Small molecule albumin binders

Abstract

Compounds having albumin binding groups are described, wherein the compounds can be complexed with therapeutic and / or diagnostic agents and can further include targeting functionality. When introduced into the circulatory system, the compounds and complexes bind to serum albumin, thereby exhibiting useful properties, including enhanced circulation half-life, improved uptake in target tissues, and increased target / non-target ratios. These properties make the compounds and complexes useful in therapeutic and diagnostic methods.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 068,259, filed on August 20, 2020, entitled “SMALL MOLECULE ALBUMIN BINDERS,” which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to small molecules that can be used as albumin binders useful in diagnostic and pharmaceutical applications. Background Art

[0004] Human serum albumin is the most predominant plasma protein in the bloodstream, accounting for approximately 55-60% of total serum proteins. With this astonishing abundance, albumin performs many physiological functions: maintaining colloid osmotic pressure within the vascular system, and being an essential multicarrier for many hydrophobic endogenous and exogenous moieties such as lipids, metal ions, hormones, amino acids, and some biomedical drugs. Since the size of albumin (approximately 66.5 kDa) exceeds the threshold of renal ultrafiltration, it cannot pass through the pores in the glomerular membrane and is therefore retained in the blood. In addition, albumin exhibits a unique interaction with the neonatal Fc receptor (FcRn) and is therefore excluded from cellular degradation through recycling and endocytic transport pathways. These characteristics give albumin a relatively long serum half-life (approximately 19 days). Due to its excellent serum stability and long serum half-life, albumin has been used for drug delivery, either by direct genetic fusion or covalent conjugation, or by non-covalent binding interactions, to provide favorable pharmacokinetics and pharmacodynamics.

[0005] Drugs incorporated with albumin binders can achieve significantly enhanced tumor uptake by binding to albumin, which can be attributed to three main reasons: 1) reversible binding to albumin can prolong serum half-life; 2) the relatively large size of the albumin-drug complex provides enhanced permeation and retention (EPR) effects; 3) albumin and albumin-drug complexes can act as a nutrient source for tumor growth. Various reversible albumin binding molecules (e.g., ABI) have been incorporated into radioligands for nuclear imaging and / or radionuclide therapy. As Figure 1As shown, an example of an albumin binder-radioligand conjugate may contain three parts: a cancer biomarker-specific ligand for tumor targeting, a radionuclide for imaging and / or radionuclide therapy, and an albumin binder for albumin binding to enhance tumor uptake. Unlike the high binding affinity between the radioligand and the tumor receptor (e.g., <50 nmol), a reversible albumin binder with a moderate binding affinity to albumin (e.g., at the μM level) can be easily dissociated from albumin and then accumulated in the tumor due to a stronger binding to the targeted tumor receptor.

[0006] To date, two classes of mobile, low molecular weight and reversible albumin binders have been investigated for nuclear imaging and radioligand therapy. One class of mobile, low molecular weight, reversible albumin binders is based on 4-(p-iodophenyl)butyric acid, which binds to the Sudlow binding site II of albumin. The other class is a truncated Evans Blue (EB), which binds to the Sudlow binding site I of albumin. Both ABI and EB albumin binders exhibited modest binding to albumin with an affinity of 3.2 μM (K for ABI). d ) and 2.5 μM (K of EB d ). Radioligands incorporated with ABI and EB exhibit prolonged blood circulation and improved tumor uptake compared to corresponding radioligands without albumin binders. Despite the enhanced tumor uptake and prolonged tumor retention, the incorporation of ABI (or) EB may also lead to considerable concerns about reduced tumor / non-tumor ratios due to much higher uptake in normal tissues (e.g., blood, bone marrow, kidney, etc.). Therefore, mobile albumin binders that can enhance tumor uptake and improve tumor / non-tumor ratios are still highly desirable for nuclear imaging and radionuclide therapy.

[0007] BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 A schematic representation of the proposed mechanism of incorporation of radioligands by albumin binders is provided.

[0009] Figure 2 The structure of the albumin binder incorporated into the binder-drug conjugate is provided, illustrating the albumin binding portion.

[0010] Figure 3 The structures of exemplary conjugates of the albumin binder, radionuclide chelator (DOTA), and targeting ligand (RGD) of the embodiments are provided.

[0011] Figures 4A-4D Examples of alternative structures of albumin binder-radionuclide chelator conjugates are shown, wherein Figure 4A S-lysine was incorporated; Figure 4B R-lysine was incorporated; Figure 4C including added amide bonds; and Figure 4D is characterized by a shift in the position of the amide bond.

[0012] Figure 5 Represents the in vitro binding evaluation of selected albumin binder-chelator conjugates to human serum albumin.

[0013] Figure 6 Representation and 64 Cu-DOTA-SFLAP3 (abbreviated as SFLAP3) compared to 64 In vitro binding evaluation of Cu-DOTA-SFLAP3-PEG4-ABCF3 (abbreviated as SFLAP3-ABCF3).

[0014] Fig. 7A and 7B In mice bearing BxPC3 xenografts 111 Evaluation of In-labeled RGD-ABCF3, RGD, and RGD-ABI: Fig. 7A ) biodistribution, and ( Figure 7B ) Tumor / non-tumor ratio (mean ± SD).

[0015] Fig. 8A and 8B In mice bearing CT26 xenografts 111 Evaluation of In-labeled RGD-ABCF3, RGD, and RGD-ABI: Fig. 8A ) biodistribution, and ( Figure 8B ) Tumor / non-tumor ratio (mean ± SD).

[0016] Fig. 9A and 9B Indicates that PSMA is more likely to be carried + PC3pip and PSMA - PC3 xenografts in mice 64 Evaluation of Cu-labeled PSMA617-ABCF3 and PSMA617: Fig. 9A ) biodistribution, and ( Fig. 9B ) Tumor / non-tumor ratio (mean ± SD).

[0017] Fig. 10A and 10B In mice bearing BXPC3 xenografts 111 Evaluation of In-labeled FRGD-ABCF3 and FRGD: Fig. 10A ) biodistribution, and ( Fig. 10B ) Tumor / non-tumor ratio. (Mean ± SD).

[0018] Fig.11A and 11B represent the evaluation (24 hours) of the in vivo performance of SFLAP3 incorporating various albumin binders in mice bearing BxPC3 xenografts:( Fig.11A )(i) biodistribution, and( Fig. 11B )(ii) tumor / non-tumor ratio. (Mean ± SD). SUMMARY OF THE INVENTION

[0019] In one embodiment of the present invention, there is provided a compound of formula (I):

[0020]

[0021] Wherein:

[0022] X is selected from:

[0023]

[0024] R 1 、R 2 、R 3 、R 4 、R 5 , and when present R 8 and R 9 , each independently selected from H, F, Cl, Br, I, SF 3 、SF 2 Cl、SF 5 、SF 4 Cl、C 1 -C 6 linear or branched alkyl, C 1 -C 6 linear or branched fluoroalkyl (including CF 3 ), C 1 -C 6 linear or branched fluorinated alkoxy and their isotopes, or substituents selected from:

[0025]

[0026]

[0027] R 6 and R 7 are each independently selected from H and F and their isotopes, or in combination with a bridging oxygen group;

[0028] R 10 and R 11 are each independently selected from H and F;

[0029] n1 is an integer selected from 1, 2, 3, 4, 5 and 6;

[0030] n 2 is an integer selected from 1, 2, 3 and 4; and

[0031] m is an integer selected from 1, 2, 3, 4, 5, 6, 7 and 8;

[0032] Provided that, when X is a substituted benzyl group, R 1 , R 2 , R 3 , R 4 and R 5 At least one of F, SF 3 , SF 5 and C 1 -C 6 Straight-chain or branched fluoroalkyl (including CF 3 ), or a substituent selected from the following:

[0033]

[0034] In some embodiments, Formula (I) is further defined, provided that R 1 , R 2 , R 3 , R 4 , R 5 And when there is R 8 and R 9 No more than 3 of them are selected from C 1 -C 6 Straight-chain or branched fluoroalkyl (including CF 3 ), SF 2 , SF 2 Cl, SF 5 and SF 4 In some embodiments, Formula (I) is further defined, provided that, when present, at least one R 10 The group must be F or 18 F.

[0035] The albumin binders shown above can be described as comprising: an albumin binding component (generally represented herein by the identifier "ABX"), which includes a 1 and a carboxylic acid of a substituent binding group X; and a spacer, such as an amino acid having a side chain of length m+1. In some embodiments, the albumin binder is a selected enantiomer of a chiral compound having a central carbon of the spacer as a chiral center. Non-limiting examples of albumin binder components are as follows:

[0036]

[0037] An aspect of the present disclosure is that the compounds described herein bind to serum albumin. More specifically, in various embodiments, this binding occurs through non-covalent interactions between one or more moieties represented by formula (I) and binding sites on albumin. Figure 2 As shown, one such binding group (binding group 1) can be a substituted aromatic group represented by X in formula (I). Another such binding group (binding group 2) can be a carboxyl group of the spacer shown in formula (I). Although the present disclosure is not bound by a particular theory, it is believed that binding can be achieved through one or both of the following interactions: a) interaction of binding group 1 with the hydrophilic pocket of albumin, and b) interaction of binding group 2 with the hydrophobic pocket of albumin.

[0038] Due to their albumin binding properties combined with the dynamics of serum albumin in the vascular circulation, it is contemplated that the various compounds described herein may be complexed with one or more chemical entities of therapeutic and / or diagnostic interest, wherein the therapeutic or diagnostic effect of the entity may be enhanced by binding of the complex to serum albumin. In one aspect, some of such enhancements come from the tendency of albumin to concentrate in the tumor microenvironment and other tissues affected by diseases (e.g., inflammatory diseases). In some embodiments, the composition comprises a reaction product in which a physiologically active molecule, such as a therapeutic agent, is complexed with an albumin-binding compound described herein. The products of such reactions are interchangeably referred to herein as "complexes" or "conjugates," and the methods of forming them are interchangeably referred to herein as "complexes" or "conjugating" / "conjugation." As used herein, the terms "complexes" and "conjugates" each refer to a molecule comprising two different molecules bound by covalent or non-covalent bonds. In some embodiments, a complex or conjugate may comprise two or more physiologically active molecules covalently bonded by a connecting molecule. In some embodiments, one of the physiologically active molecules may comprise a targeting ligand. The term "targeting moiety" or "targeting ligand" refers to any molecule that provides enhanced affinity for a selected target, such as a cell, cell type, tissue, organ, body region or compartment, such as a cell, tissue or organ compartment. Targeting moieties or targeting ligands can comprise a wide variety of entities, including naturally occurring molecules or recombinant or synthetic molecules. Targeting moieties or targeting ligands include, but are not limited to, antibodies, antigen-binding fragments of antibodies, antigens, folate, EGF, albumin, receptor ligands, carbohydrates, aptamers, integrin receptor ligands, chemokine receptor ligands, transferrin, biotin, serotonin receptor ligands, PSMA, endothelin, GCPII, somatostatin, LDL and HDL ligands.

[0039] In some embodiments, the therapeutic agent is a drug, such as an anticancer drug or an anti-inflammatory disease drug. In certain embodiments, the drug is an anticancer drug, in particular, one of the following drugs: alkylating drugs, anthracyclines, cytotoxic antibiotics, antimetabolites, vinca alkaloids, platinum antineoplastic agents, taxanes, epothilones, histone deacetylase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, kinase inhibitors, retinoids, nucleotide analogs and pro-analogs.

[0040] In various embodiments, the anticancer drug is selected from dactinomycin, all-trans retinoic acid, alitretinoin, azacytidine, azathioprine, bexarotene, leomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, dacarbazine, docetaxel, doxorubicin, epirubicin, epothilone, erlotinib, etoposide, fluorouracil, gefitinib, gemcitabine, hydroxyurea, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, melphalan, mitoxantrone, nitrosoureas, oxaliplatin, paclitaxel, pemetrexed, tafluroside, temozolomide, amine, teniposide, thioguanine, topotecan, tretinoin, valrubicin, vemurafenib, vinblastine, vincristine, vindesine, vinorelbine, vismodegib, vorinostat, cyclophosphamide, ifosfamide, busulfan, cyclohexyl lomustine, carmustine, chlormethine, hexamethylmelamine, estradiol nitrogen mustard, trioxalosulfan, thiotepa, dibromomannitol, aclarubicin, idarubicin, actinomycin D, mitomycin, pentostatin, fludarabine, cladribine, raltitrexed, fludoxime, amsacrine, asparaginase, trastuzumab and its derivatives.

[0041] Also provided are conjugated compounds, non-limiting examples of which are Figure 3 This conjugated compound may contain the following covalent or non-covalent binding units:

[0042] a) Albumin binding compounds (e.g. Figure 3 ABCF3 shown).

[0043] b) joints; and

[0044] c) One or more functional groups effective for therapy and / or imaging.

[0045] like Figure 3 As shown, such functional groups may include one or both of the following:

[0046] i. Chelating agents (e.g. Figure 3 DOTA as shown); and

[0047] ii. Targeting ligands (e.g. Figure 3 RGD shown).

[0048] Some applications of the compounds described herein, such as imaging, diagnostics, radiotherapy, and targeted drug delivery applications, may benefit from additional targeting functionality. In some embodiments, the composition comprises a reaction product in which a targeting ligand is complexed with an albumin binding compound described herein. In some embodiments, the targeting ligand is non-covalently bound to the albumin binding compound. In other embodiments, the targeting ligand is covalently linked to the albumin binding compound, optionally via a linker, to provide a level of diagnostic effect, therapeutic effect, and pharmacokinetics of the ligand or composition as a whole. The targeting ligand may be any type of molecule suitable for incorporation into a compound by known methods, including proteins, polysaccharides, nucleic acids, peptides, aptamers, and small molecules.

[0049] In various embodiments, the targeting ligand targets a receptor that is overexpressed in tissues affected by the disease. In certain embodiments, the receptor is a molecule expressed in tumor cells or inflammatory tissue cells, including but not limited to integrins, lectins, and cytokines. In specific embodiments, the receptor is an integrin, such as, but not limited to, α v β 3 , α v β 4 , α v β 5 , α v β 6 or α 5 β 1 In other embodiments, the targeting ligand targets a drug or a metabolite of the drug such that when both are administered within a certain time frame, the compound will co-localize with the drug in the individual and optionally bind thereto. In some embodiments, the targeting ligand may be an inhibitor of a target receptor, such as a receptor tyrosine kinase, such as EGFR and HER2. In some embodiments, the targeting ligand comprises a targeting nanobody.

[0050] Peptides useful as targeting ligands may include linear, branched, or cyclic peptides known for such uses. Non-limiting examples of peptides for these uses include arginylglycylaspartate (RGD), galactose-RGD 2 , P-RGD, RGD 2 、P-RGD 2 , 2G-RGD 2 、2P-RGD 2 、3G-RGD 2 、3P-RGD 2 、3P-RGK 2 RGD 4 、6G-RGD4 and 6P-RGD 4 , as described in Shi et al., Biophys Rep 2016, 2(1): 1-20, the contents of which are incorporated herein by reference in their entirety, as well as FRGD, SFLAP3, FAPI, AE105, NT20.3, A20FMDV2, Pentixafor, JR11, DOTATATE, and PSMA-617.

[0051] Vitronectin, osteopontin, fibrinogen, and fibronectin act as αvβ 1 , αvβ 3 , αvβ 5 , αvβ 6 , αvβ 8 , α 5 β 1 , α8β 1 , α IIb β 3 The natural ligand of integrin (RGD recognition sequence). Fibronectin, vascular cell adhesion molecule 1, mucosal addressin cell adhesion molecule 1 and intercellular cell adhesion molecule 1 act as α 4 β 1 , α 9 β 1 , α 4 β 7 , α E β 2 , α L β 2 , α M β 2 , α X β 2 and α D β 2 Natural ligand for integrins (LDV and related sequences). Collagen and laminin act as α 1 β 1 , α 2 β 1 , α 10 β 1 and α 11 β 1 The natural ligand of integrin (GFOGER recognition sequence). Laminin also acts as α 3 β 1 , α 6 β 1 , α 7 β 1 and α 6 β 4 Natural ligand for integrins.

[0052] In some embodiments, the complex includes a radionuclide chelator to provide radiodiagnostic or radiotherapeutic applications when chelated to a radionuclide. In various embodiments, the chelator is one of any substance known to be capable of chelating a radionuclide metal suitable for these uses, including but not limited to 177 Lu, 86 Y. 89 Zr, 47 Sc, 44 Sc, 213 Bi, 99m Tc, 188 Re, 186 Re, 153 Sm, 166 Ho, 90 Y. 89 Sr. 67 Ga, 68 Ga, 111 In, 148 Gd, 55 Fe, 225 Ac, 212 Bi, 211 At 45 Ti, 60 Cu, 61 Cu, 67 Cu and 64Cu. Such chelating agents include 2,2',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA), hexahydro-1H-1,4,7-triazacyclononene-1,4,7-triacetic acid (NOTA), 1,4,7-tris(phosphonomethyl)-1,4,7-triazacyclononane (NOTP), ((1,4,7-triazonane-1,4,7-triyl)tris(methylene))tris(phosphinic acid) (TRAP), N'-[5-[[4-[[5-(acetylhydroxyamino)phenyl]amino]-1,4-dioxobutyl]hydroxyamino]phenyl]-N-(5-aminophenyl)-N-hydroxy-succinamide (DFO), 2,2' ,2",2"'-((((carboxymethyl) azaalkanediyl)bis(ethane-2,1-diyl))bis(azaalkanetriyl))tetraacetic acid (DTPA), 3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioic acid (EGTA), 2,2',2",2"'-(ethane-1,2-diylbis(azaalkanetriyl))tetraacetic acid (EDTA), 7-[2- [Bis(carboxymethyl)amino]-3-(4-nitrophenyl)propyl]hexahydro-1H-1,4,7-triazacyclononene-1,4(5H)-diacetic acid (C-NETA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)pentanedioic acid (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,1 0-tetraazacyclododecane-1-yl)pentanedioic acid (DOTAGA), 1,4,7-triazacyclononane-1-methyl(2-carboxyethyl)-phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,1 5-tetraazabicyclo[9,3,1]pentadecane-1(1 5),1 1,1 3-Triene-3,6,9-triacetic acid (PCTA), N,N"-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N"-diacetic acid (HBED-CC), N,N'-bis(2,2-dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS), 1-(4-carboxymethoxybenzyl)-NN'-bis[(2-mercapto-2,2-dimethyl)ethyl]-1,2-ethylenediamine-N,N'-diacetic acid (B6SS), N,N'-dipyridoxylethylenediamine-N,N'-diacetic acid (PLED), 1,1,1-tris-(aminomethyl)ethane (TAME), nitrile trimethylphosphonic acid (NTP), 2,2',2",2"'-(1,4,8,11-tetraazacyclotetradecane-1,4,8,11-Tetramethyl)tetraacetic acid (TOTA) and 2-BAPEN, and their derivatives.

[0053]

[0054]

[0055]

[0056] The radionuclides used in the complexes herein may also be selected from the following non-limiting group:

[0057] a) Radioisotopes useful for radiopharmaceutical imaging, such as positron-emitting radioisotopes used for positron emission tomography (PET), including 18 F. 11 C. 13 N. 75 Br, 76 Br, 124 I. 64 Cu, 48 V. 52 Fe, 55 Co. 82 Rb, 94m Tc, 133 Xe or 68 Ga, and gamma radioisotopes used for single photon emission computed tomography (SPECT) scanning, including 99m Tc, 123 I. 125 I. 123 I. 131 In, 113m In, 15 O. 201 Tl, 67 Cu or 67 Ga;

[0058] b) Radioisotopes include therapeutic isotopes used for cancer cell destruction and pain management in palliative care of bone cancer or arthritis, including 131 I. 90 Y. 188 Rh, 177 Lu, 47 Ca, 169 2. 32 P. 223 Ra, 212 Pb and 89 Sr; and

[0059] c) Radioisotopes used for testing and diagnostic purposes, including 14 C. 51 Cr, 57 Co. 58 Co. 3 H. 59 Fe, 81m Kr, 22 Na and 24 Nah.

[0060] According to some embodiments, the albumin binding compound may also incorporate a radionuclide. Some embodiments provide compounds of formula (I), wherein at least one selected from R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 The variables contain 18 F or contain 18 Functional group of F, such as CF 2 18 F.

[0061] The linker may comprise any structure selected to provide a certain level of performance in terms of diagnostic effect, therapeutic effect, and pharmacokinetics of the ligand or composition as a whole. In various embodiments, the linker may include a structural motif for such function, for example, a polyether bond, including but not limited to polyethylene glycol. In some embodiments, the linker comprises the structure of the following formula (L1), wherein n 1 is an integer selected from 1 to 30, n 2 is an integer selected from 2 to 10. In other embodiments, the linker group is composed of a compound of formula (L1) below, wherein n 1 is an integer selected from 2 to 20, n 2 is an integer selected from 2 to 8. In a further embodiment, the linker group is composed of a compound of formula (L1) below, wherein n 1 is an integer selected from 2 to 15, n 2 is an integer selected from 2-6.

[0062]

[0063] In another embodiment, the linker comprises a structure of Formula (L2) below, wherein n 1 is an integer selected from 1 to 30, n 2is an integer selected from 2 to 10, and n 3 is an integer selected from 1 to 10. In other embodiments, the linker group is composed of a compound of formula (L2) below, wherein n 1 is an integer selected from 2 to 20, n 2 is an integer selected from 2 to 8, and n 3 is an integer selected from 2 to 8. In a further embodiment, the linker group is composed of a compound of formula (L2) below, wherein n 1 is an integer selected from 2 to 15, n 2 is an integer selected from 2 to 6, and n 3 is an integer selected from 2-6.

[0064]

[0065] The present disclosure also includes various methods and uses involving the compounds described herein. In one aspect, the circulating half-life of the compounds described herein is enhanced by their ability to bind to serum albumin due to the long circulating nature of albumin. With respect to functional entities complexed with albumin binding compounds in various embodiments, this allows these entities to exert their effects for a longer period of time after administration, particularly where functional groups as separate entities, such as stand-alone drugs, would normally be cleared rapidly if administered alone. Thus, a method of increasing the circulating half-life of a drug may include complexing the drug with one of the compounds described herein.

[0066] Another aspect provides for incorporating these compounds into targeted complexes by combining reversible binding with albumin. That is, the composition introduced into the vascular circulation will bind to albumin in the blood until the albumin reaches the tissue expressing the target receptor, at which point the affinity of the targeting moiety for its target can cause the compound to dissociate from the albumin and concentrate at the target location. In various embodiments, the binding affinity of the targeting ligand to the corresponding target is greater than the binding affinity of any part of the compound - or in particular component X - to albumin. Therefore, a smaller dose of the functional group entity may be required to produce a specific effect compared to administering the entity alone. Therefore, in some embodiments, a method of improving the efficacy of a drug may include compounding the drug with one of the compounds described herein.

[0067] In addition, a higher conjugate uptake rate in the target can make it easier to achieve effective dosing compared to other organs, while reducing the risk of toxicity to these organs. For example, high uptake in the kidney is an important problem in radioligand therapy, because the kidney is often considered to be a dose-limiting organ in such applications. One of the important benefits that the albumin binders described herein can provide is that the tumor / non-tumor (e.g., tumor / kidney) ratio is improved compared to those without albumin binders; in contrast, some previously reported albumin binders generally result in a decrease in the tumor / non-tumor (e.g., tumor / kidney) ratio, thus giving them concerns for use in the following aspects: 1) molecular imaging, when contrast is significantly reduced by high non-tumor uptake of adjacent tissues; and 2) radioligand therapy, if the radiotoxicity to tissues with high non-tumor uptake is not very tolerable.

[0068] In some embodiments, the method of treating an individual comprises administering a therapeutically effective dose of a composition comprising an albumin binding compound complexed with a therapeutic agent described herein. In specific embodiments, the therapeutically effective dose is less than the lowest therapeutically effective dose of the drug alone. In some embodiments, the method of treating an individual comprises administering to the individual a composition comprising a targeting ligand comprising a radionuclide chelator, and measuring the level of the composition in a sample from the individual. Administration can be accomplished by any route that allows the compound to contact serum albumin. In various embodiments, the compound is administered intravenously or intramuscularly.

[0069] The compounds and compositions described herein can be prepared by methods known in the art using a number of commercially available materials. In one method, a useful intermediate can be prepared by stirring a solution of a substituted X-terminated butyric acid (1) and EDC.HCl in CH2Cl2, followed by the addition of 1-hydroxypyrrolidine-2,5-dione and triethylamine (TEA). The product can then be washed with saturated sodium chloride solution and heated to 40°C over MgSO 4 Dry on.

[0070]

[0071] Also provided herein are compounds of formula (II):

[0072]

[0073] in:

[0074] X is selected from:

[0075]

[0076]

[0077] R 1 , R2 , R 3 , R 4 , R 5 , R 8 and R 9 Each independently selected from H, F, Cl, Br, I, SF 3 , SF 2 Cl, SF 5 , SF 4 Cl, C 1 -C 6 Straight or branched alkyl, C 1 -C 6 Straight or branched fluoroalkyl groups (such as, for example, CF 3 ), C 1 -C 6 A linear or branched fluorinated alkoxy group, or a substituent selected from the following:

[0078]

[0079] R 6 and R 7 In each instance, independently selected from H and F and isotopes thereof, or combined in an oxo group;

[0080] R 10 and R 11 are independently selected in each instance from H and F, provided that, when present, at least one R 10 The group must be F;

[0081] n 1 is an integer selected from 1, 2, 3, 4, 5 and 6; and

[0082] n 2 is an integer selected from 1, 2, 3 and 4.

[0083] It will be appreciated that for each "X" group (a) to (j) in formula (II), additional independent groups of compounds are provided, as shown below. In each of formulas (IIa) to (IIj), all variables, including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 、n 1 and n 2 , are as defined for formula (II).

[0084]

[0085] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to an acetic acid chain include:

[0086] a) 2-(Difluoromethyl)-4-ethyl-5-methyl-phenylacetic acid (CAS 2387367-77-1);

[0087] b) 4-Chloro-5-(difluoromethyl)-2-fluoro-phenylacetic acid (CAS 2387364-97-6);

[0088] c) 4-Chloro-2-iodo-6-(trifluoromethyl)-phenylacetic acid (CAS 2387354-96-1);

[0089] d) 5-iodo-2-methyl-3-(trifluoromethyl)-phenylacetic acid (CAS 2387342-09-6);

[0090] e) 3-Chloro-6-(difluoromethyl)-2-iodo-phenylacetic acid (CAS 2387341-72-0);

[0091] f) 4-(Difluoromethyl)-2-ethyl-6-methyl-phenylacetic acid (CAS 2387329-36-2);

[0092] g) 2-(Difluoromethyl)-5-ethyl-4-methyl-phenylacetic acid (CAS 2387321-04-0);

[0093] h) 4-Bromo-2-methyl-5-(trifluoromethyl)-phenylacetic acid (CAS 2387305-32-8);

[0094] i) 2-(Difluoromethyl)-6-fluoro-3-methyl-phenylacetic acid (CAS 2387292-94-4);

[0095] j) 3-Chloro-4-fluoro-5-iodophenylacetic acid (CAS 2387289-42-9);

[0096] k) 3-(Difluoromethyl)-5-ethyl-2-methyl-phenylacetic acid (CAS 2387288-41-5);

[0097] 1) 3-Bromo-5-methyl-2-(trifluoromethyl)-phenylacetic acid (CAS 2387285-02-9);

[0098] m) 2-Bromo-4-fluoro-5-(trifluoromethyl)-phenylacetic acid (CAS 2387265-77-0);

[0099] n) 3-(Difluoromethyl)-5-iodo-4-methyl-phenylacetic acid (CAS 2387260-33-3);

[0100] o) 3-Chloro-2-methyl-6-(trifluoromethyl)-phenylacetic acid (CAS 2387251-00-3);

[0101] p) 4-(Difluoromethyl)-3,5-diiodo-phenylacetic acid (CAS 2387228-43-3);

[0102] q) 6-Chloro-3-iodo-2-(trifluoromethyl)-phenylacetic acid (CAS 2387213-04-7);

[0103] r) 3-Bromo-4-chloro-2-(trifluoromethyl)-phenylacetic acid (CAS 2387212-65-7);

[0104] s) 2-(Difluoromethyl)-4-iodo-5-methyl-phenylacetic acid (CAS 2387172-74-7);

[0105] t) 3-(Difluoromethyl)-2,6-dimethylphenylacetic acid (CAS 2387166-75-6);

[0106] u) 4-Fluoro-2-methyl-3-(trifluoromethyl)-phenylacetic acid (CAS 2387146-20-3);

[0107] v) 5-Fluoro-4-methyl-2-(trifluoromethyl)-phenylacetic acid (CAS 2387142-35-8);

[0108] w) 2-Fluoro-6-iodo-3-(trifluoromethyl)-phenylacetic acid (CAS 2387142-33-6);

[0109] x) 5-(Difluoromethyl)-3-ethyl-2-fluoro-phenylacetic acid (CAS 2387126-96-5);

[0110] y) 3-Fluoro-5-methyl-4-(trifluoromethyl)-phenylacetic acid (CAS 2387124-99-2);

[0111] z) 3-(Difluoromethyl)-4-ethyl-phenylacetic acid (CAS 2387118-69-4);

[0112] aa) 2-(Difluoromethyl)-5-fluoro-4-methyl-phenylacetic acid (CAS 2387117-84-0);

[0113] bb) 3-Bromo-4-fluoro-2-(trifluoromethyl)-phenylacetic acid (CAS 2387096-58-2);

[0114] cc) 2-(Difluoromethyl)-6-ethyl-phenylacetic acid (CAS 2387059-13-2);

[0115] dd) 4-(Difluoromethyl)-3-ethyl-2-fluoro-phenylacetic acid (CAS 2386958-85-4);

[0116] ee) 4-(Difluoromethyl)-2-fluoro-3-iodo-phenylacetic acid (CAS 2386902-22-1);

[0117] ff) 2-(Difluoromethyl)-3-fluoro-6-methyl-phenylacetic acid (CAS 2386897-89-6);

[0118] gg) 3-chloro-2-methyl-4-(trifluoromethyl)-phenylacetic acid (CAS 2386874-41-3);

[0119] hh) 2-(Difluoromethyl)-3-fluoro-5-methyl-phenylacetic acid (CAS 2386844-79-5);

[0120] ii) 4-(Difluoromethyl)-2-fluoro-6-methyl-phenylacetic acid (CAS 2386824-64-0);

[0121] jj) 3-Fluoro-2-methyl-6-(trifluoromethyl)-phenylacetic acid (CAS 2386725-76-2);

[0122] kk) 5-Fluoro-4-iodo-2-(trifluoromethyl)-phenylacetic acid (CAS 2386686-44-6);

[0123] 11) 2-Bromo-4-fluoro-3-(trifluoromethyl)-phenylacetic acid (CAS 2386609-80-7);

[0124] mm) 3-Fluoro-5-iodo-4-(trifluoromethyl)-phenylacetic acid (CAS 2386573-15-3);

[0125] nn) 2-(3,4-difluoro-2-(trifluoromethyl)phenyl)acetic acid (CAS 2386536-41-8);

[0126] oo) α-Fluoro-2-(trifluoromethyl)-(αR)-phenylacetic acid (CAS 2382389-60-6);

[0127] pp)(R)-2-(2,6-difluorophenyl)-2-fluoroacetic acid (CAS 2382348-82-3);

[0128] qq) α,α-difluoro-4-(1,1,2,2,2-pentafluoroethyl)-phenylacetic acid (CAS 2357382-05-7);

[0129] rr) α,α-difluoro-3-(1,1,2,2,2-pentafluoroethyl)-phenylacetic acid (CAS 2355684-72-7);

[0130] ss) α,α-Difluoro-3,5-bis(trifluoromethyl)-phenylacetic acid (CAS 2244941-42-0);

[0131] tt) α,α,2,3,6-pentafluoro-phenylacetic acid (CAS 2228911-75-7);

[0132] uu) α,α,2,4,6-pentafluoro-phenylacetic acid (CAS 2228838-88-6);

[0133] vv) α,α,5-Trifluoro-2-(trifluoromethyl)-phenylacetic acid (CAS 2228728-13-8);

[0134] ww) α,α,2-Trifluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 2228693-31-8);

[0135] xx) α,α,2-Trifluoro-3-(trifluoromethyl)-phenylacetic acid (CAS 2228669-85-8);

[0136] yy) α,α,2,3,4,5-Hexafluoro-phenylacetic acid (CAS 2228563-54-8);

[0137] zz) α,α,2,3,5,6-Hexafluoro-phenylacetic acid (CAS 2228516-64-9);

[0138] aaa) α,α,3-trifluoro-5-(trifluoromethyl)-phenylacetic acid (CAS 2228224-64-2);

[0139] bbb) 4-(Difluoromethyl)-α-fluoro-phenylacetic acid (CAS 2138522-52-6);

[0140] ccc) α,α,2-Trifluoro-5-(trifluoromethyl)-phenylacetic acid (CAS 2228136-25-0);

[0141] ddd) 3-(Difluoromethyl)-α-fluoro-phenylacetic acid (CAS 2138066-99-4);

[0142] eee) 4-(Difluoromethyl)-α,α-difluoro-phenylacetic acid (CAS 2138043-77-1);

[0143] fff) 2,5-difluoro-3-(trifluoromethyl)-phenylacetic acid (CAS 2092866-67-4);

[0144] ggg) 3,5-difluoro-2-(trifluoromethyl)-phenylacetic acid (CAS 2091889-94-8);

[0145] hhh)α,α,3-Trifluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 1925367-64-1);

[0146] iii) 4-(Cyclopropyldifluoromethyl)-phenylacetic acid (CAS 1896969-02-0);

[0147] jjj) 3-(Cyclopropyldifluoromethyl)-phenylacetic acid (CAS 1895738-57-4);

[0148] kkk)α,3,4,5-Tetrafluoro-phenylacetic acid (CAS 1880969-10-7);

[0149] lll) α,α,3,4,5-pentafluoro-phenylacetic acid (CAS 1876640-60-6);

[0150] mmm) 2,4-difluoro-6-(trifluoromethyl)-phenylacetic acid (CAS 1823551-72-9);

[0151] nnn) 2,4-difluoro-3-(trifluoromethyl)-phenylacetic acid (CAS 1823268-51-4);

[0152] ooo) 2-Fluoro-4,5-bis(trifluoromethyl)-phenylacetic acid (CAS 1807026-26-1);

[0153] ppp) 3-Fluoro-2,5-bis(trifluoromethyl)-phenylacetic acid (CAS 1807109-79-0);

[0154] qqq) 2-Fluoro-3,6-bis(trifluoromethyl)-phenylacetic acid (CAS 1806050-60-1);

[0155] rrr) 2,3-Bis(trifluoromethyl)-phenylacetic acid (CAS 1805593-32-1);

[0156] sss)3-Fluoro-2,4-bis(trifluoromethyl)-phenylacetic acid (CAS 1805584-52-4);

[0157] ttt) α-Fluoro-3-(trifluoromethyl)-phenylacetic acid (CAS 1517480-45-3);

[0158] uuu) 2,5-Bis(difluoromethyl)-phenylacetic acid (CAS 1373827-32-7);

[0159] vvv) 2,3,4,6-Tetrafluoro-phenylacetic acid (CAS 1214373-68-8);

[0160] www) 2,3,6-Trifluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 1111737-49-5);

[0161] xxx) 2,3,4,5-Tetrafluoro-6-(trifluoromethyl)-phenylacetic acid (CAS 1000553-80-9);

[0162] yyy) 4-(Difluoromethyl)-phenylacetic acid (CAS);

[0163] zzz) 2,6-difluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 1000517-21-4);

[0164] aaaa)α,2-Difluoro-phenylacetic acid (CAS 915070-97-2);

[0165] bbbb)2,3,4,5-Tetrafluoro-phenylacetic acid (CAS 261952-21-0);

[0166] cccc) 2,3,4-Trifluoro-phenylacetic acid (CAS 243666-12-8);

[0167] dddd) 2,4,6-Trifluoro-phenylacetic acid (CAS 209991-63-9);

[0168] eeee)3,4,5-Trifluoro-phenylacetic acid (CAS 209991-62-8);

[0169] ffff) 2,3,4,5,6-pentafluoro-phenylacetic acid (CAS 653-21-4);

[0170] gggg)α,α,3,5-tetrafluoro-phenylacetic acid (CAS);

[0171] hhhh)α,3,5-Trifluoro-phenylacetic acid (CAS 208259-38-5);

[0172] iiii) 3,5-difluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 132992-26-8);

[0173] jjjj)α,α,4-Trifluoro-phenylacetic acid (CAS 94010-78-3);

[0174] kkkk)α,α,2,3,4,5,6-heptafluoro-phenylacetic acid (CAS 91407-89-5);

[0175] 1111) 3,5-Bis(trifluoromethyl)-phenylacetic acid (CAS 85068-33-3);

[0176] mmmm)α,α-difluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 73790-11-1);

[0177] nnnn) α-Fluoro-4-(trifluoromethyl)-phenylacetic acid (CAS 142044-52-8);

[0178] oooo) 4-(trifluoromethyl)-phenylacetic acid (CAS 32857-62-8);

[0179] pppp) 2-(Trifluoromethyl)-phenylacetic acid (CAS 3038-48-0);

[0180] qqqq) 2,3,5,6-Tetrafluoro-phenylacetic acid (CAS 3516-91-4);

[0181] rrrr) 2-Fluoro-phenylacetic acid (CAS 451-82-1);

[0182] ssss)3-Fluoro-phenylacetic acid (CAS 331-25-9);

[0183] tttt)4-Fluoro-phenylacetic acid (CAS 405-50-5);

[0184] uuuu)2-(4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetic acid (CAS 1839048-22-4);

[0185] vvvv)2-(2-fluoro-4-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetic acid (CAS 1240257-93-5);

[0186] wwww)2-(3-fluoro-5-(pentafluoro-λ 6 -sulfaneyl)phenyl)acetic acid (CAS 1240257-84-4);

[0187] xxxx)2-(3-(pentafluoro-λ 6-sulfaneyl)phenyl)acetate (CAS 1211517-00-8);

[0188] yyyy) 4-(1-fluoroethyl)-phenylacetic acid (CAS 1785087-42-4);

[0189] zzzz) 3-Bromo-4-(1-fluoroethyl)-phenylacetic acid (CAS 1781001-75-9);

[0190] aaaaa) 2-Chloro-4-(1-fluoroethyl)-phenylacetic acid (CAS 1783534-87-1);

[0191] bbbbb) 4-(1,1,2,2-tetrafluoroethyl)-phenylacetic acid (CAS 1780654-06-9); and

[0192] ccccc)4-(1,2,2,2-tetrafluoroethyl)-phenylacetic acid (CAS 1785167-81-8).

[0193] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to a propionic acid chain include:

[0194] a) 3-(3,4,5-Trifluorophenyl)propionic acid (CAS 886499-50-9);

[0195] b) 3-(4-(Trifluoromethyl)phenyl)propanoic acid (CAS 53473-36-2);

[0196] c) (αS)-α,2,5-trifluoro-phenylpropionic acid (CAS 2382690-89-1);

[0197] d) (αS)-α,2,4-trifluoro-phenylpropionic acid (CAS 2382377-15-1);

[0198] e) (αS)-2-chloro-α,3,6-trifluoro-phenylpropionic acid (CAS 2382372-20-3);

[0199] f) (αS)-4-chloro-α,3-difluoro-phenylpropionic acid (CAS 2382266-52-4);

[0200] g) (αS)-α,3,5-trifluoro-phenylpropionic acid (CAS 2382240-10-8);

[0201] h) (αS)-α,2,3,4-tetrafluoro-phenylpropionic acid (CAS 2382071-54-5);

[0202] i) (αS)-α,3,4,5-tetrafluoro-phenylpropionic acid (CAS 2382062-71-5);

[0203] j) (S)-3-(3-chloro-5-fluorophenyl)-2-fluoropropionic acid (CAS 2381761-11-9);

[0204] k) (αS)-3-chloro-α,2-difluoro-phenylpropionic acid (CAS 2381700-00-9);

[0205] l) (αS)-α,2,3-trifluoro-phenylpropionic acid (CAS 2381635-05-6);

[0206] m)(αS)-α,2,4,5-tetrafluoro-phenylpropionic acid (CAS 2381542-70-5);

[0207] n)(αS)-α,2-difluoro-phenylpropionic acid (CAS 2381458-82-6);

[0208] o)(αS)-2-Chloro-α,6-difluoro-phenylpropionic acid (CAS 2381410-60-0);

[0209] p)(αS)-3-chloro-α,4-difluoro-phenylpropionic acid (CAS 2381098-01-5);

[0210] q) (αS)-5-chloro-α,2-difluoro-phenylpropionic acid (CAS 2380960-65-4);

[0211] r)(αS)-4-chloro-α,2-difluoro-phenylpropionic acid (CAS 2380855-42-9);

[0212] s)(αS)-α,2,6-trifluoro-phenylpropionic acid (CAS 2380596-78-9);

[0213] t)(αS)-α,3,4-trifluoro-phenylpropionic acid (CAS 2380495-55-4);

[0214] u) 2-Bromo-α,α-difluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2360368-80-3);

[0215] v) α,α,2-Trifluoro-5-iodo-phenylpropionic acid (CAS 2360274-96-8);

[0216] w) 2-Bromo-β,β-difluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2360075-86-9);

[0217] x) 2-Bromo-α,α-difluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2359201-07-1);

[0218] y) 3-(4-bromo-2-(trifluoromethyl)phenyl)-2,2-difluoropropionic acid (CAS 2359191-43-6);

[0219] z) β,β-Difluoro-4-(1,1,2,2,2-pentafluoroethyl)-phenylpropionic acid (CAS 2359001-84-4);

[0220] aa) α,α-Difluoro-3-(1,1,2,2,2-pentafluoroethyl)-phenylpropionic acid (CAS 2358735-56-3);

[0221] bb) 4-Bromo-α,α-difluoro-3-(trifluoromethyl)-phenylpropanoic acid (CAS 2358678-40-5);

[0222] cc) 3-Bromo-β,β-difluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2358114-21-1);

[0223] dd) β,β-Difluoro-3,5-bis(trifluoromethyl)-phenylpropionic acid (CAS 2357694-18-7);

[0224] ee) 3-Bromo-α,α,2,4-tetrafluoro-phenylpropionic acid (CAS 2357450-02-1);

[0225] ff) α,α,4,5-tetrafluoro-2-iodo-phenylpropionic acid (CAS 2357320-28-4);

[0226] gg) 6-Bromo-3-chloro-α,α,2-trifluoro-phenylpropionic acid (CAS 2357291-57-5);

[0227] hh) α,α-Difluoro-4-(1,1,2,2,2-pentafluoroethyl)-phenylpropionic acid (CAS 2356957-11-2);

[0228] ii) β,β-difluoro-3-iodo-5-(trifluoromethyl)-phenylpropionic acid (CAS 2356935-06-1);

[0229] jj) β,β,2-trifluoro-5-iodo-phenylpropionic acid (CAS 2356884-34-7);

[0230] kk) β,β,4-trifluoro-2-iodo-phenylpropionic acid (CAS 2356726-93-5);

[0231] 11) 2-Chloro-β,β-difluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2356702-96-8);

[0232] mm) 3-(4-bromo-2-(trifluoromethyl)phenyl)-3,3-difluoropropionic acid (CAS 2356457-27-5);

[0233] nn) 3-Bromo-α,α-difluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2356381-90-1);

[0234] oo) α,α-Difluoro-3,5-bis(trifluoromethyl)-phenylpropionic acid (CAS 2356328-30-6);

[0235] pp) 4-Bromo-β,β-difluoro-3-(trifluoromethyl)-phenylpropionic acid (CAS 2356118-99-3);

[0236] qq) 4-Bromo-β,β,2,6-tetrafluoro-phenylpropionic acid (CAS 2355932-06-6);

[0237] rr) β,β,4,5-tetrafluoro-2-iodo-phenylpropionic acid (CAS 2355877-20-0);

[0238] ss) 2-Bromo-α,α,4,5-tetrafluoro-phenylpropionic acid (CAS 2355860-44-3);

[0239] tt) 2-Chloro-α,α-difluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2355830-63-4);

[0240] uu) 2-Bromo-β,β-difluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2355530-36-6);

[0241] vv) α,α,4-Trifluoro-2-iodo-phenylpropionic acid (CAS 2354996-90-8);

[0242] ww) 2-Bromo-β,β,4,5-tetrafluoro-phenylpropionic acid (CAS 2354951-14-5);

[0243] xx) 3-Bromo-β,β,2,4-tetrafluoro-phenylpropionic acid (CAS 2354947-62-7);

[0244] yy) 6-Bromo-3-chloro-β,β,2-trifluoro-phenylpropionic acid (CAS 2354922-42-0);

[0245] zz) β,β-difluoro-3-(1,1,2,2,2-pentafluoroethyl)-phenylpropionic acid (CAS 2354790-33-1);

[0246] aaa) α,α-Difluoro-3-iodo-5-(trifluoromethyl)-phenylpropionic acid (CAS 2354788-36-4);

[0247] bbb) 4-(1,1,2,2,2-pentafluoroethyl)-phenylpropanoic acid (CAS 2354177-10-7);

[0248] ccc) 3-(1,1,2,2,2-pentafluoroethyl)-phenylpropanoic acid (CAS 2354163-50-9);

[0249] ddd)4,5-difluoro-2-iodo-phenylpropionic acid (CAS 2352673-92-6);

[0250] eee) 3-Fluoro-phenylpropionic acid (CAS 2300968-80-1, as Na salt);

[0251] fff) β,β,2-trifluoro-3-(trifluoromethyl)-phenylpropionic acid (CAS 2229622-24-4);

[0252] ggg) 3-Bromo-α,α,4-trifluoro-phenylpropionic acid (CAS 2229605-71-2);

[0253] hhh)3-Bromo-β,β,2-trifluoro-phenylpropionic acid (CAS 2229592-38-3);

[0254] iii) 3-Chloro-β,β,2-trifluoro-phenylpropionic acid (CAS 2229590-96-7);

[0255] jjj) β,β,3,5-Tetrafluoro-phenylpropionic acid (CAS 2229567-47-7);

[0256] kkk) 2-Chloro-β,β,4,5-tetrafluoro-phenylpropionic acid (CAS 2229558-44-3);

[0257] 111) 4-Chloro-β,β,2-trifluoro-phenylpropionic acid (CAS 2229546-10-3);

[0258] mmm) α,α,4-trifluoro-3-(trifluoromethyl)-phenylpropionic acid (CAS 2229533-27-9);

[0259] nnn)3-Chloro-β,β,5-trifluoro-phenylpropionic acid (CAS 2229531-21-7);

[0260] ooo)2-Chloro-α,α,4-trifluoro-phenylpropionic acid (CAS 2229519-83-7);

[0261] ppp) 2,4-dichloro-5-fluoro-phenylpropionic acid (CAS 2229501-39-5);

[0262] qqq) 4-Chloro-α,α,2,5-tetrafluoro-phenylpropionic acid (CAS 2229495-59-2);

[0263] rrr)α,α,4-Trifluoro-2-(trifluoromethyl)-phenylpropionic acid (CAS 2229485-71-4);

[0264] sss)β,β,2,3,5,6-Hexafluoro-phenylpropionic acid (CAS 2229477-47-6);

[0265] ttt)4-Bromo-β,β,3-trifluoro-phenylpropionic acid (CAS 2229456-75-9);

[0266] uuu)3-Bromo-β,β,4-trifluoro-phenylpropionic acid (CAS 2229439-59-0);

[0267] vvv) 3-Chloro-α,α,2-trifluoro-phenylpropionic acid (CAS 2229421-53-6);

[0268] www)β,β,2,3,6-pentafluoro-phenylpropionic acid (CAS 2229417-51-8);

[0269] xxx) β,β,3-Trifluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2229410-48-2);

[0270] yyy)β,β,4-trifluoro-2-(trifluoromethyl)-phenylpropionic acid (CAS 2229394-98-1);

[0271] zzz) 2-Chloro-β,β,3,6-tetrafluoro-phenylpropionic acid (CAS 2229265-32-9);

[0272] aaaa)2-Chloro-α,α-difluoro-6-(trifluoromethyl)-phenylpropionic acid (CAS 2229240-08-6);

[0273] bbbb)3-Chloro-α,α,2,6-tetrafluoro-phenylpropionic acid (CAS 2229218-62-4);

[0274] cccc) 2-Chloro-α,α,3-trifluoro-phenylpropionic acid (CAS 2229205-15-4);

[0275] dddd)α,α,2,3,4,5,6-heptafluoro-phenylpropionic acid (CAS 2229177-33-5);

[0276] eeee) 4-Chloro-α,α-difluoro-2-(trifluoromethyl)-phenylpropionic acid (CAS 2229175-23-7);

[0277] ffff)β,β,2,4,5-pentafluoro-phenylpropionic acid (CAS 2229101-31-7);

[0278] gggg) 2-Chloro-α,α,4,5-tetrafluoro-phenylpropionic acid (CAS 2229008-37-9);

[0279] hhhh)3-Bromo-β,β,5-trifluoro-phenylpropionic acid (CAS 2228975-31-1);

[0280] iiii) 2-Chloro-α,α-difluoro-5-(trifluoromethyl)-phenylpropanoic acid (CAS 2228970-45-2);

[0281] jjjj)α,α,2,4,6-pentafluoro-phenylpropionic acid (CAS 2228950-57-8);

[0282] kkkk)α,α,2,3,4,5-Hexafluoro-phenylpropionic acid (CAS 2228912-69-2);

[0283] 111) β,β,5-trifluoro-2-(trifluoromethyl)-phenylpropionic acid (CAS 2228902-90-5);

[0284] mmmm) 4-chloro-α,α-difluoro-3-(trifluoromethyl)-phenylpropanoic acid (CAS 2228900-61-4);

[0285] nnnn) 2,6-Bis(trifluoromethyl)-phenylpropionic acid (CAS 1806540-97-5);

[0286] oooo)α,α,2-trifluoro-3-(trifluoromethyl)-phenylpropionic acid (CAS 2228840-45-5);

[0287] pppp) 2-Chloro-β,β,3-trifluoro-phenylpropionic acid (CAS 2228838-55-7);

[0288] qqqq)β,β,2-trifluoro-5-(trifluoromethyl)-phenylpropionic acid (CAS 2228834-61-3);

[0289] rrrr)4-Bromo-β,β,2-trifluoro-phenylpropionic acid (CAS 2228810-79-3);

[0290] ssss)β,β,2,3,4,5,6-heptafluoro-phenylpropionic acid (CAS 2228770-72-5);

[0291] tttt)β,β,2,3,4-pentafluoro-phenylpropionic acid (CAS 2228761-28-0);

[0292] uuuu)α,α,2,3,6-pentafluoro-phenylpropionic acid (CAS 2228740-39-2);

[0293] vvvv) α,α,2-Trifluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2228301-97-9);

[0294] wwww) β,β,2-trifluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2228306-35-0);

[0295] xxxx)α,α,3-trifluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2228226-24-0);

[0296] yyyy)2-(Trifluoromethyl)-phenylpropionic acid (CAS 94022-99-8);

[0297] zzzz) 3,4-Bis(trifluoromethyl)-phenylpropionic acid (CAS 1421281-58-4);

[0298] aaaaa)2,4-Bis(trifluoromethyl)-phenylpropionic acid (CAS 1092460-63-3);

[0299] bbbbb) 2,5-Bis(trifluoromethyl)-phenylpropionic acid (CAS 302912-03-4);

[0300] ccccc) 2-(Difluoromethyl)-6-(trifluoromethyl)-phenylpropanoic acid (CAS 1261606-03-4);

[0301] ddddd) 3-(difluoromethyl)-2-(trifluoromethyl)-phenylpropanoic acid (CAS 1261878-33-4);

[0302] eeeee) 4-(difluoromethyl)-2-(trifluoromethyl)-phenylpropanoic acid (CAS 1261677-41-1);

[0303] fffff) 5-(difluoromethyl)-2-(trifluoromethyl)-phenylpropanoic acid (CAS 1261617-95-1);

[0304] ggggg) 2-(difluoromethyl)-6-(trifluoromethyl)-phenylpropanoic acid (CAS 1261606-03-4);

[0305] hhhhh)4-Chloro-β,β-difluoro-3-(trifluoromethyl)-phenylpropionic acid (CAS 2228731-08-4);

[0306] iiiii) 3-Chloro-β,β-difluoro-4-(trifluoromethyl)-phenylpropionic acid (CAS 2228729-67-5);

[0307] jjjjj)(S)-4-(1-Fluoroethyl)-phenylpropanoic acid (CAS 162327-95-9);

[0308] kkkkk)4-(1-fluoroethyl)-phenylpropanoic acid (CAS 1780941-12-9);

[0309] 1111) 3-bromo-4-(1-fluoroethyl)-phenylpropanoic acid (CAS 1784269-24-4);

[0310] mmmmm) 2-chloro-4-(1-fluoroethyl)-phenylpropanoic acid (CAS 1782851-21-1);

[0311] nnnnn) 4-(1,1,2,2-tetrafluoroethyl)-phenylpropanoic acid (CAS 1781489-51-7); and

[0312] ooooo)4-(1,2,2,2-tetrafluoroethyl)-phenylpropanoic acid (CAS 1785140-35-3).

[0313] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to a butyric acid chain include:

[0314] a) 4-(2,4,5-trifluorophenyl)butanoic acid (CAS 1258638-46-8);

[0315] b) 4-(4-bromo-2,3-difluorophenyl)butanoic acid (CAS 1891704-35-0);

[0316] c) 4-(3-bromo-2,4-difluorophenyl)butanoic acid (CAS 1898360-11-6);

[0317] d) 4-(3,5-difluoro-2-methylphenyl)butanoic acid (CAS 1895515-05-5);

[0318] e) 4-(4-bromo-2,5-difluorophenyl)butanoic acid (CAS 1343072-28-5);

[0319] f) 4-(2,3,5-trifluorophenyl)butanoic acid (CAS 1892694-42-6);

[0320] g) 4-(2,3,6-Trifluorophenyl)butanoic acid (CAS 1895584-02-7);

[0321] h) 4-(2,4-difluoro-3-methylphenyl)butanoic acid (CAS 1895503-43-1);

[0322] i) 4-(2,4,6-Trifluorophenyl)butanoic acid (CAS 1042558-67-7);

[0323] j) 4-(2,3,4,5-tetrafluorophenyl)butanoic acid (CAS 1866658-81-2);

[0324] k) 4-(2,3-difluoro-5-isopropylphenyl)butanoic acid (CAS 1891501-56-6);

[0325] 1) 4-(2,6-difluoro-4-methylphenyl)butanoic acid (CAS 2228602-62-6);

[0326] m) 4-(2,3,5,6-tetrafluorophenyl)butanoic acid (CAS 1852009-46-1);

[0327] n) 4-(4-chloro-2,6-difluorophenyl)butanoic acid (CAS 1891481-94-9);

[0328] o) 4-(4-bromo-2,6-difluorophenyl)butanoic acid (CAS 1891821-67-2);

[0329] p) 4-(3,4-difluoro-5-methylphenyl)butanoic acid (CAS 1891439-79-4);

[0330] q) 4-(Perfluorophenyl)butanoic acid (CAS 1892073-55-0);

[0331] r) 4-(3,5-difluoro-4-methylphenyl)butanoic acid (CAS 1895437-98-5);

[0332] s) 4-(4-chloro-2,3,5,6-tetrafluorophenyl)butanoic acid (CAS 1892694-54-0);

[0333] t) 4-(4-bromo-2,3,5,6-tetrafluorophenyl)butanoic acid (CAS 1892860-77-3);

[0334] u) 4-(2,5-difluoro-4-methylphenyl)butanoic acid (CAS 1515548-81-8);

[0335] v) 4-(2-(Trifluoromethyl)phenyl)butanoic acid (CAS 899350-21-1);

[0336] w) 4-(4-(1,1-difluoroethyl)phenyl)butanoic acid (CAS 1892107-54-8);

[0337] x) 4-(4-(2,2-difluoroethyl)phenyl)butanoic acid (CAS 1891678-12-8);

[0338] y) 4-(4-(1,1-difluoropropyl)phenyl)butanoic acid (CAS 1893756-51-8);

[0339] z) 4-(4-(2,2,2-trifluoroethyl)phenyl)butanoic acid (CAS 1898423-39-6);

[0340] aa) 4-(6-(Trifluoromethyl)pyridin-3-yl)butanoic acid (CAS 1100766-80-0);

[0341] bb) 4-(5-(Trifluoromethyl)pyridin-2-yl)butanoic acid (CAS 1100766-65-1);

[0342] cc) 4-(3,4,5-trifluorophenyl)butanoic acid (CAS 1410187-01-7);

[0343] dd) 4-(2,3,4-trifluorophenyl)butanoic acid (CAS 1368465-86-4);

[0344] ee) 4-(3-(Fluoromethyl)phenyl)butanoic acid (CAS 1895587-73-1);

[0345] ff) 4-(4-(Fluoromethyl)phenyl)butanoic acid (CAS 1896663-99-2);

[0346] gg) 4-(4-(difluoromethyl)phenyl)butanoic acid (CAS 1549717-55-6);

[0347] hh) 4-(3-(1,1-difluoroethyl)phenyl)butanoic acid (CAS 1897047-82-3);

[0348] ii) 4-(2-(1,1-difluoroethyl)phenyl)butanoic acid (CAS 1898215-71-8);

[0349] jj) 4-(2-(Fluoromethyl)phenyl)butanoic acid (CAS 1891284-26-6);

[0350] kk) 4-(5-(1,1-difluoroethyl)-2-fluorophenyl)butanoic acid (CAS 1891846-74-7);

[0351] 11) 4-(2-(difluoromethyl)phenyl)butanoic acid (CAS 1891439-80-7);

[0352] mm) 4-(3-(difluoromethyl)phenyl)butanoic acid (CAS 1550251-61-0);

[0353] nn) 4-(2-(difluoromethyl)-3-fluorophenyl)butanoic acid (CAS 1891478-59-3);

[0354] oo) 4-(5-(difluoromethyl)-2,3-difluorophenyl)butanoic acid (CAS 1892029-96-7);

[0355] pp) 4-(5-(difluoromethyl)-2-fluorophenyl)butanoic acid (CAS 1898306-94-9);

[0356] qq) 4-(4-(difluoromethyl)-3-fluorophenyl)butanoic acid (CAS 1897322-37-0);

[0357] rr) 4-(3-(Trifluoromethyl)phenyl)butanoic acid (CAS 145485-43-4);

[0358] ss) 4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid (CAS 1892030-00-0);

[0359] tt) 4-(3-Fluoro-4-(trifluoromethyl)phenyl)butanoic acid (CAS 2353584-26-4);

[0360] uu) 4-(2-fluoro-3-(trifluoromethyl)phenyl)butanoic acid (CAS 1898256-64-8);

[0361] vv) 4-(3,5-bis(trifluoromethyl)phenyl)butanoic acid (CAS 184970-19-2);

[0362] ww) 4-(3-Fluoro-5-(trifluoromethyl)phenyl)butanoic acid (CAS 1558540-24-1);

[0363] xx) 4-(4-Fluoro-3-(trifluoromethyl)phenyl)butanoic acid (CAS 1552828-44-0);

[0364] yy) 4-(2-Fluoro-5-(trifluoromethyl)phenyl)butanoic acid (CAS 1538963-44-8);

[0365] zz) 4-(3-fluoro-2-(trifluoromethyl)phenyl)butanoic acid (CAS 1892036-09-7);

[0366] aaa) 4-(5-fluoro-2-(trifluoromethyl)phenyl)butanoic acid (CAS 2353998-39-5);

[0367] bbb) 4-(2-fluoro-6-(trifluoromethyl)phenyl)butanoic acid (CAS 1520160-59-1);

[0368] ccc) 4-(4-fluoro-2-(trifluoromethyl)phenyl)butanoic acid (CAS 1518823-88-5);

[0369] ddd) 4-(4-(1,1-difluoro-2-methylpropyl)phenyl)butanoic acid (CAS 1896965-12-0);

[0370] eee) 4-(3-(1,1-difluoro-2-methylpropyl)phenyl)butanoic acid (CAS 1895736-10-3);

[0371] fff) 4-(3-(1,1-difluorobutyl)phenyl)butanoic acid (CAS 1894439-30-5);

[0372] ggg) 4-(4-(cyclopropyldifluoromethyl)phenyl)butanoic acid (CAS 1893758-75-2);

[0373] hhh) 4-(3-(1,1-difluoropropyl)phenyl)butanoic acid (CAS 1893752-08-3);

[0374] iii) 4-(4-(1,1-difluorobutyl)phenyl)butanoic acid (CAS 1892501-36-8);

[0375] jjj) 4-(4-(2,2-difluoropropyl)phenyl)butanoic acid (CAS);

[0376] kkk) 4-(3-(2,2-difluoropropyl)phenyl)butanoic acid (CAS 1898074-87-4);

[0377] lll)(CAS);

[0378] mmm) 4-(3-(cyclopropyldifluoromethyl)phenyl)butanoic acid (CAS 1892502-75-8);

[0379] nnn) 4-(3-(2-fluoroethyl)phenyl)butanoic acid (CAS 1895492-10-0);

[0380] ooo) 4-(4-(perfluoroethyl)phenyl)butanoic acid (CAS 235997-34-1);

[0381] ppp) 4-(3-(perfluoroethyl)phenyl)butanoic acid (CAS 2359485-05-3);

[0382] qqq) 4-(4-(2,2,2-trifluoroethyl)phenyl)butanoic acid (CAS 1897395-89-9);

[0383] rrr) 4-(3-(2,2-difluoroethyl)phenyl)butanoic acid (CAS 1897137-40-4);

[0384] sss)4-(2-(2,2-difluoroethyl)phenyl)butanoic acid (CAS 1898129-58-2);

[0385] ttt) 4-(2-(2-fluoropropyl)phenyl)butanoic acid (CAS 1897883-67-8);

[0386] uuu)4-(2-(2,2-difluoropropyl)phenyl)butanoic acid (CAS 1891501-64-6);

[0387] vvv) 4-(2-(2-fluoro-2-methylpropyl)phenyl)butanoic acid (CAS 1897177-32-0);

[0388] www)4-(3-(1,1-difluoro-2-methylpropyl)phenyl)butanoic acid (CAS 1895736-10-3);

[0389] xxx) 4-(3-(2-fluoropropyl)phenyl)butanoic acid (CAS 1891542-35-0);

[0390] yyy)4-(4-(2-fluoroethyl)phenyl)butanoic acid (CAS);

[0391] zzz) 4-(4-(3-fluoropropyl)phenyl)butanoic acid (CAS 1898181-97-9);

[0392] aaaa)4-(4-(3,3-difluoropropyl)phenyl)butanoic acid (CAS 1898047-82-9);

[0393] bbbb)4-(4-(1,1,1,3,3,3-hexafluoroprop-2-yl)phenyl)butanoic acid (CAS 1898342-32-9);

[0394] cccc) 2-Chloro-4-(1-fluoroethyl)-phenylbutyric acid (CAS 1898404-80-2);

[0395] dddd)3-Bromo-4-(1-fluoroethyl)-phenylbutyric acid (CAS 1892251-33-0)

[0396] eeee) 4-(1-fluoroethyl)-phenylbutyric acid (CAS 1895445-18-7);

[0397] ffff) 5-(1,1,-difluoroethyl)-2-fluoro-phenylbutyric acid (CAS 1891846-74-4); and

[0398] gggg) 4-(4-(perfluoropropyl)phenyl)butanoic acid (CAS 1802226-54-5).

[0399] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to a valeric acid chain include:

[0400] a) 5-(2,4-difluorophenyl)pentanoic acid (CAS 1258638-46-8);

[0401] b) 5-(2,4,5-trifluorophenyl)pentanoic acid (CAS 1258638-06-0);

[0402] c) β,β,4-trifluoro-phenylvaleric acid (CAS 2357850-48-5);

[0403] d) 2,3,4-Trifluoro-phenylvaleric acid (CAS 2144094-39-1);

[0404] e) 2,4,6-Trifluoro-phenylvaleric acid (CAS 1039855-30-5);

[0405] f) 3-Bromo-2,4-difluoro-phenylvaleric acid (CAS 2411288-48-5);

[0406] g) 2-Chloro-3,6-difluoro-phenylvaleric acid (CAS 2160835-66-3);

[0407] h) 4-Chloro-2-fluoro-phenylvaleric acid (CAS 2029859-36-5);

[0408] i) 2-Bromo-6-fluoro-phenylvaleric acid (CAS 2029732-19-0);

[0409] j) 3-Bromo-5-fluoro-phenylvaleric acid (CAS 2025200-26-2);

[0410] k) 4-Chloro-3-fluoro-phenylvaleric acid (CAS 2024866-57-5);

[0411] 1) 2-Bromo-4-fluoro-phenylvaleric acid (CAS 2023507-80-2);

[0412] m) 2-Chloro-6-fluoro-phenylvaleric acid (CAS 2023189-02-6);

[0413] n) 3-Chloro-2-fluoro-phenylvaleric acid (CAS 2008328-45-6);

[0414] o) 6-Bromo-2,3,4-trifluoro-phenylvaleric acid (CAS 2007899-85-4);

[0415] p) 4-Bromo-2-fluoro-phenylvaleric acid (CAS 2006819-16-3);

[0416] q) 2-Bromo-5-fluoro-phenylvaleric acid (CAS 2006572-85-4);

[0417] r) 3-Bromo-2-fluoro-phenylvaleric acid (CAS 2005192-30-1);

[0418] s) 2-Bromo-3-fluoro-phenylvaleric acid (CAS 2002079-21-0);

[0419] t) 3-Chloro-2,4-difluoro-phenylvaleric acid (CAS 2001965-75-7);

[0420] u) 3-Chloro-2-fluoro-phenylvaleric acid (CAS 2008328-45-6);

[0421] v) 6-Bromo-2,3,4-trifluoro-phenylvaleric acid (CAS 2007899-85-4);

[0422] w) 4-Bromo-2-fluoro-phenylvaleric acid (CAS 2006819-16-3);

[0423] x) 3-Chloro-2,4-difluoro-phenylvaleric acid (CAS 2001965-75-7);

[0424] y) 2-(Trifluoromethyl)-phenylvaleric acid (CAS 1996894-39-3);

[0425] z) 3-(Trifluoromethyl)-phenylvaleric acid (CAS 1893536-03-2);

[0426] aa) 2,3,5,6-Tetrafluoro-phenylvaleric acid (CAS 1994599-71-1);

[0427] bb) 2,3,4,5-Tetrafluoro-phenylvaleric acid (CAS 1994555-37-1);

[0428] cc) 3-Fluoro-5-(trifluoromethyl)-phenylvaleric acid (CAS 1989842-02-5);

[0429] dd) 4-Fluoro-2-(trifluoromethyl)-phenylvaleric acid (CAS 1984096-41-4);

[0430] ee) 4-Bromo-5-chloro-δ,δ,2-trifluoro-phenylvaleric acid (CAS 1981499-72-2);

[0431] ff) δ,δ,3,4-tetrafluoro-phenylvaleric acid (CAS 1039856-91-1);

[0432] gg)δ,δ,2,4-tetrafluoro-phenylvaleric acid (CAS 1039856-69-3);

[0433] hh)δ,δ,2,5-Tetrafluoro-phenylvaleric acid (CAS 1039330-44-3);

[0434] ii) δ,δ,2,4,5-pentafluoro-phenylvaleric acid (CAS 1977193-72-8);

[0435] jj)δ,δ,2,4,6-pentafluoro-phenylvaleric acid (CAS 1039330-93-2);

[0436] kk) 2-Chloro-δ,δ,4,5-tetrafluoro-phenylvaleric acid (CAS 1929988-13-5);

[0437] 11) 3,5-difluoro-phenylvaleric acid (CAS 1700328-22-8);

[0438] mm) 2,4-difluoro-phenylvaleric acid (CAS 1039879-09-8);

[0439] nn) 3-(Difluoromethyl)-phenylvaleric acid (CAS 1691674-64-2);

[0440] oo) 4-(Difluoromethyl)-phenylvaleric acid (CAS 1698364-72-5);

[0441] pp) 2,6-difluoro-phenylvaleric acid (CAS 1696909-67-7);

[0442] qq) 2,3-Difluoro-phenylvaleric acid (CAS 1696342-68-3);

[0443] rr) 3,4-Difluoro-phenylvaleric acid (CAS 1037156-75-4);

[0444] ss) 2,5-difluoro-phenylvaleric acid (CAS 944950-25-8);

[0445] tt)3,4,5-Trifluoro-phenylvaleric acid (CAS 1695388-51-2);

[0446] uu) 2,4,5-trifluoro-phenylvaleric acid (benenepentanoic acid) (CAS 1258638-06-0);

[0447] vv) 2-Fluoro-phenylvaleric acid (CAS 1536031-77-2);

[0448] ww) 3-Fluoro-phenylvaleric acid (CAS 1057601-93-0);

[0449] xx) 4-Fluoro-phenylvaleric acid (CAS 24484-22-8);

[0450] yy)α,α,4-trifluoro-phenylvaleric acid (CAS 1356339-18-8);

[0451] zz) δ,δ,4-trifluoro-phenylvaleric acid (CAS 1038713-64-2); and

[0452] aaa)4-Bromo-2,5-difluoro-phenylvaleric acid (CAS 1339229-25-2).

[0453] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to a hexanoic acid chain include:

[0454] a) 6-(2,4,6-Trifluorophenyl)hexanoic acid (CAS 1153515-36-6);

[0455] b) 6,6-difluoro-6-(2,4,6-trifluorophenyl)hexanoic acid (CAS 1153517-46-4);

[0456] c) 6-(2,4,5-Trifluorophenyl)hexanoic acid (CAS 1258639-02-9);

[0457] d) ε,ε,2,4,5-pentafluoro-phenylhexanoic acid (CAS 19790006-75-1);

[0458] e) ε,ε,2,4-Tetrafluoro-phenylhexanoic acid (CAS 1156762-08-1);

[0459] f) ε,ε,3,4-Tetrafluoro-phenylhexanoic acid (CAS 1153517-35-1);

[0460] g) ε,ε,4-trifluoro-phenylhexanoic acid (CAS 1153517-16-8);

[0461] h) 6-(2,5-difluorophenyl)-6,6-difluorohexanoic acid (CAS 1153517-04-4);

[0462] i) 6-(2,4-difluorophenyl)hexanoic acid (CAS 1153515-11-7);

[0463] j) 6-(2,5-difluorophenyl)hexanoic acid (CAS 1153515-04-8);

[0464] k) 6-(3-Fluorophenyl)hexanoic acid (CAS 1057602-73-9);

[0465] 1) 6-(2,4,5-trifluorophenyl)hexanoic acid (CAS 12158639-02-9);

[0466] m) 6-(2-Fluorophenyl)hexanoic acid (CAS 1225502-16-8);

[0467] n) 4-(Trifluoromethyl)-phenylhexanoic acid (CAS 2169947-24-2);

[0468] o) 2,3,5,6-Tetrafluoro-phenylhexanoic acid (CAS 2064073-04-5);

[0469] p) 3,4-Difluoro-phenylhexanoic acid (CAS 1156768-39-6);

[0470] q) 4-Fluoro-phenylhexanoic acid (CAS 89326-72-7);

[0471] r) 3-(Trifluoromethyl)-phenylhexanoic acid (CAS 79023-02-2);

[0472] s) ε,ε-Difluoro-3-(trifluoromethyl)-phenylhexanoic acid (CAS 2170123-91-6);

[0473] t) 3-Chloro-2,4-difluoro-phenylhexanoic acid (CAS 2020718-25-4);

[0474] u) 2-Chloro-ε,ε,4,5-tetrafluoro-phenylhexanoic acid (CAS 1989914-46-6);

[0475] v) 4-Bromo-5-chloro-ε,ε,2-trifluoro-phenylhexanoic acid (CAS 1981357-46-3);

[0476] w) 4-bromo-5-chloro-2-fluoro-phenylhexanoic acid (CAS 19871357-10-1);

[0477] x) 2-Chloro-4,5-difluoro-phenylhexanoic acid (CAS 1962264-44-3);

[0478] y) 5-Chloro-2-fluoro-phenylhexanoic acid (CAS 1906779-22-3);

[0479] z) 3-Chloro-4-fluoro-phenylhexanoic acid (CAS 1907932-50-6);

[0480] aa)ε,4-Difluoro-phenylhexanoic acid (CAS 1823137-23-0);

[0481] bb) 4-Bromo-3-fluoro-phenylhexanoic acid (CAS 1531588-20-1);

[0482] cc) 3-Bromo-4-fluoro-phenylhexanoic acid (CAS 1516951-41-9);

[0483] dd) 3-Bromo-ε,ε,4-trifluoro-phenylhexanoic acid (CAS 1508153-39-6);

[0484] ee) 4-Bromo-ε,ε,2,5-tetrafluoro-phenylhexanoic acid (CAS 1409276-16-9);

[0485] ff) 4-Bromo-ε,ε,2,5-tetrafluoro-phenylhexanoic acid (CAS 1409276-16-9);

[0486] gg) 4-bromo-2,5-difluoro-phenylhexanoic acid (CAS 1408847-17-5);

[0487] hh) 2-Chloro-6-fluoro-phenylhexanoic acid (CAS 1225733-49-2); and

[0488] ii) 2,5-Difluoro-phenylhexanoic acid (CAS 1153515-04-8).

[0489] Non-limiting examples of starting materials where X is a substituted benzene ring bonded to a heptanoic acid chain include:

[0490] a) 2,3,5,6-Tetrafluoro-phenylheptanoic acid (CAS 2064073-07-8);

[0491] b) 2,4,5-Trifluoro-phenylheptanoic acid (CAS 1258639-12-1);

[0492] c) 2,4-Difluoro-phenylheptanoic acid (CAS 1258638-05-9);

[0493] d) 4-(Trifluoromethyl)-phenylheptanoic acid (CAS 952068-28-9); and

[0494] e) 4-Fluoro-phenylheptanoic acid (CAS 952068-26-7).

[0495] Non-limiting examples of starting materials where X is a substituted 2-pyridine ring include:

[0496] a) 3-Bromo-5-fluoro-2-pyridinebutyric acid (CAS 2385313-06-2);

[0497] b) α,α,6-trifluoro-2-pyridinepropionic acid (CAS 2360067-10-1);

[0498] c) 3-(Trifluoromethyl)-2-pyridinebutanoic acid (CAS 2360067-10-1);

[0499] d) 3-(Trifluoromethyl)-2-pyridinebutanoic acid (CAS 2359525-21-4);

[0500] e) β,β,6-trifluoro-2-pyridinepropionic acid (CAS 2358658-27-0);

[0501] f) 6-Fluoro-2-pyridinebutyric acid (CAS 2358175-76-3);

[0502] g) 5-bromo-3-fluoro-2-pyridinebutyric acid (CAS 2358090-86-3);

[0503] h) 5-Bromo-β,β,3-trifluoro-2-pyridinepropionic acid (CAS 2356556-99-3);

[0504] i) 5-Bromo-α,α,3-trifluoro-2-pyridinepropionic acid (CAS 2354910-41-9);

[0505] j) 5-(Difluoromethyl)-2-pyridinepropionic acid (CAS 2303431-79-8);

[0506] k) 5-Fluoro-2-pyridine valeric acid (CAS 2273487-21-9);

[0507] l) 5-Fluoro-2-pyridinepropionic acid, (CAS 2248336-33-4);

[0508] m) β,β,5-trifluoro-2-pyridinepropionic acid, (CAS 2229635-34-9);

[0509] n) 3-Fluoro-2-pyridinebutyric acid (CAS 2229605-83-6);

[0510] o) β,β-difluoro-3-(trifluoromethyl)-2-pyridinepropionic acid, (CAS 2229397-33-3);

[0511] p) α,α,5-trifluoro-2-pyridinepropionic acid (CAS 2229233-71-8);

[0512] q) β,β-difluoro-5-(trifluoromethyl)-2-pyridinepropionic acid, (CAS 2228930-65-0);

[0513] r) β,β,3-trifluoro-2-pyridinepropionic acid (CAS 2228872-67-9);

[0514] s) α,α,3-trifluoro-2-pyridinepropionic acid (CAS 2228831-51-2);

[0515] t) α,α-difluoro-3-2-pyridinepropionic acid (CAS 2228812-00-6);

[0516] u) β,β,4-trifluoro-2-pyridinepropionic acid (CAS 2228760-72-1);

[0517] v) α,α-difluoro-5-(trifluoromethyl)-2-pyridinepropionic acid (CAS 2228522-65-2);

[0518] w) α,α,4-trifluoro-2-pyridinepropionic acid (CAS 2228425-13-4);

[0519] x) α,5-difluoro-2-pyridinepropionic acid (CAS 2142211-84-3);

[0520] y) 6-Fluoro-2-pyridinepropionic acid (CAS 1934919-89-7);

[0521] z) 3-(Trifluoromethyl)-2-pyridinepropionic acid (CAS 1897547-47-5);

[0522] aa) 4-Fluoro-2-pyridinepropionic acid (CAS 1823931-38-9);

[0523] bb) 3-(Difluoromethyl)-2-pyridinepropionic acid (CAS 1785088-10-9);

[0524] cc) 4-(Difluoromethyl)-2-pyridinepropionic acid (CAS 1783679-85-5);

[0525] dd) 5-fluoro-2-pyridinepropionic acid (CAS 1783569-44-7); and

[0526] ee) 6-(Difluoromethyl)-2-pyridinepropionic acid (CAS 1783372-30-4).

[0527] Non-limiting examples of starting materials where X is a substituted 3-pyridine ring include:

[0528] a) 2-Chloro-5-3-pyridinebutyric acid (CAS 2360168-32-5);

[0529] b) 4-Chloro-2-fluoro-3-pyridinebutyric acid (CAS 2359188-55-7);

[0530] c) 6-chloro-2-3-pyridinebutyric acid (CAS 2358933-74-9);

[0531] d) 2,6-Dichloro-5-fluoro-3-pyridinebutyric acid (CAS 2358239-44-6);

[0532] e) 2-Chloro-5-fluoro-3-pyridinebutyric acid (CAS 2358222-55-4);

[0533] f) 4-(Trifluoromethyl)-3-pyridinebutanoic acid (CAS 2358080-05-2);

[0534] g) 2-(Trifluoromethyl)-3-pyridinebutanoic acid (CAS 2357391-49-0);

[0535] h) 6-Chloro-α,α-difluoro-2-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2356427-68-2);

[0536] i) 6-Chloro-β,β-difluoro-2-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2355146-27-7);

[0537] j) 4-Chloro-2-fluoro-3-pyridinepropionic acid (CAS 2355123-00-9);

[0538] k) 6-chloro-2-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2354044-83-8);

[0539] 1) 2-Chloro-5-fluoro-3-pyridinepropionic acid (CAS 2353114-96-0);

[0540] m) 4-Chloro-α,α,2-3-pyridinepropionic acid (CAS 2229566-01-0);

[0541] n) β,β-Difluoro-2-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2229452-64-4);

[0542] o) 4-Chloro-β,β,2-trifluoro-3-pyridinepropionic acid (CAS 2229401-19-6);

[0543] p) 5-Bromo-2-fluoro-3-pyridinepropionic acid (CAS 2229368-01-6);

[0544] q) α,α-Difluoro-2-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2229345-18-8);

[0545] r) 2,6-Dichloro-5-fluoro-3-pyridinepropionic acid (CAS 2229326-16-1);

[0546] s) α,α-difluoro-4-3-pyridinepropionic acid (CAS 2229303-01-7);

[0547] t) α,α,2-trifluoro-3-pyridinepropionic acid (CAS 2229268-68-0);

[0548] u) 5-bromo-2-fluoro-3-pyridinebutyric acid (CAS 2229227-20-5);

[0549] v) α,α-Difluoro-6-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2229172-52-3);

[0550] w) 6-Fluoro-3-pyridinebutyric acid (CAS 2229160-24-9);

[0551] x) 2-Chloro-α,α,5-trifluoro-3-pyridinepropionic acid (CAS 2229092-66-2);

[0552] y) 2-Chloro-β,β,5-trifluoro-3-pyridinepropionic acid (CAS 2228999-30-0);

[0553] z) 2-Chloro-β,β-difluoro-5-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2228828-92-8);

[0554] aa) 2-Chloro-α,α-difluoro-5-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2228828-83-7);

[0555] bb) 2-chloro-5-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2228811-25-2);

[0556] cc) 5-chloro-β,β,2-trifluoro-3-pyridinepropionic acid (CAS 2228808-58-8);

[0557] dd) 2,6-dichloro-α,α,5-trifluoro-3-pyridinepropionic acid (CAS 2228806-06-0);

[0558] ee) β,β-difluoro-4-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2228790-91-6);

[0559] ff) β,β,5-trifluoro-3-pyridinepropionic acid (CAS 2228687-01-0);

[0560] gg) 2-Fluoro-3-pyridinebutyric acid (CAS 2228678-28-0);

[0561] hh) 2,6-dichloro-β,β,5-trifluoro-3-pyridinepropionic acid (CAS 2228593-37-9);

[0562] ii) β,β,6-trifluoro-3-pyridinepropionic acid (CAS 2228592-54-7);

[0563] jj) β,β,2-trifluoro-3-pyridinepropionic acid (CAS 2228582-84-9);

[0564] kk) α,α,6-trifluoro-3-pyridinepropionic acid (CAS 2228582-17-8);

[0565] 11) β,β-difluoro-6-(trifluoromethyl)-3-pyridinepropionic acid (CAS 2228535-87-1);

[0566] mm) 5-chloro-α,α,2-trifluoro-3-pyridinepropionic acid (CAS 2228534-97-0);

[0567] nn) 5-chloro-2-fluoro-3-pyridinepropionic acid (CAS 2228520-72-5);

[0568] oo) 5-bromo-α,α,2-trifluoro-3-pyridinepropionic acid (CAS 2228480-20-2);

[0569] pp) 5-bromo-β,β,2-trifluoro-3-pyridinepropionic acid (CAS 2228475-66-7);

[0570] qq) 5-chloro-2-fluoro-3-pyridinebutyric acid (CAS 2228402-79-5);

[0571] rr) 2-(Trifluoromethyl)-3-pyridinepropionic acid (CAS 2142222-23-7);

[0572] ss) α,α,5-trifluoro-3-pyridinepropionic acid (CAS 2138272-98-5);

[0573] tt) 5-(Difluoromethyl)-3-pyridinepropionic acid (CAS 1785567-84-1);

[0574] uu) 6-(Difluoromethyl)-3-pyridinepropionic acid (CAS 1784836-51-6);

[0575] vv) 2-(Difluoromethyl)-3-pyridinepropionic acid (CAS 1780289-79-3);

[0576] ww) 4-(Trifluoromethyl)-3-pyridinepropionic acid (CAS 1603111-54-1);

[0577] xx) 5-Fluoro-3-pyridinebutyric acid (CAS 1198074-59-7);

[0578] yy) 6-(Trifluoromethyl)-3-pyridinebutanoic acid (CAS 1100766-80-0);

[0579] zz) 6-Fluoro-3-pyridinepropionic acid (CAS 944998-15-6);

[0580] aaa) 5-(Trifluoromethyl)-3-pyridinepropionic acid (CAS 915030-12-5);

[0581] bbb) 6-(trifluoromethyl)-3-pyridinepropionic acid (CAS 539855-70-4); and

[0582] ccc)5-Fluoro-3-pyridinepropionic acid (CAS 22620-28-6).

[0583] Non-limiting examples of starting materials where X is a substituted 4-pyridine ring include:

[0584] a) α-3,5-trifluoro-4-pyridinepropionic acid (CAS 2380978-27-6);

[0585] b) α,α,2-trifluoro-4-pyridinepropionic acid (CAS 2360119-15-7);

[0586] c) β,β,2-trifluoro-4-pyridinepropionic acid (CAS 2359059-42-8);

[0587] d) 2,3-Difluoro-4-pyridinebutyric acid (CAS 2358586-78-2);

[0588] e) β,β,2,3-tetrafluoro-4-pyridinepropionic acid (CAS 2358473-56-8);

[0589] f) 3-(Trifluoromethyl)-4-pyridinebutanoic acid (CAS 2357880-42-1);

[0590] g) α,α,2,3-tetrafluoro-4-pyridinepropionic acid (CAS 2355001-55-5);

[0591] h) 2-Fluoro-4-pyridinebutyric acid (CAS 2354443-11-9);

[0592] i) 2,3-Difluoro-4-pyridinepropionic acid (CAS 2354302-13-7);

[0593] j) 2-Fluoro-4-pyridinepropionic acid (CAS 2352744-10-4);

[0594] k) 3,5-difluoro-4-pyridine valeric acid (CAS 2285017-33-4);

[0595] 1) 3-Fluoro-4-pyridine hexanoic acid (CAS 2229808-55-1);

[0596] m) β,β,3,5-tetrafluoro-4-pyridinepropionic acid (CAS 2229498-88-6);

[0597] n) α,α-Difluoro-3-(trifluoromethyl)-4-pyridinepropionic acid (CAS 2229097-30-5);

[0598] o) β,β,3-trifluoro-4-pyridinepropionic acid (CAS 2228730-46-7);

[0599] p) β,β-Difluoro-3-(trifluoromethyl)-4-pyridinepropionic acid (CAS 2228606-55-9);

[0600] q) 3,5-difluoro-4-pyridinebutyric acid (CAS 2228325-44-6);

[0601] r) 3-Fluoro-4-pyridinebutyric acid (CAS 2228162-89-6);

[0602] s) α,3,5-trifluoro-4-pyridinepropionic acid (CAS 2166862-35-5);

[0603] t) α,α,3,5-tetrafluoro-4-pyridinepropionic acid (CAS 2138554-68-2);

[0604] u) α,α,3-trifluoro-4-pyridinepropionic acid (CAS 2137827-10-0);

[0605] v) 3,5-difluoro-4-pyridinepropionic acid (CAS 1996164-11-4);

[0606] w) 3-(Trifluoromethyl)-4-pyridinepropionic acid (CAS 1888850-59-6);

[0607] x) 2,5-difluoro-4-pyridinepropionic acid (CAS 1780779-62-5);

[0608] y) 2-(1,1-difluoroethyl)-4-pyridinepropionic acid (CAS 1780673-65-5);

[0609] z) 2-(Difluoromethyl)-4-pyridinepropionic acid (CAS 1780289-72-6);

[0610] aa) 3-Fluoro-4-pyridinepropionic acid (CAS 1256819-25-6);

[0611] bb) 2,3,5,6-tetrafluoro-4-pyridinepropionic acid (CAS 916792-08-0);

[0612] Non-limiting examples of starting materials where X is a substituted pyrazine ring include:

[0613] a) 6-(Difluoromethyl)-2-pyrazinepropionic acid (CAS 1780915-43-6);

[0614] b) 5-(Difluoromethyl)-2-pyrazinepropionic acid (CAS 1780310-08-8); and

[0615] c) 5-(Trifluoromethyl)-2-pyrazinepropionic acid (CAS 1196156-94-1).

[0616] Non-limiting examples of starting materials where X is a substituted pyridazine ring include:

[0617] a) 4-(Trifluoromethyl)-3-pyridazineacetic acid (CAS 1898213-83-6);

[0618] b) 6-(Trifluoromethyl)-3-pyridazineacetic acid (CAS 1565408-90-3);

[0619] c) 6-(Difluoromethyl)-3-pyridazineacetic acid (CAS 2303714-09-0);

[0620] d) 6-(Trifluoromethyl)-3-pyridazineacetic acid (CAS 1898214-51-1); and

[0621] e) 5-(Trifluoromethyl)-3-pyridazineacetic acid (CAS 1898213-96-1).

[0622] The substitution pattern in each of the above groups is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As a non-limiting example, regardless of R 1 , R 2 , R 3 , R 4 and R 5 The bound ring or R 6 and R 7 What is the length of the carbon chain being bonded. Example

[0623] I. Materials and Methods

[0624] 1. Overview. All reagents and solvents were purchased from Sigma-Aldrich, Chem-Impex International and ThermoFisher and used directly without further purification. Peptides RGD and FRGD were purchased from Peptides International and CPC Scientific Inc., respectively. 64 C 12 Purchased from Washington University School of Medicine in St.Louis, 111 InCl 3 Purchased from Jubilant DraxImage Radiopharmacies, Inc. (Triad Isotopes).

[0625] 2. Synthesis of the mobile ABX part

[0626]

[0627] Scheme-1: Synthesis route-1 was selected to prepare five albumin binder moieties, namely ABCF3-3F, ABCF3-2F, ABF3, ABF5 and ABF3O. Conditions: a) i) (COCl) 2 ,DMF,DCM,0℃-rt; ii)TMSCHN 2 ,MeCN,THF,0℃ 3h; b)i)PhCO 2 Ag,MeOH,Et 3 N, ultrasonic sonication for 30 min, or PhCO 2 Ag, 1,4-dioxane, H 2 O,Et 3 N, ultrasonic sonication, without step ii; ii) LiOH, H2O, THF, MeOH 0°C-rt.

[0628] a. Preparation of 4-(3,4,5-trifluorophenyl)butyric acid (ABF3):

[0629] 1-Diazo-4-(3,4,5-trifluorophenyl)butan-2-one

[0630] To a stirred solution of 3-(3,4,5-trifluorophenyl)propanoic acid (204 mg, 1.0 mmol) in anhydrous DCM (5 mL) was added oxalyl chloride (128 μL, 1.5 mmol) dropwise at 0°C; the mixture was then warmed to room temperature and stirred for an additional 2 hours. The solvent and additional oxalyl chloride were removed in vacuo, and THF (2.5 mL) and MeCN (2.5 mL) were added. The mixture was recooled to 0°C and TMSCHN was added dropwise. 2 (1.5 mL, 3 mmol), then gradually warmed to room temperature and stirred for 3 hours. 2 O (50 mL), and washed successively with 0.1 M citric acid, NaHCO3 sat aq. (saturated aqueous solution) and brine. 2 SO 4 The product was dried on silica gel and purified with hexane:EA=2:1 (Rf=0.15) to obtain 204 mg of the product as a light yellow oil with a yield of 89%.

[0631] 4-(3,4,5-Trifluorophenyl)butyric acid (ABF3)

[0632] 1-diazo-4-(3,4,5-trifluorophenyl)butan-2-one (91 mg, 0.4 mmol), PhCO2 Ag (9mg, 0.04mmol) in dioxane (3.2mL) and water (0.6mL) was ultrasonically treated for 4 hours. Then the resulting mixture was acidified to pH=4 with 1N hydrochloric acid and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and purified by column chromatography with DCM / MeOH 20:1. 33mg of the product was obtained as a yellow oil with a yield of 38%. 1 H NMR (400 MHz, CDCl 3 )δ6.86–6.74(m,2H),2.67–2.58(m,2H),2.38(t,J=7.3Hz,2H),1.98–1.88(m,2H).

[0633] b. Preparation of 4-(2-fluoro-4-(trifluoromethyl)phenyl)butyric acid (ABCF3-2F):

[0634] Methyl 4-(2-fluoro-4-(trifluoromethyl)phenyl)butyrate

[0635] 1-diazo-4-(2-fluoro-4-(trifluoromethyl)phenyl)butan-2-one (50 mg, 0.19 mmol), PhCO 2 Ag (8.8 mg, 0.04 mmol) and Et 3 A mixture of N (0.12 mL) in MeOH (1.9 mL) was sonicated for 30 min. After removing the solvent in vacuo, the residue was redissolved in EtOAc (50 mL), washed with 0.1 M citric acid, sodium bicarbonate sat aq. and brine, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography on silica gel with n-hexane / EtOAc 4:1 (Rf 0.3). 18 mg of the product was obtained as a colorless oil with a yield of 36%. 1 H NMR (400 MHz, CDCl 3 )δ7.36–7.27(m,3H),7.12–6.99(m,2H),3.67(s,3H),2.74(t,J=7.5Hz,2H),2.36(t,J=7.4Hz,2H),1.97(p,J=7.4Hz,2H).

[0636] 4-(2-Fluoro-4-(trifluoromethyl)phenyl)butanoic acid (ABCF3-2F)

[0637] Methyl 4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoate (18 mg, 0.07 mmol) and LiOH·H2O (14 mg, 0.34 mmol) were stirred in H 2A mixture of 4-(4-(2-[4-(2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2- 11 H 10 F 4 O 2 ,[MH] - calcd(calculated value)249.06,found(measured value)249.03.

[0638] c. Preparation of 4-(3-fluoro-4-(trifluoromethyl)phenyl)butyric acid (ABCF3-3F):

[0639] 4-(3-Fluoro-4-(trifluoromethyl)phenyl)butanoic acid (ABCF3-3F)

[0640] This compound was prepared using the same procedure as above for ABCF-2F, but starting from 4-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid. 1 H NMR (400 MHz, CDCl 3 )δ7.51(t,J=7.7Hz,1H),7.12–6.99(m,2H),2.80–2.67(m,2H),2.40(t,J=7.3Hz,2H),2.04–1.92(m,2H).ESI-TOF,C 11 H 10 F 4 O 2 ,[MH] - calcd 249.06, found 249.05.

[0641] d. Preparation of 4-(2-fluoro-4-(trifluoromethyl)phenyl)butanoic acid (ABCF3O):

[0642] 4-(4-(Trifluoromethoxy)phenyl)butanoic acid(ABCF3O)

[0643] This compound was prepared using the same procedure as above for ABCF-2F, but starting from 4-(4-(trifluoromethoxy)phenyl)propanoic acid. 1 H NMR (400 MHz, CDCl 3)δ7.22–7.16(m,2H),7.15–7.10(m,1H),3.67(s,1H),2.69–2.60(m,1H),2.33(t,J=7.4Hz,1H),2.00–1.89(m,1H).

[0644] e. Preparation of 4-(perfluorophenyl)butyric acid (ABF5):

[0645] 4-(Perfluorophenyl)butyric acid (ABF5)

[0646] This compound was prepared using the same procedure as described above for ABCF-2F, but starting from 4-(perfluorophenyl)propionic acid. 1 H NMR (400 MHz, CDCl 3 )δ2.78(t,J=7.6Hz,2H),2.42(t,J=7.4Hz,2H),1.94(p,J=7.5Hz,2H).

[0647] f. Preparation of 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butyric acid (ABCF3-3,5F):

[0648]

[0649] Scheme 2. Compound 3 was prepared using synthetic route 2; according to the above synthetic scheme 1, compound 3 was used to prepare the corresponding albumin binder ABCF3-3,5F. Conditions: a) malonic acid, pyridine, piperidine, 75°C; b) TES, Pd-C, MeOH.

[0650] (E)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)acrylic acid

[0651] A mixture of 3,5-difluoro-4-(trifluoromethyl)benzaldehyde (940 mg, 447 mmol), malonic acid (990 mg, 9.52 mmol) and piperidine (47 μL) in pyridine (2.5 mL) was heated to 70 °C and stirred for 18 hours. The resulting mixture was poured into 100 mL of water and acidified with 1N HCl to adjust pH = 4. The light yellow precipitate formed was filtered, rinsed with water, and collected. The crude product was dried under high vacuum to obtain 940 mg of product with a yield of 67%. 1 H NMR (400 MHz, DMSO) δ 12.79 (brs, 1H), 7.81 (d, J = 11.9 Hz, 2H), 7.59 (d, J = 16.0 Hz, 1H), 6.83 (d, J = 16.0 Hz, 1H).

[0652] 3-(3,5-Difluoro-4-(trifluoromethyl)phenyl)propanoic acid

[0653] To a stirred solution of (E)-3-(3,5-difluoro-4-(trifluoromethyl)phenyl)acrylic acid (760 mg, 3.0 mmol), Pd-C (10% wt, 76 mg) in MeOH (15 mL) was added TES (5 mL) over 40 min. The resulting mixture was filtered through Celite, concentrated in vacuo, and purified by column chromatography on silica gel DCM / MeOH 10:1. 500 mg of the product was obtained as a colorless oil with a yield of 71%. 1 H NMR (400MHz, DMSO) δ12.26 (s, 1H), 7.31 (d, J = 11.5 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 7.6 Hz, 2H). 4-(3,5-difluoro-4-(trifluoromethyl)phenyl)butanoic acid (ABCF3-3,5F)

[0654] 1 H NMR (400 MHz, CDCl 3 )δ6.86–6.74(m,2H),2.67–2.58(m,2H),2.38(t,J=7.3Hz,2H),1.98–1.88(m,2H).

[0655] g. Preparation of 4-(4-fluoronaphthalene-2-yl)butyric acid (ABNaphth-4F):

[0656]

[0657] Scheme 3. The synthetic route selected for the preparation of albumin binder ABNaphth-4F. Conditions: a) CuI, Pd(PPh 3 ) 2 Cl 2 , Et 3 N, DMF, rt (room temperature), overnight; b) H 2 (1 atm), Pt 2 O, EtOH; c) LiOH, THF, MeOH, H 2 O.

[0658] Methyl 4-(4-fluorofluoro-2-yl)buta-2,3-dienoate

[0659] 1-Fluoro-3-iodonaphthalene (54 mg, 0.2 mmol), methyl but-3-ynoate (24 mg, 0.24 mmol), Pd(PPh 3 ) 2 Cl 2 A mixture of (14 mg, 0.02 mmol), CuI (13 mg, 0.07 mmol) and Et3N (0.4 mL) in DMF (2 mL) was stirred overnight under argon. The resulting slurry mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography on silica gel with hexane / EtOAc 8:1 (Rf 0.3) to give 20 mg of the product as a colorless oil with a yield of 42%. 1 H NMR (400 MHz, CDCl 3 )δ8.24–7.95(m,1H),7.89–7.72(m,1H),7.58–7.44(m,3H),7.11(dd,J=11.2,1.3 Hz,1H),6.77(d,J=6.3 Hz,1H),6.12(d,J=6.3 Hz,1H),3.79(s,3H).

[0660] Methyl 4-(4-fluoronaphthalen-2-yl)butyrate

[0661] At room temperature, methyl 4-(4-fluoronaphthalen-2-yl)but-2,3-dienoate (20 mg, 0.08 mmol), PtO 2 A mixture of (5 mg) in MeOH (1 mL) was stirred under hydrogen (1 atm) for 3 h. The crude product was filtered, concentrated in vacuo, and purified by column chromatography on silica gel with hexane / EtOAc 10:1 (Rf 0.3) to give 20 mg of the product as a colorless oil in 98% yield. 1 HNMR (400 MHz, CDCl 3 )δ8.09–8.00(m,1H),7.85–7.72(m,1H),7.53–7.44(m,2H),7.41(s,1H),7.01(dd,J=11.5,1.4 Hz,1H),3.67(s,3H),2.80(t,J=7.5 Hz,2H),2.37(t,J=7.4Hz,2H),2.10–1.98(m,2H).

[0662] 4-(4-Fluoronaphthalen-2-yl)butyric acid (ABNaphth-4F)

[0663] Methyl 4-(4-fluoronaphthalen-2-yl)butyrate (20 mg, 0.08 mmol) and LiOH·H2O (17 mg, 0.4 mmol) were stirred in H 2 A mixture of 4-(4-(2-[4-(2-[2-[2-(2-[2-[2-(2-[2-[2-1 ...

[0664] 3. Synthesis of DOTA-albumin binder conjugates for in vitro evaluation

[0665] a. Preparation of intermediate (ABX-NHS):

[0666]

[0667] Scheme 4. The mobile AB moiety (carboxylic acid) was converted to its NHS ester using N-hydroxysuccinimide, DCC in DMF under typical coupling conditions. The product was filtered through a syringe filter and used directly without further purification.

[0668] b. Conjugation of DOTA with albumin binders:

[0669]

[0670] Scheme 5. Synthesis of DOTA-albumin binder conjugates by standard solid phase Fmoc-based peptide synthesis on pre-packed Fmoc-Lys(Mtt)-Wang resin. Conjugation of the lysine backbone on the resin with DOTA-NHS ester and ABX-NHS ester was performed directly in DIEA-basified DMF. 2 (2) After cleavage, the crude product was precipitated in cold ether and purified by HPLC. The final product was characterized as follows by ESI-MS:

[0671] DOTA-Lys(azide)-Acp-ABCF3,[M+H] + m / z:1014.8

[0672]

[0673] DOTA-Lys(azide)-Acp-D-ABCF3,[M+H] + m / z:1014.7

[0674]

[0675] DOTA-Lys(azide)-Acp-ABCF3-2F,[M+H] + m / z:1032.4

[0676]

[0677] DOTA-Lys(azide)-Acp-ABCF3-3F,[M+H] + m / z:1032.4

[0678]

[0679] DOTA-Lys(azide)-Acp-ABCF3-3,5F,[M+H] + m / z:1050.2

[0680]

[0681] DOTA-Lys(azide)-Acp-ABCF3O,[M+H] + m / z:1028.9

[0682]

[0683] DOTA-Lys(azide)-Acp-ABCF3P,[M+H] + m / z:1000.4

[0684]

[0685] DOTA-Lys(azide)-Acp-ABF,[M+H] + m / z:964.8

[0686]

[0687] DOTA-Lys(azide)-Acp-ABF3P,[M+H] + m / z:986.8

[0688]

[0689] DOTA-Lys(azide)-Acp-ABF5,[M+H] + m / z:1036.6

[0690]

[0691] DOTA-Lys(azide)-Acp-ABmCF3,[M+H] + m / z:1014.8

[0692]

[0693] DOTA-Lys(azide)-Acp-ABNaphth,[M+H] + m / z:996.8

[0694]

[0695] DOTA-Lys(azide)-Acp-ABNaphth-4F,[M+H] + m / z:1014.3

[0696]

[0697] DOTA-Lys(azide)-Acp-ABOCF3,[M+H] + m / z:1028.6

[0698]

[0699] DOTA-Lys(azide)-Acp-hLys-ABF3P,[M+H] + m / z:1000.6

[0700]

[0701] DOTA-Lys(azide)-Gly-εLys-βAla-ABCF3,[M+H] + m / z:1015.6

[0702]

[0703] 4. Synthesis of Albumin Binders and Peptide Conjugates

[0704] a. Synthesis of DOTA-RGD-ABX and DOTA-FRGD-ABX (ABX = ABCF3, ABI):

[0705]

[0706] Scheme 6. Preparation of DOTA-RGD-ABX and DOTA-FRGD-ABX (R: ABCF3, ABI).

[0707] i. Preparation of RGD-BCN and FRGD-BCN. The peptides were used directly as received without further purification. Conjugation was achieved by direct coupling of endo-BCN-PEG4-PFP ester with 1.2X peptide ligand and 4X DIEA in DMF. The resulting product was used in the next step without further purification.

[0708] ii. Conjugation of RGD-BCN, FRGD-BCN and DOTA-Lys(N3)-ABCF3 / ABI

[0709] The final conjugate was obtained by SPAAC click reaction of equal proportions of peptide-BCN derivatives and corresponding azide-containing chemical tools in 50% acetonitrile and 50% PBS buffer. The product was purified by HPLC and characterized by ESI-MS as follows:

[0710] DOTA-RGD-ABCF3,(R1=CF3),[M+2H] 2+ M / z:928.6

[0711] DOTA-RGD-ABI,(R1=I),[M+2H] 2+ M / z:957.6

[0712]

[0713] DOTA-FRGD-ABCF3,(R2=CF3),[M+2H] 2+ M / z:1205.9

[0714] DOTA-FRGD-ABI,(R2=I),[M+2H] 2+ M / z:1234.7

[0715]

[0716] As the term "linker" is used herein, a BCN-SPAAC click reaction utilizing the nitrile on the lysine of a DOTA conjugate provides a non-limiting example of generating a "linker." DOTA is a non-limiting example of a radionuclide chelator.

[0717] b. Synthesis of DOTA-SFLAP3-ABX:

[0718]

[0719] Scheme 7. Preparation of DOTA-SFLAP3-PEG-ABXs. Linear peptides were synthesized by Blue Liberty microwave-assisted peptide synthesizer (DIC, Oxyma system). DOTA-PSMA617-ABCF3 was synthesized by a similar strategy. After HPLC purification, the product was characterized by ESI-MS as follows:

[0720] DOTA-ABCF3-PSMA617,[M+2H] 2+ m / z:807.5

[0721]

[0722] DOTA-SFLAP3-ABCF3,[M+2H] 2+ m / z:1350.5

[0723]

[0724] DOTA-SFLAP3-ABCF3-2F,[M+3H] 3+ m / z:906.2

[0725]

[0726] DOTA-SFLAP3-ABCF3-3F,[M+2H] 2+ m / z:1359.2

[0727]

[0728] DOTA-SFLAP3-ABCF3-3,5F,[M+2H] 2+ m / z:1367.8

[0729]

[0730] DOTA-SFLAP3-ABF5,[M+2H] 2+ m / z:1360.8

[0731]

[0732] DOTA-SFLAP3-ABmCF3,[M+2H] 2+ m / z:1349.7

[0733]

[0734] DOTA-SFLAP3-PEG4-ABNaphth,[M+2H] 2+m / z:1340.9

[0735]

[0736] DOTA-SFLAP3-ABNaphth-4F,[M+2H] 2+ m / z:1349.9

[0737]

[0738] 5. Radiolabeling conditions. 64 For Cu labeling, the buffer solution was NH 4 OAc (0.2 M, pH = 7.0). 111 In is marked, and the buffer solution is NH 4 OAc (0.2 M, pH = 7.0). All conjugates were labeled at 80°C for 30 min. 64 The specific activity of Cu is MBq / nmol (500 μCi / nmol), while 111 The specific activity of In was 3.7 MBq / nmol (100 μCi / nmol). The radiochemical purity and labeling yield were monitored by reverse phase Radio-HPLC.

[0739] 6. Cell lines and animal models. BxPC3 and CT26 cell lines were purchased from ATCC. Cells were cultured in RPMI medium with 10% fetal bovine serum (FBS), 1% penicillin / streptomycin at 37°C in an atmosphere of 5% carbon dioxide.

[0740] 7. In vitro albumin binding affinity assay. Ultrafiltration assays were performed to assess 111 In or 64 Albumin binding properties of Cu-labeled albumin binder-radioligand conjugates. 111 In or 64 Cu radiolabeled in NH 4OAc (0.2M, pH = 7.0) buffer at 80 ° C for 30 min, with a specific activity of 3.7MBq / nmol (100μCi / nmol). The resulting albumin binder-radioligand conjugate (10μL, 10μM) was mixed with 100μL human serum albumin (HSA, 1.0mM in PBS 1×) and 90μL PBS, and then gently shaken for 30min at 37°C. After incubation, 80μL of each solution was loaded into a ZebaTM spin desalting column (7K MWCO) and centrifuged at 1500g for 2min. The radioactivity in the 20μL and 10μL mixture (before filtration) filtered each time was quantified with a γ counter. The filtration rate of each sample was calculated as filtration count / (mixture count×2)×100%, and then all the obtained results were normalized for comparison by setting the standard ABCF3 portion to 74.4%. The experiment was repeated three times. For the working curve, the same experimental protocol was followed using different final concentrations of HSA from 10-1500 μM.

[0741] 8. Biodistribution study. Biodistribution study was performed 2 weeks after tumor inoculation when the tumor size reached 5 mm. Then the drug was administered via the tail vein. 111 In-labeled albumin binder-radioligand conjugate (1.85 MBq, 100 μL). Mice were sacrificed 1, 2, 16, 24 or 48 hours after injection. Selected organs were collected and weighed, and radioactivity was measured using a gamma counter (Packard, Cobra E5003). Results were calculated as the percentage of injected dose per gram mass (% ID / g).

[0742] II. Results

[0743] 1. In vitro Albumin Binding Affinity Assessment

[0744] a. 64 Cu radiolabeled DOTA-albumin binder conjugate:

[0745] First, the albumin binding affinity of the albumin binders was assessed by in vitro ultrafiltration assay, according to Figures 4A-4D (where the X group is represented by an R-substituted benzyl group) were used to prepare DOTA-albumin binder conjugates for in vitro evaluation. These conjugates were prepared to study the affinity of different albumin binding moieties and the effects of the following factors: 1) The chiral center of lysine ( Figure 4A and 4B ABX vs. D-ABX); 2) an additional amide bond between the two binding groups ( Figure 4A and 4C ABX vs. εABX in ); 3) the position of the amide bond connecting the X group to the amino acid side chain ( Figure 4Aand 4D ABX vs. hABX in ).

[0746] All ABX filtration results are as follows Figure 5 [HSA] = 500 μM, [Tracer] = 0.5 μM. All data were normalized, and the filtration percentage of ABCF3 was set as high as 75% (average), while DOTA-Lys (N 3 )-Acp-Lys-OH was used as a negative control. In addition to the binding affinity of ABX, the filtration assay results also showed that the use of D-lysine (D-ABCF3 vs. ABCF3) or changing the position of the amide bond (hABCF3P vs. ABCF3P, hABF3P vs. ABF3P) could result in a slight increase in binding affinity, while the inclusion of an additional amide bond (εABCF3 vs. ABCF3) greatly reduced its binding affinity.

[0747] b.with 64 Cu-DOTA-SFLAP3 (abbreviated as SFLAP3) compared to 64 Cu-DOTA-SFLAP3-PEG4-ABCF3 (abbreviated as SFLAP3-ABCF3):

[0748] To validate albumin binding of the albumin binders incorporated with the targeting ligand, we measured the percentage of SFLAP3-ABCF3 / SFLAP3 bound to albumin by filtration assay. Figure 6 As shown, about 75% of SFLAP3-ABCF3 was found to bind to albumin, while under the same conditions, only about 5% of SFLAP3 could bind to albumin.

[0749] 2. In vitro biodistribution studies

[0750] a. In mice bearing BxPC3 xenografts 111 In-labeled RGD-ABCF3, RGD, and RGD-ABI:

[0751] Fig. 7A and 7B Shown is a comparison of BxPC3 xenograft-bearing mice 111 Results of In-labeled RGD-ABCF3, RGD, and RGD-ABI: Fig. 7A ) biodistribution, and ( Figure 7B) Tumor / non-tumor ratio. In a xenograft pancreatic tumor mouse model, RGD incorporated with ABCF3 showed an approximately 8-fold increase in tumor uptake at the 24-hour post-injection time point compared to integrin αvβ3-specific RGD; importantly, in addition to the increased tumor uptake, incorporation of ABCF3 also increased the tumor-to-non-tumor ratio, especially tumor / kidney, as kidney would be a dose-limiting organ for this RGD peptide. On the other hand, RGD incorporated with ABI showed increased tumor uptake compared to RGD-ABCF3, however, its non-tumor uptake was also significantly increased and resulted in a decrease in the tumor / non-tumor ratio, especially the tumor / blood ratio, as high blood uptake often brings concerns about radiotoxicity to the red bone marrow - another typical dose-limiting organ for radionuclide therapy.

[0752] b. In mice bearing CT26 allogeneic transplants 111 In-labeled RGD-ABCF3, RGD, and RGD-ABI:

[0753] Fig. 8A and 8B Shown is a comparison of the expression of CT26 (colorectal cancer) allogeneic transplants in mice 111 Results of In-labeled RGD-ABCF3, RGD, and RGD-ABI: Fig. 8A ) biodistribution, and ( Figure 8B ) tumor / non-tumor ratio. Similarly, incorporation of ABCF3 increased tumor uptake by about 5-fold and also increased the tumor / non-tumor ratio; whereas incorporation of ABI (relative to ABCF3) slightly increased tumor uptake but also resulted in an unfavorable tumor / non-tumor ratio.

[0754] c. Carrying PSMA + PC3pip and PSMA - PC3 xenografts in mice 64 Cu-labeled PSMA617-ABCF3 and PSMA617:

[0755] In addition to the αvβ3-specific RGD, ABCF3 was also incorporated into the PSMA-specific PSMA-617. Fig. 9A and 9B Shown is a comparison of PSMA+PC3pip and PSMA-PC3 xenograft-bearing mice 64 Results of Cu-labeled PSMA-617-ABCF3 and PSMA617: Fig. 9A ) biodistribution, and ( Fig. 9B) Tumor / non-tumor ratio. PC3pip overexpresses PSMA, while PC3 is PSMA negative and does not express PSMA. As shown in Figure 9, linking ABCF3 to PSMA617 not only increased its intrinsic tumor uptake by >2-fold, but also improved the tumor / non-tumor ratio, especially at late time points (24h).

[0756] d. In mice bearing BxPC3 xenografts 111 In-labeled FRGD-ABCF3 and FRGD

[0757] ABCF3 was also linked to the αvβ6-specific FRGD peptide and then used 111 The resulting FRGD-ABCF3 was radiolabeled with In and then expressed in mice bearing BxPC3 xenografts. 111 In-FRGD for comparison. Fig. 10A and 10B shows the results of this comparison: Fig. 10A ) biodistribution, and ( Fig. 10B ) Tumor / non-tumor ratio. FRGD-ABCF3 showed approximately 5-fold tumor uptake at both 1 and 16 h post-injection time points. With the exception of the 16 h tumor / blood ratio, the tumor / non-tumor ratios of FRGD-ABCF3 were higher than those of FRGD; in particular, the tumor / kidney ratio increased approximately 3-fold after ABCF3 attachment. Kidney uptake is very high and may become a dose-limiting organ without ABCF3.

[0758] e. In vivo performance of SFLAP3 incorporating various ABXs in mice bearing BxPC3 xenografts:

[0759] Fig.11A and 11B Shown is a comparison of the in vivo performance of SFLAP3 incorporating various ABXs in mice bearing BxPC3 xenografts (24 h): Fig.11A ) biodistribution, and ( Fig. 11B) tumor / non-tumor ratio. Comparing SFLAP3 itself with SFLAP3-ABCF3-2F, SFLAP3-ABNaphth-4F, and SFLAP3-ABF5, it was found that if the albumin binding of the ABX was weaker than that of SFLAP3-ABCF3-2F, the increase in tumor uptake was not obvious. The in vivo performance of other ABXs (ABCF3, ABCF-3F, ABNaphth, and ABCF-3F) linked to the SFLAP3 ligand was then studied. The results showed that among all the ABXs tested, incorporating ABCF3F into the SFLAP3 peptide resulted in the best in vivo performance. Another benefit of using ABXs with fluorine on the aromatic ring is that by replacing the non-radioactive 19F with radioactive 18F, 18F radiolabeled ligands for PET imaging can be prepared.

[0760] III. Discussion

[0761] Integrins are transmembrane proteins (receptors) that promote cell-extracellular matrix (ECM) adhesion. Activated by ligand binding, integrins participate in signal transduction pathways and mediate cell survival, differentiation, gene transcription, and apoptosis. Integrins are composed of two subunits (α and β subunits) and function as heterodimers with 24 different assemblies. A wide variety of integrins contribute to tumor progression. The integrin αvβ3 receptor (the first characterized α v Integrin), binds to fibronectin and villianin via the Arg-Gly-Asp (RGD) tripeptide motif that regulates angiogenesis. Integrin αvβ3 is preferentially overexpressed in glioblastoma, melanoma, breast cancer, prostate cancer, and pancreatic cancer cells, but is barely detectable in most adult epithelial cells, making it a fundamental hallmark of cancer biology. Therefore, inhibition of integrin αvβ3 has been studied for anti-angiogenic therapy of cancer. Cilengitide is a cyclized pentapeptide containing Arg-Gly-Glu (RGD) that selectively binds to cancer cells expressing αVβ3 integrin. Despite showing good tolerability and strong efficacy in Phase II studies, Cilengitide failed in Phase III trials; one of the reasons was rapid blood clearance, which subsequently limited tumor accumulation. Therefore, the inventors developed ABCF3 incorporating a ring (RGD) to overcome its rapid blood clearance.

[0762] Integrin alpha v β 6 It is another important member of the integrin family. It is also an epithelial receptor that is upregulated in many cancers, including oral squamous cell carcinoma, gastrointestinal cancer, non-small cell lung cancer, ovarian cancer, and pancreatic ductal adenocarcinoma; but it is not (or rarely) found in normal epithelium. Using phage display peptide library technology, several peptides with very high αv β 6 Specific peptides include A20FMDV2, SFLAP3, TP H2009.1, etc. All of these peptides contain similar RGDLXXL substructures that are essential for specific binding to αvβ6. v β 6 Targeted radioligands have been clinically tested for PET imaging of various diseases. Although the results encourage further clinical trials, based on the results obtained, pharmacokinetic improvements to these radioligands are highly desirable. Therefore, the inventors have targeted α v β 6 Specific peptides were incorporated into albumin binders to improve tumor uptake while increasing the tumor / non-tumor ratio (contrast), especially the tumor / kidney ratio, since kidney uptake contributes the highest background to pancreatic cancer imaging.

[0763] To α v β 6 The specific A20FMDV2 peptide was subjected to computational-assisted structure optimization, which successfully identified a very rigid mimetic β-sheet structure ligand (FRGD) with high binding affinity (IC 50 :~0.26nM). In addition to α v β 6 In addition to its high affinity for α v β 3 IC 50 However, further in vivo evaluation results showed that tumor uptake was relatively low and non-tumor uptake was high, which limited its further clinical translation. It was observed that compared with the ( 111 Compared with In)FRGD, 111 In)-labeled FRGD-ABCF3 showed approximately 5-fold higher tumor uptake at both 1 h and 16 h. More importantly, at the early time point after injection (1 h), compared with ( 111 Compared with the tumor / non-tumor ratio observed in FRGD, ( 111 In) FRGD-ABCF3 showed better (or at least comparable) tumor / non-tumor ratios. It is believed that the significant improvement in tumor / kidney, tumor / muscle, and tumor / liver uptake will greatly facilitate PET imaging of pancreatic tumors (where kidney and muscle are considered as background) and liver metastases. In addition to PET imaging, the increase in tumor uptake and the increase in tumor / non-tumor ratios will also be beneficial for the use of FRGD-ABCF3 in radionuclide therapy.

[0764] definition

[0765] "Theranostics" refers to the systematic integration of targeted diagnostics and therapeutics. The term "radiotherapeutics" refers to the use of radionuclides for paired imaging and therapeutic agents.

[0766] The term "alkyl" refers to a straight or branched chain hydrocarbon. For non-limiting example, an alkyl group may have 1 to 4 carbon atoms (i.e., C 1 -C 4 Alkyl or C 1-4 Alkyl) or 1-3 carbon atoms (i.e. alkyl or C 1-3 Specific examples of the alkyl group include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and isobutyl.

[0767] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

[0768] The term "fluoroalkyl" refers to a straight or branched chain alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by fluorine (F) atoms. The alkyl portion of the fluoroalkyl group may have, for example, 1 to 6 carbon atoms (i.e., C 1 -C 6 Fluoroalkyl), 1-4 carbon atoms (i.e. C 1 -C 4 Fluoroalkyl) or 1-3 carbon atoms (i.e. C 1 -C 3 Non-limiting examples of suitable fluoroalkyl groups include, but are not limited to, trifluoromethyl (-CF 3 ), difluoromethyl (-CHF 2 ), fluoromethyl (-CFH 2 ), 2-fluoroethyl (-CH 2 CH 2 F), 2-fluoropropyl (-CH 2 CHF 2 )、2,2,2-trifluoroethylene(-CH 2 CF 3 )、1,1-difluoroethyl(-CF 2 CH 3 ), 2-fluoropropyl (-CH 2 CHFCH 3 )、1,1-difluoropropyl(-CF 2 CH 2 CH 3 )、2,2-difluoropropyl(-CH 2 CF 2 CH 3 )、3,3-difluoropropyl(-CH 2 CH 2 CHF 2)、3,3,3-trifluoropropyl(-CH 2 CH 2 CHF 3 )、1,1-difluorobutyl(-CF 2 CH 2 CH 2 CH 3 ), perfluoroethyl (-CF 2 CF 3 ), perfluoropropyl (-CF 2 CF 2 CF 3 )、1,1,2,2,3,3-hexafluorobutyl(-CF 2 -CF 2 CF 2 CH 3 ), perfluorobutyl (-CF 2 CF 2 CF 2 CF 3 )、1,1,1,3,3,3-hexafluoroprop-2-yl(-CH 2 (CF 3 ) 2 ) etc. A "perfluoro" alkyl group refers to an alkyl group in which all hydrogen atoms are replaced by fluorine atoms, such as trifluoromethyl and pentafluoroethyl.

[0769] Similar to fluoroalkyl, the term "haloalkyl" refers to a straight or branched chain alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom, such as a fluorine (F) atom.

[0770] The group "SF2" refers to a difluorosulfanyl group, "SF 2 Cl” refers to the chlorodifluorosulfanyl group, “SF 5 " refers to pentafluoro "SF 5 "Sulfanyl group," SF 4 Cl" refers to a chlorotetrafluorosulfanyl group, each of which is described below.

[0771]

[0772] Wavy lines appear relative to straight lines in chemical structures Indicates that an atom or chemical group is bonded to another atom or chemical group in the structure, definition, or other context shown.

[0773] All ranges disclosed and / or claimed herein are inclusive of the referenced endpoints and are independently combinable. For example, the ranges "from 2 to 10" and "2-10" include the endpoints 2 and 10, as well as all intermediate values ​​within the unit range under consideration. Unless described in the context of an average, for example, reference to "claims 2-10" or "C 2-C 10 The term "alkyl" includes units 2, 3, 4, 5, 6, 7, 8, 9, and 10 because the claims and atoms are numbered sequentially, without fractions or decimal points. On the other hand, the context of "the pH is 5-9" or "the temperature is 5°C to 9°C" includes the integers 5, 6, 7, 8, and 9, and all fractional or decimal units in between, e.g., 6.5 and 8.24.

[0774] The abbreviation "RGD" refers to the tripeptide of arginine-glycine-aspartic acid.

[0775] "Amine protecting group" refers to a group introduced into a molecule in order to modify the chemoselectivity of the amine in a subsequent chemical reaction or in multiple reactions in a multi-step organic synthesis. The amine protecting group can be selected from: methyl carbamate, 9-fluorenylmethylcarbamate (Fmoc), 2,2,2,-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), tert-butyl carbamate (BOC), allyl carbamate (Alloc), benzyl carbamate (Cbz), m-nitrophenyl carbamate, formamide, acetamide, trifluoroacetamide, benzyl (benzylamine), allyl (allylamine) and trityl (tritylamine), 3,5-dimethoxyphenylisopropylcarbonyl (dimethoxyphenylisoproxycarbonyl, Ddz), 2-(4-diphenyl)isopropyloxycarbonyl (Bpoc), 2 -nitrophenylsulfinyl (Nps), 2-(4-nitrophenylsulfonyl)ethoxycarbonyl (Nsc), 1,1-dioxobenzo[b]thiophen-2-ylmethoxycarbonyl (Bsmoc, (1,1-dioxonaphtho[1,2-b]thiophen-2-ylyl)methyloxycarbonyl (α-Nsmoc), (1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-ethyl) (Dde), 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl (ivD de), 2-fluoro-Fmoc (Fmoc(2F)), 2-monoisooctyl (Monoisooctyl-Fmoc, mio-Fmoc), 2,7-diisooctyl (dio-Fmoc), tetrachlorophthaloyl (Tetrachlorophthaloyl, TCP), 2-[phenyl(methyl)dihydrosulfenyl]ethoxycarbonyltetrafluoroboric acid (Pms), ethylsulfonylethoxycarbonyl (Ethanesulfonylethoxycarbonyl, Esc), 2 -(4-sulfophenylsulfonyl)ethoxycarbonyl (Sps), benzyloxycarbonyl (Z), allyloxycarbonyl (Alloc), o-nitrobenzenesulfonyl (oNBS), p-nitrobenzenesulfonyl (pNBS), 2,4-dinitrobenzenesulfonyl (dNBS), benzothiazole-2-sulfonyl (Bts), 2-nitrophenylsulfanyl (Nps), dithiosuccinyl (Dts), p-nitrobenzyloxycarbonyl (pNZ), propargyloxycarbonyl (propargyloxycarbonyl, Poc), 2-(3,4-methylenedioxy-6-nitrophenyl)propyloxycarbonyl (MNPPOC), 9-(4-bromophenyl)-9-fluorenyl (BrPhF), azidomethyloxycarbonyl (Azoc), o-nitrobenzyloxycarbonyl (oNZ), 4-nitroveratryloxycarbonyl (NVOC), 4-nitroveratryloxycarbonyl (NPPOC) and hexafluoroacetone (HFA) protecting groups.

[0776] Amide protecting groups for amines include formamide, acetamide and trifluoroacetamide protecting groups. Sulfonamide protecting groups for amines include p-toluenesulfonyl (Ts), trifluoromethanesulfonyl, trimethylsilylsulfonamide (SES) and tert-butylsulfonyl (Bus) protecting groups.

Claims

1. A composition comprising a reaction product in which a radionuclide chelator is complexed with a compound of formula (I): in: X is selected from the following group: as well as R 1 , R 2 , R 3 , R 4 , R 5 , and when present R 8 and R 9 , are each independently selected from the following group: H, F, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 and OCF 3 ; R 6 and R 7 is independently H or an isotope thereof in each instance; n 1 is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6; and m is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8; The condition is that when X is When R 1 , R 2 , R 3 , R 4 and R 5 At least one of the following is selected from the group consisting of: F, CH 2 F. CHF 2 CF 3 、OCH 2 F. OCHF 2 and OCF 3 and its isotopes, And, wherein the radionuclide chelator is complexed with the compound by: a) Connector L1: b) Connector L2: or c) Linker Lys(azide)-Acp; in: n in connector 1 is an integer selected from the group consisting of 1-30; n in connector 2 is an integer selected from the group consisting of 2-10; n in connector 3 is an integer selected from the group consisting of 1-10; and The radionuclide chelator is 2,2',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA).

2. The composition according to claim 1, wherein X is a group:

3. The composition according to claim 1, wherein R 1 , R 2 , R 3 , R 4 and R 5 In The missing one is F.

4. The composition according to claim 1, wherein R 1 , R 2 , R 3 , R 4 and R 5 At least two of them are F.

5. The composition according to claim 1, wherein at least one of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group: -CH 2 F, -CHF 2 and -CF 3 .

6. The composition according to claim 1, wherein R 1 , R 2 , R 3 , R 4 and R 5 At least one of them is -OCF 3 .

7. The composition according to claim 1, in, At each occurrence, R 6 and R 7 It's all hydrogen.

8. A composition comprising a reaction product in which a targeting ligand is complexed with the compound defined in claim 1, wherein the targeting ligand is a peptide selected from the group consisting of arginylglycylaspartate (RGD), SFLAP3 and PSMA-617.

9. The composition of claim 1, wherein X is 10. The composition of claim 1, wherein X is 11. The composition of claim 1, wherein X is selected from the group consisting of:

12. The composition according to claim 8, wherein the compound is selected from the group consisting of:

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