X 6 independently are (11) In the compounds of formula (A), (B), (C), and (D) described above, R 7 independently -(CH2) a1 -R 7 - 1 , a1 is 1, 2, 3, or 4, R 7 for example -(CH2)-R 7-1 ; (12) In the compounds of formula (A), in each of cases 1, 2, 3, 4, and 6, R 7-1 independently C6-Ci0aryl, 5-6 membered heteroaryl, or C5-C6cycloalkyl, for example phenyl, naphthyl, cyclohexyl, or pyridyl; and 10 independently C6-Ci0aryl, 5-6 membered heteroaryl, or C5-C6cycloalkyl, for example phenyl, naphthyl, cyclohexyl, or pyridyl; and (13) In the compound of formula (A), in the case 5, R 7-1 C5-C6-cycloalkyl, for example cyclohexyl; (14) In the compound represented by formula (B), formula (C) or formula (D), R 7-1 is C6-C 10 aryl, 5-6 membered heteroaryl or C5-C6cycloalkyl, for example phenyl, naphthyl, cyclohexyl or pyridyl; (15) In the compounds of formula (A), in cases 1, 2, 4, 5, and 6, X 5 independently a bond, for example a bond, (16) In the compound represented by formula (A), in the case 3, X 5 is a bond, for example a bond, (17) the compound represented by formula (B) wherein X 5 is a bond, for example a bond, (18) In the compounds of formula (A) as described in (1) above, in each of the cases 1, 2, 3, 5, and 6, L 5 is independently a bond, for example a bond, (19) In the compound represented by formula (A), in the case 4, L 5 is a bond, for example a bond, (20) In the compound of Formula (B), R 3 is -H or -(CH2) a3 R 3-1 , a3 is 1, 2, 3 or 4, R 3 is, for example, -H, (21) the compound represented by formula (B) wherein L 4 is L 4-1 for a bond, L 4 For example, as (22) the compound represented by formula (C) wherein L 3 is a bond; (23) In the compound represented by formula (D), in the case 1, X 2 is wherein the b end is connected to X 1 and the c end is connected to X 3 ​ (24) In the compound of formula (D), in the case 1, X 3 is (25) In the compound of formula (D), in the case 2, X 2 is (26) In the compound of Formula (D), in the case 3, L 6 is For example (27) In the compound of formula (D), in the case 3, L c is (28) In the compound of Formula (D), in the case 4, X 2 is (29) In the compound of Formula (D), in the case 4, L d is For example, as 4. The compound as shown in formula (A), formula (B), formula (C), formula (D), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, one or more of the following conditions are satisfied: (1) In the compound represented by formula (A), formula (B), formula (C), or formula (D), R 4 is (2) In the above-mentioned compounds represented by the formula (A), in the cases 1, 2, 3, 4 and 6, R 7 independently are (3) In the compound represented by formula (A), in the case 5, R 7 is (4) In the compounds of formula (B), (C), and (D) described above, R 7 independently are (5) In the compound represented by formula (D), in the case 1, L 1 is L 1-1 for a bond, For example wherein the "#3" end is attached to R x3 x3 L 1 by forming an amide bond, wherein n2, n7, n8, n 10 , n 11 , n 12 , n 18 , L a , L b , ring C, ring D and ring E are as defined in any one of claims 1-3;​ Preferably, in the compound of formula (D), in the case 1, L 1 is wherein the "#3" end is attached to R x3 x3 L 1 by forming an amide bond;​ (6) In the compound of formula (D), in the case 2, L 2 is a bond, For example wherein the "#4" end is attached to R x4 x4 2 by forming an amide bond, wherein n2, n7, n8, n 10 , n 11 , n 12 , n 18 , L a , L b , ring C, ring D and ring E are as defined in any one of claims 1-3;​​ Preferably, in the compound of formula (D), the case 2, L 2 is wherein the "#4" end is attached to R x4 x4 2 by forming an amide bond;​​ (7) said R x , R x1 , R x2 , R x3 , R x4 , R x5 and R x6 are each independently: H, Preferably 5. The compound of formula (A), (B), (C), (D), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that: The compound as shown in formula (A) is a compound as shown in formula (A-1): The compound represented by the formula (B) is a compound represented by the formula (B-1): The compound as shown in formula (C) is a compound as shown in formula (C-1): wherein the carbon atom marked with "*" is in R configuration, S configuration or a mixture thereof; The compound represented by formula (D) is a compound represented by formula (D-1): Preferably, in the compound of formula (D), in the case 1, -X 2 - is: 3 - is:

6. The compound of formula (A), (B), (C), (D), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, the compound of formula (A-1) is any one of the following: Scheme A: X 4 , R 8 , X 5 , L 5 , R 7 and X 7 are as defined in case 6 of any one of claims 1-4, and the remaining variables are as defined in any one of claims 1-4; preferably, X 7 for wherein the "#6" end is connected to L 5 ; ring Z is a 5-6 membered nitrogen-containing saturated heterocyclic ring; L 5 for wherein "g" is connected to R x ; n10 is 1; L a each independently is substituted C1-C4alkyl substituted with one or more L a-1 substituted C1-C4alkyl; L a-1 independently -SO3H; m is 1 or 2; R 4 For one or more R 4-1 Substituted C1-C4 alkyl; R 4-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 4-1-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6 R 4-1-1 independently -OH or halogen; R 8 is O or NH; R 7 substituted by one or more R 7-1 C1-C4alkyl; R 7-1 is C6-C 10 aryl; X 5 for n7 is 1 or 2; X 4 is a bond; R x is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 5 by forming an amide bond; Scheme 2: X 4 , R 8 , X 5 , L 5 , R 7 and X 7 are as defined in case 4 of any one of claims 1-4, and the remaining variables are as defined in any one of claims 1-4. preferably, L 5 for wherein "g" is connected to R x ; n 11 independently 0 or 1 ; n 12 independently 1 ; ring C is a 5-6 membered nitrogen-containing saturated heterocyclic ring; ring D is a benzene ring; ring E is a 5-6 membered nitrogen-containing heterocyclic olefin; L a Independently for one or more L a-1 Substituted C1-C4 alkyl; L a-1 is -SO3H or -COOH; X 7 is NH; m is 3 or 4; R 4 substituted by one or more R 4-1 C1-C4alkyl; R 4-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 4-1-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6 R 4-1-1 independently -OH or halogen; R 8 is O or NH; R 7 substituted by one or more R 7-1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R 7-1 is C6-C 10 aryl; X 5 for n7 is 1 or 2; X 4 is a bond; R x is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 5 by forming an amide bond; in the compound of formula (B-1), X 4 is a bond; R 3 substituted by one or more R 3-1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R 3-1 -COOH or -SO3H; R 4 For one or more R 4-1 Substituted C1-C4 alkyl; R 4-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 4-1-1 C6-Ci0-alkyl or C6-Ci0-alkyl substituted by one or more R 10 C6 R 4-1-1 independently -OH or halogen; R 8 is NH or O; R 7 substituted by one or more R 7-1 C1-C4alkyl; R 7-1 is C6-C 10 aryl; X 5 for wherein the "a2" end is attached to "and X 5 adjacent to a "C(=O) R 5 -H or C1-C4alkyl; n 10 is 1 or 2; L 4 for L 4-1 for n11 is 0; ring D is a benzene ring; ring E is a 5-6 membered nitrogen-containing heterocyclic olefin; ring C is a 5-6 membered nitrogen-containing saturated monocyclic heterocyclic ring or a 9-11 membered nitrogen-containing saturated spirocyclic heterocyclic ring; L b Ci-C6-alkylene; L a independently substituted C1-C4alkyl; or a-1 C1-C4alkyl; L a-1 independently -SO3H or -COOH; R x1 is H; or a metal chelating group capable of binding to a radioisotope, which is linked to L 4 by forming an amide bond.

7. The compound of formula (A), (B), (C), (D), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound as shown in formula (A) is any one of the following compounds: The compound as shown in formula (B) is any one of the following compounds: The compound of Formula (C) is any one of the following compounds: The compound represented by formula (D) is any one of the following compounds:

8. A compound E, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, the compound E is a compound of formula (A), (B), (C) or (D) according to any one of claims 1-7, chelated with a radioisotope to form a compound; Preferably, the radioisotope is 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 165 Er, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 111 In, 47 Sc, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 223 Ra, 224 Ra, 227 Th, 64 Cu, 67 Cu, 68 Ga, 177 Lu, 67 Ga, 61 Cu, 99m Tc, 114m In, 44 Sc, 86 Y, 89 Zr or 90 Nb, for example 177 Lu or 68 Ga.

9. The compound of claim 8, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein, the compound E is any one of the following: (1) In the compound E, the radioisotope is a therapeutic radioisotope, for example 177 Lu, 90 Y, 89 Sr, 188 Re, 225 Ac, 212 Bi, 213 Bi, 203 Pb, 212 Pb, 165 Er, 211 At, 166 Ho, 149 Pm, 159 Gd, 105 Rh, 109 Pd, 198 Au, 199 Au, 175 Yb, 142 Pr, 111 In, 47 Sc, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 223 Ra, 224 Ra, 227 Th or 67 Cu, further for example 177 Lu; (2) In the compound E, the radioisotope is a diagnostic radioisotope, for example 68 Ga, 177 Lu, 67 Ga, 61 Cu, 64 Cu, 99m Tc, 114m In, 111 In, 44 Sc, 86 Y, 89 Zr or 90 Nb, for example 68 Ga or 177 Lu.

10. A pharmaceutical combination comprising a substance X and a substance Y, said substance X being a compound E according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, wherein, in the compound E, the radioisotope is a diagnostic radioisotope according to claim 9; the substance Y is a compound E according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, wherein in the compound E, the radioisotope is a therapeutic radioisotope according to claim 9.

11. A pharmaceutical composition comprising a compound E according to claim 8 or 9, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. Use of the compound E according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the diagnosis of a disease, characterized in that, in the compound E, the radioisotope is a diagnostic radioisotope according to claim 9, and the disease is a disease associated with CXCR4; preferably, the disease is a disease positive for CXCR4 expression; more preferably, the disease is a solid tumor, for example fibrosarcoma.

13. Use of the compound E according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the diagnosis of a disease, characterized in that, In the compound E, the radioisotope is a therapeutic radioisotope as defined in claim 9, and the disease is a disease associated with CXCR4; preferably, the disease is a disease positive for CXCR4 expression; more preferably, the disease is a solid tumor, such as fibrosarcoma.

14. A compound of Formula (a), Formula (b), or Formula (d), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: wherein, In the compound of formula (a), X 6 , and m are as defined in any one of claims 1-7; X 4 , R 4 , R 8 , X 5 , R 7 and X 7 are defined as any of the following: Case A: X 4 for wherein the "a1" end is attached to the "and X 4 adjacent to the "C(=O) n7, R 4 n7, R 8 n7, R 5 n7, R 7 n7, R 7 n7, R Preferably, X 4 The definitions of the variables are as follows: X in any one of claims 1 to 7 4 As described in the definitions of the corresponding variables; Case B: R 4 For one or more R 4-1 Substituted C1-C4 alkyl, R 4-1 For one or more R 4-1-1 Substituted C6-C 10 Aryl or one or more R 4-1-1 Substituted 5-10 membered heteroaryl, R 4-1-1 are independently halogen; X 4 , R 8 , X 5 , R 7 and X 7 are as defined in any one of claims 1 to 7; Preferably, R 4 the definitions of the variables in any one of claims 1 to 7 4 the definitions of the corresponding variables of R Case C: X 5 for a bond, n 10 is 2, 3 or 4; R 6 R is C1-C4alkyl substituted by one or more R 6-1 R is C1-C4alkyl substituted by one or more R 6-1 R is C1-C4alkyl substituted by one or more R or -COOH; X 4 , R 4 , R 8 , R 5 , R 7 and X 7 are as defined in any one of claims 1 to 7; Preferably, X 5 The definitions of the variables are as follows: X in any one of claims 1 to 7 5 As described in the definitions of the corresponding variables; Case D: R 8 is O; X 4 , R 4 , X 5 , R 7 and X 7 are as defined in any one of claims 1 to 7; Case E: R 7 For one or more R 7-1 Substituted C1-C4 alkyl; R 7-1 is phenyl, 5-10 membered heteroaryl, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; X 4 , R 4 , R 8 , X 5 and X 7 are as defined in any one of claims 1 to 7; Preferably, R 7 the definitions of the variables in any one of claims 1 to 7 7 the definitions of the corresponding variables of R Case F: X 7 for wherein the "#6" end is attached to H; Ring Z is a 3-12 membered nitrogen-containing heterocyclic ring; X 4 , R 4 , R 8 , X 5 and R 7 are as defined in any one of claims 1 to 7; Preferably, X 7 The definitions of the variables are as follows: X in any one of claims 1 to 7 7 As described in the definitions of the corresponding variables; In the compound of formula (b), X 4 , R 4 , X 6 , "*", X 5 , and R 7 are as defined in any one of claims 1-7. R 3 and the definition of R 8 is any one of the following: Case 1: R 3 -H or C1-C4alkyl substituted by one or more R 3-1 substituted by one or more R R 3-1 C1-C4alkoxy, -COOH, -SO3H, -C(=O)NH2, C3-C 12 cycloalkyl or 3-12 membered heterocycloalkyl; R a substituted by one or more R a1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R a1 independently or -COOH; R b substituted by one or more R b1 substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R substituted by one or more R b1 C6-C10aryl, 5-10 membered heteroaryl, 10 C6-C10aryl, 5-10 membered heteroaryl, By one or more R b12 Substituted C6-C 10 Aryl or one or more R b12 substituted 5-10 membered heteroaryl; R b11 C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R b11-1 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R 10 substituted C6-C10aryl, 5-10 membered heteroaryl, C6-C10aryl substituted by one or more R b11- 1 substituted C6-C10aryl, 5-10 membered R b11-1 independently halogen; R b12 independently C1-C4alkyl; R 8 is NH or O; Preferably, R 3 the definitions of the variables in any one of claims 1 to 7 3 the definitions of the corresponding variables of R Case 2: R 8 is O; R 3 of any one of claims 1-7; In the compound of formula (d), X 1 , R 7 , R 8 , "*, X 6 , and R 4 are as defined in any one of claims 1-7; X 2’ and X 3’ is defined as any one of the following: Case i: X 2’ for wherein the b end is connected to X 1 and the c end is connected to X 3’ and the c end is connected to X n and n1 are each independently 0, 1, 2, 3, 4, or 5; X 3’ for wherein d is connected to X 2’ ; Ring A is a C6-C10 aryl or 5-10 membered heteroaryl ring; 10 a phenyl ring or a 5-10 membered heteroaryl ring; Ring B is C3-C 12 carbocyclic or 3-12 membered heterocyclic ring; n4, n5, and n6 are each independently 0, 1, 2, 3, 4, or 5; Preferably, X 2’ The definitions of the variables are as follows: X in any one of claims 1 to 7 2 As described in the definitions of the corresponding variables; X 3’ the definitions of the variables in any one of claims 1 to 7 for X 3 the definitions of the corresponding variables for X; Case ii: X 2’ for wherein the b end is connected to X 1 and the c end is connected to X 3’ ​ n and n1 are each independently 0, 1, 2, 3, 4, or 5; X 3’ for wherein d is connected to X 2’ ; Preferably, X 2’ The definitions of the variables are as follows: X in any one of claims 1 to 7 2 As described in the definitions of the corresponding variables; X 3’ the definitions of the variables in any one of claims 1 to 7 for X 3 the definitions of the corresponding variables for X.

15. Any one of the compounds described as follows:

16. A pharmaceutical composition comprising a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the compound e being a compound as defined in claim 14 or 15.

17. Use of a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 16, the compound e being a compound as defined in claim 14 or 15, for the manufacture of a CXCR4 antagonist or a CXCR4 binding agent.

18. Use of a compound e, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 16, the compound e being a compound as defined in claim 14 or 15, for the manufacture of a medicament for the prevention and / or treatment of a disease associated with CXCR4; preferably, the disease is a disease positive for CXCR4 expression; more preferably, the disease is a solid tumor, such as fibrosarcoma.

19. A compound represented by formula (II): wherein, Pg is an amino protecting group; m, ring Z, n10and L a as defined in any one of claims 1 to 7; R xp R is protected by a protecting group xp1 R xp1 is a metal chelating group capable of binding to a radioisotope as defined in claims 1-7; Preferably, Pg is an amino protecting group that is removed under acidic conditions, such as Fmoc; m is 1 or 2; Ring Z is a 5-6 membered nitrogen-containing saturated heterocyclic ring; L a each independently is C1-C4alkyl substituted with one or more L a-1 substituted C1-C4alkyl; L a-1 independently -SO3H; R xp for Pg 1 independently C1-C6alkyl; More preferably, the compound of formula (II) is:

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