PET imaging diagnosis of cardiac amyloidosis

Abstract

The present disclosure relates to compounds, or pharmaceutically acceptable salts thereof, comprising at least one bisphosphonate or bisphosphonate ester group and a positron-emitting radionuclide Po, and their use in methods for diagnosing amyloidosis, such as cardiac amyloidosis.

Description

[Technical Field]

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

[0002] Bisphosphonates are a type of drug that prevents bone mineral density loss and are used to treat osteoporosis, elevated blood calcium levels caused by cancer and similar diseases, and are therefore the most commonly prescribed drug for treating osteoporosis.

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

[0004] Therefore, bisphosphonate drugs have in common that they contain two phosphonate groups attached 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 as the free acid in its neutral form; when X is Na, the bisphosphonate exists as the free acid. + When X is a pharmaceutically acceptable cation such as , the bisphosphonate exists as a pharmaceutically acceptable salt in its charged form. When X is alkyl, the bisphosphonate exists as an ester, i.e., a prodrug. When the ester is hydrolyzed in the body, the bisphosphonate is produced.

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

[0006] The most prominent drugs in the bisphosphonate class are pamidronate, neridronate, olpadronate, alendronate, ibandronate, risedronate, and zoledronic acid.

[0007] Due to the affinity of bisphosphonate compounds for bone, they can also be used in conjunction with positron-emitting radionucleotides as imaging probes for bone.

[0008] Patent Document 1 describes derivatives of risedronate and zoledronic acid conjugated with positron-emitting radionuclides as imaging probes for use in positron emission tomography of bone, as well as methods for synthesizing the above bisphosphonate conjugates.

[0009] Cardiac amyloidosis is a cardiac condition associated with extracellular amyloid infiltration associated with abnormal cardiac function. Because cardiac amyloidosis has high morbidity and mortality, early and accurate detection and differentiation between types of cardiac lesions are important for selecting appropriate therapy and patient prognosis. The present invention provides novel bisphosphonate positron emission tomography (PET) tracers for accurately diagnosing cardiac amyloidosis in a highly sensitive and quantitative manner.

[0010] PET imaging has the inherent advantages of high spatial / temporal resolution, sensitivity, and accuracy for detecting radionuclide concentrations. Among the radionuclides available for PET imaging: 18 F-labeled tracers hold several advantages: 1) they can be produced from a cyclotron, facilitating transport from distant sources due to their longer half-life; 2) such transport offers the possibility of distribution to locations where local radiotracer production is not permitted or lacks facilities; 3) higher positron yields and lower positron energies reduce image noise, improve contrast resolution, and maximize detection of subtle lesions; and 4) their longer half-life allows for improved delayed imaging protocols. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] U.S. Patent Application Publication No. 2016 / 310621 Summary of the Invention

[0012] The present invention provides novel tracers and their use in methods for diagnosing cardiac amyloidosis using PET imaging techniques, improving diagnostic accuracy compared to currently used scintigraphy techniques. From the perspective of structural design, the inventors have provided various strategies for carrying out radiolabeling of bisphosphonate compounds.

[0013] The inventors of the present disclosure have surprisingly found that radiolabeled tracers based on bisphosphonates or bisphosphonate esters can be advantageously used in methods for diagnosing cardiac amyloidosis, a disease not related to bone or other previously described uses of bisphosphonates.

[0014] In one aspect, the present disclosure relates to a compound, or a pharmaceutically acceptable salt thereof, comprising at least one bisphosphonate group or bisphosphonate ester group and a positron-emitting radionuclide, Po, wherein Po is bound to the at least one bisphosphonate group or bisphosphonate ester group.

[0015] In a further aspect, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof for use in a method for diagnosing cardiac amyloidosis, the compound or a pharmaceutically acceptable salt thereof comprising at least one bisphosphonate or bisphosphonate ester group and a positron-emitting radionuclide Po, wherein Po is bound to the at least one bisphosphonate or bisphosphonate ester group.

[0016] In a further aspect, the present disclosure relates to methods for preparing the compounds or pharmaceutically acceptable salts thereof. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the time-activity curve of IVa. [Figure 2] FIG. 1 shows the time-activity curve of 18F-NaF as a control. [Figure 3] PET image (left panel) and enlarged view of the cardiac region (right panel) 120 minutes after injection of IVa. [Figure 4] FIG. 1 shows PET images 120 minutes after injection of 18F-NaF as a control. [Figure 5] FIG. 1 shows PET images that are dynamic images using IVa (upper panel) and IVb (lower panel) up to 120 minutes after tracer injection. [Figure 6] FIG. 1 shows a comparison of IVa uptake in human cardiac tissue with amyloidosis (upper panel) and H&E staining of the same tissue (lower panel). DETAILED DESCRIPTION OF THE INVENTION

[0018] Compound or a pharmaceutically acceptable salt thereof According to one embodiment, the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof, comprising at least one bisphosphonate or bisphosphonate ester group and a positron-emitting radionuclide Po, wherein Po is bound to the at least one bisphosphonate or bisphosphonate ester group.

[0019] According to a preferred embodiment of the present disclosure, the compound or a pharmaceutically acceptable salt thereof has the formula (I): TIFF2025530407000002.tif49170 (in the formula, z is an integer selected from the group consisting of 1, 2, and 3, preferably z is 1, and each R 1are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; 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 ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramide, or (5- to 6-membered ring) heteroaryl, or phenyl; R 2 is hydrogen or a straight or branched chain (C1-C6) alkyl, L and Q are absent or L is a divalent linker group, and Q is -NH, -NR Q , -N + R Q 2X - , -O, N,N-substituted piperazine, or TIFF2025530407000003.tif18170, X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q is methyl and R 3 is a group containing a positron-emitting radionuclide Po), or a pharmaceutically acceptable salt thereof.

[0020] 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 a further preferred embodiment, the positron-emitting radionuclide Po is 11 C. 18 F, or 68In a further preferred embodiment, the positron-emitting radionuclide is 18 F or 68 In a further preferred embodiment, the positron-emitting radionuclide is 18 F. In a further preferred embodiment, the positron-emitting radionuclide is 68 In a further preferred embodiment, the positron-emitting radionuclide is 11 It is C.

[0021] According to another preferred embodiment, the present disclosure relates to a compound of formula (I) where z is 1. In other words, the compound has the structure (I.1): I have TIFF2025530407000004.tif34170.

[0022] According to another preferred embodiment, the present disclosure relates to a compound of formula (I) where z is 2. In other words, the compound has the structure (I.2): I have TIFF2025530407000005.tif47170.

[0023] According to another preferred embodiment, the present disclosure relates to a compound of formula (I) where z is 3. In other words, the compound has the structure (I.3): I have TIFF2025530407000006.tif47170.

[0024] According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), where 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 a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), where n is 0. When n is 0, A is attached to the methylene group attached to the bisphosphonate group or bisphosphonate ester group via a single bond. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), where n is 1. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), where 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.

[0025] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 and R are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group. 1 is hydrogen. In another preferred embodiment, each R 1 is a pharmaceutically acceptable cation. In a further preferred embodiment, each R 1 Na + , or Li + , or K + or 1 / 2Ca 2+ , or 1 / 2Mg 2+ In a further preferred embodiment, each R 1 Na + In a further preferred embodiment, each R 1 Li + In a further preferred embodiment, each R 1 is K + In a further preferred embodiment, each R 1 is 1 / 2Ca 2+ In a further preferred embodiment, each R 1is 1 / 2Mg 2+ is.

[0026] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is a protecting group. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), formula (I.1), formula (I.2) or formula (I.3), wherein each R 1 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH2-O(CO)-CH3, -CH2-O(CO)-CH2CH3, -CH2-O(CO)-CH(CH3)2, -CH2-O(CO)-C(CH3)3, and TIFF2025530407000007.tif15170 (wherein R' is (C1 to C 10 ) alkyl, preferably methyl or ethyl). According to another preferred embodiment, the present disclosure relates to compounds of formula (I), formula (I.1), formula (I.2) or formula (I.3), wherein each R 1 is a protecting group selected from the group consisting of methyl, ethyl, and i-propyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 According to another preferred embodiment, the present disclosure relates to a compound of formula (I), formula (I.1), formula (I.2) or formula (I.3), wherein each R 1 is i-propyl).

[0027] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3), wherein each R 1 is a protecting group, and two R 1 Both TIFF2025530407000008.tif23170 (wherein R' is hydrogen or (C1 to C 10 ) relates to compounds of which the structure is alkyl.

[0028] According to another preferred embodiment, the present disclosure provides a compound 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 a compound 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 a compound 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 a compound 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 a compound of formula (I), (I.1), (I.2) or (I.3) (wherein A is a (5- to 6-membered ring) heteroaryl). According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) (wherein A is phenyl).

[0029] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) wherein A is -NR 2 and R 2 is hydrogen or a straight or branched chain (C1-C6) alkyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) 2 and R 2 is hydrogen. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein A is -NR 2 and R 2 is a straight or branched chain (C1-C6) alkyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) 2 and R2 According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein A is -NR 2 and R 2 is ethyl).

[0030] The inventors of the present disclosure have found that it is advantageous for group A to contain a basic center such as a secondary or tertiary amine group.

[0031] According to another preferred embodiment, the present disclosure relates to compounds of formula (I), (I.1), (I.2) or (I.3) where L and Q are absent. In other words, the groups A and R 3 are directly bonded via a covalent bond.

[0032] According to another preferred embodiment, the present disclosure provides a compound represented by formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -NH, -NR Q , -N + R Q 2X - , -O, N,N-substituted piperazine, or TIFF2025530407000009.tif18170). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) wherein L is a divalent linker group and Q is -NH. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) wherein L is a divalent linker group and Q is -O (oxygen). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) wherein L is a divalent linker group and Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is TIFF2025530407000010.tif18170). According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -NR Q and R Q is a straight or branched chain (C1-C6) alkyl. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -NR Q and R Q In another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -N + R Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, and X - is a pharmaceutically acceptable anion. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -N + R Q 2X - and R Q is methyl and X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein L is a divalent linker group and Q is -N + R Q 2X - and R Q is methyl and X - Br - The present invention relates to a compound of formula (I)

[0033] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000011.tif45170, X - is a pharmaceutically acceptable anion. According to another preferred embodiment, the present disclosure relates to a compound of formula (I), formula (I.1), formula (I.2) or formula (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000012.tif18170)

[0034] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000013.tif21170, X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate).

[0035] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000014.tif20170, X - is F - , Cl - , Br - , I - , O.H. -, tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate).

[0036] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000015.tif19170)

[0037] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000016.tif18170)

[0038] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QLA- is TIFF2025530407000017.tif23170)

[0039] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is TIFF2025530407000018.tif14170, l is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 7, preferably l is 1, 2, or 3; Q is -NH, -NR Q , -N + R Q 2X - , -O, N,N-substituted piperazine, or TIFF2025530407000019.tif18170, X -is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q is methyl).

[0040] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is -CH2-CH2-NH-R 3 According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-NH-R 3 According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-CH2-NH-R 3 The present invention relates to a compound of formula (I)

[0041] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is -CH2-CH2-N(CH3)-R 3 According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-N(CH3)-R 3According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-CH2-N(CH3)-R 3 The present invention relates to a compound of formula (I)

[0042] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is -CH2-CH2-N + (CH3)2-R 3 X - and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-N + (CH3)2-R 3 X - and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br -According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein the moiety R 3 -QL- is -CH2-CH2-CH2-CH2-N + (CH3)2-R 3 X - and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - The present invention relates to a compound of formula (I)

[0043] According to another preferred embodiment, the present disclosure provides a compound 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 a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) (wherein L is substituted or unsubstituted aryl). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) (wherein L is substituted or unsubstituted heteroaryl). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) (wherein L is substituted or unsubstituted heteroaryl). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) (wherein L is (5-8 membered)heterocyclyl). According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) (wherein L is (C1-C 10) alkyl-substituted (5- to 8-membered) heterocyclyl. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), wherein L is a dipeptide. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), wherein L is a tripeptide. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2), or Formula (I.3), wherein L is a PEG linker.

[0044] According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) where Q is -NH. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) where Q is O. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) where Q is N,N-substituted piperazine. According to another preferred embodiment, the present disclosure relates to a compound of Formula (I), Formula (I.1), Formula (I.2) or Formula (I.3) where Q is -NR Q and R Q is a straight or branched chain (C1-C6) alkyl, preferably R Q According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3) wherein Q is -N + R Q 2X - and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - and RQ are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q According to another preferred embodiment, the present disclosure relates to a compound of formula (I), (I.1), (I.2) or (I.3), wherein Q is TIFF2025530407000020.tif17170) compound.

[0045] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is TIFF2025530407000021.tif21170).

[0046] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is TIFF2025530407000022.tif18170)

[0047] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein the moiety R 3 -QL- is TIFF2025530407000023.tif20170) compound.

[0048] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 is a group comprising a positron-emitting radionuclide Po. According to further embodiments, the present disclosure relates to compounds of formula (I), formula (I.1), formula (I.2) or formula (I.3) (wherein R 3 teeth, TIFF2025530407000024.tif191170 and Po is 64 Cu or 68 This relates to compounds in which the compound is Ga.

[0049] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000025.tif16170, Po is 18 F or -O 11 CH3, preferably 18 F).

[0050] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth- 11 This relates to compounds in which the carboxyl group is CH3.

[0051] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000026.tif15170, M is O, or —NH, or CHO.

[0052] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000027.tif23170)

[0053] According to another preferred embodiment, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000028.tif25170)

[0054] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000029.tif22170)

[0055] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000030.tif29170) compound.

[0056] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000031.tif41170)

[0057] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000032.tif24170)

[0058] According to further embodiments, the present disclosure provides a compound of formula (I), (I.1), (I.2) or (I.3) (wherein R 3 teeth, TIFF2025530407000033.tif18170)

[0059] Ibandronic acid derivatives According to one embodiment, the present invention relates to a derivative of ibandronic acid. In other words, according to one embodiment, the present invention relates to a derivative of ibandronic acid represented by formula (Ia) (wherein n is 1 and A is -NR 2 and L and Q are absent. Thus, the present disclosure relates to compounds of formula (II): TIFF2025530407000034.tif32170 (in the formula, R 3 is a group containing a positron-emitting radionuclide Po, and R 2 is hydrogen or straight or branched chain (C1-C6) alkyl, and each R 1are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0060] According to a preferred embodiment, the present disclosure provides a compound of formula (II) 3 teeth, TIFF2025530407000035.tif16170 (wherein Po is 18 F or -O 11 CH3, preferably 18 F), or TIFF2025530407000036.tif26170) or a pharmaceutically acceptable salt thereof.

[0061] According to a preferred embodiment, the present disclosure provides a compound of formula (II) 3 teeth, TIFF2025530407000037.tif16170 and Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (II) (wherein R 3 teeth, TIFF2025530407000038.tif17170) or a pharmaceutically acceptable salt thereof.

[0062] According to a preferred embodiment, the present disclosure provides a compound of formula (II) 2 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 2 is methyl) or a pharmaceutically acceptable salt thereof.

[0063] According to a preferred embodiment, the present disclosure provides a compound of formula (II) 1is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 1 and R is methyl, or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (II) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0064] According to a preferred embodiment, the present disclosure provides a compound of formula (IIa): TIFF2025530407000039.tif32170 or a pharmaceutically acceptable salt thereof.

[0065] According to a preferred embodiment, the present disclosure provides a compound of formula (IIb): TIFF2025530407000040.tif33170 (in the formula, each R 1 is methyl, ethyl, i-propyl, or —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0066] According to a preferred embodiment, the present disclosure provides a compound of formula (IIc): TIFF2025530407000041.tif33170 (in the formula, each R 1 is methyl, ethyl, i-propyl, or —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0067] According to another preferred embodiment, the present disclosure provides a compound of formula (IId): TIFF2025530407000042.tif35170 or a pharmaceutically acceptable salt thereof.

[0068] According to another preferred embodiment, the present disclosure provides a compound of formula (IIe): TIFF2025530407000043.tif35170 or a pharmaceutically acceptable salt thereof.

[0069] According to another preferred embodiment, the present disclosure provides a compound of formula (IIf): TIFF2025530407000044.tif40170 or a pharmaceutically acceptable salt thereof.

[0070] According to another preferred embodiment, the present invention provides a compound of formula (Ia), wherein n is 1 and A is —NR 2 The present invention relates to a compound of formula (I)

[0071] According to a preferred embodiment, the present disclosure provides a compound of formula (III): TIFF2025530407000045.tif37170 (in the formula, R 3 is a group containing a positron-emitting radionuclide Po, and R 2 is hydrogen or straight or branched chain (C1-C6) alkyl, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0072] According to a preferred embodiment, the present disclosure provides a compound of formula (III) 3 teeth, TIFF2025530407000046.tif16170 (wherein Po is 18 F or -O 11 CH3, preferably 18 F), or TIFF2025530407000047.tif26170) or a pharmaceutically acceptable salt thereof.

[0073] According to a preferred embodiment, the present disclosure provides a compound of formula (III) 2 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) 2 is methyl) or a pharmaceutically acceptable salt thereof.

[0074] According to a preferred embodiment, the present disclosure provides a compound of formula (III): 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III): 1 and R is methyl, or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III): 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0075] According to a preferred embodiment, the present disclosure provides a compound of formula (III) 3 teeth, TIFF2025530407000048.tif16170 and Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (III) (wherein R3 teeth, TIFF2025530407000049.tif24170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (III) 3 teeth, TIFF2025530407000050.tif25170) or a pharmaceutically acceptable salt thereof.

[0076] According to a further preferred embodiment, the present disclosure provides a compound of formula (IIIa): TIFF2025530407000051.tif31170 or a pharmaceutically acceptable salt thereof.

[0077] According to a further preferred embodiment, the present disclosure provides a compound of formula (IIIb): TIFF2025530407000052.tif31170 or a pharmaceutically acceptable salt thereof.

[0078] According to another preferred embodiment, the present disclosure provides a compound of formula (IIIc): TIFF2025530407000053.tif34170 (in the formula, R 3 is a group containing a positron-emitting radionuclide Po, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0079] According to another preferred embodiment, the present disclosure provides a compound of formula (IIIc): (In the formula, R 3 teeth, TIFF2025530407000054.tif16170 (wherein Po is 18 F or -O 11 CH3, preferably 18 F), or TIFF2025530407000055.tif26170, and each R 1are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0080] Alendronic acid derivatives According to one embodiment, the present invention relates to a derivative of alendronic acid. In other words, according to one embodiment, the present invention relates to a derivative of alendronic acid represented by formula (Ia) (wherein n is 2 and 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): TIFF2025530407000056.tif33170 (in the formula, R 3 is a group containing a positron-emitting radionuclide Po, and R 2 is hydrogen or straight or branched chain (C1-C6) alkyl, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0081] According to a preferred embodiment, the present disclosure provides a compound of formula (IV) 3 teeth, TIFF2025530407000057.tif16170 (wherein Po is 18 F or -O 11 CH3, preferably 18 F), or TIFF2025530407000058.tif26170, R 2 is hydrogen or straight or branched chain (C1-C6) alkyl, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl), or a pharmaceutically acceptable salt thereof.

[0082] According to a preferred embodiment, the present disclosure provides a compound of formula (IV) 3 teeth, TIFF2025530407000059.tif16170 and Po is 18 F or -O 11 According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) (wherein R 3 teeth, TIFF2025530407000060.tif17170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) (wherein R 3 teeth, TIFF2025530407000061.tif24170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) (wherein R 3 teeth, TIFF2025530407000062.tif26170) or a pharmaceutically acceptable salt thereof.

[0083] According to a preferred embodiment, the present disclosure provides a compound of formula (IV) 2 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) 2 is methyl) or a pharmaceutically acceptable salt thereof.

[0084] According to a preferred embodiment, the present disclosure provides a compound of formula (IV), 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV): 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) 1is ethyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IV) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0085] According to a further preferred embodiment, the present disclosure provides a compound of formula (IVa): TIFF2025530407000063.tif33170 or a pharmaceutically acceptable salt thereof.

[0086] According to a further preferred embodiment, the present disclosure provides a compound of formula (IVb): TIFF2025530407000064.tif34170 (in the formula, each R 1 is methyl or ethyl, preferably ethyl), or a pharmaceutically acceptable salt thereof.

[0087] According to one embodiment, the present invention provides a compound of formula (Ia), wherein n is 1 and A is -NR 2 The present invention relates to a compound of formula (I)

[0088] According to a preferred embodiment, the present disclosure provides a compound of formula (VI): TIFF2025530407000065.tif35170 (wherein Q is -NH, -NR Q , -N + R Q 2X - , or -O, and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. -, tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - and R Q is a straight or branched chain (C1-C6) alkyl, p is 0 or 1, and R 3 teeth, TIFF2025530407000066.tif26170, R 2 is hydrogen or straight or branched chain (C1-C6) alkyl, preferably R 2 is hydrogen or methyl, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, i-propyl, or —O(CO)—C(CH3)3, and more preferably each R 1 is hydrogen or methyl, and most preferably each R 1 is hydrogen) or a pharmaceutically acceptable salt thereof.

[0089] According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) where Q is -NH or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) where Q is -O or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) where Q is -NR Q and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI): Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl, and X - is F - , Cl - , Br - , I -, or OH - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate), or a pharmaceutically acceptable salt thereof.

[0090] According to another preferred embodiment, the present disclosure provides a compound of formula (VI), wherein Q is -N + R Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl, and X - is F - , Cl - , Br - , I - , or OH - According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) (wherein X - is F - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) wherein X - is Cl - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) wherein X - Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) wherein X - I - According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) wherein X - OH - or a pharmaceutically acceptable salt thereof.

[0091] According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein p is 0. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0092] According to a preferred embodiment, the present disclosure provides a compound of formula (VI) 2 is hydrogen or a straight or branched chain (C1-C6) alkyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI), 2 is hydrogen or methyl), or a pharmaceutically acceptable salt thereof.

[0093] According to a preferred embodiment, the present disclosure provides a compound of formula (VI) 3 teeth, TIFF2025530407000067.tif22170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) 3 teeth, TIFF2025530407000068.tif25170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) 3 teeth, TIFF2025530407000069.tif24170) or a pharmaceutically acceptable salt thereof.

[0094] According to a preferred embodiment, the present disclosure provides a compound of formula (VI), 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) 1 is hydrogen, methyl, ethyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI): 1 is hydrogen, methyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI): 1is hydrogen) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VI) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VI) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0095] According to a further preferred embodiment, the present disclosure provides a compound of formula (VIa): TIFF2025530407000070.tif41170 or a pharmaceutically acceptable salt thereof.

[0096] According to a further preferred embodiment, the present disclosure provides a compound of formula (VIb): TIFF2025530407000071.tif34170 or a pharmaceutically acceptable salt thereof.

[0097] According to a further preferred embodiment, the present disclosure provides a compound of formula (VIc): TIFF2025530407000072.tif35170 or a pharmaceutically acceptable salt thereof.

[0098] Zolendronic acid derivatives According to one embodiment, the present invention relates to a derivative of zoledronic acid. In other words, according to one embodiment, the present invention relates to a derivative of zoledronic acid of formula (Ia) (wherein n is 2 and A is TIFF2025530407000073.tif20170, X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl- , Br - , I - , or OH - , more preferably Br - and L and Q are absent. According to a further preferred embodiment, the present disclosure relates to compounds of formula (V): TIFF2025530407000074.tif32168(in the formula, - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , or OH - , more preferably Br - and R 3 teeth, TIFF2025530407000075.tif17170 (wherein Po is 18 F or O 11 CH3, preferably 18 F), or TIFF2025530407000076.tif26170, preferably R 3 teeth, TIFF2025530407000077.tif26170, and more preferably R 3 teeth, TIFF2025530407000078.tif23170, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, or i-propyl, and more preferably each R 1 is hydrogen, methyl, or i-propyl, and most preferably each R 1 is hydrogen or methyl), or a pharmaceutically acceptable salt thereof.

[0099] According to a further preferred embodiment, the present disclosure provides a compound of formula (V): TIFF2025530407000079.tif33168(in the formula, -is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , or OH - , more preferably Br - and R 3 is a group containing a positron-emitting radionuclide Po, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, or i-propyl, and more preferably each R 1 is hydrogen, methyl, or i-propyl, and most preferably each R 1 is hydrogen or methyl), or a pharmaceutically acceptable salt thereof.

[0100] According to a preferred embodiment, the present disclosure provides a compound of formula (V) 3 teeth, TIFF2025530407000080.tif21170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein R 3 teeth, TIFF2025530407000081.tif24170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein R 3 teeth, TIFF2025530407000082.tif25170) or a pharmaceutically acceptable salt thereof.

[0101] According to a preferred embodiment, the present disclosure provides a compound of formula (V) (wherein X - is F - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein X - is Cl -According to another preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein X - Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein X - I - According to another preferred embodiment, the present disclosure relates to a compound of formula (V) (wherein X - OH - or a pharmaceutically acceptable salt thereof.

[0102] According to a preferred embodiment, the present disclosure provides a compound of formula (V), wherein each R 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is hydrogen, methyl, ethyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is hydrogen, methyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (V): 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is i-propyl). According to another preferred embodiment, the present disclosure relates to a compound of formula (V) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0103] According to a further preferred embodiment, the present disclosure provides a compound of formula (Va): TIFF2025530407000083.tif44170(in the formula, - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , or OH - , more preferably Br - or a pharmaceutically acceptable salt thereof.

[0104] According to one embodiment, the present invention provides a compound of formula (Ia) wherein n is 2 and A is TIFF2025530407000084.tif20170, X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , or OH - , more preferably Br - The present invention relates to a compound of formula (I)

[0105] According to a further preferred embodiment, the present disclosure provides a compound of formula (VII): TIFF2025530407000085.tif32170 (wherein Q is -NH, -NR Q , -N + R Q 2X - , N,N-substituted piperazine or -O, and X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , or OH - , more preferably Br - and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Qis methyl, preferably Q is —NH, and R 3 teeth, TIFF2025530407000086.tif26170, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, i-propyl, or —O(CO)—C(CH3)3, and more preferably each R 1 is hydrogen or methyl, and most preferably each R 1 is hydrogen) or a pharmaceutically acceptable salt thereof.

[0106] According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) where Q is -NH or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) where Q is -O or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) where Q is N,N-substituted piperazine or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) where Q is -NR Q and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) + R Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl, and X - is F - , Cl - , Br - , I - , or OH -, tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate), or a pharmaceutically acceptable salt thereof.

[0107] According to another preferred embodiment, the present disclosure provides a compound of formula (VII) + R Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl, and X - is F - , Cl - , Br - , I - , or OH - According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) (wherein X - is F - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) wherein X - is Cl - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) wherein X - Br - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) wherein X - I - According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) wherein X - OH - or a pharmaceutically acceptable salt thereof.

[0108] According to a preferred embodiment, the present disclosure provides a compound of formula (VII) 3 teeth, TIFF2025530407000087.tif21170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) (wherein R 3 teeth, TIFF2025530407000088.tif24170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) (wherein R 3 teeth, TIFF2025530407000089.tif25170) or a pharmaceutically acceptable salt thereof.

[0109] According to a preferred embodiment, the present disclosure provides a compound of formula (VII) 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is hydrogen, methyl, ethyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is hydrogen, methyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VII) 1is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0110] According to a further preferred embodiment, the present disclosure provides a compound of formula (VIIa): TIFF2025530407000090.tif34170 or a pharmaceutically acceptable salt thereof.

[0111] Risedronic acid derivatives According to one embodiment, the present invention relates to a derivative of risedronic acid. In other words, according to one embodiment, the present invention relates to a derivative of risedronic acid represented by formula (Ia) (wherein n is 0 and R 3 -QLA- is TIFF2025530407000091.tif21170). According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII): TIFF2025530407000092.tif32170 (wherein L and Q are absent or L is a divalent linker group and Q is -NH, -NR Q , -N + R Q 2X - , -O, N,N-substituted piperazine, or TIFF2025530407000093.tif19170, X - is a pharmaceutically acceptable anion, preferably X - is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br - and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q is methyl and R 3 is a group containing a positron-emitting radionuclide Po, and each R 1are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, or i-propyl, and more preferably each R 1 is hydrogen, methyl, or i-propyl, and most preferably each R 1 is hydrogen or methyl), or a pharmaceutically acceptable salt thereof.

[0112] According to a preferred embodiment, the present disclosure provides a compound of formula (VIII) 3 teeth, TIFF2025530407000094.tif17170 (wherein Po is 18 F or O 11 CH3, preferably 18 F), or TIFF2025530407000095.tif28170, preferably R 3 teeth, TIFF2025530407000096.tif26170, and more preferably R 3 teeth, TIFF2025530407000097.tif23170) or a pharmaceutically acceptable salt thereof.

[0113] According to a preferred embodiment, the present disclosure provides a compound of formula (VIII) 3 teeth, TIFF2025530407000098.tif22170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) 3 teeth, TIFF2025530407000099.tif26170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) (wherein R 3 teeth, TIFF2025530407000100.tif24170) or a pharmaceutically acceptable salt thereof.

[0114] According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) where Q is -NH or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) where Q is -O or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) where Q is N,N-substituted piperazine or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) where Q is -NR Q and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII): + R Q 2X - and R Q is a straight or branched chain (C1-C6) alkyl, preferably methyl, and X - is F - , Cl - , Br - , I - , or OH - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate), or a pharmaceutically acceptable salt thereof.

[0115] According to a preferred embodiment, the present disclosure provides a compound of formula (VIII): 1 is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) 1 is hydrogen, methyl, ethyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII): 1is hydrogen, methyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII): 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII): 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (VIII) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (VIII) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0116] According to a further preferred embodiment, the present disclosure provides a compound of formula (VIIIa): TIFF2025530407000101.tif39170 or a pharmaceutically acceptable salt thereof.

[0117] According to another preferred embodiment, the present invention provides a compound of formula (Ia), wherein n is 0 and R 3 -QLA- is TIFF2025530407000102.tif21170 (wherein LQ is -CH2-CH2-NH-). In other words, the present disclosure relates to a compound of formula (IX): TIFF2025530407000103.tif33170 (in the formula, R 3 is a group containing a positron-emitting radionuclide Po, and each R 1 are independently selected from the group consisting of hydrogen, straight or branched chain (C1-C6) alkyl, and —CH2—O—CO—O—(C1-C6) alkyl, and preferably each R 1 is hydrogen, methyl, ethyl, or i-propyl, and more preferably each R 1is hydrogen, methyl, or i-propyl, and most preferably each R 1 is hydrogen or methyl), or a pharmaceutically acceptable salt thereof.

[0118] According to a preferred embodiment, the present disclosure provides a compound of formula (IX) 3 teeth, TIFF2025530407000104.tif17170 (wherein Po is 18 F or O 11 CH3, preferably 18 F), or TIFF2025530407000105.tif26170, preferably R 3 teeth, TIFF2025530407000106.tif27170, and more preferably R 3 teeth, TIFF2025530407000107.tif23170) or a pharmaceutically acceptable salt thereof.

[0119] According to a preferred embodiment, the present disclosure provides a compound of formula (IX) 3 teeth, TIFF2025530407000108.tif22170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) (wherein R 3 teeth, TIFF2025530407000109.tif25170) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) (wherein R 3 teeth, TIFF2025530407000110.tif25170) or a pharmaceutically acceptable salt thereof.

[0120] According to a preferred embodiment, the present disclosure provides a compound of formula (IX), 1is hydrogen, methyl, ethyl, i-propyl, or —CH—O—CO—OC(CH) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) 1 is hydrogen, methyl, ethyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX), wherein each R 1 is hydrogen, methyl, or i-propyl), or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX), wherein each R 1 is hydrogen) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) 1 is methyl) or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the present disclosure relates to a compound of formula (IX) 1 is ethyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) 1 is i-propyl) or a pharmaceutically acceptable salt thereof. According to another preferred embodiment, the present disclosure relates to a compound of formula (IX) 1 is —CH2—O—CO—OC(CH3)3), or a pharmaceutically acceptable salt thereof.

[0121] According to a further preferred embodiment, the present disclosure provides a compound of formula (IXa): TIFF2025530407000111.tif36170 or a pharmaceutically acceptable salt thereof.

[0122] Medical Use In a further aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in medicine.

[0123] In a further 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.

[0124] In a further aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method for diagnosing amyloidosis.

[0125] In a further aspect, the present disclosure relates to a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, for use in a method for diagnosing cardiac amyloidosis.

[0126] Manufacturing method According to a further aspect, the present disclosure provides a first method for preparing a compound according to the present disclosure, comprising: a) Formula (Ia): TIFF2025530407000112.tif34170 (in the formula, each R 1 are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; 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 ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramide, or (5- to 6-membered ring) heteroaryl, or phenyl; R 2 is hydrogen or a straight or branched chain (C1-C6) alkyl, L and Q are absent or L is a divalent linker group, and Q is -NH, -NR Q , -N + R Q 2X - , —O, or N,N-substituted piperazine, and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q is methyl; b) Formula R 3 -Y(wherein, R 3 -Y is TIFF2025530407000113.tif50170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000114.tif34170 (wherein Po is 64 Cu or 68 Ga, preferably68 Ga), or TIFF2025530407000115.tif29170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000116.tif49170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000117.tif42170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000118.tif49170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000119.tif50170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000120.tif44170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000121.tif35170 (wherein Po is 64 Cu or 68 Ga, preferably 68 Ga), or TIFF2025530407000122.tif14170 (wherein Po is 18 F or -O 11 CH3, preferably 18 F), or Y- 11 CH3 or HO- 11 CH3, TIFF2025530407000123.tif15170 (wherein M is O, or —NH, or CHO), or TIFF2025530407000124.tif68170 or and Y is an electron withdrawing group, preferably Y is selected from the group consisting of -Cl, -Br, -O-CFH, -O(CO)-(C1-C6)alkyl, and -OH; c) a compound of formula (Ia) and R 3 -Y at a temperature of about 60°C to about 140°C; and 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.

[0127] 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 carried out for about 1 minute to about 60 minutes.

[0128] 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 carried out in dry DMF or dry DMSO.

[0129] According to another aspect, the present disclosure provides a second method for preparing a compound according to the present disclosure, comprising: a) Formula (Ib): TIFF2025530407000125.tif57170 (wherein z is 1, 2, or 3, preferably z is 1, and each R 1 are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; 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 ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramide, or (5- to 6-membered ring) heteroaryl, or phenyl; R 2is hydrogen or a straight or branched chain (C1-C6) alkyl, L and Q are absent or L is a divalent linker group, and Q is -NH, -NR Q , -N + R Q 2X - , —O, or N,N-substituted piperazine, and R Q are each independently a straight or branched chain (C1-C6) alkyl, and preferably each R Q is methyl and R 3a teeth, TIFF2025530407000126.tif218170 (in the formula, R 5 is OTs, OMs, OTf, or I), or TIFF2025530407000127.tif15170 (wherein M is O, or —NH, or CHO), or TIFF2025530407000128.tif93170 (in the formula, R 9 is an ammonium salt, or H); b) reacting a compound of formula (Ib) with a group Po containing a positron-emitting radionuclide Po * (Po * teeth- 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 and reacting the compound with a compound selected from the group consisting of gallium arsenide (Ga); The present invention relates to a method, including:

[0130] According to a preferred embodiment, the present disclosure relates to a method for preparing a compound according to the present disclosure, wherein step b) is carried out for a period of time ranging from about 1 minute to about 60 minutes.

[0131] According to a preferred embodiment, the present disclosure relates to a second method for preparing a compound according to the present disclosure, wherein step b) is carried out at a temperature of about 80°C to about 140°C.

[0132] According to a preferred embodiment, the present disclosure relates to a second method for preparing a compound according to the present disclosure, wherein step b) is carried out in dry DMF or dry DMSO.

[0133] According to another aspect, the present disclosure provides a third method for preparing a compound according to the present disclosure, comprising: a) Formula (Ic): TIFF2025530407000129.tif33170 (in the formula, each R 1 are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; 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 ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramide, or (5- to 6-membered ring) heteroaryl, or phenyl; R 2 is hydrogen or a straight or branched chain (C1-C6) alkyl, and L is (C1-C 10 ) alkyl and Q is —C≡CH; b) Formula: preparing a compound of TIFF2025530407000130.tif19170; c) reacting the compound of formula (Ic) with the compound of step b) in the presence of a Cu(I) salt at a temperature of about 60°C to about 140°C; The present invention relates to a method, including:

[0134] 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 carried out for a period of time ranging from about 1 minute to about 60 minutes.

[0135] 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 carried out at a temperature of about 80°C to about 140°C.

[0136] 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 carried out in dry DMF or dry DMSO.

[0137] General Aspects and Definitions In further embodiments, 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.

[0138] In a further 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 TIFF2025530407000131.tif196170.

[0139] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the above-identified compounds, including pharmaceutically acceptable acid addition salts and base addition salts. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present disclosure can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from the aliphatic, alicyclic, aromatic, and heterocyclic carboxylic and sulfonic acid classes, including 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, and arylsulfonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of the present disclosure include metal salts prepared from lithium, sodium, potassium, aluminum, and zinc, and organic salts prepared from organic bases such as choline, diethanolamine, and morpholine. Other examples of organic salts are ammonium salts, quaternary salts such as tetramethylammonium salts, amino acid addition salts such as salts with glycine and arginine.

[0140] As used herein, the term "pharmaceutically acceptable cation" refers to a cation that is not toxic to mammals. Preferred pharmaceutically acceptable cations are lithium, sodium, potassium, aluminum, and zinc, cations prepared from organic bases such as choline, diethanolamine, morpholine, and the like, ammonium salts, quaternary salts such as tetramethylammonium salts, and amino acid addition salts such as salts with glycine and arginine.

[0141] As used herein, the term "pharmaceutically acceptable anion" refers to an anion that is not toxic to mammals. The pharmaceutically acceptable anion may have one, two, three, or more negative charges. A preferred pharmaceutically acceptable anion is F - , Cl - , Br - , I - , O.H. - , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate. A more preferred pharmaceutically acceptable anion is F - , Cl - , Br - , I - , or OH - A particularly preferred pharmaceutically acceptable anion is Br - is.

[0142] 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 from a bisphosphonate metabolically in a mammal. Preferred protecting groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH2-O(CO)-CH3, -CH2-O(CO)-CH2CH3, -CH2-O(CO)-CH(CH3), -CH2-O(CO)-C(CH3), and TIFF2025530407000132.tif14170, where R' is methyl or ethyl. Other preferred protecting groups are: TIFF2025530407000133.tif23170 (wherein R' is hydrogen or (C1 to C 10 ) alkyl) is bonded to two functional groups forming the structure.

[0143] Further 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 (incorporated herein by reference).

[0144] 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, at least one of which is a heteroatom selected from nitrogen, sulfur, or oxygen, and preferably the "(4- to 8-membered)heterocyclyl" denotes 1 to 3 heteroatoms. Preferred (4- to 8-membered)heterocyclyl groups are selected from pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. The group may be a terminal group or a bridging group. Further (4- to 8-membered)heterocyclyl groups include: TIFF2025530407000134.tif134170 is an example.

[0145] As used herein, reference to a normal chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group.

[0146] For purposes of this disclosure, the term "(4- to 8-membered)cyclyl," when used by itself or as part of another group, refers to a saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic aliphatic hydrocarbon containing one or two rings having four to eight carbon atoms (i.e., C4-C8 cycloalkyl) or the specified number of carbon atoms. In one embodiment, a (4- to 8-membered)cyclyl group has two rings. In one embodiment, a (4- to 8-membered)cyclyl group has one ring. In one embodiment, a (4- to 8-membered)cyclyl 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, a (4- to 8-membered)cyclyl group is selected as a C4-C6 cycloalkyl group. Non-limiting exemplary (4-8 membered) cyclyl groups include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The group may be a terminal group or a bridging group.

[0147] For purposes of this disclosure, the term "aryl," when used by itself or as part of another group, refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 6 to 14 carbon atoms, i.e., 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms (i.e., C6-C 14 "aryl" refers to an aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is selected from phenyl or naphthyl.

[0148] For purposes of this disclosure, the term "substituted aryl," as used herein by itself or as part of another group, means an aryl, as defined above, substituted with 1 to 10, preferably 1 to 8, and more preferably 1 to 5, substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (cycloalkylamino)alkyl, (C1-C4 haloalkoxy)alkyl, or (heteroaryl)alkyl. In one embodiment, the substituted aryl is a 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 is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclic rings. Examples include: TIFF2025530407000135.tif22170 is an example.

[0149] For purposes of this disclosure, the term "haloalkyl," when used by itself 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 and / or chlorine atoms. In another embodiment, a haloalkyl group is selected from the group consisting of C 1~4 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.

[0150] For purposes of this disclosure, the term "(hydroxy)haloalkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one or more halogen atoms and a hydroxy group. A non-limiting exemplary (hydroxy)haloalkyl group is -CH(OH)CF.

[0151] For purposes of this disclosure, the term "hydroxyalkyl," when used by itself or as part of another group, refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. In another embodiment, the hydroxyalkyl group is a C 1~4 Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and 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.

[0152] For purposes of this disclosure, the term "cycloalkyl," when used by itself or as part of another group, refers to alkyl groups containing 3 to 12 carbon atoms (i.e., C 3~12"Cycloalkyl" refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings, or the specified number of carbon atoms. In one embodiment, a cycloalkyl group has two rings. In one embodiment, a cycloalkyl group has one ring. In one embodiment, a cycloalkyl group is a saturated cyclic aliphatic hydrocarbon containing one or two rings, preferably one ring, and having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. In another embodiment, a cycloalkyl group is a C 3~8 In another embodiment, the cycloalkyl group is selected from C 3~6 Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and the like.

[0153] For purposes of this disclosure, the term "(cycloalkyl)alkyl," when used by itself 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: TIFF2025530407000136.tif19170 is an example.

[0154] For purposes of this disclosure, the term "hydroxy(cycloalkyl)alkyl," when used by itself or as part of another group, refers to a (cycloalkyl)alkyl group substituted with at least one hydroxy group. The hydroxy group(s) can be located at any available position. Non-limiting exemplary hydroxy(cycloalkyl)alkyl groups include: TIFF2025530407000137.tif20170 is an example.

[0155] For purposes of this disclosure, the term "alkoxy," when used by itself 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, an alkoxy group is 1~4 In another embodiment, the alkoxy group is selected from a C bonded to a terminal oxygen atom. 1~4 Alkyl is selected from, for example, methoxy, ethoxy, and tert-butoxy.

[0156] For purposes of this disclosure, the term "alkylthio," when used by itself or as part of another group, refers to a sulfur atom substituted by an optionally substituted alkyl group. In one embodiment, an alkylthio group is 1~4 Non-limiting exemplary alkylthio groups include -SCH3 and -SCH2CH3.

[0157] For purposes of this disclosure, the term "alkoxyalkyl," when used by itself 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, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

[0158] For purposes of this disclosure, the term "haloalkoxy" when used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0159] "(5-membered to 6-membered ring) heteroaryl" refers to a group containing an aromatic ring containing 5 to 6 ring atoms, in which 1, 2, or 3, preferably 1, of the ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon atoms. Preferred (5-membered to 6-membered ring) heteroaryls include 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-indole, and the like. Examples of suitable alkyl groups include azole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazan, phenoxazine, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolinyl, 1-, 2-, or 3-indolyl, and 2- or 3-thienyl. The groups may be terminal or bridging groups.

[0160] For the purposes of this disclosure, "(C1-C 10 The term "alkyl" by itself or as part of another group refers to an alkyl group having 1 to 10 carbon atoms (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms (i.e., C1-C 10 alkyl) or a specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, an alkyl group is a straight chain (C1-C 10 In another embodiment, the alkyl group is selected from branched chain (C3-C 10) alkyl groups. In another embodiment, the alkyl group is selected from straight chain (C1-C6) alkyl groups. In another embodiment, the alkyl group is selected from branched chain (C3-C6) alkyl groups. In another embodiment, the alkyl group is selected from straight chain (C1-C4) alkyl groups. In another embodiment, the alkyl group is selected from branched chain (C3-C4) alkyl groups. In another embodiment, the alkyl group is selected from straight chain or branched chain (C3-C4) alkyl groups. 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.

[0161] As used herein, the term "straight or branched (C1-C6) alkyl" refers to an aliphatic hydrocarbon group having 1 to 6 carbon atoms in the chain, preferably 1 to 4 carbon atoms, which may be straight or branched. Preferred straight or branched (C1-C6) alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. t-Butyl is also known as tBu. The group may be a terminal group or a bridging group.

[0162] As used herein, the term "absent" means that a group is not present in a compound. Alternatively, the absent group is a single bond.

[0163] "Heteroalkyl" refers to a straight- or branched-chain alkyl group preferably having 2 to 14 carbons in the chain, more preferably 2 to 10 carbons, one or more of which are replaced by a heteroatom selected from S, O, and N. Exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like. The group may be a terminal group or a bridging group. As used herein, reference to a normal chain when used in the context of a bridging group refers to a direct chain of atoms connecting the two terminal positions of the bridging group. Non-limiting exemplary heteroalkyl groups include -CHN(H)CHCHN(CH), -CHN(CH)CHCHN(CH), -CHN(H)CHCHCHN(CH), -CHN(H)CHCHOH, -CHN(CH)CHCHOH, -CHOCHCHOCH, -OCHCHOCHCHOCH, -CHNHCHCHOCH, -OCHCHNH, and -NHCHCHN(H)CH.

[0164] As used herein, the term "unsubstituted" means that there are no substituents or that the substituents are only hydrogen.

[0165] The term "substituted," as used throughout this specification, means that a group contains one or more substituents. Preferably, the substituents are independently selected from the group consisting of halogen, =0, =S, -CN, -NO, -CF, -OCF, 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, and alkoxyaryl. , alkoxyheteroaryl, alkoxycarbonyl, alkylaminocarbonyl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, phenoxy, benzyloxy, heteroaryloxy, arylalkyloxy, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, alkylsulfinyl, arylsulfinyl, aminosulfinylaminoalkyl, and -COOH.

[0166] For purposes of this disclosure, the term "optionally substituted alkyl," when used by itself or as part of another group, means that alkyl, 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, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, and the like. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Non-limiting exemplary optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, -CH2CH6H 11 etc.

[0167] The term "electron-withdrawing group," as used herein, refers to an atom or group that attracts electron density from a neighboring atom(s) toward itself, typically by resonance or inductive effects. Preferred examples of electron-withdrawing groups are -Cl, -Br, -O-CFH, -O(CO)-(C1-C6)alkyl, and -OH.

[0168] The term "ω-amino acid" refers to an amino acid in which o is an integer of 1, 2, 3, 4, 5, 6, or 7. It has the general structure of TIFF2025530407000138.tif16170. Preferred examples of ω-amino acids are glycine, 2-aminoacetic acid, 3-aminopropionic acid, 4-aminobutyric acid, 4-aminovaleric acid, and 6-aminohexanoic acid.

[0169] As used herein, the term "dipeptide" refers to a peptide consisting of two standard amino acids.

[0170] As used herein, the term "tripeptide" refers to a peptide consisting of three standard amino acids.

[0171] As used herein, the term "divalent linker group" refers to a group having a chemical valency of two. In other words, the divalent linker group is attached to two groups. According to one embodiment, the divalent linker group is attached to a group A and a group Q. The divalent linker group according to the present disclosure can be a linear or branched (C1-C 10 ) alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, (5- to 8-membered ring) heterocyclyl, (C1-C 10 ) alkyl-substituted (5- to 8-membered) heterocyclyl. Preferred divalent linker groups are -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-CH2-, or -CH2-CH2-CH2-CH2-CH2-CH2-CH2-.

[0172] As used herein, the term "PEG linker" refers to a PEG linker having the formula: TIFF2025530407000139.tif22170 (wherein peg is 1, 2, 3, 4, or 5, preferably peg is 2 or 3).

[0173] The terms "a" and "an" refer to one or more. [Example]

[0174] chemical properties All starting materials used herein were obtained from commercial suppliers.

[0175] formula( 19 Synthesis of Compound F-Va) The compound of formula (Va) was synthesized as follows. TIFF2025530407000140.tif49170

[0176] Tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobutane-1,1-diyl)bis(phosphonate) To stirring 4-chlorobutanoyl chloride (50 g, 354.62 mmol) was added triethyl phosphite (58.92 g, 354.62 mmol) dropwise under N at 0 °C, and the mixture was then warmed to 20 °C and stirred for 15 min. The mixture was diluted with DCM (1000 mL), and then 1-ethoxyphosphonoyloxyethane (48.97 g, 354.62 mmol) was added at 0 °C. The mixture was stirred at 20 °C for 15 min, and then 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, and the mixture was warmed to 20 °C and stirred for 15 h. The reaction mixture was washed with HO (300 mL), saturated NH4Cl (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: Phenomenex Luna C18 250 mm × 100 mm × 15 μm, mobile phase: [water (FA)-ACN], B%: 60% → 90%, 20 min to obtain a mixture of tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobutane-1,1-diyl)bis(phosphonate) and (Z)-diethyl (1-((tert-butyldimethylsilyl)oxy)-4-chlorobut-1-en-1-yl)phosphonate (71 g) 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). C 18 H 41 LC-MS calculated value for ClO7P2Si m / z 494.18 [M+H] + , actual measured value 495.2.

[0177] Tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-(1H-imidazol-1-yl)butane-1,1-diyl)bis(phosphonate) To a solution of NaH (5.66 g, 141.41 mmol, 60% purity) in THF (200 mL) and DMF (200 mL) was added imidazole (9.63 g, 141.41 mmol) at 0 °C. 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 saturated NH Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na SO , 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) δ 7.56 (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). C 21 H 44 LC-MS calculated value for N2O7P2Si m / z 526.27 [M+H] + , actual measured value 527.1.

[0178] ((4-Bromobenzyl)oxy)(tert-butyl)dimethylsilane 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 HO (400 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 1:0 → 10:1) to give ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (77 g, 255.56 mmol, 96%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 4.69 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

[0179] Di-tert-butyl(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)fluorosilane To a solution of ((4-bromobenzyl)oxy)(tert-butyl)dimethylsilane (30 g, 99.57 mmol) in THF (300 mL) was added t-BuLi (1.3 M, 176.16 mL, 229.00 mmol) at −78° C. 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 into saturated 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. 1H-NMR (400 MHz, CDCl3) δ 7.52 (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).

[0180] (4-(di-tert-butylfluorosilyl)phenyl)methanol 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 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether: EtOAc = 1:0 → 3:1) to give (4-(di-tert-butylfluorosilyl) phenyl) methanol (14.8 g, 49% yield) as a white solid. 1 H-NMR (400 MHz, CDCl3) δ 7.62 (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).

[0181] (4-(bromomethyl)phenyl)di-tert-butylfluorosilane To a mixture of (4-(di-tert-butylfluorosilyl)phenyl)methanol (14.8 g, 55.13 mmol) and CBr (21.94 g, 66.16 mmol) in DCM (200 mL) was added a solution of PPh (17.35 g, 66.16 mmol) in DCM (50 mL) at 0 °C under N. 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 → 10:1) to give (4-(bromomethyl)phenyl)di-tert-butylfluorosilane (21 g, 95.8% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.59 (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).

[0182] 1-(4-((tert-butyldimethylsilyl)oxy)-4,4-bis(diethoxyphosphoryl)butyl)-3-(4-(di-tert-butylfluorosilyl)benzyl)-1H-imidazol-3-ium hydrobromide 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 hours. The mixture was filtered, and 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 material) as a white solid. 36 H 68 FN2O7P2Si2 + LC-MS calculated value m / z 777.40 [M] + , actual measured value 777.4.

[0183] 3-(4-(di-tert-butylfluorosilyl)benzyl)-1-(4-hydroxy-4,4-diphosphonobutyl)-1H-imidazol-3-ium bromide (Va) 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) was added TMSBr (3.54 g, 0.023 mmol) at 20° C. The mixture was stirred at 20° C. for 12 h. HO (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 preparative HPLC under the following conditions: Column: Phenomenex luna C18 100 × 40 mm × 3 μm, Mobile phase: [water (TFA)-ACN], B%: 25% → 55%, 8 min 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 (400 MHz, DMSO) δ 9.38 (br s, 1H), 7.81 (br d, J = 12.4 Hz, 2H), 7.62 (br d, J = 4.4 Hz, 2H), 7.41 (br d, J = 4.8 Hz, 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). C 22 H 38 FN2O7P2Si + LC-MS calculated value m / z 551.19 [M] + , actual measured value 551.1.

[0184] Radiolabeling protocol for (Va) The synthetic scheme for the preparation of (Va) was carried out as follows: TIFF2025530407000141.tif31170

[0185] Method 1 Obtained from the cyclotron 18 O] in H2O 18[F]HF (200 μL–500 μL) was added to a solution of FSi-Zole precursor in DMSO (50 μL–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 via HPLC: column COSMOSIL 5C18-ARII 6.0 ID x 150 mm, mobile phase: A: HO + 0.1% TFA, B: acetonitrile + 0.1% TFA, method: 0 min → 20 min, 5% → 90% B, 20 min → 25 min, 90% B, 25 min → 27 min, 90% → 5% B, 27 min → 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. The column was eluted with PBS buffer in 0.5 mL fractions. The radioactive fractions were combined, passed through a 0.2 μM sterile filter, and prepared for ex vivo and in vivo applications.

[0186] Method 2 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Waters QMA cartridge pretreated with 15 mL of pure water). The cartridge was rinsed with 2 mL of pure water and dried with 10 mL of air. [F]HF was removed from the cartridge using a solution containing potassium carbonate and Kryptofix 222 (300 μL, 0.025 M / 0.05 M, respectively, in acetonitrile / water 3:1). 18 F]F -The solution was azeotropically dried under a stream of nitrogen at 120 °C. After adding anhydrous acetonitrile (0.5 mL), this procedure was repeated twice. To the residue after concentration, anhydrous acetonitrile (200 μL) and a solution of FSi-Zole precursor (50 μL, 1 mg / mL solution in dry DMSO) were added, followed by reaction at room temperature for 15 minutes. The reaction solution was diluted with 1.5 mL of 70% acetonitrile / water and purified via HPLC: Column COSMOSIL 5C18-ARII 6.0 ID × 150 mm, Mobile phase: A: HO + 0.1% TFA, B: acetonitrile + 0.1% TFA, Method: 0 min → 20 min, 5% → 90% B, 20 min → 25 min, 90% B, 25 min → 27 min, 90% → 5% B, 27 min → 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 column. The column was eluted with PBS buffer in 0.5 mL fractions. The radioactive fractions were combined, passed through a 0.2 μM sterile filter, and prepared for ex vivo and in vivo applications.

[0187] Method 3 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Waters QMA cartridge pre-treated with 15 mL of pure water). The cartridge was rinsed with 2 mL of pure water and dried with 10 mL of air. An aqueous solution of EtNHCO (0.075 M, 80 μL) was used with water (120 μL) and acetonitrile (400 μL) to remove [F]HF from the cartridge. 18 F]F -The solution was azeotropically dried under a stream of nitrogen at 120 °C. After adding anhydrous acetonitrile (0.5 mL), this procedure was repeated twice. To the residue after concentration, anhydrous acetonitrile (200 μL) and a solution of FSi-Zole precursor (50 μL, 1 mg / mL solution in dry DMSO) were added, followed by a 15-minute reaction at room temperature. The reaction solution was diluted with 1.5 mL of water and captured on a Waters Sep-Pak tC18 cartridge (pre-treated with 5 mL of ethanol and 5 mL of water). The cartridge was washed with 5 mL of water, dried with 10 mL of air, and eluted with ethanol / PBS (2 mL, 1:1 mixture). The ethanol was removed with a stream of nitrogen, and the residue was diluted with PBS buffer. The solution was passed through a 0.2 μM sterile filter and then prepared for ex vivo and in vivo applications.

[0188] formula( 19 Synthesis of Compound F-IVa) formula( 19 Compound F-IVa) was synthesized as follows. TIFF2025530407000142.tif19170

[0189] Tetraethyl (4-azido-1-((tert-butyldimethylsilyl)oxy)butane-1,1-diyl)bis(phosphonate) A mixture of diethyl diethyl 1-[(tert-butyldimethylsilyl)oxy]-4-chloro-1-(diethoxyphosphoryl)butylphosphonate (13.6 g, 27.475 mmol, 1.00 equiv.) and sodium azide (3.57 g, 54.950 mmol, 2 equiv.) 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 (3×200 mL). The combined organic layers were washed with brine (5×100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give diethyl diethyl 4-azido-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (13 g, crude material) as a yellow oil. The crude product was used in the next step without further purification. 18 H 41 LC-MS calculated value for N3O7P2Si m / z 502.57 [M+H] + , actual measured value 502.3.

[0190] Tetraethyl (4-amino-1-((tert-butyldimethylsilyl)oxy)butane-1,1-diyl)bis(phosphonate) To a solution of diethyl 4-azido-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (13 g, 25.91 mmol, 1.00 equiv.) in 200 mL of ethyl acetate was added Pd / C (10%, 1.38 g) in a pressure tank. The mixture was hydrogenated at room temperature under 50 psi hydrogen pressure for 15 hours, filtered through a Celite pad, and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure to give diethyl 4-amino-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (10 g, crude material) 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). C 18H 43 LCMS calculated value of NO7P2Si m / z 476.57 [M+H] + , actual measured value 476.3.

[0191] Tetraethyl (1-((tert-butyldimethylsilyl)oxy)-4-(6-fluoronicotinamido)butane-1,1-diyl)bis(phosphonate) To a stirred solution of diethyl 4-amino-1-[(tert-butyldimethylsilyl)oxy]-1-(diethoxyphosphoryl)butylphosphonate (1.69 g, 3.544 mmol, 1 equiv) and 6-fluoropyridine-3-carboxylic acid (500 mg, 3.544 mmol, 1.00 equiv) in DMF (10 mL) was added HATU (2.02 g, 5.316 mmol, 1.50 equiv) and DIEA (1.25 mL, 7.194 mmol, 2.03 equiv) at 20 °C. The reaction was stirred at 20 °C for 2 h. The reaction was quenched with water. The aqueous layer was extracted with EA (3 × 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (7%) in EA to give 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). C 24 H 45 LCMS calculated value for FN2O8P2Si m / z 599.24 [M+H] + , actual measured value 599.3.

[0192] Radiolabeling protocol for (IVa) Radiolabeling was carried out as follows. TIFF2025530407000143.tif22170

[0193] Method 1 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F - The column was slowly eluted with a solution of quaternary ammonium triflate precursor (5 mg to 10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL) over 5 min. The eluate was diluted with 8 mL of water and added to AFFINIMIP™ SPE. 18The F-sulfate was captured on an F-sulfate-aromatic nucleophilic displacement cartridge (pre-treated with 2 mL of acetonitrile). The cartridge was washed with 5 mL of water and eluted with 1.5 mL of 65% acetonitrile / water. A 0.5-1 MBq aliquot of the eluate was removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 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 via HPLC using a COSMOSIL 5C18-PAQ 10 ID x 250 mm column with mobile phases A: PBS and B: ethanol. The procedure was: 0 min → 5 min, 5% B; 5 min → 20 min, 5% B → 35% B; 20 min → 23 min, 35% B → 90% B; 23 min → 28 min, 90% B; 28 min → 33 min, 90% B → 5% B; 33 min → 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 ex vivo and in vivo applications.

[0194] Method 2 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F - The column was slowly eluted with a solution of quaternary ammonium triflate precursor (5 mg to 10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL) over 5 min. The eluate was diluted with 8 mL of water and added to AFFINIMIP™ SPE. 18The F-sulfate was captured on an F-nucleophilic aromatic cartridge (pre-treated with 2 mL of acetonitrile). The cartridge was washed with 5 mL of water and eluted with 1.0 mL of acetone. A 0.5-1 MBq aliquot of the eluate was removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 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, 200 μL) was added to the concentrated residue, and the resulting solution was heated at 40°C for 20 minutes. The reaction solution was diluted with 1 mL of PBS buffer and purified via HPLC: column COSMOSIL 5C18-PAQ 10 ID x 250 mm, mobile phase: A: PBS, B: ethanol, method: 0 min → 5 min, 5% B, 5 min → 20 min, 5% → 35% B, 20 min → 23 min, 35% → 90% B, 23 min → 28 min, 90% B, 28 min → 33 min, 90% → 5% B, 33 min → 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 ex vivo and in vivo applications.

[0195] Method 3 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pretreated with 5 mL of 0.1 M NaHCO3 and 5 mL of water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F -The product was slowly eluted over 5 min with a solution of quaternary ammonium triflate precursor (5 mg–10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL). The eluate was diluted with 8 mL of water and captured on a Waters Oasis MCX cartridge (preconditioned 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. Aliquots of 0.5 MBq to 1 MBq of the eluate were removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 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 via HPLC using a COSMOSIL 5C18-PAQ 10 ID x 250 mm column with mobile phases: A: saline, B: ethanol. The procedure was: 0 min → 5 min, 5% B; 5 min → 20 min, 5% → 35% B; 20 min → 23 min, 35% → 90% B; 23 min → 28 min, 90% B; 28 min → 33 min, 90% → 5% B; 33 min → 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 ex vivo and in vivo applications.

[0196] Method 4 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pretreated with 5 mL of 0.1 M NaHCO3 and 5 mL of water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F -The eluate was slowly eluted with a solution of quaternary ammonium triflate precursor (5 mg–10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL) over 5 min. The eluate was diluted with 8 mL of water and captured on a Waters Oasis MCX cartridge (preconditioned 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. Aliquots of 0.5 MBq to 1 MBq of the eluate were removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 30 min, 95% → 30% B; Flow rate: 2.0 mL / min; Retention time: 15.2 min. The solvent was removed by 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 via HPLC using a COSMOSIL 5C18-PAQ 10 ID x 250 mm column with mobile phases: A: saline, B: ethanol. The procedure was: 0 min → 5 min, 5% B; 5 min → 20 min, 5% → 35% B; 20 min → 23 min, 35% → 90% B; 23 min → 28 min, 90% B; 28 min → 33 min, 90% → 5% B; 33 min → 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 ex vivo and in vivo applications.

[0197] Method 5 Obtained from the cyclotron 18 O] in H2O 18 [F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F -The eluate was slowly eluted with a solution of quaternary ammonium triflate precursor (5 mg–10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL) over 5 min. The eluate was diluted with 8 mL of water and then passed through stacked Waters Sep-Pak Plus CM and PS-2 cartridges (pre-conditioned with 5 mL of ethanol and 5 mL of water, respectively). The cartridges were washed with 5 mL of water. The PS-2 cartridge was eluted with 1.0 mL of dichloromethane. Aliquots of 0.5 MBq to 1 MBq of the eluate were removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 30 min, 95% → 30% B; Flow rate: 2.0 mL / min; Retention time: 15.2 min. The solvent was removed by 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 via HPLC using a COSMOSIL 5C18-PAQ 10 ID x 250 mm column with mobile phases A: PBS and B: ethanol. The procedure was: 0 min → 5 min, 5% B; 5 min → 20 min, 5% B → 35% B; 20 min → 23 min, 35% B → 90% B; 23 min → 28 min, 90% B; 28 min → 33 min, 90% B → 5% B; 33 min → 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 ex vivo and in vivo applications.

[0198] Radiolabeling protocol for (IVb) The synthetic scheme for the preparation of (IVb) is as follows: TIFF2025530407000144.tif22170

[0199] Obtained from the cyclotron 18 O] in H2O 18[F]HF was passed through an anion exchange cartridge (Chromafix PS-OH pre-wetted with 10 mL of distilled water). The original vial was rinsed with 2 mL of pure water, which was also applied to the cartridge. The cartridge was washed with 3 mL of anhydrous acetonitrile and dried under a stream of nitrogen for 5 minutes. 18 F]F - The FPy-TFP was slowly eluted with a solution of quaternary ammonium triflate precursor (5 mg–10 mg) in anhydrous isobutanol:acetonitrile (4:1, 1 mL) over 5 min. The eluate was diluted with 8 mL of water and captured on stacked Waters Sep-Pak Plus CM and PS-2 cartridges (pretreated with 5 mL of ethanol and 5 mL of water, respectively). The cartridges were washed with 5 mL of water, and FPy-TFP was eluted from the PS-2 cartridge with 1.0 mL of dichloromethane. Aliquots of 0.5 MBq to 1 MBq of the eluate were removed for quality control using HPLC: Column: COSMOSIL 5C18-ARII 6.0 ID x 150 mm; Mobile phase: A: HO + 0.1% TFA; B: Acetonitrile + 0.1% TFA; Method: 0 min → 20 min, 30% → 80% B; 20 min → 22 min, 80% → 95% B; 22 min → 27 min, 95% B; 27 min → 30 min, 95% → 30% B; Flow rate: 2.0 mL / min; Retention time: 15.2 min. The eluate was concentrated under a stream of nitrogen at room temperature. 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. Aqueous hydrochloric acid (4 M, 300 μL) was added to the reaction solution, which was then further heated at 100 °C for 10 min. The reaction solution was diluted with 1 mL of PBS buffer and purified via HPLC: column COSMOSIL 5C18-ARII 6.0 ID x 150 mm, mobile phase: A: HO, B: ethanol, method: 0 min → 20 min, 40% → 80% B, 20 min → 22 min, 80% → 95% B, 22 min → 25 min, 95% B, 25 min → 27 min, 95% → 40% B, 27 min → 30 min, 40% B, flow rate: 2.0 mL / min, retention time: 16.5 ± 0.5 min. The collected fractions were filtered through a 0.2 μM sterile filter and prepared for ex vivo and in vivo applications.

[0200] Animal treatment Male Wistar rats (weight 250-400 g) were used for cardiac uptake studies. Anesthesia was induced with 5% isoflurane in pure oxygen and maintained at 2% isoflurane throughout the experiment.

[0201] PET imaging and dynamic studies A small animal PET system (Inveon, Siemens, Erlangen, Germany) was used for rat studies. A 120-minute dynamic scan was initiated immediately after injection of IVa (10–20 MBq) via the tail vein. Reconstructed images were analyzed using AMIDE imaging software (version 1.0.1). For rat kinetic studies, tissue uptake was calculated as a percentage of radiotracer retention, from which time-activity curves for various organs, specifically bone, kidney, liver, heart, and intestine, were constructed, as shown in Figures 1–5.

[0202] Cardiac tissue binding studies Frozen cardiac tissue sections were incubated in saline containing IVa (approximately 5 MBq) with or without alendronate (final concentration 1 mM) as a blocking agent. After 30 min of incubation at 25 °C, the sections were rinsed in PBS buffer for 1 min and then in water four times for 2 s 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 6.

Claims

1. A compound or a pharmaceutically acceptable salt thereof for use in a method for diagnosing cardiac amyloidosis, comprising at least one bisphosphonate group or bisphosphonate ester group; a positron-emitting radionuclide Po, wherein Po is attached to said at least one bisphosphonate group or bisphosphonate ester group, or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof has the formula (I): (In the formula, z is an integer selected from the group consisting of 1, 2, and 3, preferably z is 1; Each R １ are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; n is an integer selected from the group consisting of 0, 1, 2, and 3; A is -NR ２ or (4- to 8-membered ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramido, or (5- to 6-membered ring) heteroaryl, or phenyl; R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, i) L and Q are absent, or ii) L is a divalent linker group; Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , —O,N,N-substituted piperazine, or and X － is a pharmaceutically acceptable anion, preferably X － is F － , Cl － ,Br － , I － , O.H. － , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br － and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ is methyl, R ３ is a group containing the positron-emitting radionuclide Po), or a pharmaceutically acceptable salt thereof.

3. 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, the positron-emitting radionuclide Po is １８ F or ６８ 3. The compound of claim 1 or 2, wherein R is H or H. Ga, or a pharmaceutically acceptable salt thereof.

4. Each R １ but, i) Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, -CH ２ —O(CO)—CH ３ , -CH ２ —O(CO)—CH ２ CH ３ , -CH ２ -O(CO)-CH(CH ３ ) ２ , -CH ２ -O(CO)-C(CH ３ ) ３ , and (wherein R' is methyl, ethyl), preferably Each R １ is selected from the group consisting of methyl, ethyl, and i-propyl, and more preferably each R １ is methyl or i-propyl, or ii) Each R １ but, Two R protecting groups are attached to one phosphonate group. １ But both, (wherein R′ is hydrogen or (C １ ~C １０ 4. The compound according to claim 2 or 3, wherein the compound forms the structure:

5. i) Said portion R ３ -Q-L-A- is R ３ -Q-L-NR ２ - (In the formula, R ２ is hydrogen, or a straight or branched chain (C １ ~C ６ ) alkyl, Preferably R ２ is hydrogen, methyl or ethyl, More preferably, R ２ is hydrogen or methyl), or ii) the part R ３ -Q-L-A-, (In the formula, X － is a pharmaceutically acceptable anion, Preferably X － is F － , Cl － ,Br － , I － , O.H. － , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br － The compound according to any one of claims 2 to 4, wherein

6. a) L and Q are absent, or b) L is a straight chain or branched chain (C １ ~C １０ ) alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted (5-membered to 6-membered ring) heteroaryl, or (C １ ~C １０ ) (5- to 8-membered) heterocyclyl substituted with alkyl, or (C １ ~C ６ ) an ω-amino acid, or polyethylene glycol, or a dipeptide, or a tripeptide, or a combination thereof; Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , —O,N,N-substituted piperazine, or and X － is a pharmaceutically acceptable anion, preferably X － is F － , Cl － ,Br － , I － , O.H. － , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br － and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ The compound according to any one of claims 2 to 5, or a pharmaceutically acceptable salt thereof, wherein is methyl.

7. a) the part R ３ -Q-L-, (In the formula, l is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, and 7, preferably l is 1, 2, or 3; Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , —O,N,N-substituted piperazine, or and X － is a pharmaceutically acceptable anion, preferably X － is F － , Cl － ,Br － , I － , O.H. － , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br － and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ is methyl), or b) the part R ３ -Q-L-, wherein m is 1, 2, or 3; or c) Said portion R ３ -Q-L-, 7. The compound according to any one of claims 2 to 6, wherein m is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

8. R ３ but, i) (Where Po is ６４ Cu or ６８ Ga, preferably ６８ Ga), or ii) (Wherein, Po is ６４ Cu or ６８ Ga, preferably ６８ Ga), or iii) (Wherein, 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) (Wherein, 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) (Wherein, 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) (Wherein, Po is １８ F or -O １１ CH ３ , preferably １８ F), or xi) Or, xii) (Wherein, M is O, or —NH, or CH ２ O), or xiii) Or, xiv) Or, xv) Or, xvi) Or, xvii) Or, xviii) Or, xix) Or, xx) The compound according to any one of claims 2 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. The compound or a pharmaceutically acceptable salt thereof has the formula (II): (In the formula, R ３ but, i) (Wherein, Po is １８ F or -O １１ CH ３ , preferably １８ F), or ii) Or, iii) Or, iv) and preferably R ３ but, and R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, Preferably R ２ is hydrogen or methyl, More preferably, R ２ is methyl, Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, i-propyl, or —O(CO)—C(CH ３ ) ３ and More preferably, each R １ is hydrogen, methyl, or -CH ２ -O(CO)-C(CH ３ ) ３ and even more preferably each R １ is hydrogen or -CH ２ -O(CO)-C(CH ３ ) ３ and most preferably The compound, or a pharmaceutically acceptable salt thereof, has the structure (IIa) or the structure (IIb): (In the formula, R １ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is methyl or ethyl.

10. The compound or a pharmaceutically acceptable salt thereof is a) Formula (III): (In the formula, R ３ but, i) (Wherein, Po is １８ F or -O １１ CH ３ , preferably １８ F), or ii) Or, iii) Or, iv) and preferably R ３ but, and R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, Preferably R ２ is hydrogen or methyl, More preferably, R ２ is methyl, Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, or i-propyl; More preferably, each R １ is hydrogen, methyl, or i-propyl; Even more preferably, each R １ is hydrogen or methyl, most preferably The compound, or a pharmaceutically acceptable salt thereof, has the structure (IIIa) or the structure (IIIb): a compound having the formula Or, b) Formula (V): (In the formula, X － is a pharmaceutically acceptable anion, Preferably X － is F － , Cl － ,Br － , I － , or OH － , More preferably, Br － and R ３ but, i) (Wherein, Po is １８ F or O １１ CH ３ , preferably １８ F), or ii) Or, iii) Or, iv) and preferably R ３ but, and more preferably, R ３ but, and Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, or i-propyl; More preferably, each R １ is hydrogen, methyl, or i-propyl; Even more preferably, each R １ is hydrogen or methyl, most preferably The compound, or a pharmaceutically acceptable salt thereof, has the structure (Va): or c) Formula (VI): (In the formula, Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － or —O, X － is a pharmaceutically acceptable anion, preferably X － is F － , Cl － ,Br － , I － , O.H. － , tosylate, mesylate, triflate, trifluoroacetate, sulfate, acetate, tartrate, benzoate, oxylate, salicylate, or camphorsulfonate, more preferably Br － and R Ｑ is a straight chain or branched chain (C １ ~C ６ ) alkyl, p is 0 or 1; R ３ but, i) Or, ii) Or, iii) and R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, Preferably R ２ is hydrogen or methyl, Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, i-propyl, or —O(CO)—C(CH ３ ) ３ and More preferably, each R １ is hydrogen or methyl, and even more preferably Each R １ is hydrogen, most preferably The compound, or a pharmaceutically acceptable salt thereof, has the structure (VIa), the structure (VIb), or the structure (VIc): or d) Formula (VII): (In the formula, Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , N,N-substituted piperazine or —O; X － is a pharmaceutically acceptable anion, preferably X － is F － , Cl － ,Br － , I － , or OH － , more preferably Br － and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ is methyl, preferably Q is —NH; R ３ but, i) Or, ii) Or, iii) and Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, i-propyl, or —O(CO)—C(CH ３ ) ３ and More preferably, each R １ is hydrogen or methyl, and even more preferably each R １ is hydrogen, most preferably The compound, or a pharmaceutically acceptable salt thereof, has the structure (VIIa): The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is a compound of the formula:

11. The compound or a pharmaceutically acceptable salt thereof has the formula (IV): (In the formula, R ３ but, i) (Where Po is １８ F or -O １１ CH ３ , preferably １８ F), or ii) Or, iii) Or, iv) and preferably R ３ but, and more preferably, R ３ but, and R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, Preferably R ２ is hydrogen or methyl, More preferably, R ２ is hydrogen, Each R １ are independently hydrogen, straight or branched chain (C １ ~C ６ ) alkyl, and —CH ２ -O-CO-O-(C １ ~C ６ ) alkyl; Preferably, each R １ is hydrogen, methyl, ethyl, or i-propyl; More preferably, each R １ is hydrogen, methyl, or i-propyl; Even more preferably, each R １ is hydrogen or methyl, and most preferably the compound, or a pharmaceutically acceptable salt thereof, has structure (IVa) or structure (IVb): (In the formula, R １ or a pharmaceutically acceptable salt thereof) of the compound according to any one of claims 1 to 8, wherein R is methyl or ethyl, preferably ethyl.

12. The compound is 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, which is not:

13. A process for preparing a compound according to any one of claims 1 to 12, comprising the steps of: a) Formula (Ia): (In the formula, Each R １ are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; n is an integer selected from the group consisting of 0, 1, 2, and 3; A is -NR ２ or (4- to 8-membered ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramido, or (5- to 6-membered ring) heteroaryl, or phenyl; R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, L and Q are absent, or L is a divalent linker group; Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , —O, or N,N-substituted piperazine, and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ is methyl; b) Formula R ３ -Y (wherein, R ３ -Y is i) (Wherein, Po is ６４ Cu or ６８ Ga, preferably ６８ Ga), or ii) (Wherein, 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) (Wherein, 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) (Wherein, Po is ６４ Cu or ６８ Ga, preferably ６８ Ga), or x) (Where Po is １８ F or -O １１ CH ３ , preferably １８ F), or xi) Y- １１ CH ３ 、 or HO- １１ CH ３ 、 xii) (Wherein, M is O, or —NH, or CH ２ O), or xiii) Or, xiv) Or, xv) Or, xvi) Or, xvii) Or, xviii) Or, xix) and Y is an electron-withdrawing group; Preferably, Y is —Cl, —Br, —O—C ６ F ５ H, -O(CO)-(C １ ~C ６ providing a compound of formula (I) selected from the group consisting of: -a) alkyl; and -OH; c) a compound of formula (Ia) and R ３ -Y at a temperature of about 60°C to about 140°C; Including, 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: step c) is carried out for about 1 minute to about 60 minutes; and / or A method wherein step c) is carried out in dry DMF or dry DMSO.

14. A process for preparing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, comprising: a) Formula (Ib): (In the formula, z is 1, 2, or 3, preferably z is 1; Each R １ are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; n is an integer selected from the group consisting of 0, 1, 2, and 3; A is -NR ２ or (4- to 8-membered ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramido, or (5- to 6-membered ring) heteroaryl, or phenyl; R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, L and Q are absent, or L is a divalent linker group; Q is -NH, -NR Ｑ , -N ＋ R Ｑ ２ X － , —O, or N,N-substituted piperazine, and R Ｑ are each independently a straight chain or branched chain (C １ ~C ６ ) alkyl, and preferably each R Ｑ is methyl, R ３ａ but, i) Or, ii) Or, iii) Or, iv) Or, v) Or, vi) Or, vii) Or, viii) Or, ix) Or, x) (In the formula, R ５ is OTs, OMs, OTf, or I), or xi) (Wherein, M is O, or —NH, or CH ２ O), or xii) Or, xiii) Or, xiv) Or, xv) Or, xvi) Or, xvii) Or, xviii) (In the formula, R ９ is an ammonium salt, or H; b) reacting said compound of formula (Ib) with a group Po containing said positron-emitting radionuclide Po ＊ and reacting the compound with Po ＊ but- １１ CH ３ , １３ N. １５ O. １８ F － , ６４ Cu or ６８ Ga, Preferably- １１ CH ３ , １８ F － , and ６８ Ga, More preferably １８ F － or ６８ Ga, and most preferably step b) is carried out for a time period of about 1 minute to about 60 minutes; and / or step b) is carried out at a temperature of about 80°C to about 140°C; and / or step b) is carried out in dry DMF or dry DMSO; A method comprising:

15. A process for preparing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, comprising: a) Formula (Ic): (In the formula, Each R １ are independently hydrogen, a pharmaceutically acceptable cation, or a protecting group; n is an integer selected from the group consisting of 0, 1, 2, and 3; A is -NR ２ or (4- to 8-membered ring) heterocyclyl, or (4- to 8-membered ring) cyclyl, or squaramido, or (5- to 6-membered ring) heteroaryl, or phenyl; R ２ is hydrogen or a straight or branched chain (C １ ~C ６ ) alkyl, L is (C １ ~C １０ ) alkyl and Q is —C≡CH; b) Formula: providing a compound of c) reacting said compound of formula (Ic) and said compound of step b) in the presence of a Cu(I) salt at a temperature of about 60°C to about 140°C, preferably step c) is carried out for a time period of about 1 minute to about 60 minutes; and / or step c) is carried out at a temperature of about 80°C to about 140°C; and / or step c) is carried out in dry DMF or dry DMSO; A method comprising:

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