Diagnostic PET imaging of cardiac amyloidosis using bisphosphonate tracers

Abstract

The present disclosure relates to a compound comprising at least one bisphosphonate or bisphosphonate group and a positron emitting radionuclide Po, or a pharmaceutically acceptable salt thereof, and its use in a method of diagnosing amyloidosis, such as cardiac amyloidosis.

Description

Technical Field

[0001] The present disclosure relates to compounds comprising a bisphosphonate or a bisphosphonate group and a positron emitting radionuclide or a pharmaceutically acceptable salt thereof, their preparation and their use in diagnostic methods, such as diagnostic methods for cardiac amyloidosis. Background Art

[0002] Bisphosphonates are a class of drugs that prevent the loss of bone density and are used to treat osteoporosis, high blood calcium levels caused by cancer, and similar conditions. As a result, they are the most commonly prescribed drugs used to treat osteoporosis.

[0003] The inventors of the present disclosure have unexpectedly discovered that such bisphosphonate drugs can also be advantageously used in methods of diagnosing cardiac amyloidosis.

[0004] Therefore, drugs in the class of bisphosphonates have in common that they contain two phosphonate groups bound to only one carbon atom. In other words, all bisphosphonate drugs contain the structure R'R"C-(PO(OX)2)2. When X is hydrogen, the bisphosphonate exists in its neutral form as a free acid; when X is a pharmaceutically acceptable cation (e.g., Na + ), the bisphosphonate exists as a pharmaceutically acceptable salt in its charged form. When X is an alkyl group, etc., the bisphosphonate exists as an ester (i.e., a prodrug). After the ester is hydrolyzed in vivo, the bisphosphonate is formed.

[0005] Without being bound by theory, the bisphosphonate group mimics the structure of pyrophosphate, therefore, it can inhibit the activation of pyrophosphate utilizing enzymes, and its two phosphonate groups together coordinate calcium ions. The largest store of calcium in the human body is in the bone, so bisphosphonates accumulate to high concentrations only in the bone.

[0006] The most prominent drugs in the bisphosphonate class are pamidronic acid, nedridronic acid, olpadronic acid, alendronic acid, ibandronic acid, risedronic acid, and zolendronic acid.

[0007] Due to their affinity for bone, bisphosphonates can also be used in conjunction with positron-emitting radionuclides for use as imaging probes of bone.

[0008] US2016 / 310621 A1 describes derivatives of risedronic acid and zoledronic acid conjugated to positron-emitting radionuclides as imaging probes for use in positron emission tomography of bone, and methods for synthesizing the bisphosphonate conjugates.

[0009] Cardiac amyloidosis is a heart disease with extracellular amyloid infiltration associated with abnormal cardiac function. Because of the high morbidity and mortality of cardiac amyloidosis, early and accurate detection of cardiac involvement and differentiation between types are critical for appropriate treatment selection and patient prognosis. The present invention provides new bisphosphonate positron emission tomography (PET) tracers for accurate diagnosis of cardiac amyloidosis in a highly sensitive and quantitative manner.

[0010] PET imaging has inherent advantages in detecting radionuclide concentrations, such as high spatial- / temporal-resolution, sensitivity, and accuracy. Among the radionuclides available for PET imaging, 18 F-labeled tracers have several advantages: 1) they can be produced by cyclotrons and, due to their longer half-life, can be conveniently delivered by remote suppliers; 2) such delivery offers the possibility of distribution to locations where on-site production of radiotracers is not permitted or where the equipment to do so is lacking; 3) higher positron yields and lower positron energies, which reduce imaging noise, improve contrast resolution, and maximize detection of subtle lesions; and 4) longer half-life allows for improved delayed imaging protocols. Summary of the invention

[0011] The present invention provides novel tracers and their use in the diagnosis of cardiac amyloidosis by PET imaging technology, and improves the accuracy of diagnosis compared to the currently used scintigraphy technology. From the perspective of structural design, the inventors provide different strategies for radiolabeling of bisphosphonate compounds.

[0012] The inventors of the present disclosure have surprisingly discovered that bisphosphonate-based or radiolabeled tracers of bisphosphonates can be advantageously used in diagnostic methods for cardiac amyloidosis, ie, a disease not related to bone or to other uses of bisphosphonates previously described.

[0013] In one aspect, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof comprises at least one bisphosphonate or bisphosphonate group and a positron emitting radionuclide Po, wherein Po is linked to the at least one bisphosphonate or bisphosphonate group.

[0014] In yet another aspect, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof for use in a method for diagnosing cardiac amyloidosis, wherein the compound or a pharmaceutically acceptable salt thereof comprises at least one bisphosphonate or bisphosphonate group and a positron emitting radionuclide Po, wherein Po is linked to the at least one bisphosphonate or bisphosphonate group.

[0015] In yet another aspect, the present disclosure relates to a method for preparing a compound or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 :Time-activity curve of IVa

[0017] Figure 2 : As a control 18 Time-activity curve of F-NaF

[0018] Figure 3 : PET imaging (left) and magnified view of the heart area (right) 120 minutes after IVa injection.

[0019] Figure 4 : As a control 18 PET imaging 120 min after F-NaF injection

[0020] Figure 5 : Dynamic PET images using IVa (upper panels) and IVb (lower panels) were performed until 120 minutes after tracer injection.

[0021] Figure 6 : Comparison of IVa uptake in human cardiac tissue with amyloidosis (upper panel) and H&E staining of the same tissue (lower panel). DETAILED DESCRIPTION

[0022] Compound or a pharmaceutically acceptable salt thereof

[0023] According to one embodiment, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof comprises at least one bisphosphonate or bisphosphonate group and a positron emitting radionuclide Po, wherein Po is attached to the at least one bisphosphonate or bisphosphonate group.

[0024] According to a preferred embodiment of the present disclosure, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0025]

[0026] wherein z is an integer selected from the group consisting of 1, 2 and 3, preferably, z is 1; and wherein each R 1are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L and Q are absent; or wherein L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or And where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and wherein R 3 It is a group containing the positron-emitting radionuclide Po.

[0027] According to another preferred embodiment, the positron emitting radionuclide Po is 11 C. 13 N. 15 O. 18 F. 64 Cu or 68 According to another preferred embodiment, the positron emitting radionuclide Po is 11 C. 18 F or 68 In another preferred embodiment, the positron emitting radionuclide is 18 F or 68 In another preferred embodiment, the positron emitting radionuclide is 18 F. In another preferred embodiment, the positron emitting radionuclide is 68 In another preferred embodiment, the positron emitting radionuclide is 11 C.

[0028] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), wherein z is 1. In other words, the compound has the structure (I.1)

[0029]

[0030] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), wherein z is 2. In other words, the compound has the structure (I.2)

[0031]

[0032] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), wherein z is 3. In other words, the compound has the structure (I.3)

[0033]

[0034] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein n is an integer selected from the group consisting of 0, 1, 2 and 3. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein n is 0. When n is 0, A is bound to the methylene group connected to the bisphosphonate or bisphosphonate group by a single bond. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein n is 1. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein n is 2. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein n is 3.

[0035] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is independently hydrogen, a pharmaceutically acceptable cation or a protecting group. In another preferred embodiment, each R 1 In another preferred embodiment, each R 1 is a pharmaceutically acceptable cation. In another preferred embodiment, each R 1 Yes + , or Li + , or K + or 1 / 2Ca 2+ , or 1 / 2Mg 2+ In another preferred embodiment, each R 1 Yes + In another preferred embodiment, each R 1It's Li + In another preferred embodiment, each R 1 It's K + In another preferred embodiment, each R 1 1 / 2Ca 2+ In another preferred embodiment, each R 1 1 / 2Mg 2+ .

[0036] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2-O(CO)-CH3, -CH2-O(CO)-CH2CH3, -CH2-O(CO)-CH(CH3)2, -CH2-O(CO)-C(CH3)3 and The protective group of the group consisting of 10 ) alkyl, preferably methyl or ethyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is a protecting group selected from the group consisting of methyl, ethyl and isopropyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 It is isopropyl.

[0037] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is a protecting group in which the two R 1 Together we form or or wherein R' is hydrogen or (C1-C 10 )alkyl.

[0038] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2, or (4 to 8 membered) heterocyclyl, or (4 to 8 membered) cyclyl, or squaramide, or (5 to 6 membered) heteroaryl, or phenyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is a (4 to 8 membered) heterocyclyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is a (4 to 8 membered) cyclyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is a squaramide. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is a (5 to 6 membered) heteroaryl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is phenyl.

[0039] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2 , and where R 2 is hydrogen or a linear or branched (C1-C6) alkyl group. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2 , and where R 2 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2 , and where R 2 is a linear or branched (C1-C6) alkyl group. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2 , and where R 2 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein A is -NR 2 , and where R 2 It is ethyl.

[0040] The inventors of the present disclosure have discovered that it is advantageous for group A to contain a basic center, such as a secondary amine group or a tertiary amine group.

[0041] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L and Q are absent. In other words, the groups A and R 3 Directly linked by covalent bonds.

[0042] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group and wherein Q is -NH. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group and wherein Q is -O (oxygen). According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group and wherein Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group and wherein Q is According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -NR Q , where R Q is a linear or branched (C1-C6) alkyl group. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -NR Q , where R Q According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -N + R Q 2 X - , R Q is a linear or branched (C1-C6) alkyl group, and wherein X - is a pharmaceutically acceptable anion. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -N + R Q 2X - , where R Q is methyl, and wherein X - Yes F - , Cl - Br - ,I -OH - , toluenesulfonate, mesylate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linking group, and wherein Q is -N + R Q 2 X - , R Q is methyl, and wherein X - It's Br - .

[0043] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0044] or or or or

[0045] or

[0046] Where X - is a pharmaceutically acceptable anion. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0047]

[0048] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0049]

[0050] Where X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate.

[0051] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0052]

[0053] Where X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate.

[0054] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0055]

[0056] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0057]

[0058] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 -QLA-part is

[0059]

[0060] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- part is

[0061] in

[0062] I is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7, preferably, wherein I is 1, 2 or 3; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or Where X -is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q It's methyl.

[0063] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-NH-R 3 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-CH2-NH-R 3 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-CH2-CH2-NH-R 3 .

[0064] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-N(CH3)-R 3 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-CH2-N(CH3)-R 3 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-CH2-CH2-N(CH3)-R 3 .

[0065] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3The -QL- part is -CH2-CH2-N + (CH3)2-R 3 X - , where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- part is -CH2-CH2-CH2-N + (CH3)2-R 3 X - , where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- moiety is -CH2-CH2-CH2-CH2-N + (CH3)2-R 3 X - , where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - .

[0066] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a linear or branched (C1-C 10 )alkyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a substituted or unsubstituted aryl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a substituted or unsubstituted heteroaryl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a (5- to 8-membered) heterocyclyl. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a or substituted with (C1-C 10 According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a dipeptide. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a tripeptide. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein L is a PEG linker.

[0067] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is -NH. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is O. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is -NR Q , where R Q is a linear or branched (C1-C6) alkyl group, preferably, R Q According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is -N + R Q 2 X - , where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH -, toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein Q is

[0068] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- part is

[0069]

[0070] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- part is

[0071]

[0072] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 The -QL- part is

[0073]

[0074] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 is a group containing a positron emitting radionuclide Po. According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0075] or or

[0076] or or or

[0077] or or

[0078] or

[0079] And where Po is 64 Cu or 68 Ga.

[0080] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0081]

[0082] Where Po is 18 F or -O 11 CH3, preferably 18 F.

[0083] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes- 11 CH3. According to another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0084]

[0085] wherein M is O or -NH or CH2O.

[0086] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0087]

[0088] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0089]

[0090] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0091]

[0092] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0093] or According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0094]

[0095] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0096]

[0097] According to yet another embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3), wherein R 3 yes

[0098]

[0099] Ibandronic acid derivatives

[0100] According to one embodiment, the present invention relates to derivatives of ibandronic acid. In other words, according to one embodiment, the present invention relates to compounds of formula (Ia), wherein n is 1, A is -NR 2 , and L and Q are absent. Therefore, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof

[0101]

[0102] Where R 3 is a group containing a positron-emitting radionuclide Po; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein each R 1 Independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl.

[0103] According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0104] Where Po is 18 F or -O 11 CH3, preferably 18 F; or

[0105] or or

[0106] According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 yes Where Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0107] According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 2 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0108] According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0109] According to a preferred embodiment, the present disclosure relates to a compound of formula (IIa) or a pharmaceutically acceptable salt thereof

[0110]

[0111] According to a preferred embodiment, the present disclosure relates to a compound of formula (IIb) or a pharmaceutically acceptable salt thereof

[0112]

[0113] Each R 1 It is methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3.

[0114] According to a preferred embodiment, the present disclosure relates to a compound of formula (IIc) or a pharmaceutically acceptable salt thereof

[0115]

[0116] Each R 1 It is methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3.

[0117] According to another preferred embodiment, the present disclosure relates to a compound of formula (IId) or a pharmaceutically acceptable salt thereof

[0118]

[0119] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIe) or a pharmaceutically acceptable salt thereof

[0120]

[0121] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIf) or a pharmaceutically acceptable salt thereof

[0122]

[0123] According to another preferred embodiment, the present invention relates to compounds of formula (Ia), wherein n is 1, and A is -NR 2 .

[0124] According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof

[0125]

[0126] Where R 3 is a group containing a positron-emitting radionuclide Po and in which R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein each R 1 independently selected from hydrogen, linear or branched (C1-C6) alkyl

[0127] and -CH2-O-CO-O-(C1-C6)alkyl.

[0128] According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0129] Where Po is 18 F or -O 11CH3, preferably 18 F; or

[0130] or or

[0131] According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0132] According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0133] According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 yes Where Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0134] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIIa) or a pharmaceutically acceptable salt thereof

[0135]

[0136] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIIb) or a pharmaceutically acceptable salt thereof,

[0137]

[0138] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIIc) or a pharmaceutically acceptable salt thereof,

[0139]

[0140] Where R 3 is a group containing a positron-emitting radionuclide Po; and wherein each R 1 Independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl.

[0141] According to another preferred embodiment, the present disclosure relates to a compound of formula (IIIc) or a pharmaceutically acceptable salt thereof,

[0142] Where R 3 yes Where Po is 18 F or -O 11 CH3, preferably 18 F; or

[0143] or or And each R 1 Independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl.

[0144] Derivatives of alendronic acid

[0145] According to one embodiment, the present invention relates to derivatives of alendronic acid. In other words, according to one embodiment, the present invention relates to compounds of formula (Ia), wherein n is 2, A is -NR 2 , and L and Q are absent. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof

[0146]

[0147] Where R 3 is a group containing a positron-emitting radionuclide Po; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein each R 1Independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl.

[0148] According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0149] Where Po is 18 F or -O 11 CH3, preferably 18 F; or or or And where R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein each R 1 Independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl.

[0150] According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 yes Where Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0151] According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0152] According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0153] According to another preferred embodiment, the present disclosure relates to a compound of formula (IVa) or a pharmaceutically acceptable salt thereof

[0154]

[0155] According to another preferred embodiment, the present disclosure relates to a compound of formula (IVb) or a pharmaceutically acceptable salt thereof

[0156]

[0157] Each R 1 It is methyl or ethyl, preferably ethyl.

[0158] According to one embodiment, the invention relates to compounds of formula (Ia), wherein n is 1, and A is -NR 2 .

[0159] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof

[0160]

[0161] Where Q is -NH, -NR Q 、-N + R Q 2 X - or -O; where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Qis a linear or branched (C1-C6) alkyl group; and wherein p is 0 or 1; and wherein R 3 yes

[0162] or or Where R 2 is hydrogen or a linear or branched (C1-C6) alkyl group, preferably, R 2 is hydrogen or methyl; and wherein each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl, isopropyl or -O(CO)-C(CH3)3, more preferably, each R 1 is hydrogen or methyl, most preferably, each R 1 It's hydrogen.

[0163] According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein Q is -NH. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein Q is -O. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein Q is -NR Q , where R Q is a straight or branched (C1-C6) alkyl group, preferably a methyl group. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein Q is -NR Q 2 X - , where R Q is a linear or branched (C1-C6) alkyl group, preferably a methyl group, and wherein X - Yes F - , Cl - Br - ,I - or OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate.

[0164] According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein Q is -N + R Q 2 X - , where R Q is a linear or branched (C1-C6) alkyl group, preferably a methyl group, and wherein X - Yes F - , Cl- Br - ,I - or OH - According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein X - Yes F - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, X - It is Cl - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, X - It's Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, X - isI - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, X - Yes OH - .

[0165] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, p is 0. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, p is 1.

[0166] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or methyl.

[0167] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0168] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0169] According to another preferred embodiment, the present disclosure relates to a compound of formula (VIa) or a pharmaceutically acceptable salt thereof

[0170]

[0171] According to another preferred embodiment, the present disclosure relates to a compound of formula (VIb) or a pharmaceutically acceptable salt thereof

[0172]

[0173] According to another preferred embodiment, the present disclosure relates to a compound of formula (VIc) or a pharmaceutically acceptable salt thereof

[0174]

[0175] Zoledronic acid derivatives

[0176] According to one embodiment, the present invention relates to derivatives of zoledronic acid. In other words, according to one embodiment, the present invention relates to compounds of formula (Ia), wherein n is 2, A is And where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br- ,I - or OH - More preferably, Br - ; and wherein L and Q are absent. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof

[0177]

[0178] in

[0179] X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - or OH - More preferably, Br - ; and where R 3 yes

[0180] Where Po is 18 F or O 11 CH3, preferably 18 F; or or or Preferably, wherein R 3 yes or More preferably, R 3 yes And each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl, more preferably, each R 1 is hydrogen, methyl or isopropyl, most preferably, each R 1 is hydrogen or methyl.

[0181] According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof

[0182]

[0183] in

[0184] X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br- ,I - or OH - More preferably, Br - ; and where R 3 YesR 3 is a group containing a positron-emitting radionuclide Po; and wherein each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl, more preferably, each R 1 is hydrogen, methyl or isopropyl, most preferably, each R 1 is hydrogen or methyl.

[0185] According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0186] According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein X - Yes F - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein X - It is Cl - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein X - It's Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein X - isI - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein X - Yes OH - .

[0187] According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R1 is hydrogen, methyl, ethyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0188] According to another preferred embodiment, the present disclosure relates to a compound of formula (Va) or a pharmaceutically acceptable salt thereof

[0189]

[0190] Where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - or OH - More preferably, Br - .

[0191] According to one embodiment, the invention relates to compounds of formula (Ia), wherein n is 2, A is And where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - or OH - More preferably, Br - .

[0192] According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof

[0193]

[0194] Where Q is -NH, -NR Q 、-N + R Q 2 X - , N,N-substituted piperazine or -O; and wherein X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - or OH - More preferably, Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; preferably, Q is -NH; and wherein R 3 yes

[0195] or or And each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl, isopropyl or -O(CO)-C(CH3)3, more preferably, each R 1 is hydrogen or methyl, most preferably, each R 1 It's hydrogen.

[0196] According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is -NH. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is -O. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is -NR Q , where R Q is a straight or branched (C1-C6) alkyl group, preferably a methyl group. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is -N + R Q 2X - , where R Q is a linear or branched (C1-C6) alkyl group, preferably a methyl group, and wherein X - Yes F - , Cl- Br - ,I - or OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate.

[0197] According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein Q is -N + R Q 2 X - , where R Q is a linear or branched (C1-C6) alkyl group, preferably a methyl group, and wherein X - Yes F - , Cl - Br - ,I - or OH - According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein X - Yes F - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein X - It is Cl - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein X - It's Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein X - isI - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein X - Yes OH - .

[0198] According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0199] According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0200] According to another preferred embodiment, the present disclosure relates to a compound of formula (VIIa) or a pharmaceutically acceptable salt thereof

[0201]

[0202] Derivatives of risedronic acid

[0203] According to one embodiment, the present invention relates to derivatives of risedronic acid. In other words, according to one embodiment, the present invention relates to compounds of formula (Ia), wherein n is 0 and R 3 -QLA-Yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof

[0204]

[0205]

[0206] wherein L and Q are absent; or wherein L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2X - , -O, N,N-substituted piperazine or And where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and wherein R 3 is a group containing a positron-emitting radionuclide Po; and wherein each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl, more preferably, each R 1 is hydrogen, methyl or isopropyl, most preferably, each R 1 is hydrogen or methyl.

[0207] According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes Where Po is 18 F or O 11 CH3, preferably 18 F; or or or Preferably, wherein R 3 yes or More preferably, R 3 yes

[0208] According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0209] According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein Q is -NH. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein Q is -O. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein Q is -NR Q , where R Q is a straight or branched (C1-C6) alkyl group, preferably a methyl group. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein Q is -N + R Q 2 X - , where R Q is a linear or branched (C1-C6) alkyl group, preferably a methyl group, and wherein X - Yes F - , Cl - Br - ,I - or OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate.

[0210] According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0211] According to another preferred embodiment, the present disclosure relates to a compound of formula (VIIIa) or a pharmaceutically acceptable salt thereof

[0212]

[0213] According to another preferred embodiment, the invention relates to compounds of formula (Ia), wherein n is 0 and R 3 -QLA-Yes wherein LQ is -CH2-CH2-NH-. In other words, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof

[0214]

[0215] Where R 3 is a group containing a positron-emitting radionuclide Po; and wherein each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl, more preferably, each R 1 is hydrogen, methyl or isopropyl, most preferably, each R 1 is hydrogen or methyl.

[0216] According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein R 3 yes Where Po is 18 F or O 11 CH3, preferably 18 F; or or or Preferably, wherein R 3 yes or More preferably, R 3 yes

[0217] According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein R 3 yes According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein R 3 yes

[0218] According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl, isopropyl or -CH2-O-CO-OC(CH3)3. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl, ethyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 is hydrogen, methyl or isopropyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof, wherein each R 1 It is -CH2-O-CO-OC(CH3)3.

[0219] According to another preferred embodiment, the present disclosure relates to a compound of formula (IXa) or a pharmaceutically acceptable salt thereof

[0220]

[0221] Medical Uses

[0222] In yet another aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in medicine.

[0223] In yet another aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a diagnostic method.

[0224] In yet another aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method of diagnosing amyloidosis.

[0225] In yet another aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method of diagnosing cardiac amyloidosis.

[0226] Manufacturing method

[0227] According to yet another aspect, the present disclosure relates to a first method for preparing a compound according to the present disclosure, the method comprising the steps of:

[0228] a) providing a compound of formula (Ia)

[0229]

[0230] Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L and Q are absent; or wherein L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2X - , -O or N,N-substituted piperazine; wherein R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and

[0231] b) Provide formula R 3 -Y compound, wherein R 3 -Y is

[0232] Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is64 Cu or 68 Ga, preferably 68 Ga; or

[0233] Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or Where Po is 18 F or -O 11 CH3, preferably 18 F; or

[0234] Y- 11 CH3 or HO- 11 CH3; wherein M is O or -NH or CH2O; or or or or or or or and wherein Y is an electron withdrawing group, preferably, Y is selected from the group consisting of -Cl, -Br, -O-C6F5H, -O(CO)-(C1-C6)alkyl and -OH; and

[0235] c) reacting the compound of formula (Ia) with any one of R 3 -Y is reacted at a temperature of about 60°C to about 140°C, wherein when Y is -OH, step b) further comprises providing dry DMF and a coupling agent selected from the group consisting of EDC, HATU, HOBt, HBTU and HATU.

[0236] According to a preferred embodiment, the present disclosure relates to a first method for preparing a compound according to the present disclosure, wherein step c) is performed for a time of about 1 min to about 60 min.

[0237] According to a preferred embodiment, the present disclosure relates to a first preparation process of the compounds according to the present disclosure, wherein step c) is performed in dry DMF or dry DMSO.

[0238] According to another aspect, the present disclosure relates to a second method for preparing a compound according to the present disclosure, the method comprising the steps of:

[0239] a) providing a compound of formula (Ib)

[0240]

[0241] wherein z is 1, 2 or 3, preferably z is 1; and wherein each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L and Q are absent; or L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O or N,N-substituted piperazine; wherein R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and wherein R 3a yes

[0242] or or or or or or or or or Where R 5 is OTs, OMs, OTf, or I; or wherein M is O or -NH or CH2O; or or or or or or or Where R 9 is an ammonium salt or H; and

[0243] b) reacting a compound of formula (Ib) with a Po* group comprising a positron emitting radionuclide Po, wherein Po* is - 11 CH3, 13 N. 15 O.18 F - , 64 Cu or 68 Ga, preferably - 11 CH3, 18 F - and 68 Ga, more preferably 18 F - or 68 Ga.

[0244] According to a preferred embodiment, the present disclosure relates to a process for the preparation of a compound according to the present disclosure, wherein step b) is performed for a period of about 1 min to about 60 min.

[0245] According to a preferred embodiment, the present disclosure relates to a second process for preparing the compounds according to the present disclosure, wherein step b) is carried out at a temperature of about 80°C to about 140°C.

[0246] According to a preferred embodiment, the present disclosure relates to a second preparation process of the compounds according to the present disclosure, wherein step b) is performed in dry DMF or dry DMSO.

[0247] According to another aspect, the present disclosure relates to a third method for preparing a compound according to the present disclosure, the method comprising the steps of:

[0248] a) providing a compound of formula (Ic)

[0249]

[0250] Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L is (C1-C 10 )alkyl, and Q is -C≡CH; and

[0251] b) Provide Compounds of

[0252] and

[0253] c) reacting the compound of formula (Ic) with the compound of step b) at a temperature of about 60°C to about 140°C in the presence of a Cu(I) salt.

[0254] According to a preferred embodiment, the present disclosure relates to a third method for preparing a compound according to the present disclosure, wherein step c) is performed for a period of about 1 min to about 60 min.

[0255] According to a preferred embodiment, the present disclosure relates to a third method for preparing the compound according to the present disclosure, wherein step c) is performed at a temperature of about 80°C to about 140°C.

[0256] According to a preferred embodiment, the present disclosure relates to a third preparation method of the compounds according to the present disclosure, step c) is carried out in dry DMF or dry DMSO.

[0257] General aspects and definitions

[0258] In another embodiment, the present disclosure relates to a compound of formula (I) or formula (II) or formula (III) or formula (IV) or formula (V) or formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein the compound is not a derivative of risedronic acid.

[0259] In another embodiment, the present disclosure relates to a compound of formula (I) or formula (II) or formula (III) or formula (IV) or formula (V) or formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein the compound is not

[0260] or or

[0261] or or

[0262] or or

[0263] or or

[0264]

[0265] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-mentioned compound and includes pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds disclosed herein can be prepared from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, heterocyclic carboxyl and sulfonic acid organic acids, examples of which are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, arylsulfonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds disclosed herein include metal salts made from lithium, sodium, potassium, aluminum and zinc and organic salts made from organic bases (such as choline, diethanolamine, morpholine). Other examples of organic salts are: ammonium salts, quaternary salts (such as tetramethylammonium salt); amino acid addition salts (such as glycine salt and arginine salt).

[0266] As used herein, the term "pharmaceutically acceptable cation" refers to a cation that is non-toxic to mammals. Preferred pharmaceutically acceptable cations are lithium, sodium, potassium, aluminum and zinc; cations prepared from organic bases (such as choline, diethanolamine, morpholine, ammonium salts, quaternary salts (such as tetramethylammonium salts)), amino acid addition salts (such as glycine salts and arginine salts).

[0267] As used herein, the term "pharmaceutically acceptable anion" refers to an anion that is non-toxic to mammals. Pharmaceutically acceptable anions may have one, two, three or more negative charges. Preferred pharmaceutically acceptable anions are F - , Cl - Br - ,I - OH - , toluenesulfonate, mesylate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate. Further preferred pharmaceutically acceptable anions are F - , Cl - Br - ,I - or OH - A particularly preferred pharmaceutically acceptable anion is Br - .

[0268] As used herein, "protecting group" refers to a group that can be selectively cleaved from a bisphosphonate under acidic or basic conditions or a group that can be selectively cleaved metabolically from a bisphosphonate in a mammal. Preferred protecting groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2-O(CO)-CH3, -CH2-O(CO)-CH2CH3, -CH2-O(CO)-CH(CH3)2, -CH2-O(CO)-C(CH3)3 and Wherein R' is methyl or ethyl. Other preferred protecting groups are connected to two functional groups to form or or wherein R' is hydrogen or (C1-C 10 )alkyl.

[0269] Other suitable protecting groups can be found in Heidel, H.-K.; et al. Phosphonate prodrugs: an overview and recent advances. Future Med. Chem. 2019, 11, 1625-1643, which is incorporated herein by reference.

[0270] As used herein, the term "(4- to 8-membered) heterocyclyl" refers to a saturated or partially saturated monocyclic or bicyclic ring containing 4 to 8 atoms, wherein at least one of the 4 to 8 atoms is a heteroatom selected from nitrogen, sulfur or oxygen, preferably, the (4- to 8-membered) heterocyclyl has 1 to 3 heteroatoms. Preferred (4- to 8-membered) heterocyclyl groups are selected from pyrrolidinyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane and 1,4-oxathiapane. The group may be a terminal group or a bridging group. Other (4- to 8-membered) heterocyclyl groups include:

[0271]

[0272] and

[0273] As used herein, when a bridging group is used in the context of a normal chain, reference to the normal chain refers to the direct chain of atoms connecting the two terminal positions of the bridging group.

[0274] For the purpose of this disclosure, the term "(4 to 8 yuan) cyclic radical" used alone or as part of another group refers to a cyclic aliphatic hydrocarbon containing one or two rings (i.e., C4-C8 cycloalkyl) with four to eight carbon atoms or containing one or two rings with a specified number of carbon atoms, which are saturated or partially unsaturated (e.g., containing one or two double bonds). In some embodiments, the (4 to 8 yuan) cyclic radical group has two rings. In some embodiments, the (4 to 8 yuan) cyclic radical group has one ring. In some embodiments, the (4 to 8 yuan) cyclic radical group is a saturated cyclic aliphatic hydrocarbon containing one or two rings (preferably one ring) and having 4, 5, 6, 7 or 8 carbon atoms. In another embodiment, the (4 to 8 yuan) cyclic radical group is selected from a C4-C6 cycloalkyl group. Non-limiting exemplary (4 to 8 yuan) cyclic radical groups include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The group can be a terminal group or a bridging group.

[0275] For the purpose of the present disclosure, the term "aryl" as used alone or as part of another group refers to a mono-, bi- or tricyclic aromatic ring system (i.e., C6-C8) having six to fourteen (i.e., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms. 14 Aryl). Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylalkenyl, and fluorenyl groups. In one embodiment, the aryl group is selected from phenyl or naphthyl.

[0276] For the purpose of the present disclosure, the term "substituted aryl" as used herein alone or as part of another group means that the aryl group as defined above is replaced by one to ten, preferably one to eight, more preferably one to five, independently selected from halogen, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, alkylc In one embodiment, the substituted aryl is substituted with a substituent of alkyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxylalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclyl)alkyl, (cycloalkylamino)alkyl, (C1-C4 haloalkoxy)alkyl, or (heteroaryl)alkyl. In one embodiment, the substituted aryl is substituted phenyl. In one embodiment, the substituted phenyl has four substituents. In another embodiment, the substituted phenyl has three substituents. In another embodiment, the substituted phenyl has two substituents. In another embodiment, the substituted phenyl has one substituent. Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3 chlorophenyl and 3-chloro-4 fluorophenyl. The term substituted aryl means including groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocycles. Examples include:

[0277]

[0278] For the purposes of this disclosure, the term "haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine atoms and / or chlorine atoms. In another embodiment, the haloalkyl group is selected from C 1-4Haloalkyl Groups. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

[0279] For the purpose of this disclosure, the term "(hydroxy)haloalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more halogen atoms and a hydroxyl group. A non-limiting exemplary (hydroxy)haloalkyl group is -CH(OH)CF3.

[0280] For the purposes of this disclosure, the term "hydroxyalkyl" used alone or as part of another group refers to an alkyl group substituted with one or more (e.g., one, two, or three) hydroxyl groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxyl group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxyl groups. In another embodiment, the hydroxyalkyl group is selected from C 1-4 Hydroxyalkyl groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1,3-dihydroxyprop-2-yl.

[0281] For the purpose of this disclosure, the term "cycloalkyl" as used alone or as part of another group refers to a cycloalkyl group containing one to three rings having three to twelve carbon atoms (i.e., C 3-12 In one embodiment, the cycloalkyl group is a saturated cyclic aliphatic hydrocarbon containing one or two rings (preferably one ring) and 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. In another embodiment, the cycloalkyl group is selected from C 3-8 In another embodiment, the cycloalkyl group is selected from C 3-6 Cycloalkyl Groups. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and the like.

[0282] For the purposes of this disclosure, the term "(cycloalkyl)alkyl" used alone or as part of another group refers to an alkyl group substituted with at least one optionally substituted cycloalkyl group. Non-limiting exemplary (cycloalkyl)alkyl groups include:

[0283] and

[0284] For the purposes of this disclosure, the term "hydroxy(cycloalkyl)alkyl" used alone or as part of another group refers to a (cycloalkyl)alkyl group substituted with at least one hydroxyl group. The hydroxyl group may be in any available position. Non-limiting exemplary hydroxy(cycloalkyl)alkyl groups include:

[0285] and

[0286] For the purpose of this disclosure, the term "alkoxy" used alone or as part of another group refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom. In one embodiment, the alkoxy group is selected from C 1-4 In another embodiment, the alkoxy group is selected from C 1-4 Alkyl groups such as methoxy, ethoxy and tert-butoxy.

[0287] For the purpose of this disclosure, the term "alkylthio" used alone or as part of another group refers to a sulfur atom substituted with an optionally substituted alkyl group. 1-4 Alkylthio groups. Non-limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3.

[0288] For purposes of this disclosure, the term "alkoxyalkyl" used alone or as part of another group refers to an alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include: methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0289] For the purpose of this disclosure, the term "haloalkoxy" used alone or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include: fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0290] "(5- to 6-membered)heteroaryl" alternatively refers to a group containing an aromatic ring comprising 5 to 6 ring atoms, wherein one or two or three, preferably one, of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur; the rest of the ring atoms are carbon atoms. Preferred (5- to 6-membered) heteroaryl groups are thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl and 2- or 3-thienyl. The group may be a terminal group or a bridging group.

[0291] For the purposes of this disclosure, the term "(C1-C 10 The term "alkyl" refers to a straight- or branched-chain aliphatic hydrocarbon (i.e., C1-C2) containing from one to ten (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms. 10 In one embodiment, the alkyl group is selected from a straight chain (C1-C 10 In another embodiment, the alkyl group is selected from branched (C3-C 10 ) alkyl groups. In another embodiment, the alkyl group is selected from a straight chain (C1-C6) alkyl group. In another embodiment, the alkyl group is selected from a branched chain (C3-C6) alkyl group. In another embodiment, the alkyl group is selected from a straight chain (C1-C4) alkyl group. In another embodiment, the alkyl group is selected from a branched chain (C3-C4) alkyl group. In another embodiment, the alkyl group is selected from a straight or branched chain (C3-C4) alkyl group. Non-limiting exemplary (C1-C 10 ) Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplary C 1-4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and iso-butyl.

[0292] As used herein, the term "straight or branched (C1-C6) alkyl" refers to an aliphatic hydrocarbon group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms in the chain, which may be straight or branched. Preferred straight or branched (C1-C6) alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The term is also referred to as tBu. The group may be a terminal group or a bridging group.

[0293] As used herein, the term "absent" means that a group does not occur in a compound. Alternatively, the absent group is a single bond.

[0294] "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 14 carbon atoms, more preferably 2 to 10 carbon atoms in the chain, wherein one or more carbon atoms have been replaced by heteroatoms selected from S, O and N. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein, when a bridging group is used in the context, the normal chain referred to refers to the direct chain of atoms connecting the two terminal positions of the bridging group. Non-limiting exemplary heteroalkyl groups include: -CH2N(H)CH2CH2N(CH3)2; -CH2N(CH3)CH2CH2N(CH3)2; -CH2N(H)CH2CH2CH2N(CH3)2; -CH2N(H)CH2CH2OH; -CH2N(CH3)CH2CH2OH; -CH2OCH2CH2OCH3, -OCH2CH2OCH2CH2OCH3, -CH2NHCH2CH2OCH2, -OCH2CH2NH2; and -NHCH2CH2N(H)CH3.

[0295] As used herein, the term "unsubstituted" means there are no substituents or the only substituent is hydrogen.

[0296] The term "substituted" as used throughout the specification means that a group contains one or more substituent groups. Preferably, the substituent groups are one or more independently selected from halogen, =O, =S, -CN, -NO2, -CF3, -OCF3, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkenyl, heterocycloalkylalkenyl, arylalkenyl, heteroarylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, arylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxycycloalkyl, alkoxyheterocycloalkyl The invention also includes a group consisting of an alkyl group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group, an alkyloxy group

[0297] For the purposes of this disclosure, the term "optionally substituted alkyl" used alone or as part of another group means that the alkyl group as defined above is unsubstituted or substituted with one, two or three substituents independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidino, carboxyl, carboxyalkyl, cycloalkyl, and the like. In one embodiment, the optionally substituted alkyl group is substituted with two substituents. In another embodiment, the optionally substituted alkyl group is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include: -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, -CH2C6H 11 wait.

[0298] As used herein, the term "electron withdrawing group" refers to an atom or group that attracts the electron density of adjacent atoms to itself, usually through resonance or inductive effects. Examples of preferred electron withdrawing groups are -Cl, -Br, -O-C6F5H, -O(CO)-(C1-C6)alkyl and -OH.

[0299] The term "ω-amino acid" has The general structure of wherein o is an integer of 1, 2, 3, 4, 5, 6 or 7. Examples of preferred ω-amino acids are glycine, 2-aminoacetic acid, 3-aminopropionic acid, 4-aminobutyric acid, 4-aminopentanoic acid and 6-aminohexanoic acid.

[0300] As used herein, the term "dipeptide" relates to a peptide consisting of two standard amino acids.

[0301] As used herein, the term "tripeptide" relates to a peptide consisting of three standard amino acids.

[0302] As used herein, the term "divalent linking group" refers to a group having 2 valences. In other words, the divalent linking group is bonded to two groups. According to one embodiment, the divalent linking group is bonded to group A and group Q. The divalent linking group according to the present disclosure can be a straight chain or branched chain (C1-C 10 )alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, (5- to 8-membered) heterocyclic group, substituted with (C1-C 10 Preferred divalent linking groups are -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, or -CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-.

[0303] As used herein, the term "PEG linking group" is a A group wherein peg is 1, 2, 3, 4 or 5, preferably, peg is 2 or 3.

[0304] The terms "a" and "an" refer to one or more.

[0305] Example

[0306] Chemical

[0307] All starting materials used herein were obtained from commercial suppliers.

[0308] Mode( 19 Synthesis of compounds of F-Va)

[0309] The synthesis of the compound of formula (Va) is carried out as follows:

[0310]

[0311] Tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobutane-1,1-diyl) bisphosphonate

[0312] Triethyl phosphite (58.92 g, 354.62 mmol) was added dropwise to 4-chlorobutyryl chloride (50 g, 354.62 mmol) under N2 at 0°C, and the mixture was then heated to 20°C and stirred for 15 min. The mixture was diluted with DCM (1000 mL), and 1-ethoxyphosphonoyloxyethane (48.97 g, 354.62 mmol) was added at 0°C. The mixture was stirred at 20°C for 15 min, and DMAP (43.32 g, 354.62 mmol) was added at 20°C and stirred for 1 h. The mixture was cooled to 0°C, TBSCl (58.79 g, 390.08 mmol) was added, heated to 20°C and stirred for 15 h. The reaction mixture was washed with H2O (300 mL), sat.-NH4Cl (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-HPLC under the following conditions: column: Phenomenex luna c18 250mm*100mm*15um; mobile phase: [water (FA)-ACN]; B%: 60%-90%, and tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobutane-1,1-diyl) bisphosphonate and (Z)-diethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobut-1-en-1-yl) phosphonate (71 g) were obtained in 20 minutes as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.20 (m, 8H), 3.58–3.48 (m, 2H), 2.26–2.10 (m, 4H), 1.33 (t, J = 7.2 Hz, 12H), 0.92 (d, J = 24.0 Hz, 9H), 0.19 (s, 6H). LC-MS calculated for C18H41ClO7P2Si m / z 494.18 [M+H] + , measured 495.2.

[0313] Tetraethyl(1-((tert-butyldimethylsilyl)oxy)-4-(1H-imidazol-1-yl)butane-1,1-diyl)bis(phosphonate)

[0314] To a solution of NaH (5.66 g, 141.41 mmol, 60% purity) in THF (200 mL) and DMF (200 mL) at 0°C was added imidazole (9.63 g, 141.41 mmol). The mixture was stirred at 20°C for 1 h. Tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobutane-1,1-diyl) bis(phosphonate) (70 g, 141.41 mmol) and NaI (10.60 g, 70.71 mmol) were added at 0°C, and the mixture was stirred at 40°C for 36 h. The mixture was quenched with sat. NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase MPLC (neutral) to give tetraethyl(1-((tert-butyldimethylsilyl)oxy)-4-(1H-imidazol-1-yl)butane-1,1-diyl)bis(phosphonate) (6 g, 8%) as a yellow oil. 1 H-NMR (400 MHz, CDCl3) δ7.56 (s, 1H), 7.08 (s, 1H), 6.95-6.92 (m, 1H), 4.25-4.12 (m, 8H), 3.96 (t, J = 6.8 Hz, 2H), 2.14 (br s, 4H), 1.32 (dt, J = 2.4, 7.2 Hz, 12H), 0.88 (s, 9H), 0.14 (s, 6H). LC-MS calculated for C 21 H 44 N2O7P2Si m / z526.27[M+H] + , measured 527.1.

[0315] ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane

[0316] To a solution of (4-bromophenyl)methanol (50 g, 267.33 mmol) in DCM (600 mL) was added imidazole (27.30 g, 401.00 mmol) and TBSCl (60.44 g, 401.00 mmol) at 0°C. The mixture was stirred at 20°C for 12 h. The mixture was diluted with H2O (400 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:0 to 10:1) to give ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (77 g, 255.56 mmol, 96%) as a colorless oil.

[0317] 1H-NMR (400MHz, CDCl3) δ7.46 (d, J = 8.4Hz, 2H), 7.21 (d, J = 8.4Hz, 2H), 4.69 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

[0318] Di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane

[0319] To a solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (30 g, 99.57 mmol) in THF (300 mL) at -78°C was added t-BuLi (1.3 M, 176.16 mL, 229.00 mmol). The mixture was stirred at -78°C for 0.5 h and then added dropwise to a solution of di-tert-butyldifluorosilane (21.54 g, 119.48 mmol) in THF (200 mL) at -78°C. The mixture was stirred at 20°C for 12 h. The reaction mixture was quenched by pouring sat. NH4Cl (500 mL) at 0°C and extracted with MTBE (3×200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane (43 g, crude) as a colorless oil. 1 H-NMR (400MHz, CDCl3) δ7.52 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 6.4 Hz, 2H), 4.71 (s, 2H), 1.00 (s, 18H), 0.90 (s, 9H), 0.06 (s, 6H).

[0320] (4-(Di-tert-butylfluorosilyl)phenyl)methanol

[0321] To a solution of di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane (43 g, 112.36 mmol) in MeOH (300 mL) was added HCl (12 M, 3 mL) at 20°C. The mixture was stirred at 20°C for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc = 1:0 to 3:1) to give (4-(di-tert-butylfluorosilyl)phenyl)methanol (14.8 g, 49% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ7.62 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 4.73 (s, 2H), 1.07 (d, J = 0.8 Hz, 18H).

[0322] (4-(Bromomethyl)phenyl)di-tert-butylfluorosilane

[0323] To a mixture of (4-(di-tert-butylfluorosilyl)phenyl)methanol (14.8 g, 55.13 mmol) and CBr4 (21.94 g, 66.16 mmol) in DCM (200 mL) was added a solution of PPh3 (17.35 g, 66.16 mmol) in DCM (50 mL) at 0°C under N2. The reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc = 1:0 to 10:1) to give (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (21 g, 95.8% yield) as a white solid. 1 H-NMR (400MHz, CDCl3) δ7.59 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.51 (s, 2H), 1.06 (d, J = 1.2 Hz, 18H).

[0324] 1-(4-((tert-butyldimethylsilyl)oxy)-4,4-bis(diethoxyphosphoryl)butyl)-3-(4-(di-tert-butylfluorosilyl)benzyl)-1H-imidazol-3-ium hydrobromide

[0325] To a solution of (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (200 mg, 0.60 mmol) in EtOAc (5 mL) was added tetraethyl(1-((tert-butyldimethylsilyl)oxy)-4-(1H-imidazol-1-yl)butane-1,1-diyl)bis(phosphonate) (477 mg, 0.90 mmol) at 20°C. The mixture was stirred at 50°C for 32 h. The mixture was filtered. The filter cake was dried under reduced pressure to give 1-(4-((tert-butyldimethylsilyl)oxy)-4,4-bis(diethoxyphosphoryl)butyl)-3-(4-(di-tert-butylfluorosilyl)benzyl)-1H-imidazol-3-ium hydrobromide (700 mg, crude) as a white solid. LC-MS calculated as C 36 H 68 FN2O7P2Si2 + m / z 777.40[M] + , measured 777.4.

[0326] 3-(4-(Di-tert-butylfluorosilyl)benzyl)-1-(4-hydroxy-4,4-diphosphonobutyl)-1H-imidazol-3-ium bromide (Va)

[0327] To a solution of 1-(4-((tert-butyldimethylsilyl)oxy)-4,4-bis(diethoxyphosphoryl)butyl)-3-(4-(di-tert-butylfluorosilyl)benzyl)-1H-imidazol-3-ium hydrobromide (300 mg, 0.349 mmol) in ACN (6 mL) at 20° C. was added TMSBr (3.54 g, 0.023 mmol). The mixture was stirred at 20° C. for 12 h. H 2 O (2 mL) was added and the mixture was stirred at 20° C. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC under the following conditions: column: Phenomenex luna C18 100*40mm*3μm; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 8min to give 3-(4-(di-tert-butylfluorosilyl)benzyl)-1-(4-hydroxy-4,4-diphosphonobutyl)-1H-imidazol-3-ium bromide (48.35 mg) as a white solid. 1 H-NMR (400MHz, DMSO) δ9.38(br s,1H),7.81(br d,J=12.4Hz,2H),7.62(br d,J=4.4Hz,2H),7.41(br d,J=4.8Hz,2H),5.48(br s,2H),4.22(br s,2H),2.24-2.03(m,2H),1.97-1.73(m,2H),1.26-0.76(m,18H)LC-MS calculated as C 22 H 38 FN2O7P2Si + m / z551.19[M] + , measured 551.1.

[0328] (Va) Radiolabeling Protocol

[0329] The synthetic scheme for the preparation of (Va) was carried out as follows:

[0330]

[0331] Method 1

[0332] The cyclotron obtained in [ 18 O]H2O 18F]HF (200-500 μL) was added to a solution of FSi-Zole precursor in DMSO (50-100 μL). The resulting solution was heated at 95°C for 30 min. The reaction solution was diluted with 1.5 mL of 70% acetonitrile / water and purified by HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 5%->90% B, 20-25 min 90% B, 25-27 min, 90%->5% B, 27-30 min, 5% B, flow rate 1.5 mL / min, retention time 15.6±0.5 min. The collected fractions were diluted to 2.5 mL with PBS and applied to a pre-treated PD-10 desalting column, and the column was eluted with PBS buffer at 0.5 mL per fraction. Fractions containing radioactivity were pooled and passed through a 0.2 μM sterile filter in preparation for in vitro and in vivo applications.

[0333] Method 2

[0334] The cyclotron obtained in [ 18 O]H2O 18 F]HF was passed through an anion exchange column (Waters QMA column pretreated with 15 mL of pure water). The column was rinsed with 2 mL of pure water and air dried with 10 mL. A solution containing potassium carbonate and Kryptofix 222 (300 μL, 0.025 M / 0.05 M, in acetonitrile / water 3:1) was used to elute from the column. 18 F]F –. The solution was azeotropically dried at 120°C under a nitrogen stream. After adding anhydrous acetonitrile (0.5 mL), the process was repeated twice. After concentration, anhydrous acetonitrile (200 μL) and a solution of FSi-Zole precursor (50 μL, 1 mg / mL solution in dry DMSO) were added to the residue, followed by reaction at room temperature for 15 min. The reaction solution was diluted with 1.5 mL 70% acetonitrile / water and purified by HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 5%->90% B, 20-25 min 90% B, 25-27 min, 90%->5% B, 27-30 min, 5% B, flow rate 1.5 mL / min, retention time 15.6±0.5 min. The collected fractions were diluted to 2.5 mL with PBS and applied to the pre-treated PD-10 column, and the column was eluted with PBS buffer at 0.5 mL per fraction. Fractions containing radioactivity were pooled and passed through a 0.2 μM sterile filter in preparation for in vitro and in vivo applications.

[0335] Method 3

[0336] The cyclotron obtained in [ 18 O]H2O 18 F]HF was passed through an anion exchange column (Waters QMA column pre-treated with 15 mL of pure water). The column was rinsed with 2 mL of pure water and dried with 10 mL of air. A solution of Et4NHCO3aq. (0.075 M, 80 μL), water (120 μL) and acetonitrile (400 μL) was used to elute from the column. 18 F]F – . The solution was azeotropically dried at 120° C. under a nitrogen stream. After adding anhydrous acetonitrile (0.5 mL), the process was repeated twice. After concentration, anhydrous acetonitrile (200 μL) and a solution of FSi-Zole precursor (50 μL, 1 mg / mL solution in dry DMSO) were added to the residue, and then reacted at room temperature for 15 min. The reaction solution was diluted with 1.5 mL of water and captured on a Waters Sep-Pak tC18 column (pretreated with 5 mL of ethanol and 5 mL of water). The column was washed with 5 mL of water, air dried with 10 mL, and eluted with ethanol / PBS (2 mL, 1:1 mixture). Ethanol was removed by a nitrogen stream and the residue was diluted with PBS buffer. The solution was passed through a 0.2 μM sterile filter and then prepared for in vitro and in vivo applications.

[0337] Mode( 19 Synthesis of Compounds F-IVa)

[0338] Mode( 19The synthesis of the compound of F-IVa) was carried out as follows:

[0339]

[0340] Tetraethyl(4-azido-1-((tert-butyldimethylsilyl)oxy)butane-1,1-diyl)bis(phosphonate)

[0341] A mixture of diethyl diethyl 1-[(tert-butyldimethylsilyl) oxygen]-4 chloro-1-(diethoxyphosphoryl) butylphosphonate (13.6 g, 27.475 mmol, 1.00 equiv.) and sodium azide (3.57 g, 54.950 mmol, 2 eq.) in anhydrous DMF (100.00 mL) was stirred at 80 ° C for 4 hours under a nitrogen atmosphere. The reaction was quenched with water (100 mL) at 25 ° C. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (5 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide diethyl diethyl 4-azido-1-[(tert-butyldimethylsilyl) oxygen]-1-(diethoxyphosphoryl) butylphosphonate (13 g, crude product) as a yellow oil. The crude product was used in the next step without further purification. LC-MS calculated for C 18 H 41 N3O7P2Si m / z 502.57[M+H] + , the actual measured value is 502.3.

[0342] Tetraethyl(4-amino-1-((tert-butyldimethylsilyl)oxy)butane-1,1-diyl)bis(phosphonate)

[0343] In a pressure tank, Pd / C (10%, 1.38 g) was added to a solution of diethyl 4-azido-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (13 g, 25.91 mmol, 1.00 eq.) in 200 mL of ethyl acetate. The mixture was hydrogenated at room temperature, 50 psi of hydrogen pressure for 15 hours, filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to provide diethyl 4-amino-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (10 g, crude) as a yellow oil. 1 H-NMR (400 MHz, DMSO) δ 4.06 (m, 8H), 2.53 (m, 2H), 2.04 (m, 2H), 1.64 (m, 2H), 1.25 (dt, 12H), 0.87 (s, 9H), 0.16 (s, 6H). LCMS calculated as C 18 H43 NO7P2Si m / z 476.57[M+H] + , the actual measured value is 476.3.

[0344] Tetraethyl(1-((tert-butyldimethylsilyl)oxy)-4-(6-fluoronicotinamido)butane-1,1-diyl)bis(phosphonate)

[0345] To a stirred solution of diethyl 4-amino-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (1.69 g, 3.544 mmol, 1 eq) and 6-fluoropyridine-3-carboxylic acid (500 mg, 3.544 mmol, 1.00 eq) in DMF (10 mL) was added HATU (2.02 g, 5.316 mmol, 1.50 eq) and DIEA (1.25 mL, 7.194 mmol, 2.03 eq) at 20 °C. The reaction was stirred at 20 °C for 2 hours. The reaction was quenched with water. The aqueous layer was extracted with EA (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in EA (7%) to afford diethyl 1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)-4-[(6-fluoropyridin-3-yl)formamido]butylphosphonate (691 mg, 32.57%) as a yellow oil. 1 H NMR (400 MHz, Methanol-d4) δ 8.64 (d, J = 2.4 Hz, 1H), 8.37–8.28 (m, 1H), 7.17 (dd, J = 8.8, 2.4 Hz, 1H), 4.30–4.10 (m, 9H), 3.40 (t, J = 6.4 Hz, 2H), 2.25–2.05 (m, 2H), 2.05–1.92 (m, 2H), 1.36–1.30 (m, 12H), 0.91 (s, 9H), 0.21 (s, 6H). LCMS calculated for C 24 H 45 FN2O8P2Si m / z 599.24[M+H] + , the actual measured value is 599.3.

[0346] (IVa) Radiolabeling Protocol

[0347] Radiolabeling was performed as follows:

[0348]

[0349] Method 1

[0350] The cyclotron obtained in [ 18 O]H2O18 F]HF was passed through an anion-exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original bottle was rinsed with 2 mL of pure water and also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. A solution of the quaternary amine triflate precursor (5-10 mg) in anhydrous isobutyl alcohol:acetonitrile (4:1, 1 mL) was slowly eluted. 18 F]F – More than 5 minutes. Dilute the eluate with 8 mL of water and SPE 18 F-aromatic nucleophilic substitution was captured on a small column (pretreated with 2 mL of acetonitrile). The small column was washed with 5 mL of water and eluted with 1.5 mL of 65% acetonitrile / water. A sample of 0.5-1 MBq of the eluate was taken for quality control using HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 30%->80% B, 20-22 min 80%->95% B, 22-27 min, 95% B, 27-30 min, 95%->30% B, flow rate 2.0 mL / min, retention time 15.2 min. A solution of alendronate in borate buffer (pH 9.5, 200 μL) was added to the eluate, and the resulting solution was heated at 40°C for 20 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-PAQ 10ID*250 mm; mobile phase: A: PBS, B: ethanol; method: 0->5 min, 5% B, 5-20 min 5%->35% B, 20-23 min, 35%->90% B, 23-28 min, 90% B, 28-33 min, 90%->5% B, 33-40 min, 5% B, flow rate 3.0 mL / min, retention time 6.0±0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for in vitro and in vivo applications.

[0351] Method 2

[0352] The cyclotron obtained in [ 18 O]H2O 18F]HF was passed through an anion-exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original bottle was rinsed with 2 mL of pure water and also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. A solution of the quaternary amine triflate precursor (5-10 mg) in anhydrous isobutyl alcohol:acetonitrile (4:1, 1 mL) was slowly eluted. 18 F]F – More than 5 minutes. Dilute the eluate with 8 mL of water and SPE 18 F-aromatic nucleophilic substitution was captured on a small column (pretreated with 2 mL of acetonitrile). The small column was washed with 5 mL of water and eluted with 1 mL of acetone. A sample of 0.5-1 MBq of the eluate was taken for quality control using HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 30%->80% B, 20-22 min 80%->95% B, 22-27 min, 95% B, 27-30 min, 95%->30% B, flow rate 2.0 mL / min, retention time 15.2 min. The solvent was removed under a nitrogen stream at room temperature. After concentration, a solution of alendronate in borate buffer (pH 9.5, 200 μL) was added to the residue, and the resulting solution was heated at 40°C for 20 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-PAQ 10ID*250 mm; mobile phase: A: PBS, B: ethanol; method: 0->5 min, 5% B, 5-20 min 5%->35% B, 20-23 min, 35%->90% B, 23-28 min, 90% B, 28-33 min, 90%->5% B, 33-40 min, 5% B, flow rate 3.0 mL / min, retention time 6.0±0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for in vitro and in vivo applications.

[0353] Method 3

[0354] The cyclotron obtained in [ 18 O]H2O 18F]HF was passed through an anion-exchange column (Chromafix PS-OH pretreated with 5 mL 0.1 M NaHCO3 and 5 mL water). The original bottle was rinsed with 2 mL pure water and also applied to the column. The column was washed with 3 mL anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. The quaternary amine triflate precursor (5-10 mg) was slowly eluted with a solution of anhydrous isobutyl alcohol: acetonitrile (4:1, 1 mL). 18 F]F – More than 5 min. The eluate was diluted with 8 mL of water and captured on a Waters Oasis MCX cartridge (pre-treated with 5 mL of ethanol and 5 mL of water). The cartridge was washed with 5 mL of water and eluted with 1.5 mL of 65% acetonitrile / water. A sample of 0.5-1 MBq of the eluate was taken for quality control using HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 30%->80% B, 20-22 min 80%->95% B, 22-27 min, 95% B, 27-30 min, 95%->30% B, flow rate 2.0 mL / min, retention time 15.2 min. A solution of alendronate in borate buffer (pH 9.5, 200 μL) was added to the eluate, and the resulting solution was heated at 40°C for 20 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-PAQ 10ID*250 mm; mobile phase: A: saline, B: ethanol; method: 0->5min, 5% B, 5-20min 5%->35% B, 20-23min, 35%->90% B, 23-28min, 90% B, 28-33min, 90%->5% B, 33-40min, 5% B, flow rate 3.0 mL / min, retention time 6.0±0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for in vitro and in vivo applications.

[0355] Method 4

[0356] The cyclotron obtained in [ 18 O]H2O 18F]HF was passed through an anion-exchange column (Chromafix PS-OH pretreated with 5 mL 0.1 M NaHCO3 and 5 mL water). The original bottle was rinsed with 2 mL pure water and also applied to the column. The column was washed with 3 mL anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. The quaternary amine triflate precursor (5-10 mg) was slowly eluted with a solution of anhydrous isobutyl alcohol: acetonitrile (4:1, 1 mL). 18 F]F – More than 5 min. The eluate was diluted with 8 mL of water and captured on a Waters Oasis MCX cartridge (pre-treated with 5 mL of ethanol and 5 mL of water). The cartridge was washed with 5 mL of water and eluted with 1.0 mL of acetonitrile. A sample of 0.5-1 MBq of the eluate was taken for quality control using HPLC: column COSMOSIL5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20 min, 30%->80% B, 20-22 min 80%->95% B, 22-27 min, 95% B, 27-30 min, 95%->30% B, flow rate 2.0 mL / min, retention time 15.2 min. The solvent was removed under a stream of nitrogen at room temperature. A solution of alendronate in borate buffer (pH 9.5, 100 μL) was added to the residue and the resulting solution was heated at 40°C for 20 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-PAQ 10ID*250 mm; mobile phase: A: saline, B: ethanol; method: 0->5min, 5% B, 5-20min 5%->35% B, 20-23min, 35%->90% B, 23-28min, 90% B, 28-33min, 90%->5% B, 33-40min, 5% B, flow rate 3.0 mL / min, retention time 6.0±0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for in vitro and in vivo applications.

[0357] Method 5

[0358] The cyclotron obtained in [ 18 O]H2O 18 F]HF was passed through an anion-exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original bottle was rinsed with 2 mL of pure water and also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. A solution of the quaternary amine triflate precursor (5-10 mg) in anhydrous isobutyl alcohol:acetonitrile (4:1, 1 mL) was slowly eluted.18 F]F – More than 5min. The eluent was diluted with 8mL of water and then passed through a stacked Waters Sep-Pak Plus CM column and a PS-2 column (each column was pretreated with 5mL of ethanol and 5mL of water). The column was washed with 5mL of water. The PS-2 column was eluted with 1.0mL of dichloromethane. A sample of 0.5-1MBq of the eluent was taken for quality control using HPLC: column COSMOSIL 5C18-ARII 6.0ID*150mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20min, 30%->80% B, 20-22min 80%->95% B, 22-27min, 95% B, 27-30min, 95%->30% B, flow rate 2.0mL / min, retention time 15.2min. The solvent was removed under a stream of nitrogen at room temperature. A solution of alendronate in borate buffer (pH 9.5, 100 μL) was added to the residue and the resulting solution was heated at 40°C for 20 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-PAQ10ID*250 mm; mobile phase: A: PBS, B: ethanol; method: 0->5 min, 5% B, 5-20 min 5%->35% B, 20-23 min, 35%->90% B, 23-28 min, 90% B, 28-33 min, 90%->5% B, 33-40 min, 5% B, flow rate 3.0 mL / min, retention time 6.0±0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for in vitro and in vivo applications.

[0359] (IVb) Radiolabeling Protocol

[0360] The synthetic scheme for the preparation of (IVb) is as follows:

[0361]

[0362] The cyclotron obtained in [ 18 O]H2O 18 F]HF was passed through an anion-exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original bottle was rinsed with 2 mL of pure water and also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried with a stream of nitrogen for 5 min. A solution of the quaternary amine triflate precursor (5-10 mg) in anhydrous isobutyl alcohol:acetonitrile (4:1, 1 mL) was slowly eluted. 18 F]F –More than 5min. The eluent was diluted with 8mL of water and captured on a stacked Waters Sep-Pak Plus CM cartridge and a PS-2 cartridge (each cartridge was pre-treated with 5mL of ethanol and 5mL of water). The cartridge was washed with 5mL of water, and FPy-TFP was eluted from the PS-2 cartridge with 1.0mL of dichloromethane. A sample of 0.5-1MBq of the eluent was taken for quality control using HPLC: column COSMOSIL 5C18-ARII 6.0ID*150mm; mobile phase: A: H2O+0.1% TFA, B: acetonitrile+0.1% TFA; method: 0->20min, 30%->80% B, 20-22min 80%->95% B, 22-27min, 95% B, 27-30min, 95%->30% B, flow rate 2.0mL / min, retention time 15.2min. The eluate was concentrated at room temperature under nitrogen flow. A solution of TBS-protected alendronate ethyl ester in DMSO (200 μL) was added to the residue, and the resulting solution was heated at 50°C for 15 min. Aq. hydrochloric acid (4M, 300 μL) was added to the reaction solution, which was further heated at 100°C for 10 min. The reaction solution was diluted with 1 mL of PBS buffer and purified by HPLC: column COSMOSIL 5C18-ARII 6.0 ID*150 mm; mobile phase: A: H2O, B: ethanol; method: 0->20 min, 40%->80% B, 20-22 min 80%->95% B, 22-25 min, 95% B, 25-27 min, 95%->40% B, 27-30 min, 40% B, flow rate 2.0 mL / min, retention time 16.5±0.5 min. Collected fractions were filtered through a 0.2 μM sterile filter and were ready for in vitro and in vivo applications.

[0363] Animal preparation

[0364] Male Wistar rats (weighing 250-400 g) were used for cardiac uptake studies. Anesthesia was induced by 5% isoflurane in pure oxygen and maintained by 2% isoflurane during the experiment.

[0365] PET imaging and kinetic studies

[0366] A small animal PET system (Inveon, Siemens, Erlangen, Germany) was used for the rat studies. After injection of Iva (10-20 MBq) via the tail vein, a 120-min dynamic scan was immediately started. Reconstructed images were analyzed using AMIDE imaging software (version 1.0.1). For the kinetic studies in rats, tissue uptake was calculated as the percentage of radiotracer retention, from which time-activity curves for different organs (particularly bone, kidney, liver, heart, and intestine) were generated, as shown in Figure 2. Figure 1-5 shown.

[0367] Cardiac tissue binding studies

[0368] Frozen cardiac tissue sections were incubated in saline containing IVa (about 5 MBq) with or without alendronate as a blocking agent (final concentration 1 mM). After incubation at 25°C for 30 min, the sections were rinsed in PBS buffer for 1 min and then in water four times for 2 sec each. After immediate drying with a hair dryer to remove water and moisture, the sections were exposed to a phosphor imaging plate for 20 min. Images were obtained using a digital autoradiography system, as shown in Figure 2. Figure 6 shown.

Claims

1. A compound or a pharmaceutically acceptable salt thereof for use in a method for diagnosing cardiac amyloidosis, wherein the compound or a pharmaceutically acceptable salt thereof comprises at least one bisphosphonate or bisphosphonate group, and A positron emitting radionuclide Po, wherein Po is attached to the at least one bisphosphonate or bisphosphonate group.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof is a compound of formula (I): in z is an integer selected from the group consisting of 1, 2 and 3, preferably, z is 1; and wherein Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2, and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein i) L and Q do not exist; or ii) L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or And among them X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and among them R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and wherein R 3 is a group comprising the positron-emitting radionuclide Po.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the positron emitting radionuclide Po is 11 C. 13 N. 15 O. 18 F. 64 Cu or 68 Ga, Preferably 11 C. 18 F or 68 Ga, More preferably, wherein the positron emitting radionuclide Po is 18 F or 68 Ga.

4. The compound according to claim 2 or 3, wherein each R 1 yes i) is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2-O(CO)-CH3, -CH2-O(CO)-CH2CH3, -CH2-O(CO)-CH(CH3)2, -CH2-O(CO)-C(CH3)3 and The protecting group of the group consisting of, wherein R' is methyl, ethyl; Preferably, each R 1 selected from the group consisting of methyl, ethyl and isopropyl; More preferably, each R 1 is methyl or isopropyl; or ii) where each R 1 yes A protecting group wherein the two R 1 Together we form or wherein R' is hydrogen or (C1-C 10 )alkyl.

5. A compound according to any one of claims 2 to 4, wherein i)R 3 -QLA- part is R 3 -QL-NR 2 -, and where R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; Preferably, R 2 is hydrogen, methyl or ethyl; More preferably, R 2 is hydrogen or methyl; or ii) R 3 -QLA-part is in X - is a pharmaceutically acceptable anion, Preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - .

6. The compound according to any one of claims 2 to 5 or a pharmaceutically acceptable salt thereof, wherein a) L and Q do not exist; or b) L is a straight chain or branched chain (C1-C 10 )alkyl, substituted or unsubstituted phenyl; substituted or unsubstituted (5- to 6-membered) heteroaryl, or substituted with (C1-C 10 )alkyl (5 to 8 membered) heterocyclic group, or (C1-C6) ω amino acid, or polyethylene glycol, or dipeptide, or tripeptide, or a combination thereof; and wherein, Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or and in X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and among them R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q It's methyl.

7. A compound according to any one of claims 2 to 6 or a pharmaceutically acceptable salt thereof, wherein a) R 3 The -QL- part is in I is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6 and 7, preferably, wherein I is 1, 2 or 3; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O, N,N-substituted piperazine or in X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and where R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; or b) R 3 The -QL- part is in m is 1, 2, or 3; or c) R 3 The -QL- part is in m is 1, 2, or 3.

8. A compound according to any one of claims 2 to 7 or a pharmaceutically acceptable salt thereof, wherein R 3 yes i) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or ii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or iii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or iv) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or v) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or vi) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or vii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or viii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or ix) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or x) Where Po is 18 F or -O 11 CH3, preferably 18 F; or xi) or xii) wherein M is O, or -NH, or CH2O; or xiii) or xiv) or xv) or xvi) or xvii) or xviii) or xix) or xx) 9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound or pharmaceutically acceptable salt thereof is a compound of formula (II) in R 3 yes i) Where Po is 18 F or -O 11 CH3, preferably 18 F; or ii) or iii) or iv) Preferably, R 3 yes And among them R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; Preferably, R 2 is hydrogen or methyl; More preferably, R 2 methyl; and wherein Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl, isopropyl or -O(CO)--C(CH3)3, More preferably, each R 1 is hydrogen, methyl or -CH2-O(CO)-C(CH3)3, Even more preferably, each R 1 is hydrogen or -CH2-O(CO)--C(CH3)3; most preferably, wherein The compound or a pharmaceutically acceptable salt thereof has structure (IIa) or (IIb) Where R 1 It is methyl or ethyl.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound or pharmaceutically acceptable salt thereof is a) Compounds of formula (III) Where R 3 yes i) Where Po is 18 F or -O 11 CH3, preferably 18 F; or ii) or iii) or iv) Preferably, wherein R 3 yes And among them R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; Preferably, R 2 is hydrogen or methyl; More preferably, R 2 methyl; and wherein Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl, More preferably, each R 1 is hydrogen, methyl or isopropyl; Even more preferably, each R 1 is hydrogen or methyl; most preferably, The compound or a pharmaceutically acceptable salt thereof has structure (IIIa) or (IIIb) or b) Compounds of formula (V) in X - is a pharmaceutically acceptable anion, Preferably, X - Yes F - , Cl - Br - ,I - or OH - ; More preferably, Br - ; and among them R 3 yes i) Where Po is 18 F or O 11 CH3, preferably 18 F; or ii) or iii) or iv) Preferably, wherein R 3 yes More preferably, R 3 yes And among them Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl; More preferably, each R 1 is hydrogen, methyl or isopropyl; Even more preferably, each R 1 is hydrogen or methyl; most preferably, wherein the compound or a pharmaceutically acceptable salt thereof has structure (Va) or c) Compounds of formula (VI) in Q is -NH, -NR Q 、-N + R Q 2 X - or -O; where X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - OH - , toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxalate, salicylate or camphorsulfonate; more preferably Br - ; and among them R Q is a linear or branched (C1-C6) alkyl group; and wherein p is 0 or 1; and wherein R 3 yes i) or ii) or iii) And among them R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; Preferably, R 2 is hydrogen or methyl; and wherein Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl, isopropyl or -O(CO)-C(CH3)3, More preferably, each R 1 is hydrogen or methyl; even more preferably, each R 1 is hydrogen; most preferably, wherein the compound or a pharmaceutically acceptable salt thereof has structure (VIa), (VIb) or (VIc) or or or d) Compounds of formula (VII) in Q is -NH, -NR Q 、-N + R Q 2 X - , N,N-substituted piperazine or -O; and wherein X - is a pharmaceutically acceptable anion, preferably, X - Yes F - , Cl - Br - ,I - or OH - ; More preferably, Br - ; and among them R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; preferably, Q is -NH; and wherein R 3 yes i) or ii) or iii) And among them Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl, isopropyl or -O(CO)-C(CH3)3, More preferably, each R 1 is hydrogen or methyl; even more preferably, each R 1 is hydrogen; most preferably, Wherein the compound or a pharmaceutically acceptable salt thereof has structure (VIIa) 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein the compound or pharmaceutically acceptable salt thereof is a compound of formula (IV) Where R 3 yes i) Where Po is 18 F or -O 11 CH3, preferably 18 F; or ii) or iii) or iv) Preferably, wherein R 3 yes More preferably, wherein R 3 yes And among them R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; Preferably, R 2 is hydrogen or methyl; More preferably, R 2 is hydrogen; and wherein Each R 1 independently selected from the group consisting of hydrogen, linear or branched (C1-C6) alkyl and -CH2-O-CO-O-(C1-C6) alkyl, Preferably, each R 1 is hydrogen, methyl, ethyl or isopropyl; More preferably, each R 1 is hydrogen, methyl or isopropyl; Even more preferably, each R 1 is hydrogen or methyl; most preferably, wherein the compound or a pharmaceutically acceptable salt thereof has structure (IVa) or (IVb) Where R 1 It is methyl or ethyl, preferably ethyl.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is not 13. A method for preparing a compound according to any one of claims 1 to 12, the method comprising the following steps: a) providing a compound of formula (Ia) in Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and in A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L and Q do not exist; or L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O or N,N-substituted piperazine; wherein R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and b) Provide formula R 3 -Y compound, wherein R 3 -Y is i) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or ii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or iii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or iv) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or v) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or vi) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or vii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or viii) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or ix) Where Po is 64 Cu or 68 Ga, preferably 68 Ga; or x) Where Po is 18 F or -O 11 CH3, preferably 18 F; or xi)Y- 11 CH3 or HO- 11 CH3; xii) wherein M is O, or -NH, or CH2O; or xiii) or xiv) or xv) or xvi) or xvii) or xviii) or xix) And among them Y is an electron withdrawing group, Preferably, Y is selected from the group consisting of -Cl, -Br, -O-C6F5H, -O(CO)-(C1-C6)alkyl and -OH; and c) making the compound of formula (Ia) and any one of R 3 -Y is reacted at a temperature of about 60°C to about 140°C, wherein When Y is -OH, step b) further comprises providing dry DMF and a coupling agent selected from the group consisting of EDC, HATU, HOBt, HBTU and HATU; most preferably, wherein step c) is performed for a period of about 1 min to about 60 min; and / or Wherein step c) is carried out in dry DMF or dry DMSO.

14. A method for preparing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, the method comprising the following steps a) providing a compound of formula (Ib) in z is 1, 2 or 3, preferably, z is 1; and wherein Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2 and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L and Q do not exist; or L is a divalent linking group; and wherein Q is -NH, -NR Q 、-N + R Q 2 X - , -O or N,N-substituted piperazine; wherein R Q Each independently is a linear or branched (C1-C6) alkyl group. Preferably, each R Q is methyl; and wherein R 3a yes i) or ii) or iii) or iv) or v) or vi) or vii) or viii) or ix) or x) Where R 5 is OTs, OMs, OTf, or I; or xi) wherein M is O or -NH or CH2O; or xii) or xiii) or xiv) or xv) or xvi) or xvii) or xviii) Where R 9 is an ammonium salt or H; and b) reacting the compound of formula (Ib) with a Po* group containing a positron-emitting radionuclide Po, wherein Po* is - 11 CH3, 13 N. 15 O. 18 F - , 64 Cu or 68 Ga, Preferably - 11 CH3, 18 F - and 68 Ga, More preferably 18 F - or 68 Ga; most preferably, wherein step b) is performed for a period of about 1 min to about 60 min; and / or wherein step b) is carried out at a temperature of about 80°C to about 140°C; and / or Wherein step b) is carried out in dry DMF or dry DMSO.

15. A method for preparing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, the method comprising the following steps a) providing a compound of formula (Ic) in Each R 1 are independently hydrogen, a pharmaceutically acceptable cation or a protecting group; and wherein n is an integer selected from the group consisting of 0, 1, 2, and 3; and wherein A is -NR 2 , or (4- to 8-membered) heterocyclyl, or (4- to 8-membered) cyclyl, or squaramide, or (5- to 6-membered) heteroaryl, or phenyl; and wherein R 2 is hydrogen or a linear or branched (C1-C6) alkyl group; and wherein L is (C1-C 10 )alkyl, and Q is -C≡CH; and b) providing a compound of the formula c) reacting the compound of formula (Ic) and the compound of step b) at a temperature of about 60° C. to about 140° C. in the presence of a Cu(I) salt, preferably, wherein step c) is performed for a period of about 1 min to about 60 min; and / or wherein step c) is carried out at a temperature of about 80°C to about 140°C; and / or Wherein step c) is carried out in dry DMF or dry DMSO.

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