Preparation and use of prostate-specific membrane antigen small molecule inhibitor and radionuclide complex thereof

Abstract

The present invention relates to the field of nuclear medicine, and relates to preparation and use of a prostate-specific membrane antigen small molecule inhibitor and a radionuclide complex thereof. The prostate-specific membrane antigen small molecule inhibitor of the present invention has a structure represented by the following general formula (I). The present invention also provides a radionuclide complex comprising a radionuclide and the prostate-specific membrane antigen small molecule inhibitor. According to the present invention, on the basis of the prostate-specific membrane antigen small molecule inhibitor, the complexes formed by labeling with a plurality of medical radionuclides such as 68Ga or 177Lu can be used for PSMA-specific SPECT / CT, PET / CT imaging or prostate cancer treatment, respectively. The complex is characterized by a high labeling rate, good stability, good tumor tissue targeting, etc., providing a new idea for the integration of prostate cancer diagnosis and treatment, and demonstrating broad application prospects. R-X-R1 (I)

Description

Preparation and application of prostate-specific membrane antigen small molecule inhibitor and radionuclide complex thereof TECHNICAL FIELD

[0001] The present application relates to the field of nuclear medicine, in particular to the preparation and application of a prostate-specific membrane antigen small molecule inhibitor and radionuclide complex thereof. BACKGROUND

[0002] In recent years, the incidence of prostate cancer in China has increased significantly, and has become the fastest growing disease among all malignant tumors.

[0003] Early imaging diagnosis and treatment of prostate cancer has become an urgent problem to be solved in China and even the whole world. Prostate cancer begins to occur in the tissue around the prostate, and as it grows, it gradually metastasizes to other important organs such as the lungs and the bone. In the early stage, there are no obvious symptoms, but as the prostate cancer grows, it can cause problems such as urethral compression and urinary tract obstruction, and further metastasize to the spine or pelvis. For the diagnosis of prostate cancer, imaging diagnosis methods such as SPECT (single photon emission computed tomography) and PET (positron emission tomography) are currently being used, the principle of which is to use a polypeptide substance labeled with a gamma-ray or positron emitting radioisotope targeting PSMA, and to display the presence and distribution of tumor cells in the tomographic image and three-dimensional image by prostate cancer specific targeting distribution. These imaging diagnosis methods have recently been greatly promoted due to the development of SPECT-CT / MRI and PET-CT / MRI combined with CT or MRI, which has greatly improved image quality. The current radio-pharmaceuticals used for prostate cancer specific imaging are PSMA ligands as targeting groups, which can bind to the protein PSMA (prostate-specific membrane antigen) specifically expressed in prostate cancer. PSMA is a type II transmembrane glycoprotein also known as glutamate carboxypeptidase, and is a prostate cancer specific molecular marker, with expression levels in tumor tissues much higher than in normal tissues, and is overexpressed on the surface of almost all prostate cancer cells, and the expression is further increased in low differentiation, metastatic and androgen-independent prostate cancer cells, while the expression level in normal tissues such as the kidney, intestine and brain is more than 1000 times lower. PSMA has become an effective target for the diagnosis and treatment of prostate cancer.

[0004] Currently, castration, anti-androgen castration methods and androgen receptor inhibitors are the mainstream treatment options for prostate cancer. Although these treatment options are very effective in the initial stage, a large number of patients will develop castration-resistant prostate cancer (CRPC) or even metastatic castration-resistant prostate cancer (mCRPC).

[0005] mCRPC is a disease with limited treatment options and significant unmet medical needs, so radiopharmaceuticals targeting PSMA have become a research hotspot in recent years. Representative ligands of PSMA are peptide derivatives such as Glu-urea-Lys (EUK) or Glu-urea-Cys (EUC). Therefore, by labeling a radioisotope on a peptide ligand containing such a peptide ligand, a radiopharmaceutical can be prepared for prostate cancer imaging by PET or SPECT, or for the treatment of prostate cancer (Meder, et al., Bioconjugate Chem 2012, 23: 688-697).

[0006] Nucleus-labeled small molecule inhibitors targeting PSMA have shown superior diagnostic and therapeutic properties in clinical trials. Ahmadzadehfar H et al. administered Lu177 (177Lu)-labeled PSMA-617 to 22 patients with metastatic castration-resistant prostate cancer (mCRPC), and the results showed that 79.1% of the patients had a decrease in prostate-specific antigen (PSA), and 41.6% of the patients had a decrease in PSA of more than 50%. (Ahmadzadehfar H et al. Oncotarget. 2016; 7: 12477-88.) Kratochwil C et al. administered 177Lu-PSMA-617 to 30 patients with mCRPC, and the results showed that 70% of the patients had a decrease in PSA, and 43.3% of the patients had a decrease in PSA of more than 50%. Kratochwil C et al. also administered 225Ac-labeled PSMA617 to 2 patients with CRPC, and the results showed that both patients achieved complete image response (CR) and the PSA decreased to normal. (Kratochwil C et al. Society of Nuclear Medicine. 2017.)

[0007] A series of clinical studies have been carried out on radiopharmaceuticals using PSMA as a target to treat mCRPC patients, although the preliminary clinical results of radiopharmaceuticals such as 177Lu-PSMA-617 and 177Lu-PSMA-I&T are encouraging, there are still some problems, such as nearly 30% of patients have no response to this treatment method, and one possible explanation is that the unsatisfactory pharmacokinetics of the drug leads to insufficient radiopharmaceuticals being delivered to the tumor lesion.

[0008] Therefore, a high-activity and high-selectivity radiopharmaceutical targeting PSMA is a continuing hot spot in the field of treating and diagnosing mCRPC. The goal of the present application is to develop a ligand that interacts with PSMA and carries an appropriate radionuclide, which provides a promising and novel targeted selection for detecting, treating and managing prostate cancer. SUMMARY

[0009] The present application is based on the clinical accessibility problem of existing radionuclide-labeled prostate-specific membrane antigen small molecule inhibitors, and provides a prostate-specific membrane antigen small molecule inhibitor, which 68 Ga or 177 The Lu complex can be used for target tissue SPECT / CT imaging and tumor targeted therapy, respectively, and provides a new idea for the integration of prostate cancer diagnosis and treatment.

[0010] To solve the above technical problems, the technical scheme adopted by the present application is as follows:

[0011] The first aspect of the present application provides a prostate-specific membrane antigen small molecule inhibitor, which has the structure shown in the following general formula (I): R-X-R 1 (I)

[0012] wherein,

[0013] X is a divalent linking small molecule tyrosine kinase inhibitor moiety; preferably, the small molecule tyrosine kinase inhibitor is selected from the group consisting of linifanib, lazertinib, fuqinotinib, quazatinib, repotrectinib, momelotinib, lirtanib, pyrotinib, fobamintinib, abocinumab, deucinumab, packitnib, mubositinib, tivozanib, infigratinib, temetekinib, alectinib, tucatinib, pemigatinib, pralsetinib, seproctinib, avatinib, repotrectinib, camatimib, semetrexanib, encorafenib, entrectinib, pesoditnib, ficlatuzumab, upatinib, zanabatinib, dacomitinib, loratinib, gilteritinib, larotrectinib, baricitinib, fotatinib, binimetinib, neratinib, brigatinib, osimertinib, ruxolitinib, alectinib, cobimetinib, nintedanib, seritnib, afatinib, ibrutinib, trametinib, axitinib, cabozantinib, tofacitinib, bosutinib, ponatinib, vandetanib, crizotinib, ruxolitinib, pazopanib, lapatinib, nilotinib, sunitinib, dasatinib, erlotinib, gefitinib, imatinib, and salts thereof;

[0014] R is -L 1 -R 2 , R 1 is -L 2 -R 3 ; or R is -L 2 -R 3 , R 1 is -L 1 -R 2 ;

[0015] wherein, L 1 , L 2 is a divalent linking group -(L) p -; each L is independently selected from the group consisting of a bond, CO, substituted or unsubstituted CH2, substituted or unsubstituted NH, S(O), S(O)2, -O-, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted Co-C6 alkyl aryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted (-O-CH2-CH2-) t , substituted or unsubstituted (-CO-CH2-O-CH2-CH2-O-CH2-CH2-NH-) t; said substitution means having one or more substituents selected from the group consisting of: deuterium, halogen, amino, hydroxyl, carboxyl, cyano, C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6alkylamino, C1-C6alkylthio, C1-C6haloalkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, -NR 5 R 6 , -Z-C(O)-OR 7 , -C(O)-Z-OR 7 , -C(O)NR 5 R 6 , -Z-R 5 R 6 ;

[0016] Z is a bond, -O-, -NH-, or C1-C3alkylene;

[0017] R 5 , R 6 and R 7 are each independently selected from the group consisting of: hydrogen, deuterium, halogen, C1-C6alkyl, C3-C8cycloalkyl, R 3 , C6-C10aryl, 5-10 membered heteroaryl, biphenyl, anilino, phenol, halophenyl;

[0018] t is selected from 0, 1, 2, 3, 4, or 5;

[0019] p is an integer selected from 0-50;

[0020] R 2 is H or selected from the following structures:

[0021] * is the point of attachment of R 2 to L;

[0022] R 3H or is a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane- N,N',N",N"' -tetraacetic acid (= DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N"-diacetic acid (= HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (= NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1 -yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1 -yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1 -[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1 (15),1 1,13-triene-3,6,9-triacetic acid (= PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenediamine pentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriamine pentaacetic acid (CHX-DTPA), 1 -oxa-4,7,10- tetraazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1 -(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p- isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B), 1 -(2)-methyl-4-isothiocyanatobenzyl-DTPA (MX-DTPA);

[0023] R 4 is selected from the group consisting of -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, PO3H or PO4H2;

[0024] with the proviso that R 2 and R 3 are not simultaneously H.

[0025] In another preferred embodiment, the small molecule tyrosine kinase inhibitor is linifanib.

[0026] In another preferred embodiment, the compound has the structure shown in formula (II):

[0027] wherein R and R 1 are as defined above.

[0028] In another preferred embodiment, R 2 is selected from the group consisting of the following structures:

[0029] In another preferred embodiment, p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0030] In another preferred embodiment, L 1 and L 2 are each independently selected from the group consisting of a bond, -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-;

[0031] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0032] In another preferred embodiment, R is -L 2 -R 3 , R 1 is -L 1 -R 2 .

[0033] In another preferred embodiment, L 1 is selected from -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-.

[0034] In another preferred embodiment, L 2 is selected from a bond, -CO-(CH2) n -NH-.

[0035] In another preferred embodiment, R is H, R 1 is -(L) a -CH(NHR 3 )-(L) b -R 2 ; L is as defined above; a, b are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and the sum of a, b is less than p.

[0036] In another preferred embodiment, R 3 is DOTA.

[0037] In another preferred embodiment, R 4 is -CO2H.

[0038] In another preferred embodiment, n is 10 or 11.

[0039] In another preferred embodiment, the compound A, as shown in formula (I), is chelated with the radioactive metal nuclide (e.g., 68Ga or 177Lu), and the structure of compound A is shown in any of the following:

[0040] A second aspect of the invention provides the use of the compounds described in the first aspect of the invention for the preparation of radiolabeled compounds.

[0041] A third aspect of the present invention provides a metal complex comprising a radionuclide and the compound described in the first aspect of the present invention.

[0042] In another preferred embodiment, the radioactive metal nuclide is a radioactive metal nuclide that emits α, β or γ rays.

[0043] In another preferred embodiment, the radionuclide is 111 In、 90 Y、 18 F, 89 Zr、 67 Cu、 212 Pb, 211 At、 161 Tb, 123 I, 125 I, 131 I, 153 Sm、 226 Th、 89 Sr、 68 Ga、 177 Lu、 99m Tc, 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bi, or 225 Ac.

[0044] In another preferred embodiment, the radionuclide is 68 Ga or 177 Lu.

[0045] The fourth aspect of the present invention provides a method for preparing the metal complex described in the third aspect of the present invention, which is simple, efficient and easy to automate.

[0046] Specifically (taking M006 as an example), the preparation of M006 can use 3DASM01 and 3DASM02 as starting materials, and includes 5 steps:

[0047] Step 1: The starting material compounds 3DASM01 and 3DASM02 undergo a dehydration reaction to synthesize intermediate 1 solution;

[0048] Step 2: Intermediate 1 undergoes dehydration with 3DASM03 to form an amide bond, yielding intermediate 2;

[0049] Step 3: Remove the benzyl protecting group from intermediate 2 to obtain intermediate 3;

[0050] Step 4: Intermediate 3 undergoes dehydration with 3DASM04 to form an amide bond, yielding intermediate 4;

[0051] Step 5: Remove the tert-butyl protecting group from intermediate 4 to obtain M006;

[0052] The specific synthetic route information is as follows:

[0053] Based on the method described above, various metal complexes of the present invention can be prepared by using other starting materials.

[0054] A fifth aspect of the present invention provides a pharmaceutical composition comprising (i) a compound described in the first aspect of the present invention, or a metal complex described in the third aspect of the present invention, or a pharmaceutically acceptable salt or ester thereof, and (ii) a pharmaceutically acceptable carrier.

[0055] The sixth aspect of the invention is the use of the compounds described in the first aspect of the invention, or the metal complexes described in the third aspect of the invention, in the preparation of pharmaceutical agents for imaging in patients, and pharmaceutical agents for diagnosing and / or treating prostate cancer and / or its metastases.

[0056] The present invention further provides a method for preparing the aforementioned radionuclide complex.

[0057] Specifically (with) 68 (Taking Ga labeling as an example), the preparation method includes: from... 68 Ge / 68 The Ga generator was rinsed with HCl solution. 68 GaCl3 eluent, to 68 Sodium acetate solution was added to the GaCl3 eluent and shaken well. Then, the small molecule inhibitor of prostate-specific membrane antigen described in this invention, dissolved in pure water, was added. The mixture was reacted at a certain temperature for an appropriate time. The reaction solution was diluted with sterile water for injection and purified by passing through a C18 column. The C18 column was then rinsed with water, and the product was eluted from the C18 column with an ethanol / water (1 / 1, v / v) mixture. 68 Ga-labeled complexes.

[0058] Preferably, the dosage of the prostate-specific membrane antigen small molecule inhibitor is 5-15 nmol.

[0059] Preferably, the concentration of the HCI solution is 0.3-0.9 M.

[0060] Preferably, the concentration of the sodium acetate solution is 1-5 M.

[0061] Preferably, the reaction temperature is 90-110 °C.

[0062] Preferably, the reaction time is 10-20 min.

[0063] Preferably, the reaction temperature is 100 °C and the reaction time is 15 min.

[0064] The present application also relates to pharmaceutically acceptable salts of the compounds of general formula (I). The present application also relates to solvates of the compounds, including their salts and active metabolites, and, where appropriate, to their tautomers according to general formula (I), including prodrug formulations.

[0065] A "pharmaceutically acceptable salt" is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound of the present application. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkaline earth salts, ammonium salts, water-soluble and water- insoluble salts, such as acetate, carbonate, chloride, gluconate, glutamate, lactate, laurate, malate, or tartrate.

[0066] A "prodrug" means a precursor of a drug which, when administered to a patient, must undergo chemical conversion by metabolic processes before becoming the active pharmacological agent. Exemplary prodrugs of the compounds according to formula (I) are esters and amides, preferably alkyl esters of fatty acid esters. Prodrug formulations herein include all substances formed by enzymatic, metabolic or any other way of simple conversion, including hydrolysis, oxidation or reduction. Suitable prodrugs contain, for example, a material bound to the compound of general formula (I) by an enzymatically cleavable linkage (e.g. a carbamate, phosphate, N-glucoside or sulphur group) to a solubility-improving material (e.g. tetraethylene glycol, a sugar, formic acid or glucuronic acid, etc.). Such prodrugs of the compounds according to the present application can be applied to a patient and the prodrug can be converted to the compound of general formula (I) to obtain the desired pharmacological effect.

[0067] Some of the compounds of formula (I) are contained as racemates, their enantiomers, and optionally as their mixtures in all ratios of non- corresponding isomers.

[0068] According to the present application, all chiral C atoms should have the R- and / or S- configuration: combinations within one compound should also be possible, i.e. some chiral C atoms can be R- and others S- configuration.

[0069] The compounds according to the application can be appropriately formulated together with further active substances and with the excipients and carriers customarily used in pharmaceutical compositions, for example (depending on the formulation to be produced) talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, fatty bodies of animal or vegetable origin, paraffin derivatives, ethylene glycol (in particular polyethylene glycol), various plasticizers, dispersants or emulsifiers, pharmaceutically compatible gases (for example air, oxygen, carbon monoxide, etc.), preservatives.

[0070] For the production of liquid preparations, additives such as sodium chloride solution, ethanol, sorbitol, glycerol, olive oil, almond oil, propylene glycol or ethylene glycol can be used.

[0071] When solutions for infusion or injection are used, they are preferably aqueous solutions or suspensions, which can be produced before use, for example from lyophilized preparations, which contain such active substances together with carriers, such as mannitol, lactose, glucose, albumin, etc. The sterilized solutions are already produced and are appropriately mixed with excipients, for example with preservatives, stabilizers, emulsifiers, solubilizers, buffers and / or salts for the adjustment of the osmotic pressure. The sterilization can be achieved by sterile filtration using filters with a smaller pore size, according to which the composition can be appropriately lyophilized. A small amount of antibiotic can also be added to ensure the maintenance of sterility.

[0072] In another preferred embodiment, the pharmaceutical composition can be a pharmaceutical composition for treating or diagnosing prostate cancer.

[0073] In another preferred embodiment, the pharmaceutical composition can be a pharmaceutical composition for imaging prostate cancer.

[0074] In another preferred embodiment, the prostate cancer is castration-resistant prostate cancer.

[0075] In another preferred embodiment, the prostate cancer is metastatic castration-resistant prostate cancer.

[0076] In another preferred embodiment, the prostate cancer is PSMA-positive prostate cancer.

[0077] It should be understood that, within the scope of the present application, all combinations between the above-mentioned technical features of the present application and the technical features specifically described hereinafter (for example, in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here.

[0078] After adopting the above technical solutions, the positive progress effect of the present application is that:

[0079] (1) The prostate specific membrane antigen small molecule inhibitor provided by the application has stable properties, good imaging effect, high affinity and functional activity for PSMA, can be used for preoperative imaging diagnosis and grading of PSMA positive prostate cancer, and can be used for treatment of prostate cancer of various types and stages, achieves diagnosis and treatment integration, and has a wide application prospect.

[0080] (2) The prostate specific membrane antigen small molecule inhibitor has a simple and efficient preparation method, and automation can be easily realized.

[0081] (3) The prostate specific membrane antigen small molecule inhibitor has high stability, high affinity for PSMA, and high functional activity. 177 The Lu-labeled product has the characteristics of high uptake, high exposure and low clearance in PSMA-positive tumor tissues, can achieve ideal efficacy at a lower dose, can reduce the use of radionuclides, reduce medical costs, and provide higher accessibility of radiopharmaceuticals.

[0082] The specific embodiments of the application will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF DRAWINGS

[0083] Figure 1 is an HPLC spectrum of M006 in Example 1 of the application.

[0084] Figure 2 is an HPLC spectrum of M001 in Example 2 of the application.

[0085] Figure 3 is an HPLC spectrum of Ga-M006 complex 0h in Example 5 of the application. 68 Ga-M006 complex 0h in Example 5 of the application.

[0086] Figure 4 is an HPLC spectrum of Ga-M006 complex 1h in Example 5 of the application. 68 Ga-M006 complex 1h in Example 5 of the application.

[0087] Figure 5 is an HPLC spectrum of Ga-M006 complex 2h in Example 5 of the application. 68 Ga-M006 complex 2h in Example 5 of the application.

[0088] Figure 6 is an HPLC spectrum of Ga-M001 complex 0h in Example 5 of the application. 68 Ga-M001 complex 0h in Example 5 of the application.

[0089] Figure 7 is an HPLC spectrum of Ga-M001 complex 1h in Example 5 of the application. 68 Ga-M001 complex 1h in Example 5 of the application.

[0090] Figure 8 is an HPLC spectrum of Ga-M001 complex 2h in Example 5 of the application. 68 Ga-M001 complex 2h in Example 5 of the application.

[0091] Figure 9 is an HPLC spectrum of Lu-M006 complex in Example 6 of the application. 177 Lu-M006 complex in Example 6 of the application.

[0092] Figure 10 is a PET / MR imaging picture of Ga-M006 complex in animals in vivo for 1.5h in the embodiment 8 of the present application. 68 Ga-M006 complex in animals in vivo for 1.5h in the embodiment 8 of the present application.

[0093] Figure 11 is a tumor volume trend chart of tumor-bearing mouse models after treatment with different doses of Ga-M006, Lu-M006, Lu-PSMA-617 and physiological saline in the embodiment 10 of the present application. 177 Lu-M006, 177 Figure 11 is a tumor volume trend chart of tumor-bearing mouse models after treatment with different doses of Ga-M006, Lu-M006, Lu-PSMA-617 and physiological saline in the embodiment 10 of the present application.

[0094] It should be noted that the drawings and the written description herein are not intended to limit the scope of the present application in any way, but are merely to illustrate the concept of the present application to those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0095] After extensive and in-depth research, the present inventors developed a small molecule inhibitor of prostate-specific membrane antigen as shown in formula (I). Specifically, a targeting moiety Lys-Ureido-Glu specifically targeting prostate membrane antigen is connected on the parent nucleus structure shown in formula (I), while a group with metal ion chelation function is introduced, thereby realizing the labeling of radionuclide 68 Ga or 177 Lu, the labeling method is simple, convenient, fast, has high labeling rate and good stability, the combination structure of the parent nucleus structure of the present application and the targeting moiety and the chelating group realizes excellent targeting of tumor tissues of prostate cancer, which can be used for imaging diagnosis with 68 Ga labeling, and can be used for treatment with 177 Lu labeling, which provides a new idea for realizing the integration of diagnosis and treatment of prostate cancer.

[0096] The term

[0097] In this text, unless otherwise specified, each abbreviation has the conventional meaning understood by those skilled in the art.

[0098] "Alkyl" refers to a straight chain or branched chain saturated aliphatic hydrocarbon group, for example, "C1-C6 alkyl" refers to a straight chain alkyl group and a branched chain alkyl group including 1-6 (1, 2, 3, 4, 5, 6) carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, etc.

[0099] "Alkenyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur in any stable point of the chain. Non-limiting examples are C2-C8 alkenyl (such as C2, C3, C4, C5, C6, C7, C8), C2-C6 alkenyl, and C2-C4 alkenyl. The specified ranges as used herein indicate that alkenyl groups can be taken as independent classes, having each value of the range of alkenyl groups as described herein, as part of the alkyl moieties described herein. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl). In one embodiment, alkenyl is optionally substituted as described herein.

[0100] "Cycloalkyl" refers to saturated or partially unsaturated cyclic alkyl groups having a single ring or multiple rings that are fused, bridged or spiro systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, C3-C8 cycloalkyl groups have from 3 to 8 ring carbon atoms (e.g., 3, 4, 5, 6, 7, or 8 ring carbon atoms). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.

[0101] "Carbocyclic," "carbocyclic group," "carbocycle," or "cycloalkyl" is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. Carbocyclic groups typically comprise a ring of 1 to 7 carbon atoms or 2 fused rings each comprising 3, 4, 5, 6, or 7 carbon atoms. Cycloalkyl substituents can be pendant from a substituted nitrogen atom or carbon atom, or a substituted carbon atom with two substituents can have a cycloalkyl group attached as a spiro group. Examples of carbocycles include the rings of cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl. In one embodiment, carbocycles are optionally substituted as described herein. In one embodiment, cycloalkyl is a partially unsaturated (i.e., non-aromatic) group containing all carbon ring atoms. In another embodiment, cycloalkyl is a saturated group containing all carbon ring atoms.

[0102] "Heterocyclyl" is a saturated ring group. For example, it can have 1, 2, 3, or 4 heteroatoms independently selected from N, S, and O, with the remaining ring atoms being carbon atoms. In a representative embodiment, the heteroatom is nitrogen. Monocyclic heterocycloalkyl groups typically have from 3 to about 8 ring atoms or from 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, pyrrolinyl.

[0103] "Aryl" refers to a fully carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system (i.e., rings which share adjacent pairs of carbon atoms), including but not limited to phenyl and naphthyl.

[0104] "Heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, including nitrogen, oxygen and S, for example, 5-7 membered heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furanyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, indolyl, benzothiazolyl, and the like.

[0105] "Alkoxy" is an alkyl group as defined above covalently bonded through an oxygen bridge (-O-) of the indicated number of carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, i-pentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylsulfanyl" or "thioalkyl" group is an alkyl group as defined above covalently bonded through a sulfur bridge (-S-) of the indicated number of carbon atoms. In one embodiment, the alkoxy group is optionally substituted, as described herein.

[0106] "Substituted" means that one or more hydrogen atoms on a particular group is replaced with a particular substituent. The particular substituent is the substituent described in the preceding paragraph, or the substituent as it appears in each instance. Unless otherwise indicated, a substituted group can have, at each substitutable position, one substituent selected from the indicated group, which can be the same or different at different positions on the group. It is understood by those skilled in the art that combinations of substituents envisioned by this application are those stable or chemically feasible combinations. The substituents are, for example, but not limited to, halogen, hydroxyl, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehydic, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0107] Compounds of the present application

[0108] The compounds of the present application are conjugates with high activity and high selectivity targeting PSMA by covalently linking the group with metal ion chelation function and the targeting moiety specifically targeting prostate membrane antigen (PSMA) to small molecule tyrosine kinase inhibitors. Compared with existing radio nucleic acid complexes, the use of the compounds of the present application as radio nucleic acid complexes, the combination of the group with metal ion chelation function and the targeting moiety specifically targeting prostate membrane antigen (PSMA) to small molecule tyrosine kinase inhibitors obtains excellent targeting efficiency and higher affinity, and can achieve higher treatment effect with lower dose.

[0109] As used herein, there are two attachment sites in the small molecule tyrosine kinase inhibitor, each covalently linked to a group that functions in metal ion chelation, and a targeting moiety that specifically targets prostate membrane antigen. There is no particular limitation on the small molecule tyrosine kinase inhibitor, and exemplary tyrosine kinase inhibitors include, but are not limited to, Linifanib, Lazertinib, Fruquintinib, Quizartinib, Repotrectinib, Momelotinib, Ritlecitinib, Pirtobrutinib, Futibatinib, Abrocitinib, Deucravacitinib, Pacritinib, Mobocertinib, Tivozanib, Infigratinib, Tepotinib, Asciminib, Tucatinib, Pemigatinib, Pralsetinib, Selpercatinib, Avapritinib, Ripretinib, Capmatinib, Selumetinib, Erdafitinib, Entrectinib, Pexidartinib, Fedratinib, Upadacitinib, Zanubrutinib, Dacomitinib, Lorlatinib, Gilteritinib, Larotrectinib, Baricitinib, Fostamatinib, Binimetinib, Neratinib, Brigatini, Acalabrutinib, Osimertinib, Lenvatinib, Alectinib, Cobimetinib, Nintedanib, Ceritinib, Afatinib, Ibrutinib, Trametinib,Axitinib, Cabozantinib, Tofacitinib, Bosutinib, Ponatinib, Vandetanib, Crizotinib, Ruxolitinib, Pazopanib, Lapatinib, Nilotinib, Sunitinib, Dasatinib, Erlotinib, Gefitinib, Imatinib, and salts thereof, and the like.

[0110] In the present text, the terms "metal complex", "complex", "coordination complex" are used interchangeably and refer to the structure formed after the chelation of the radioactive metal nuclide with the compound of the first aspect of the present application.

[0111] As used herein, unless otherwise specified, the manner of adding solvent or solution is direct pouring or uniform addition, etc.

[0112] As used herein, the term "room temperature" generally refers to 4-30°C, preferably 20±5°C.

[0113] As used herein, the manner of "slow addition" includes, but is not limited to: dropwise addition, slow addition along the wall of the container, etc.

[0114] The term "pharmaceutical excipient" refers to excipients and additional agents used in the production of pharmaceutical products and dispensing of prescriptions, and is all substances contained in a pharmaceutical preparation other than active ingredients. See the People's Republic of China Pharmacopoeia (2020 edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009) for details.

[0115] Lys represents L-lysine

[0116] Ureido represents the structure of urea

[0117] Glu represents L-glutamic acid

[0118] The present application will be further described in conjunction with specific examples. It should be understood that these examples are used to illustrate but not to limit the scope of the present application. The experimental methods in the following examples, if not specified, are generally carried out under conventional conditions, or under the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The exemplary methods and materials described herein are intended to be illustrative only and are not intended to be limiting.

[0120] General methods and reagents

[0121] The solvents used in the present application are all of analytical purity, and the water content is about 0.1%.

[0122] All test methods of the present application are general methods, and the test parameters are as follows:

[0123] High Performance Liquid Chromatography (HPLC) method of the present application:

[0124] Test method:

[0125] Chromatographic column: SunFire C18 5um 4.6x150mm

[0126] Column temperature: 25℃

[0127] Flow rate: 1.000ml / min

[0128] Mobile phase:

[0129] A: 0.03% TFA in H2O

[0130] B: 0.03% TFA in ACN

[0131] Gradient:

[0132] Liquid Chromatograph Mass Spectrometer (LCMS) method of the present application:

[0133] Chromatographic column: Waters SunFire C18 50*4.6mm 5um 2.000ml / min 2.6min

[0134] Column temperature: 40℃

[0135] Gradient: 5% B hold for 0.2min, increase to 95% B within 1.40min, hold at 95% B for 0.9min, then back to 5% B within 0.01min

[0136] A: 0.03% TFA in H2O

[0137] B: 0.03% TFA in ACN

[0138] H-NMR method of the present application:

[0139] Test method:

[0140] Spectrometer: Avance

[0141] Solvent: DMSO-d6

[0142] Number of scans: 8

[0143] Spectrum frequency: 400 MHz

[0144] Scan time: 50 s

[0145] F-NMR method of the present application:

[0146] Test method:

[0147] Spectrometer: Avance

[0148] Solvent: DMSO-d6

[0149] Number of scans: 32

[0150] Spectrum frequency: 377 MHz

[0151] Scan time: 70 s

[0152] Radio-HPLC method of the present application:

[0153] Test method:

[0154] Column: C18, 3 μm, 150 x 4.6 mm

[0155] Flow rate: 1.000 ml / min

[0156] Mobile phase:

[0157] A: 0.03% TFA in Water

[0158] B: 0.03% TFA in ACN

[0159] Gradient:

[0160] Example 1: Preparation of Inhibitor M006

[0161] Take 3.2 g of 3DASM01 dissolved in 30 mL of DMF, add 4.13 g of 3DASM02, 2.88 g of EDCI, 2.03 g of HOBt and 6.45 g of DIEA, stir at 30°C for 16 h, then dilute with 50 mL of water, extract with EA three times 150 mL each time, then combine the organic layers, concentrate, purify to obtain 4.1 g of intermediate 1; take 500 mg of 3DASM03 dissolved in 10 mL of DCM, add a drop of DMF, stir evenly, then slowly add 132 mg of (COCl)2, then stir at room temperature for 1 h, then concentrate under vacuum to obtain 648 mg of acyl chloride compound, add the acyl chloride compound to 500 mg of intermediate 1 and 481 mg of Cs2CO3, a total of 8 mL of solution, stir at 80°C for 16 h, after the reaction is complete, filter, dilute with 30 mL, extract with EA three times 80 mL each time, combine the organic layers, dry, filter, concentrate, purify to obtain 510 mg of intermediate 2; dissolve 510 mg of intermediate 2 in methanol, add 35 mg of Pd / C (10% w / w) at room temperature, then stir under H2at room temperature for 0.3 h, filter and concentrate after the reaction is complete to obtain 450 mg of intermediate 3; dissolve 450 mg of intermediate 3 and 191 mg of 3DASM04 and 331 mg of TCFH in 20 mL of ACN, add 193 mg of NMI, then stir at room temperature for 3 h, concentrate and purify after the reaction is complete to obtain 300 mg of intermediate 4; dissolve 300 mg of intermediate 4 in TFA / DCM (10 mL / 10 mL), then stir at room temperature for 36 h, concentrate after the reaction is complete, then purify with preparative HPLC to obtain 65.9 g of white solid of the final product M006 sample, purity 95.03% (214 nm), and its HPLC spectrum is shown in Figure 1. LCMS (ESI): RT 1.443 min; m / z 638.8 [M+2H] 2+ ,1276.0 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 4H), 10.77 (s, 1H), 9.41 (s, 1H), 8.70 (s, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.80 - 7.64 (m, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.20 - 7.07 (m, 1H), 6.83 (s, 1H), 6.33 (dd, J = 12.7, 8.3 Hz, 2H), 4.15 - 3.99 (m, 2H), 3.58 (s, 13H), 3.20 - 2.92 (m, 15H), 2.36 - 2.19 (m, 5H), 2.03 (t, J = 7.3 Hz, 2H), 1.92 (dt, J = 13.8, 7.2 Hz, 1H), 1.82 - 1.58 (m, 4H), 1.58 - 1.15 (m, 19H).19F NMR (376.5 MHz, DMSO-d6) δ -134.23.

[0162] Example 2: Preparation of Inhibitor M001

[0163] Take 1.70 g 3DA01 dissolved in 20 mL DCM, then add 454 mg (COCl)2and a drop of dry DMF, mix well under nitrogen protection at room temperature for 10 minutes. Concentrate the solution, add 1 g 3DA02 and 1.44 g K2CO3 dissolved in dry THF, stir under nitrogen protection at room temperature for 16 h, filter the reaction solution, dilute with 30 mL water, then extract with EA for 3 times, each 100 mL. Dry the organic layer with Na2SO4, then filter, concentrate, purify with H2O / ACN reverse phase to obtain 1.23 g of intermediate 1; take 1.23 g of intermediate 1 dissolved in 18 mL DCM, then add 3 mL TFA, then stir at 0 °C for 0.5 h. Then concentrate, dilute with 30 mL NaHCO3, extract with EA for 3 times, each 80 mL. Dry the organic layer with Na2SO4, then filter, concentrate, purify with H2O / ACN reverse phase to obtain 1.08 g of intermediate 2; take 400 mg of intermediate 2, dissolve in 20 mL DMF, then add 365.6 mg 3DA03, 136.3 mg EDCI, 100 mg HOBt, 143.4 mg 4-Methylmorpholine, then stir at room temperature for 16 h. Then dilute the reaction solution with 30 mL water, extract with EA for 3 times, each 80 mL. Dry the organic layer with Na2SO4, then filter, concentrate, purify with H2O / ACN reverse phase to obtain 0.56 g of intermediate 3; take 0.56 g of intermediate 3 dissolved in 10 mL DCM, then add 10 mL TFA and 301.6 mg Et3SiH. Then stir at 35 oC was stirred for 16 h. After the reaction solution was concentrated, it was purified by preparative HPLC using a H2O / CAN mobile phase system containing 0.1% TFA to give 59 mg of M001 as a white solid with 95.41% purity (254 nm), and its HPLC profile is shown in Figure 2. LCMS (ESI): RT 4.01 min; m / z 796.3 [M+2H]2+, 1591.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.83 (s, 1H), 9.18 (s, 1H), 8.72 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.24 (s, 1H), 8.16 - 8.05 (m, 3H), 7.90 (s, 1H), 7.66 (d, J = 6.9 Hz, 1H), 7.51 (s, 2H), 7.33 (dd, J = 23.9, 6.0 Hz, 3H), 7.13 - 7.02 (m, 1H), 6.80 (s, 1H), 4.16 - 4.15 (m, 5H), 3.50 (d, J = 47.3 Hz, 6H), 3.18 - 2.86 (m, 17H), 2.72 (d, J = 14.8 Hz, 2H), 2.56 (d, J = 17.7 Hz, 3H), 2.29 - 2.15 (m, 11H), 2.04 - 1.90 (m, 4H), 1.83 - 1.67 (m, 6H), 1.38 - 1.23 (m, 18H).19F NMR (376.5 MHz, DMSO-d6) δ -132.98. The reaction scheme is as follows:

[0164] Example 3: Compound binding to PSMA protein in vitro test

[0165] Biacore 8K (Cytiva) instrument was used to detect the ligand binding of PSMA protein (Sinobiological). Using NTA chip capture method, first activate NTA chip with 0.5 mM NiCl2 at a flow rate of 10 μL / min for 60 seconds, then capture Human PSMA protein on NTA chip: dilute Human PSMA protein to 20 μg / mL with running buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% P20, 1% DMSO) and couple for 30 seconds at a flow rate of 5 μL / min, then use the samples of M006 and M001 obtained in Example 1 and Example 2 and positive reference PSMA-617 as analyte, dilute them to the required concentration gradient with running buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 0.05% P20, 1% DMSO), and perform multi-cycle kinetics detection, each cycle for 180 seconds of injection and 180 seconds of dissociation, then proceed to the next cycle, to obtain the affinity kinetics analysis data of the analyte and Human PSMA protein. The final data is analyzed by Kinetics fitting analysis with Biacore Insight Evaluation Software (V 2.0.15.12933) according to the 1:1 model.

[0166] The Biacore results are shown in the table below: where KD is the binding of the compound to PSMA protein measured by Biacore. The results show that M006 exhibits comparable or superior affinity to PSMA-617, which is 5 times the affinity of PSMA-617.

[0167] Example 4: IC by AlphaLisa method 50 Determination

[0168] The compounds M006, M001 obtained in Example 1 and Example 2 and the positive reference PSMA-617 were diluted to 6 concentrations of appropriate concentrations using Buffer solution (1X PBS, 0.1% BSA, 0.05% P20), and 5 μL was added to each well.

[0169] Dilute PSMA protein (Recombinant Human PSMA / FOLH1 Protein) to 10 nM, add 5 pL per well. Then add 5 pL biotin-probe and 5 pL Streptavidin Donor Beads: Histidine acceptor beads (1:100) per well, incubate at room temperature for 120 minutes. Measure the fluorescence signal at 680 nm and 570 nm (AlphaScreen) with a microplate reader. Compound IC 50 The following table.

[0170] The results show that, compared with PSMA-617, compound M006 shows lower IC 50 values.

[0171] Example 5: 68 Ga-M006 and 68 Ga-M001 complex preparation and stability study

[0172] From 68 Ge / 68 Ga generator, elute 68 GaCl3eluate with 0.6 M HC1 solution, add 350 pL of 3 M sodium acetate solution to 2 mL of 68 GaCl3eluate, shake well, then add 10 pL of M006 and M001 (10 nmol) obtained in Example 1 and Example 2 dissolved in pure water respectively. React the mixture at 100°C for 15 min respectively. Dilute the reaction solution with sterilized water (2 mL), then purify through a C18 column, then elute the C18 column with 2 mL of water, and elute the product from the C18 column with 2 mL of ethanol / water (1 / 1, v / v) mixture to obtain labeled 68 Ga-M006 and 68 Ga-M001 complex. Detect the total radioactivity before labeling and the radioactivity of the product after labeling and purification with a gamma counter to calculate the labeling yield, which is 18.2% (M006) and 35.0% (M001) respectively. 68 Ga-M006 and 68 Ga-M001. Different times respectively obtain 68 Ga-M006 radiochemical purity of 97.55% (0h), 97.83% (1h) and 97.92% (2h), and obtain 68 Ga-M001 radiochemical purity of 91.58% (0h), 91.56% (1h) and 91.60% (2h), indicating that the labeled 68 Ga-M006 and68 The Ga-M001 complex was stable for at least 2 h, and its HPLC profile is shown in FIGS. 3 to 8.

[0173] Example 6: 177 Preparation of Lu-M006 complex

[0174] After the M006 prepared in Example 1 was dissolved in DMSO to form a 1 mM solution, it was diluted with 0.5 M sodium acetate buffer (pH 5.5) to 0.1 mM, and 150 μL of the diluted solution and about 15 mCi of 177 LuCl3were mixed and heated at 55 °C with 300 rpm oscillation for 15 min, 1500 μL of a preparation buffer (4 mg / mL gentisic acid: 1 mg / mL DTPA: 100 mg / mL sodium ascorbate = 2: 1.5: 3.5 (v:v:v)) was added to obtain the labeled complex. Its HPLC profile is shown in FIG. 9.

[0175] Example 7: Cell uptake and endocytosis experiment

[0176] LNCaP cells (Nanjing Keye Biotechnology Co., Ltd.) in the logarithmic growth phase were prepared into a cell suspension, and the cell density was adjusted to 1 x 10 5 / ml was inoculated into a 24-well cell culture plate. After incubation in a 37 °C incubator for 48 h, the cells were observed under a microscope to ensure that the cells were adherent. Three hours before the experiment, the serum-free 1640 medium (2 mL / well) was replaced, and then the plate was incubated in a carbon dioxide incubator for 2 h.

[0177] The medium was removed and 10 nM of 68 Ga-M006 and 68 Ga-M001 used in Example 5 were added, respectively, and the total radioactivity was recorded. After the addition, the 24-well plate was shaken gently and incubated in a 37 °C incubator for 45 min. After the incubation, the supernatant was removed, and the cells were washed with PBS (precooled at 2-8 °C) for 3 times. 1 mL of 1 M glycine hydrochloride buffer was added to each well, and incubated at 2-8 °C for 10 min. The well chamber was washed with PBS (precooled at 2-8 °C) for two times, and all the glycine hydrochloride buffer and PBS washings were collected and detected for total radioactivity using a gamma counter. 0.5 mL of 1 M NaOH solution was added to each well and incubated at room temperature for 10 min to completely lyse the cells. The cells were washed with PBS until the washings were free of radioactivity. The 1 M NaOH and PBS washings were collected and detected for total radioactivity using a gamma counter. The cell uptake and endocytosis results of 68 Ga-M006 and 68 Ga-M001 are shown in the following table.

[0178] The results show that, 68Ga-M001 can be effectively taken up and internalized into prostate cancer cells.

[0179] Example 8: 68 PET / MR Imaging Experiments of Ga-labeled Inhibitors in Animals

[0180] B-NDG mice with human prostate cancer LNCaP cells implanted in the right upper limb axilla; the tumor diameter was approximately 100 mm. 3 The result obtained by injecting 5 MBq via the tail vein in Example 5 68 Ga-M006 was anesthetized and fixed with isoflurane for 1.5 hours, followed by PET / MR imaging. Pmod software was used to process the data and calculate the %ID / g (percentage of radioactive material per gram of tissue relative to the total injected dose) for organs such as the brain, heart, liver, lungs, kidneys, muscles, spleen (if radioactive distribution was observed), bones, and tumors. The results are shown in the table below and Figure 10. The results show significant uptake by axillary tumor tissue at 1.5 hours, and that the radioactive material can be metabolized through multiple pathways, including the liver and kidneys.

[0181] Example 9: 177 Tissue distribution experiment of Lu-labeled inhibitors in animals

[0182] B-NDG mice with human prostate cancer LNCaP cells implanted in the right upper limb axilla; the tumor diameter was approximately 100 mm. 3 100 μCi was injected via the tail vein. 177 Animals were sacrificed at 0.5h, 4h, 24h, 72h, and 120h after administration of Lu-M006. Blood plasma, urine, brain, salivary glands, thyroid gland, heart, lungs, liver, stomach, small intestine, large intestine, spleen, pancreas, adrenal glands, kidneys, bladder, testes, prostate, bone, bone marrow, muscle, fat, and tumors were collected. Radioactivity %ID / g (the percentage of radioactivity in each gram of tissue relative to the total injected dose) was measured using a gamma counter. The results are shown in the table below. The uptake and distribution results in tumor tissue show… 177 Lu-M006 showed an increasing trend from 0 to 120 hours. The %ID / g measured on the tumor at the 24h, 72h, and 120h time points were 31.29, 31.13, and 36.5, respectively, indicating that the drug had a very high uptake value in the tumor tissue. Moreover, the uptake value on the tumor did not decrease within the 24-120h time range, indicating that the drug could remain in the tumor tissue for a long time without being cleared or metabolized.

[0183] Example 10: 177 Antitumor effects of Lu-labeled inhibitors in animals

[0184] LNCaP Clone FGC cells (5 × 10⁻⁶) were subcutaneously injected into the right anterior side of 45 B-NDG male mice. 6 A tumor-bearing mouse model was constructed using cells. When the average tumor volume reached 100 mm², the tumor was successfully isolated. 3 Around 10:00 AM, 30 mice were randomly divided into five groups, with 6 mice in each group: G1 (saline), G2 (...), G3 (...), G4 (...), G5 (...), G6 (...), G7 (...), G8 (...), G9 (...), G1 (...), G1 (...), G9 (...), G1 (...), G1 (...), G2 ...1 ( 177 Lu-M006, 0.1mCi / piece), G3 ( 177 Lu-M006, 0.5mCi / piece), G4 ( 177 Lu-M006, 1.0mCi / each) and G5 ( 177 Lu-PSMA-617 (1.0 mCi / animal). At the experimental endpoint (D38), the mean tumor volume in groups G2-G5 was significantly smaller than that in group G1 (P<0.01). The tumor inhibition rates (TGI, %) in groups G2-G5 were 79.97%, 98.34%, 99.84%, and 94.00%, respectively. The tumor weight in groups G2-G5 was significantly lower than that in the solvent group G1 (P<0.01). Test sample 177 Lu-M006 showed significant antitumor effects at doses ≥0.1 mCi / animal, and its inhibitory effect on tumor growth was dose-dependent. At a dose of 0.5 mCi / animal... 177 Lu-M006 with a dose of 1.0 mCi / animal 177 Compared to Lu-PSMA-617, 177 Lu-M006 showed better tumor suppression. At the experimental endpoint (D38), there was no statistically significant difference in body weight between the G2-G5 groups and the G1 group (P>0.05). The trend of tumor volume in each group is shown in Figure 11.

[0185] The above research results indicate that 177 Lu-M006 is expected to achieve the therapeutic effect of 177Lu-PSMA-617 at a lower dose in clinical practice, and has the potential to reduce the dosage, reduce the frequency of administration, further improve safety, and reduce treatment costs.

[0186] For medical institutions using radionuclides for disease diagnosis and treatment, the use of radionuclides is subject to strict quota management. 177 The potential dosage of Lu-M006 is significantly reduced, which will allow nuclear medicine wards to treat more patients and benefit more patients. At the same time, it will also significantly reduce the disposal of nuclear medicine waste, which has positive social benefits.

[0187] The above merely describes the preferred embodiments of the present application, and is not intended to limit the present application in any form. Although the present application has been disclosed with the preferred embodiments as above, it is not intended to limit the present application, and any skilled person in the art can make some changes or modifications to the above-mentioned technical content with the prompt as equivalent embodiments of equivalent changes without departing from the technical solution of the present application. Any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present application, which does not depart from the technical solution of the present application, still belongs to the scope of the present application.

Claims

1. A compound of Formula (I): R-X-R (I) or a pharmaceutically acceptable salt or ester thereof. 1 (I) in, X represents a divalently linked small molecule tyrosine kinase inhibitor moiety; preferably, the small molecule tyrosine kinase inhibitor is selected from the group consisting of: linivab, lazatinib, fruquintinib, quezartinib, repretinib, molotinib, litexicitinib, pitobrutinib, fabatinib, abuxicitinib, deuterocelexicitinib, paclitinib, mobotinib, tevozaniib, inflavraglatinib, terpoxtinib, asnibu, tacardinib, pemitinib, pralatinib, ceprotinib, avatinib, repretinib, carmatinib, sumetinib, erdatinib, entrectinib, pericidatinib, and others. Zotinib, utpatinib, zanubrutinib, dacomitinib, lolatinib, giritinib, larotrectinib, baricitinib, fortaminophen, bimetinib, neratinib, brigatinib, acalatinib, osimertinib, lenvatinib, alectinib, cobitinib, nintedanib, ceritinib, afatinib, ibrutinib, trametinib, axitinib, cabozantinib, tofatinib, bosutinib, ponatinib, vandetanib, crizotinib, ruxolitinib, pazopanib, lapatinib, nilotinib, sunitinib, dasatinib, erlotinib, gefitinib, imatinib, and their salts; R is -L 1 -R 2 , R 1 is -L 2 -R 3 ; or R is -L 2 -R 3 , R 1 is -L 1 -R 2 ; wherein L 1 , L 2 is a divalent linking group -(L) p ; each L is independently selected from the group consisting of a bond, CO, substituted or unsubstituted CH2, substituted or unsubstituted NH, S(O), S(O)2, -O-, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C0-C6alkylaryl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted (-O-CH2-CH2-) t , substituted or unsubstituted (-CO-CH2-O-CH2-CH2-O-CH2-CH2-NH-) t ; said substitution with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxyl, carboxyl, cyano, C1-C6alkyl, C1-C6alkenyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6alkylamino, C1-C6alkylthio, C1-C6haloalkoxy, C3-C8cycloalkyl, 3-8 membered heterocyclyl, C6-C10aryl, 5-10 membered heteroaryl, -NR 5 R 6 , -Z-C(O)-OR 7 , -C(O)-Z-OR 7 , -C(O)NR 5 R 6 , -Z-R 5 R 6 ; Z is a chemical bond, -O-, -NH-, or C1-C3 alkylene; R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-C6alkyl, C3-C8cycloalkyl, R 3 , C6-C10aryl, 5-10 membered heteroaryl, biphenyl, anilino, phenolyl, halophenyl; t is selected from 0, 1, 2, 3, 4, or 5; p is an integer selected from 0 to 50; R 2 It can be H or selected from the following structures: * for R 2 the point of attachment to L; R 3 is H or is a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane- N,N',N",N"' -tetraacetic acid (= DOTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N,N"-diacetic acid (= HBED-CC), 1,4,7-triazacyclononane-1,4,7-triacetic acid (= NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1 -yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1 -yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1 -[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo[9.3.1.]pentadeca-1 (15),1 1,13-triene-3,6,9-triacetic acid (= PCTA), N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4- oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), diethylenediamine pentaacetic acid (DTPA), trans-cyclohexyl-diethylenetriamine pentaacetic acid (CHX-DTPA), 1 -oxa-4,7,10- tetraazacyclododecane-4,7,10-triacetic acid (oxo-Do3A), p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1 -(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B), 1 -(2)-methyl-4-isothiocyanobenzyl-DTPA (MX-DTPA); R 4 selected from -CO2H, -SO2H, -SO3H, -SO4H, -PO2H, PO3H or PO4H2; with the proviso that R 2 and R 3 are not simultaneously H.

2. The compound according to claim 1, characterized in that, The small molecule tyrosine kinase inhibitor is linevani.

3. The compound according to claim 1, characterized in that, The compound has the structure shown in formula (II): wherein R and R 1 As defined in claim 1.

4. The compound according to claim 1, characterized in that, L 1 and L 2 are each independently selected from the group consisting of a bond, -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-; Preferably, L 1 selected from -CO-(CH2) n -CO-, -CO-(CH2) n -NH-, -CH2-CO-; Preferably, L 2 Selected from chemical bonds, -CO-(CH2) n -NH-; n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

5. The compound according to claim 1, characterized in that, R 3 For DOTA.

6. The compound according to claim 1, characterized in that, R 4 It is -CO2H.

7. The compound according to claim 1, characterized in that, n is 10 or 11.

8. The compound according to any one of claims 1 to 4, characterized in that, The compounds are selected from the group consisting of:

9. Use of the compound according to any one of claims 1 to 8 for the preparation of radiolabeled compounds.

10. A metal complex, characterized in that, The metal complex comprises: a radionuclide, and a compound according to any one of claims 1 to 8.

11. The metal complex according to claim 10, characterized in that, The radioactive nuclide is 111 In、 90 Y、 18 F, 89 Zr、 67 Cu、 212 Pb, 211 At、 161 Tb, 123 I, 125 I, 131 I, 153 Sm、 226 Th、 89 Sr、 68 Ga、 177 Lu、 99m Tc, 64 Cu、 153 Gd, 155 Gd, 157 Gd, 213 Bi, or 225 Ac.

12. A pharmaceutical composition comprising (i) a compound according to any one of claims 1 to 8, or a metal complex according to claim 10 or 11, or a pharmaceutically acceptable salt or ester thereof, and (ii) a pharmaceutically acceptable carrier.

13. The use of the compound of any one of claims 1 to 8 or the metal complex of claim 10 or 11 in the preparation of a pharmaceutical agent for imaging in a patient.

14. The use of the compound of any one of claims 1 to 8 or the metal complex of claim 10 or 11 in the preparation of a medicament for the diagnosis or treatment of prostate cancer and / or its metastases.

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