Conjugates with di- to penta-substituted n-tethered pyridinium permanent cations to deliver cargo to mitochondria

Abstract

The present invention relates to mitochondria targeting conjugates of formula (I) with di- to penta-substituted pyridinium delocalized lipophilic cations to deliver molecular cargo into mitochondria, processes for their preparation, and pharmaceutical compositions containing them as the active ingredient, or dyes Conjugates of the present invention may be useful as modulators of mitochondrial targets (e.g. mitoKV1.3, HSP90, NCLX, cyclophilin D) to treat cancer, cardiovascular, neurological diseases and other diseases, as mitochondria-targeting antioxidants, and as reporters to study the delivery of molecular cargo into mitochondria.

Description

[0001] CONJUGATES WITH DI- TO PENTA-SUBSTITUTED JV-TETHERED PYRIDINIUM PERMANENT CATIONS TO DELIVER CARGO TO MITOCHONDRIA

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to medicine, organic chemistry, treatment of diseases including cancers, to compounds useful for such treatments and to the use of such compounds. Specifically the present invention relates to compounds that are mitochondria targeting conjugates of formula (I) with di- to penta-substituted pyridinium delocalized lipophilic cations to deliver molecular cargo into mitochondria, processes for their preparation, and pharmaceutical compositions containing them as the active ingredient, or as dyes.

[0004] BACKGROUND ART

[0005] Mitochondria-targeting moieties

[0006] The ability to deliver compounds selectively to the mitochondria is rapidly growing in importance due to the increasing relevance of this organelle in disease treatment. The concept of selective targeting of ligands to mitochondria depends on the mitochondrial membrane potential, which is 3- to 5-fold larger than that of the plasma membrane, so that positively charged and lipophilic molecules tend to accumulate in the organelles to achieve electrochemical equilibrium (Battogtokh, G., et al. Front. Pharmacol. 2018, 9, 922). Triphenylphosphonium as delocalized lipophilic cation has been used extensively as a mitochondria-targeting moiety (MTM), i.e. molecular fragment capable of selectively delivering covalently tethered active cargo into mitochondria (Battogtokh et al., Acta Pharm. Sinica B 2008, 8, 862-880) (Murphy, Biochimica et Biophysica Acta 2008, 1777, 1028 - 1031) (Jeena et al., Cancers 2020, 12, 4) (Guo et al., Adv. Mater. 2021, 33, 2007778)(Liew et al., Angew. Chem. Int. Ed. 2021, 60, 2232 - 2256) (Cho et al.; Biochimica et Biophysica Acta 2020, 1866, 165808) (Wang et al., ChemMedChem 2020, 15, 404-410).

[0007] Mitochondria, central to bioenergetic processes such as the Krebs cycle and ROS production, have distinct features in cancer and normal cells, making them an oncological target. Selectively targeting ligands to mitochondria can reduce drug dosing and off-target effects, maximizing harm to cancer cells while minimizing damage to healthy cells. Two strategies leverage these properties to deliver drugs to mitochondria: attaching a mitochondria-targeting ligand to the active compound or using nanocarriers to deliver drugs specifically to mitochondrial compartments. It is well-established that the triphenylphosphonium cation, even when attached to a short carbon chain without an active inhibitor, exhibits anti-proliferative activity in cancer cell lines in the submicromolar range, owing to its intrinsic cytotoxic activity (Millard et al., PLoS ONE 2010, 5, el3131). Nevertheless, gamitrinib, a triphenylphosphonim conjugate with a heat shock protein 90 inhibitor has shown a favorable safety profile in rats and dogs and activity in a murine cancer model (Hayat et al., Cancer Biol. Ther. 2022, 23, 117-126), and is being evaluated in a Phase I clinical trial (NCT04827810).Nitrogen-based permanent cations, including pyridinium, were shown to accumulate in mitochondria and were used as fluorescent probes for visualization of mitochondria and their homeostasis. (Zhang et al., Sensors & Actuators: B. Chemical 2020, 321, 128460) (Reedy et al, Bioconjugate Chem. 2016, 27, 2424-243) (Shen et al., Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2020, 228, 117762) (Ji et al., Dyes and Pigments 2021, 187, 109089) (Tian et al., Dyes and Pigments 2017, 147, 90-98) (Wu et al., Sensors and Actuators B: Chemical 2023, 381, 133471) (Shaikh et al., J. Org. Chem. 2019, 84, 1766-1777) (Jiao et al., Anal. Methods. 2023, 15, 3149-3155). (Ej-4-(2-(lH-indol-3-yl)vinyl)-l-methylpyridin-l-ium cation, dubbed F16 (Fantin et al., Cancer Cell 2002, 2, 29-42), is a monosubstituted pyridinium-based mitochondriotoxic small molecule that was shown to accumulate in mitochondria, and to possess uncoupling propeties, which is related to the (E)-3-(2-(pyridin-4-yl)vinyl)-lH-indole core rather than to its positive charge (Wang et al., Tox. Sci. 2018, 161, 431-442). / V-alkyl-4-methylpyridinium was used as a nitrogen-based mitochondria-targeting moiety to deliver caffeic acid derivatives with antioxidant activity to mitochondria (Benfeito et al., J. Med. Chem. 2023, 66, 1835-1851). / V-Alkyl-4-methylpyridinium and / V-alkyl-3,5-dimethylpyridinium cations, conjugated to betulin were reported. The membranotropic properties of the conjugates were studied, including the effect on the mitochondrial membrane (Dubinin et al., Chem. Biol. Interact. 2021349, 109678).

[0008] Conjugates with di- to penta-substituted / V-tethered pyridinium permanent cations have not been described in the known art to efficiently deliver cargo to mitochondria.

[0009] Mitochondriotropic Kv1.3 channel inhibitors

[0010] The mitochondria of cancerous cells have emerged as an oncological target, as they are involved in bioenergetic processes, such as the Krebs cycle and reactive oxygen species (ROS) production (Nguyen et al., Cancers 2019, 11, 916). Advantages of selective delivery of ligands to mitochondria are reducing off-target effects and drug dosage, thus the use of mitoKv1.3 inhibitors is expected to maximize damage to cancer while minimizing damage to healthy cells (Szabo et al., Redox Biol. 2021, 42, 101846). The specific mitochondria-targeting Kvl.3 inhibitors are lipophilic and membrane-permeable conjugates of the active Kvl.3 channel inhibitors and mitochondria-targeting cations, mostly TPP+. Cations are attached to the active compounds through a stable or labile linker (Battogtokh et al., Frontiers in Pharmacology 2018, 9, 922) (Hayat et al., Cancer Biol. Ther. 2022, 23, 117-126).

[0011] Mitochondriotropic TRAP1 inhibitors

[0012] TRAP1 is the mitochondrial isoform of heat shock protein (Hsp)90 chaperones (Serapian et al., Trends Pharmacol. Sci. 2021, 42, 566-576). Conjugates of non-pyridinium MTM with Hsp90 inhibitors have been prepared and are potentially useful for the treatment of cancer (Lee et al., J. Am. Chem. Soc. 2015, 137, 4358-4367) (Hu et al., J. Med. Chem. 2020, 63, 2930-2940) (Hayat et al., Cancer Biol. Ther. 2022, 23, 117-126). Mitochondriotropic antioxidantsMitochondrial reactive oxygen species (ROS) play essential roles in normal cells' adaptation to stress. However, overproduction of ROS in cells that have lost their normal physiological constraints contributes to some human pathologies (Palma et al., Oncogene 2024, 43, 295-303). Mitochondria-targeted antioxidants are conjugates of mitochondria-targeting moiety, typically TPP+, and antioxidants such as vitamin C, vitamin E, ubiquinone, spin traps, phenols, carotenoids, thiol compounds etc (Wang et al., ChemMedChem 2020, 15, 404-410) (Jiang et al., Oxid. Med. Cell. Longev. 2020, 2020, 8837893). Mitochondria-targeted antioxidants based on known non-pyridinium MTM have shown promising preclinical data and could potentially be used in the treatment of traumatic brain injury (Zhou et al., Am. J. Transl. Res. 2018, 10, 1887-1889) (Ji et al., Nature Neuroscience 2012, 15, 1407-1413), and cardiovascular diseases (Chatfrield et al., J. Am. Coll. Cardiol. Basic Trans. Science 2019, 4, 147-157) and other diseases related to ROS overproduction.

[0013] Mitochondriotropic cyclophilin modulators

[0014] Mitochondria-targeting modulators of cyclophilin family of proteins have been prepared and consist of cyclosporin, tethered to triphenylphosphonium or quinolinium mitochondria-targeting moiety via a covalent linker. (Malouitre et al. Biochem. J. 2010, 425, 137-148)(Dube et al. Biochem. J. 2012, 441, 901-907)(Warne et al. J. Biol. Chem. 2016, 291, 4356-4373)(Pingitore et al. Sci. Adv. 2024, 10, eado3201). They are potentially useful as cytoprotective agents for the treatment of cardiovascular and neurological diseases.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention is based on a new class of conjugates that are useful for delivering molecular cargo into mitochondria based on positively charged di- to penta-substituted lipophilic pyridines. The compounds of the present invention are effective for the treatment of cancer including metastatic cancer and chemoresistance, and other diseases, and for studying transport of molecular cargo into mitochondria. More specifically, the present invention relates in a main aspect to a compound of Formula (I):

[0017]

[0018] wherein R1, R2, R3, R4, R5, W, linker and cargo (reporter, antioxidant or ligand) are as defined herein, and their pharmaceutically acceptable salts, racemates, diastereomers, enantiomers, esters, carbamates, sulphates, phosphates and prodrugs thereof.

[0019] Conjugates of the present invention may be useful as modulators of mitochondrial targets (e.g. mitoKvl.3, HSP90, NCLX) to treat cancer diseases and other diseases, as mitochondria-targeting antioxidants, and as reporters to study the delivery of molecular cargo into mitochondria.

[0020] In other aspects, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or any of its various embodiments.

[0021] Also encompassed by the present invention is the use of compounds of formula (I) or any of its various embodiments in the preparation of a medicament, as well as methods for treatment employing compounds of formula (I) or any of its various embodiments.

[0022] The various aspects of the present invention, including the compound of formula (I) and its various embodiments, are described in more detail below. It should become clear that any details described in connection with one aspect of the present invention applies mutatis mutandis to any other aspect of the present invention.

[0023] The present invention can be summarized by the following items:

[0024] 1. Compound of Formula (I):

[0025]

[0026] wherein:

[0027] "cargo" is an antioxidant, ligand or a reporter;

[0028] R1, R2, R3, R4and R5are independently selected from the group consisting of hydrogen, (Ci-CuJ-alkyl, substituted or unsubstituted aryl, such as phenyl or naphtyl, and substituted or unsubstituted five or six membered heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S, such as a five or six membered aromatic heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S; halo, wherein halo is fluoro, chloro, bromo, or iodo;hydroxy, HO(Ci-Cg)-alkyloxy, (Ci-C4)-perfluoroalkyl, O(CO)CCl3, (Ci-C6)-alkyl-S(O)n-, phenyl-(CH2)r-S(O)n-, cyano, nitro, COOH, CO(Ci-C6)-alkyl, COO(Ci-C6)-alkyl, CONR6R7, NR6R7, O(CO)NR6R7, azido, NR6(CO)NR6R7, (Ci-Ci2)-alkyl, (C2-Cio)-alkenyl, (C2-Cio)-alkynyl, O[(C=O)Or]s(Ci-C6)-alkyl, O[(C=O)Or]s(C2-Cg)-alkenyl, O[(C=O)Or]saryl, O[(C=O)Or]sheteroaryl, O(CH2)nheteroaryl, O(CH2)naryl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0029] wherein the aryl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci-Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-C6)-alkyl-S(O)n-, 0(Co-C6)-alkyl-S(0)n-, phenyl, phenoxy, cycloalkyl, cyano, nitro, COOH, CO(Ci-Cg)-alkyl, COO(Ci-Cg)-alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0030] wherein the heterocyclyl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci-Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-Cg)-alkyl-S(O)n-, 0(Co-C6)-alkyl-S(0)n-, phenyl, phenoxy, cycloalkyl, cyano, nitro, COOH, CO(Ci-Cg)-alkyl, COO(Ci-Cg)-alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0031] wherein R6and R7are independently selected from the group consisting of hydrogen, [(C=O)Or]saryl, [(C=O)Or]s(C2-C8)-alkenyl, [(C=O)Or]s(Ci-C8)-alkyl, (C=O)rS(O)n(Ci-C8)-alkyl, (C=O)rS(O)naryl, and heterocyclyl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0032] wherein R1and R2are optionally connected to form an unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring.

[0033] W is a suitable functional group depending on the available site on the particular cargo of interest which is attached to the linker;

[0034] Linker is selected from:

[0035] -(C(R8)(R9))I-, wherein I is from 1 to 20, preferably from 1 to 10, more preferably 3 to 5; and R8and R9are independently of one another — H, halogen, -CF3,-OH, -(Ci-Cg)-alkyl, -OC(O)(Ci-Cg)- alkyl, [(C=O)Or]saryl, [(C=O)Or]sheteroaryl, or [(C=O)Or]s(Ci-C6)-alkyl;

[0036] A non-peptidic polymeric linker, such as a non-peptidic polymeric linker selected from polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone as well as derivatives and copolymers thereof;A non-polymeric aliphatic linker, such as a non-polymeric aliphatic linker comprising a divalent, linear or branched, straight or cyclic, saturated or unsaturated hydrocarbon chain having from 2 to 20 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)-, -OC(=O)-, -N(CI-C6alkyl)-, NHC(=O)-, -N(CI-C6alkyl)C(=O)-, -S(=O)- or -S(=O)2- and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3 or 4) substituents;

[0037] A divalent radical formed from an amino acid or peptide; and

[0038]

[0039] or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester, carbamate, sulphate, phosphate and prodrug thereof.

[0040] The compound according to item 1, having structural Formula II, wherein pyridinium cation is disubstituted, such that R1and R2are not hydrogen and R3, R4and R5are hydrogen.

[0041]

[0042] The compound according to item 1, having structural Formula III, wherein pyridinium cation is trisubstituted, such that R1, R2and R3are not hydrogen and R4and R5are hydrogen.

[0043] cargo

[0044]

[0045] linker

[0046]

[0047] The compound according to item 1, having structural Formula IV, wherein pyridinium cation is tetrasubstituted, such that R1, R2, R3and R4are not hydrogen and R5is hydrogen.cargo

[0048]

[0049] linker

[0050]

[0051] 5. The compound according to item 1, having structural Formula V, wherein pyridinium cation is pentasubstituted, such that none of R1, R2, R3, R4and R5are hydrogen

[0052]

[0053] 6. The compound according to item 2, wherein R1and R2each are independently selected from the group consisting of substituted or unsubtituted aryl and substituted or unsubstituted five or six membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S.

[0054] 7. The compound according to any one of items 1, 2 and 6 having structural Formula VI

[0055]

[0056] wherein R10is independently of one another — H, halogen, — CF3, —OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl, , or [(C=O)Or]s(Ci-C6)-alkyl.8. The compound according to item 3, wherein R1, R2and R3each are (Ci-CuJ-alkyl, such as a linear or branched alkyl or cycloalkyl.

[0057] 9. The compound according to item 8, wherein Ri is unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring.

[0058] 10. The compound according to any one of the preceding items, wherein R1and R2are not connected to each other to form an unsubstituted cycloalkyl.

[0059] 11. The compound according to item 4, wherein R1and R2are connected to form an unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring, and wherein R3and R4each are independently selected from alkyl or cycloalkyl.

[0060] 12. The compound according to item 3, wherein Ri is a disubstituted phenyl where each of these substituents are independently selected from — H, halogen, — CF3,— OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl or [(C=O)Or]s(Ci-C6)-alkyl.

[0061] 13. The compound according to item 1, wherein R3is hydrogen.

[0062] 14. The compound according to any one of the preceding claims which is selected from the group consisting of

[0063] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium iodide,

[0064] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-4-phenylpyridin-l-ium iodide,

[0065] 2,6-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0066] 3.5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0067] 3.5-dicyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0068] 3-cyclopropyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0069] 2-methyl-5-cyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0070] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)quinolin-l-ium iodide. 2.4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0071] 3.5-bis(4-methoxyphenyl)-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium saccharinate,

[0072] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium acesulfamate,

[0073] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium p-toluenesulfonate,

[0074] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium tetrafluoroborate,

[0075] 3.5-dicyclohexyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0076] 3.5-dicyclopentyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0077] 3-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,

[0078] 5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide,

[0079] 2-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,

[0080] 2.3.5-trimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0081] 3-chloro-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0082] 3-cyclopentyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0083] 3-cyclohexyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0084] 5-cyclopropyl-2,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0085] 2-cyclopropyl-3,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)

[0086] pyridin-l-ium iodide,

[0087] l-(3-(2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)acetamido) propyl)-3,5-diphenylpyridin-l-ium iodide,

[0088] l-(6-(((4E,6Z,9S,10E,12S,13R,14S)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-l(21),4,6,10,18-pentaen-19-yl)amino)hexyl)-3,5-diphenylpyridin-l-ium hexafluorophosphate(V) (Gamitrinib DPPy PF6-),l-(6-((9-(2-(methoxycarbonyl)phenyl)-3-oxo-3H-xanthen-6-yl)oxy)hexyl)-3,5-diphenylpyridin-l-ium iodide,

[0089] l-(10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)decyl)-3,5-diphenylpyridin-l-ium iodide,

[0090] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,5-diphenylpyridin-l-ium iodide,

[0091] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,4-diphenylpyridin-l-ium iodide,

[0092] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chrornen-4-yl)oxy)butoxy)phenyl)propyl)-2,3-diphenylpyridin-l-ium iodide,

[0093] 3-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,

[0094] 4-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide, and

[0095] 5-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide.

[0096] 15. The compound according to anyone of the preceding items, wherein cargo is an anticancer agent selected from the group consisting of Abemaciclib, Abiraterone, Acalabrutinib, Aclarubicin, Actinomycin D, Adagrasib, Adriamycin, Afatinib, Alectinib, Alitretinoin, All-trans-retinoic acid, Alpelisib, Altretamine, Amifostine, Aminolevulinic Acid, Amrubicin, Amsacrine, Anastrozole, Apalutamide, Ara C, Arsenic Trioxide, Asciminib, Avapritinib, Axitinib, Azacitidine, Belinostat, Belzutifan, Bendamustine, Bexarotene, Bicalutamide, Binimetinib, Bleomycin, Bortezomib, Bosutinib, Brigatinib, Buserelin, Busulfan, Cabazitaxel, Cabozantinib, Cabozantinib-S-Malate), Capecitabine, Capivasertib, Capmatinib, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cyproterone acetate, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin), Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dexamethasone, Diethylstilbestrol, Docetaxel, Doxorubicin, Duvelisib, Edotreotide, Eflornithine, Elacestrant, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, Epirubicin, Erdafitinib, Eribulin, Erlotinib, Estramustine, Etoposide, Everolimus, Exemestane, Fedratinib, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, Fostamatinib, Fotemustine, Fruquintinib, Fulvestrant, Futibatinib, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Goserelin, Histamine dihydrochloride, Histrelin, Hydrocortisone, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imetelstat, Imiquimod, Inavolisib, Infigratinib, Irinotecan, Ivosidenib, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Larotrectinib, Lazertinib, Lenalidomide, Lenvatinib, Letrozole, Leuprorelin, Lomustine, Lorlatinib, Lurbinectedin, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan,Mercaptopurine, Methotrexate, Methylnaltrexone Bromide, methylprednisolone, Midostaurin, Mifamurtide, Mitomycin, Mitotane, Mitoxantrone, Mobocertinib, Momelotinib, Nelarabine, Neratinib, Nilotinib, Nilutamide, Nintedanib, Niraparib, Nirogacestat, Octreotide, Olaparib, Olutasidenib, Omacetaxine, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib Citrate, Padeliporfin, Palbociclib, Pamidronate, Panobinostat, Pazopanib, Pemetrexed, Pemigatinib, Pentostatin, Pexidartinib, Pipobroman, Pirarubicin, Pirtobrutinib, Pixantrone, Polyestradiol Phosphate, Pomalidomide, Ponatinib, Porfimer, Pralatrexate, Pralsetinib, Prednisolone, Prednisone, Procarbazine, Quizartinib, Raltitrexed, Ranimustine, Regorafenib, Relugolix, Repotrectinib, Revumenib, Ribociclib, Ripretinib, Rolapitant, Romidepsin, Rucaparib, Ruxolitinib, Selinexor, Selpercatinib, Selumetinib, Sirolimus, Sonidegib, Sorafenib, Sotorasib, Streptozocin, Sunitinib, Talazoparib, Tamoxifen, Tazemetostat, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Tepotinib, Thalidomide, Thioguanine, Thiotepa, Tivozanib, Topotecan, Toremifene, Tovorafenib, Trabectedin, Trametinib, Treosulfan, Tretinoin, Triptorelin, Trofosfamide, Tucatinib, Umbralisib, Uridine Triacetate, Valrubicin, Vandetanib, Vemurafenib, Venetoclax, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorasidenib, Vorinostat, and Zanubrutinib.

[0097] 16. The compound according to any one of items 1 to 14, wherein cargo is a protein ligand moiety selected from modulators of mitochondrial targets.

[0098] 17. The compound according to any one of items 1 to 14 and 16, wherein cargo is an inhibitor of the ion channels in mitochondria (Kv1.3, SK, NCLX)

[0099] 18. The compound according to any one of items 1 to 14 and 16 to 17, wherein cargo is inhibitor of HSP90 in mitochondria.

[0100] 19. The compound according to any one of items 1 to 14, wherein cargo is a reporter like fluorescent dye.

[0101] 20. The compound according to any one of items 1 to 14, wherein cargo is an antioxidant.

[0102] 21. The compound according to any one of items 1 to 14, wherein cargo is an inhibitor of cyclophilin D.

[0103] 22. The compound according to any one of items 1 to 21, which is an enantiomerically pure compound or an enantiomerically enriched compound.

[0104] 23. The compound according to any one of items 1 to 22, wherein W comprises a cleavable group, such as a cleavable group selected from esters, carbamates, disulfide linkers, oxime linkers, hydrazine groups, diazolinkers, carbonyloxyethylsulfone groups, amino acid groups, or phenylacetamide groups.

[0105] 24. The compound according to any one of items 1 to 23, wherein W is selected from the group consisting of (Ci-Cg)-alkyl, (Cj-CgJ-alkenyl, (Cj-CgJ-alkynyl, (Cs-Cgjcycloalkyl, aryl, heteroaryl, -OC(O)NR6-, -COO-, -0C(0)-, -CONR8-, -NHR8-, -SO-, -SO2NR8-, -CHR8-, -SO2-, -CO-, -S-, -O-, -CH2-, -OC(O)-CH2-C(O)O-, and -CH(OH)-CH(OH)-;

[0106] wherein R8is -H, -F, -Cl, -Br, -OH, -(Ci-C6)-alkyl, or -OC(O)(Ci-C6)-alkyl, [(C=O)Or]saryl, or [(C=O)Or]s(Ci-C6)-alkyl.

[0107] 25. The compound according to any one of the preceding items, wherein the linker is -(C(R8)(R9))I-, wherein I is from 1 to 20, preferably from 1 to 10, more preferably 3 to 5; and R8and R9are independently of one another — H, halogen, -CF3,-OH, -(Ci-Cg)-alkyl, -OC(O)(Ci-Cg)-alkyl, [(C=O)Or]saryl, [(C=O)Or]sheteroaryl, or [(C=O)Or]s(Ci-C6)-alkyl.

[0108] 26. The compound according to any one of items 1 to 24, wherein the linker is a non-peptidic polymeric linker, such as a non-peptidic polymeric linker selected from polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone as well as derivatives and copolymers thereof.

[0109] 27. The compound according to any one of items 1 to 24, wherein the linker is a non-polymeric aliphatic linker, such as a non-polymeric aliphatic linker comprising a divalent, linear or branched, straight or cyclic, saturated or unsaturated hydrocarbon chain having from 2 to 20 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)-, -OC(=O)-, -N(Ci-Cg alkyl)-, NHC(=O)-, -N(Ci-Cg alkyl)C(=O)-, -S(=O)- or -S(=O)2- and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3 or 4) substituents.

[0110] 28. The compound according to any one of items 1 to 24, wherein the linker is a divalent radical formed from an amino acid or peptide.

[0111] 29. The compound according to any one of items 1 to 24, wherein the linker is

[0112]

[0113] 30. The compound according to any one of the preceding items, wherein R1is hydrogen.

[0114] 31. The compound according to any one of items 1 to 7, 10, 12 and 15 to 24, wherein R1is substituted or unsubstituted aryl.

[0115] 32. The compound according to any one of items 1 to 5 and 15 to 24, wherein R1is substituted or unsubstituted heterocyclyl.

[0116] 33. The compoundaccording to any one of the preceding items, wherein R1is halogen.

[0117] 34. The compound according to any one of the preceding items, wherein R1is hydroxy.

[0118] 35. The compound according to any one of the preceding items, wherein R1is HOfCi-CgJ-alkyloxy.36. The compound according to any one of the preceding items, wherein R1is (Ci-C4)-perfluoroalkyl. 37. The compound according to any one of the preceding items, wherein R1is O(CO)CCl3

[0119] 38. The compound according to any one of the preceding items, wherein R1is (Ci-C6)-alkyl-S(O)n-.

[0120] 39. The compound according to any one of the preceding items, wherein R1is phenyl-(CH2)r-S(O)n40. The compound according to any one of the preceding items, wherein R1is cyano.

[0121] 41. The compound according to any one of the preceding items, wherein R1is nitro.

[0122] 42. The compound according to any one of the preceding items, wherein R1is COOH.

[0123] 43. The compound according to any one of the preceding items, wherein R1is CO(Ci-Cs)-alkyl.

[0124] 44. The compound according to any one of the preceding items, wherein R1is COO(Ci-Cs)-alkyl.

[0125] 45. The compound according to any one of the preceding items, wherein R1is CONR6R7.

[0126] 46. The compound according to any one of the preceding items, wherein R1is NR6R7.

[0127] 47. The compound according to any one of the preceding items, wherein R1is O(CO)NR6R7.

[0128] 48. The compound according to any one of the preceding items, wherein R1is azido.

[0129] 49. The compound according to any one of the preceding items, wherein R1is NR6(CO)NR6R7.

[0130] 50. The compound according to any one of the preceding items, wherein R1is (Ci-Cio)-alkyl.

[0131] 51. The compound according to any one of the preceding items, wherein R1is (C2-Cio)-alkenyl.

[0132] 52. The compound according to any one of the preceding items, wherein R1is (C2-Cio)-alkynyl.

[0133] 53. The compound according to any one of the preceding items, wherein R1is O[(C=O)Or]s(Ci-C6)-alkyl.

[0134] 54. The compound according to any one of the preceding items, wherein R1is O[(C=O)Or]s(C2-C6)-alkenyl.

[0135] 55. The compound according to any one of the preceding items, wherein R1is O[(C=O)Or]saryl.

[0136] 56. The compound according to any one of the preceding items, wherein R1is O[(C=O)Or]sheteroaryl. 57. The compound according to any one of the preceding items, wherein R1is O(CH2)nheteroaryl.

[0137] 58. The compound according to any one of the preceding items, wherein R1is O(CH2)naryl.

[0138] 59. The compound according to any one of the preceding items, wherein R2is hydrogen.

[0139] 60. The compound according to any one of the preceding items, wherein R2is substituted or unsubstituted aryl.61. The compound according to any one of the preceding items, wherein R2is substituted or unsubstituted heterocyclyl.

[0140] 62. The compound according to any one of the preceding items, wherein R2is halogen.

[0141] 63. The compound according to any one of the preceding items, wherein R2is hydroxy.

[0142] 64. The compound according to any one of the preceding items, wherein R2is HO(Ci-C6)-alkyloxy.

[0143] 65. The compound according to any one of the preceding items, wherein R2is (Ci-C4)-perfluoroalkyl. 66. The compound according to any one of the preceding items, wherein R2is O(CO)CCl3

[0144] 67. The compound according to any one of the preceding items, wherein R2is (Ci-C6)-alkyl-S(O)n-.

[0145] 68. The compound according to any one of the preceding items, wherein R2is phenyl-(CH2)r-S(O)n69. The compound according to any one of the preceding items, wherein R2is cyano.

[0146] 70. The compound according to any one of the preceding items, wherein R2is nitro.

[0147] 71. The compound according to any one of the preceding items, wherein R2is COOH.

[0148] 72. The compound according to any one of the preceding items, wherein R2is CO(Ci-Cs)-alkyl.

[0149] 73. The compound according to any one of the preceding items, wherein R2is COO(Ci-Cs)-alkyl.

[0150] 74. The compound according to any one of the preceding items, wherein R2is CONR6R7.

[0151] 75. The compound according to any one of the preceding items, wherein R2is NR6R7.

[0152] 76. The compound according to any one of the preceding items, wherein R2is O(CO)NR6R7.

[0153] 77. The compound according to any one of the preceding items, wherein R2is azido.

[0154] 78. The compound according to any one of the preceding items, wherein R2is NR6(CO)NR6R7.

[0155] 79. The compound according to any one of the preceding items, wherein R2is (Ci-Cio)-alkyl.

[0156] 80. The compound according to any one of the preceding items, wherein R2is (C2-Cio)-alkenyl.

[0157] 81. The compound according to any one of the preceding items, wherein R2is (C2-Cio)-alkynyl.

[0158] 82. The compound according to any one of the preceding items, wherein R2is O[(C=O)Or]s(Ci-C6)-alkyl.

[0159] 83. The compound according to any one of the preceding items, wherein R2is O[(C=O)Or]s(C2-C6)-alkenyl.

[0160] 84. The compound according to any one of the preceding items, wherein R2is O[(C=O)Or]saryl.

[0161] 85. The compound according to any one of the preceding items, wherein R2is O[(C=O)Or]sheteroaryl.86. The compound according to any one of the preceding items, wherein R2is O(CH2)nheteroaryl.

[0162] 87. The compound according to any one of the preceding items, wherein R2is O(CH2)naryl.

[0163] 88. The compound according to any one of the preceding items, wherein R3is hydrogen.

[0164] 89. The compound according to any one of the preceding items, wherein R3is substituted or unsubstituted aryl.

[0165] 90. The compound according to any one of the preceding items, wherein R3is substituted or unsubstituted heterocyclyl.

[0166] 91. The compound according to any one of the preceding items, wherein R3is halogen.

[0167] 92. The compound according to any one of the preceding items, wherein R3is hydroxy.

[0168] 93. The compound according to any one of the preceding items, wherein R3is HO(Ci-C6)-alkyloxy.

[0169] 94. The compound according to any one of the preceding items, wherein R3is (Ci-C4)-perfluoroalkyl. 95. The compound according to any one of the preceding items, wherein R3is O(CO)CCl3

[0170] 96. The compound according to any one of the preceding items, wherein R3is (Ci-C6)-alkyl-S(O)n-.

[0171] 97. The compound according to any one of the preceding items, wherein R3is phenyl-(CH2)r-S(O)n98. The compound according to any one of the preceding items, wherein R3is cyano.

[0172] 99. The compound according to any one of the preceding items, wherein R3is nitro.

[0173] 100. The compound according to any one of the preceding items, wherein R3is COOH.

[0174] 101. The compound according to any one of the preceding items, wherein R3is CO(Ci-Cs)-alkyl.

[0175] 102. The compound according to any one of the preceding items, wherein R3is COO(Ci-Cs)-alkyl.

[0176] 103. The compound according to any one of the preceding items, wherein R3is CONR6R7.

[0177] 104. The compound according to any one of the preceding items, wherein R3is NR6R7.

[0178] 105. The compound according to any one of the preceding items, wherein R3is O(CO)NR6R7.

[0179] 106. The compound according to any one of the preceding items, wherein R3is azido.

[0180] 107. The compound according to any one of the preceding items, wherein R3is NR6(CO)NR6R7.

[0181] 108. The compound according to any one of the preceding items, wherein R3is (Ci-Cio)-alkyl.

[0182] 109. The compound according to any one of the preceding items, wherein R3is (C2-Cio)-alkenyl.110. The compound according to any one of the preceding items, wherein R3is (C2-Cio)-alkynyl.

[0183] 111. The compound according to any one of the preceding items, wherein R3is O[(C=O)Or]s(Ci-C6)-alkyl.

[0184] 112. The compound according to any one of the preceding items, wherein R3is O[(C=O)Or]s(C2-C6)-alkenyl.

[0185] 113. The compound according to any one of the preceding items, wherein R3is O[(C=O)Or]saryl.

[0186] 114. The compound according to any one of the preceding items, wherein R3is O[(C=O)Or]sheteroaryl.

[0187] 115. The compound according to any one of the preceding items, wherein R3is O(CH2)nheteroaryl. 116. The compound according to any one of the preceding items, wherein R3is O(CH2)naryl.

[0188] 117. The compound according to any one of the preceding items, wherein R4is hydrogen.

[0189] 118. The compound according to any one of the preceding items, wherein R4is substituted or unsubstituted aryl.

[0190] 119. The compound according to any one of the preceding items, wherein R4is substituted or unsubstituted heterocyclyl.

[0191] 120. The compound according to any one of the preceding items, wherein R4is halogen.

[0192] 121. The compound according to any one of the preceding items, wherein R4is hydroxy.

[0193] 122. The compound according to any one of the preceding items, wherein R4is HO(Ci-C6)-alkyloxy. 123. The compound according to any one of the preceding items, wherein R4is (Ci-C4)-perfluoroalkyl.

[0194] 124. The compound according to any one of the preceding items, wherein R4is O(CO)CCl3

[0195] 125. The compound according to any one of the preceding items, wherein R4is (Ci-C6)-alkyl-S(O)n-. 126. The compound according to any one of the preceding items, wherein R4is phenyl-(CH2)r-S(O)n127. The compound according to any one of the preceding items, wherein R4is cyano.

[0196] 128. The compound according to any one of the preceding items, wherein R4is nitro.

[0197] 129. The compound according to any one of the preceding items, wherein R4is COOH.

[0198] 130. The compound according to any one of the preceding items, wherein R4is CO(Ci-Cs)-alkyl.

[0199] 131. The compound according to any one of the preceding items, wherein R4is COO(Ci-Cs)-alkyl.

[0200] 132. The compound according to any one of the preceding items, wherein R4is CONR6R7.

[0201] 133. The compound according to any one of the preceding items, wherein R4is NR6R7.134. The compound according to any one of the preceding items, wherein R4is O(CO)NR6R7.

[0202] 135. The compound according to any one of the preceding items, wherein R4is azido.

[0203] 136. The compound according to any one of the preceding items, wherein R4is NR6(CO)NR6R7.

[0204] 137. The compound according to any one of the preceding items, wherein R4is (Ci-Cio)-alkyl.

[0205] 138. The compound according to any one of the preceding items, wherein R4is (C2-Cio)-alkenyl.

[0206] 139. The compound according to any one of the preceding items, wherein R4is (C2-Cio)-alkynyl.

[0207] 140. The compound according to any one of the preceding items, wherein R4is O[(C=O)Or]s(Ci-C6)-alkyl.

[0208] 141. The compound according to any one of the preceding items, wherein R4is O[(C=O)Or]s(C2-C6)-alkenyl.

[0209] 142. The compound according to any one of the preceding items, wherein R4is O[(C=O)Or]saryl.

[0210] 143. The compound according to any one of the preceding items, wherein R4is O[(C=O)Or]sheteroaryl.

[0211] 144. The compound according to any one of the preceding items, wherein R4is O(CH2)nheteroaryl. 145. The compound according to any one of the preceding items, wherein R4is O(CH2)naryl.

[0212] 146. The compound according to any one of the preceding items, wherein R5is hydrogen.

[0213] 147. The compound according to any one of the preceding items, wherein R5is substituted or unsubstituted aryl.

[0214] 148. The compound according to any one of the preceding items, wherein R5is substituted or unsubstituted heterocyclyl.

[0215] 149. The compound according to any one of the preceding items, wherein R5is halogen.

[0216] 150. The compound according to any one of the preceding items, wherein R5is hydroxy.

[0217] 151. The compound according to any one of the preceding items, wherein R5is HO(Ci-C6)-alkyloxy. 152. The compound according to any one of the preceding items, wherein R5is (Ci-C4)-perfluoroalkyl.

[0218] 153. The compound according to any one of the preceding items, wherein R5is O(CO)CCl3

[0219] 154. The compound according to any one of the preceding items, wherein R5is (Ci-C6)-alkyl-S(O)n-. 155. The compound according to any one of the preceding items, wherein R5is phenyl-(CH2)r-S(O)n156. The compound according to any one of the preceding items, wherein R5is cyano.

[0220] 157. The compound according to any one of the preceding items, wherein R5is nitro.158. The compound according to any one of the preceding items, wherein R5is COOH.

[0221] 159. The compound according to any one of the preceding items, wherein R5is CO(Ci-Cs)-alkyl.

[0222] 160. The compound according to any one of the preceding items, wherein R5is COO(Ci-Cs)-alkyl.

[0223] 161. The compound according to any one of the preceding items, wherein R5is CONR6R7.

[0224] 162. The compound according to any one of the preceding items, wherein R5is NR6R7.

[0225] 163. The compound according to any one of the preceding items, wherein R5is O(CO)NR6R7.

[0226] 164. The compound according to any one of the preceding items, wherein R5is azido.

[0227] 165. The compound according to any one of the preceding items, wherein R5is NR6(CO)NR6R7.

[0228] 166. The compound according to any one of the preceding items, wherein R5is (Ci-Cio)-alkyl.

[0229] 167. The compound according to any one of the preceding items, wherein R5is (C2-Cio)-alkenyl.

[0230] 168. The compound according to any one of the preceding items, wherein R5is (C2-Cio)-alkynyl.

[0231] 169. The compound according to any one of the preceding items, wherein R5is O[(C=O)Or]s(Ci-C6)-alkyl.

[0232] 170. The compound according to any one of the preceding items, wherein R5is O[(C=O)Or]s(C2-C6)-alkenyl.

[0233] 171. The compound according to any one of the preceding items, wherein R5is O[(C=O)Or]saryl.

[0234] 172. The compound according to any one of the preceding items, wherein R5is O[(C=O)Or]sheteroaryl.

[0235] 173. The compound according to any one of the preceding items, wherein R5is O(CH2)nheteroaryl. 174. The compound according to any one of the preceding items, wherein R5is O(CH2)naryl.

[0236] 175. The compound according to any one of the preceding items, wherein R2is phenyl.

[0237] 176. The compound according to any one of the preceding items, wherein R5is phenyl.

[0238] 177. The compound according to any one of the preceding items, wherein R1and R2are aryl.

[0239] 178. The compound according to any one of the preceding items, wherein R1and R2are phenyl.

[0240] 179. The compound according to any one of the preceding items, wherein R1and R2are thienyl.

[0241] 180. The compound according to any one of the preceding items, wherein R1and R2are cyclopropyl. 181. The compound according to any one of the preceding items, wherein R1and R2are 4-methoxyphenyl.

[0242] 182. The compound according to any one of the preceding items, wherein R1is methyl and R2is phenyl.183. The compound according to any one of the preceding items, wherein R1is methyl and R2is cyclopropyl.

[0243] 184. The compound according to any one of the preceding items, wherein R1is methyl and R2is cyclopentyl.

[0244] 185. The compound according to any one of the preceding items, wherein R1is methyl and R2is cyclohexyl.

[0245] 186. The compound according to any one of the preceding items, wherein R1, R2and R3are methyl. 187. The compound according to any one of the preceding items, wherein R1, R2are methyl and R3is cyclopropyl.

[0246] 188. The compound according to any one of the preceding items, wherein R1, R2are methyl and R3is cyclopentyl.

[0247] 189. The compound according to any one of the preceding items for use in medicine.

[0248] 190. The compound according to any one of the preceding items for use in the treatment or prevention of a condition, the treatment of which is affected or facilitated by mitochondrial Kvl.3 inhibition, in a warm-blooded animal, such as a mammal (for example, rat, mouse, guinea pig, rabbit, sheep, horse, pig, cow, monkey, human), preferably human.

[0249] 191. The compound for use according to item 190, wherein the condition is a cancer.

[0250] 192. The compound for use according to item 191, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, smooth muscle cancer, skeletal muscle cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, cancer and / or tumors of the anus, bile duct cancer, bone cancer, bone marrow cancer, , eye cancer, gall bladder cancer, kidney cancer, mouth cancer, laryngeal cancer, esophagus cancer, stomach cancer, cervix cancer, mesothelioma cancer, neuroendocrine cancer, spinal cord, thyroid cancer, vaginal cancer, vulva cancer, uterus cancer, liver cancer, muscle cancer and blood cell cancer (including lymphomas and leukemias).

[0251] 193. The compound for use according to item 191 or 192, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, prostate cancer, melanoma, smooth muscle cancer, skeletal muscle cancer, chronic lymphocytic leukemia, glioblastoma, and pancreatic ductal adenocarcinoma.

[0252] 194. Pharmaceutical composition comprising the compound as defined in any one of items 1 to 188, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient and / or carrier.5. The pharmaceutical composition according to item 194, further comprising a (further) anticancer agent.

[0253] 6. The pharmaceutical composition according to item 195, wherein the anticancer agent is selected from the group consisting of Abemaciclib, Abiraterone, Acalabrutinib, Aclarubicin, Actinomycin D, Adagrasib, Adriamycin, Afatinib, Alectinib, Alitretinoin, All-trans-retinoic acid, Alpelisib, Altretamine, Amifostine, Aminolevulinic Acid, Amrubicin, Amsacrine, Anastrozole, Apalutamide, Ara C, Arsenic Trioxide, Asciminib, Avapritinib, Axitinib, Azacitidine, Belinostat, Belzutifan, Bendamustine, Bexarotene, Bicalutamide, Binimetinib, Bleomycin, Bortezomib, Bosutinib, Brigatinib, Buserelin, Busulfan, Cabazitaxel, Cabozantinib, Cabozantinib-S-Malate), Capecitabine, Capivasertib, Capmatinib, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cyproterone acetate, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin), Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dexamethasone, Diethylstilbestrol, Docetaxel, Doxorubicin, Duvelisib, Edotreotide, Eflornithine, Elacestrant, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, Epirubicin, Erdafitinib, Eribulin, Erlotinib, Estramustine, Etoposide, Everolimus, Exemestane, Fedratinib, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, Fostamatinib, Fotemustine, Fruquintinib, Fulvestrant, Futibatinib, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Goserelin, Histamine dihydrochloride, Histrelin, Hydrocortisone, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imetelstat, Imiquimod, Inavolisib, Infigratinib, Irinotecan, Ivosidenib, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Larotrectinib, Lazertinib, Lenalidomide, Lenvatinib, Letrozole, Leuprorelin, Lomustine, Lorlatinib, Lurbinectedin, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Methylnaltrexone Bromide, methylprednisolone, Midostaurin, Mifamurtide, Mitomycin, Mitotane, Mitoxantrone, Mobocertinib, Momelotinib, Nelarabine, Neratinib, Nilotinib, Nilutamide, Nintedanib, Niraparib, Nirogacestat, Octreotide, Olaparib, Olutasidenib, Omacetaxine, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib Citrate, Padeliporfin, Palbociclib, Pamidronate, Panobinostat, Pazopanib, Pemetrexed, Pemigatinib, Pentostatin, Pexidartinib, Pipobroman, Pirarubicin, Pirtobrutinib, Pixantrone, Polyestradiol Phosphate, Pomalidomide, Ponatinib, Porfimer, Pralatrexate, Pralsetinib, Prednisolone, Prednisone, Procarbazine, Quizartinib, Raltitrexed, Ranimustine, Regorafenib, Relugolix, Repotrectinib, Revumenib, Ribociclib, Ripretinib, Rolapitant, Romidepsin, Rucaparib, Ruxolitinib, Selinexor, Selpercatinib, Selumetinib, Sirolimus, Sonidegib, Sorafenib, Sotorasib, Streptozocin, Sunitinib, Talazoparib, Tamoxifen, Tazemetostat, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Tepotinib, Thalidomide, Thioguanine, Thiotepa, Tivozanib, Topotecan, Toremifene, Tovorafenib, Trabectedin, Trametinib, Treosulfan, Tretinoin, Triptorelin, Trofosfamide, Tucatinib, Umbralisib, Uridine Triacetate, Valrubicin, Vandetanib, Vemurafenib, Venetoclax, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorasidenib, Vorinostat, Zanubrutinib,Alemtuzumab, Amivantamab, Atezolizumab, Avelumab, Belantamab, Bevacizumab, Blinatumomab, Brentuximab, Caplacizumab, Cemiplimab, Cetuximab, Daratumumab, Denosumab, Dinutuximab, Dostarlimab, Durvalumab, Elotuzumab, Elranatamab, Emapalumab, Enfortumab, Epcoritamab, Gemtuzumab, Glofitamab, Ibritumomab, Inotuzumab, Ipilimumab, Isatuximab, Loncastuximab, Margetuximab, Mirvetuximab, Mogamulizumab, Mosunetuzumab, Moxetumomab, Naxitamab, Necitumumab, Nivolumab, Obinutuzumab, Odronextamab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Polatuzumab, Racotumomab, Ramucirumab, Ravulizumab, Relatlimab, Retifanlimab, Rituximab, Sacituzumab, Siltuximab, Sugemalimab, Tafasitamab, Talquetamab, Tarlatamab, Teclistamab, Tislelizumab, Tocilizumab, Toripalimab, Trastuzumab, Tremelimumab, Zanidatamab, Zolbetuximab, Asparaginase, Calaspargase, Epoetin Alfa, Interferon Alfa-2b, Recombinant, lnterleukin-2, Ropeginterferon Alfa, Recombinant HPV bi, tetra or nonvalent vaccine, Nogapendekin Alfa Inbakicept, Granulocyte colony stimulating factor (G-CSF), lobenguane I 131, Lu 177-Dotatate, Radium 223 Dichloride, Idecabtagene Vicleucel, Lisocabtagene Maraleucel, Afamitresgene Autoleucel, Brexucabtagene Autoleucel, Ciltacabtagene Autoleucel, Obecabtagene Autoleucel, , Nadofaragene Firadenovec and Talimogene Laherparepvec.

[0254] 197. The pharmaceutical composition according to any one of items 194 to 196, which comprises nanoparticles having a core comprising one or more of the compounds as defined in items 1 to 188.

[0255] 198. The pharmaceutical composition according to item 197, wherein said core is biodegradable.

[0256] 199. The pharmaceutical composition according to any one of items 194 to 198 for use in medicine. 200. The pharmaceutical composition according to any one of items 194 to 196 for use in the treatment or prevention of a condition, the treatment of which is affected or facilitated by mitochondrial Kvl.3 inhibition, in a warm-blooded animal, such as a mammal (for example, rat, mouse, guinea pig, rabbit, sheep, horse, pig, cow, monkey, human), preferably human.

[0257] 201. The pharmaceutical composition for use according to item 200, wherein the condition is a cancer.

[0258] 202. The pharmaceutical composition for use according to item 201, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, smooth muscle cancer, skeletal muscle cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, cancer and / or tumors of the anus, bile duct cancer, bone cancer, bone marrow cancer, , eye cancer, gall bladder cancer, kidney cancer, mouth cancer, laryngeal cancer, esophagus cancer, stomach cancer, cervix cancer, mesothelioma cancer, neuroendocrine cancer, spinal cord, thyroid cancer, vaginal cancer, vulva cancer, uterus cancer, liver cancer, muscle cancer and blood cell cancer (including lymphomas and leukemias).

[0259] 203. The pharmaceutical composition for use according to item 201 or 202, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, prostate cancer, melanoma, smoothmuscle cancer, skeletal muscle cancer, chronic lymphocytic leukemia, glioblastoma, and pancreatic ductal adenocarcinoma.

[0260] 204. A method of inhibiting Kv1.3 channels in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of compound as defined in any one of items 1 to 188.

[0261] 205. The compound for use according to any one of items 189-193, the pharmaceutical composition for use according to any one of items 201 to 203, or the method of item 204, wherein the warm-blooded animal is a mammal.

[0262] 206. The compound for use of any one of items 189 to 193, the pharmaceutical composition for use of any one of items 201 to 203, or the method of item 204, wherein the warm-blooded animal is a human.

[0263] BRIEF DESCRIPTION OF THE DRAWINGS

[0264] Figure 1. 3-D reconstruction obtained from a z-stack of confocal super-resolution images of cells treated with MitoTracker Deep Red.

[0265] Figure 2. Illustration of the apoptosis where the differences are not significant for normal epithelial cells, but where significantly more apoptosis was detected in cancer-derived cells.

[0266] DETAILED DESCRIPTION OF THE INVENTION

[0267] Definitions

[0268] The compounds, compositions, articles, devices, and methods described herein can be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples and Figures. Before the present compounds, compositions, and methods are disclosed and described it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0269] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.Definitions in this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings: As used in the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "the compound" includes mixtures of two or more such compounds, and the like. When ranges of values are disclosed, and the notation "from m ... to nj" is used, where m and n2are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range can be integral or continuous between and including the end values. By way of example, the range "from 2 to 6 carbons" is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range "from 1 to 3 pM," which is intended to include 1 pM, 3 pM, and everything in between to any number of significant figures (e.g., 1.255 pM, 2.1 pM, 2.9999 pM, etc.).

[0270] The term "about" as used herein is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term "about" should be understood to mean that range which would encompass the recited value itself and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. By "reduce" or other forms of the word, such as "reducing" or "reduction," is meant lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, "reduces tumor growth" means reducing the rate of growth of a tumor relative to a standard or a control.

[0271] By "prevent" or other forms of the word, such as "preventing" or "prevention," is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.

[0272] As used herein, the terms "treating" and "treatment" refer to delaying the onset of, retarding or reversing the progress of, or alleviating or preventing either the disease or condition to which the term applies, or one or more symptoms of such disease or condition.

[0273] The term "individual" (and, equivalently, "subject" or "patient") means all mammals including humans. Examples of individuals include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the individual is a human.The term "disease" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of an individual (e.g., a human or animal body or of one or more of its parts that impairs normal functioning), is typically manifested by distinguishing signs and symptoms, and / or causes the individual to have a reduced duration or quality of life.

[0274] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses useof each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0275] As used herein, the term "administering" means oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a miniosmotic pump, to a subject. Administration is by any route including parenteral, and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0276] The term "therapeutically acceptable" refers to those compounds (or salts, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0277] Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated in the accompanying Examples and Figures. The examples below are intended to further illustrate certain aspects of the methods and compounds described herein, and are not intended to limit the scope of the claims.

[0278] As used herein, the term "alkyl", unless otherwise indicated, includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration (carbocycles). Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. Wherein alkyl includes cyclic as well as acyclic groups and is unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of: halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, oxo, O[(C=O)Or]s(Cl-C6)-alkyl, (Cl-C6)-alkyl-S(0)n-, aryl-(Cl-C6)-alkyloxy, cyano, nitro, vinyl, NR7R8, O(CO)NR7R8, CHO, COOH, CO(Cl-C6)-alkyl, COO(Cl-C6)-alkyl, CONR7R8, aryl, heteroaryl, heterocyclyl, benzyl-S(O)n-, O[(C=O)Or]s(C2-C6)alkenyl, O[(C=O)Or]saryl, O[(C=O)Or]sheteroaryl, O(CH2)nheteroaryl, O(CH2)naryl, fused benzo, CF3, =N-O-(Cl-C6)alkyl-COO-(Cl-C3)alkyl, S(O)n-(C0-C6)alkyl-aryl, wherein aryl is as defined above, or S(O)n-(C0-C6)alkyl-heteroaryl, wherein heteroaryl is as defined above;

[0279] "Alkoxy" represents an alkyl group attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. The following illustrate the foregoing definitions: "(Cl-C3)-al kyl" may be methyl, ethyl, propyl, isopropyl, or cyclopropyl. Similarly, "O-(Cl-C3)-al kyl" may be methoxy, ethoxy, n-propoxy, / -propoxy, or cyclopropoxy. In some cases, a CO designation is used, as in "-(C0-C2)-alkyl-phenyl." In such a case, the substituent is intended to be any of the following: phenyl, benzyl, 1-phenylethyl, or 2-phenylethyl. In certain definitions, the alkyl may be substituted with one or more substituents. For example, a definition which reads "(Cl-C2)-alkyl, substituted with one or two substitutents selected from oxo, hydroxy, and halo" is intended to include C(O)CH3, CH2BrCH3, COOH, C(OH)CH3, CH2CH2(OH), CH2COOH, CHBrCH2CI, CHO, and so on.

[0280] Wherein alkenyl is unsubstituted or substituted with one or two of the substituents selected from the group consisting of: halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, oxo, (Cl-C6)-alkyl-S(O)n-, phenyl-(Cl-C6)-alkyloxy, cyano, nitro, NR7R8, CHO, COOH, CO(Cl-C6)-alkyl, COO(Cl-C6)-alkyl, CONR7R8, aryl, heteroaryl, heterocyclyl,

[0281] Wherein alkynyl is unsubstituted or substituted with one or two of the substituents selected from the group consisting of: halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, oxo, (Cl-C6)-alkyloxy, (C1-C6)-S(O)n-, phenyl-(Cl-C6)-alkyloxy, cyano, nitro, vinyl, NR7R8, NR7CO(Cl-C6)-alkyl, CHO, COOH, CO(Cl-C6)-alkyl, COOC(Cl-C6)-alkyl, CONR7R8, aryl, heteroaryl, heterocyclyl, O[(C=O)Or]s(Cl-C6)-alkyl, O[(C=O)Or]s(C2-C6)-alkenyl, O[(C=O)Or]saryl, O[(C=O)Or]sheteroaryl, O(CH2)nheteroaryl, and O(CH2)naryl.

[0282] Wherein heterocyclyl is defined as a 3 to 7 atom cyclic, non-aromatic substituent containing from 1 to 3 heteroatoms selected from the group consisting of O, N, and S, said heterocycle being unsubstituted or substituted with one, two or three substituents selected from the group consisting of: halo, as defined above, hydroxy, (Cl-C6)-alkyl, (Cl-C4)-perfluoroalkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (Cl-C6)-alkyloxy, (C1-C6)-alkyl-S(O)n-, phenyl, phenoxy, cyano, nitro, COOH, CO(Cl-C6)-alkyl, COO(Cl-C6)-alkyl, CONR7R8, NR7R8, NR4CO(Cl-C6)-alkyl, oxo, thioxo, fused benzo, and fused pyridyl group.

[0283] "Alkenyl" is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched- configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethyl pentenyl, and the like, and includes E and Z forms, where applicable. "Halogen" and "halo", as used herein, mean fluoro, chloro, bromo and iodo. The term "aryl," unless specifically defined otherwise, defined as phenyl or naphthyl, unsubstituted or substituted with one, two or three of the substituents selected from the group consisting of halo, hydroxy,alkyl, perfluoroalkyl, alkenyl, alkynyl, alkyloxy, alkyl- S(O)n-, phenyl, phenoxy, cyano, nitro, COOH, CO-alkyl, COO-alkyl, CONR7R8, and NR7R8.

[0284] The term "heteroaryl" as utilized herein, unless specifically defined otherwise, is intended to include the following: an unsubstituted, monosubstituted, or disubstituted five or six membered aromatic heterocycle containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituent is halo, hydroxy, alkyl, perfluoroalkyl, alkenyl, alkynyl, alkyloxy, -alkyl-S(O)n-, phenyl, phenoxy, cyano, nitro, COOH, CO-alkyl, COO-alkyl, CONR7R8,and NR7R8; Or a fused benzo or pyridyl group. Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and pyrrolyl which are substituted or unsubstituted as defined above.

[0285] In the compounds of Formula I, the heteroaryl or aryl groups may be optionally substituted with the substituents listed above at any available carbon atom or nitrogen atom (if present), but compounds bearing certain substitutents, directly substituted to a nitrogen may be relatively unstable and are not preferred. The heteroaryl may also be fused to a second 5-, 6-, or 7-membered ring containing one or two oxygens such as: dioxolanyl, dihydrofuranyl, dihydropyranyl, and dioxanyl. Disubstituted aryl groups may be ortho, para or meta and all three are intended unless specifically defined otherwise.

[0286] The term "halogen" is used to denote fluoro, chloro, bromo, or iodo. Particular halogens are chloro and bromo. More particular halogen is chloro.

[0287] The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, / V-acetylcysteine and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, / V-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of compounds of formula (I) are the hydrochloride salts, methanesulfonic acid salts and citric acid salts.The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the following Derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well-known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drug design and Discovery" Taylor & Francis (April 2002).

[0288] The term "warm-blooded animal" refers to a member of the animal kingdom which possesses a homeostatic mechanism and includes mammals and birds.

[0289] Compound of the present invention

[0290] The present invention provide is a main aspect compounds of formula (I) which are conjugates of substituted pyridinium-based mitochondria targeting moiety and cargo moiety, which is selected from modulators of mitochondrial targets, a fluorescent dye or antioxidant. More specifically, the present invention provides a compound of formula (I):

[0291]

[0292] wherein:

[0293] "cargo" is a ligand, antioxidant or a reporter;

[0294] R1, R2, R3, R4and R5are independently selected from the group consisting of hydrogen, (Ci-Cio)-alkyl substituted or unsubstituted aryl, such as phenyl or naphtyl, and substituted or unsubstituted five or six membered heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S, such as a five or six membered aromatic heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S; halo, wherein halo is fluoro, chloro, bromo, or iodo; hydroxy, HOfCi-Cg)-alkyloxy, (Ci-C4)-perfluoroalkyl, O(CO)CCl3, (Ci-C6)-alkyl-S(O)n-, phenyl-(CH2)r-S(O)n-, cyano, nitro, COOH, CO(Ci-C6)-alkyl, COO(Ci-C6)-alkyl, CONR6R7, NR6R7, O(CO)NR6R7, azido, NR6(CO)NR6R7, (Ci-Cio)-alkyl, (C2-Cio)-alkenyl, (C2-Cio)-alkynyl, O[(C=O)Or]s(Ci-C6)-alkyl, O[(C=O)Or]s(C2-C6)-alkenyl, O[(C=O)Or]saryl, O[(C=O)Or]sheteroaryl, O(CH2)nheteroaryl, O(CH2)naryl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0295] wherein the aryl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci-Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-C6)-alkyl-S(O)n-, 0(Co-C6)-alkyl-S(0)n-, phenyl, phenoxy, cyano, nitro, COOH, CO(Ci-Cg)-alkyl, COO(Ci-Cg)-alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0296] wherein the heterocyclyl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci-Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-C6)-alkyl-S(O)n-, O(Co-Cg)-alkyl-S(O)n-, phenyl, phenoxy, cyano, nitro, COOH, CO(Ci-Cg)-alkyl, COO(Ci-Cg)-alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0297] wherein R6and R7are independently selected from the group consisting of hydrogen, [(C=O)Or]saryl, [(C=O)Or]s(C2-Cg)-alkenyl, [(C=O)Or]s(Ci-Cg)-alkyl, (C=O)rS(O)n(Ci-Cg)-alkyl, (C=O)rS(O)naryl, and heterocyclyl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;

[0298] W is a suitable functional group depending on the available site on the particular cargo of interest which is attached to the linker;

[0299] Linker is selected from:

[0300] -(C(R8)(R9))I-, wherein I is from 1 to 20, preferably from 1 to 10, more preferably 3 to 5; and R8and R9are independently of one another — H, halogen, -CF3,-OH, -(Ci-Cg)-alkyl, -OC(O)(Ci-Cg)-alkyl, [(C=O)Or]saryl, [(C=O)Or]sheteroaryl, or [(C=O)Or]s(Ci-C6)-alkyl;

[0301] Non-peptidic polymeric linkers, such as non-peptidic polymeric linkers selected from polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone as well as derivatives and copolymers thereof;

[0302] Non-polymeric aliphatic linkers, such as non-polymeric aliphatic linkers comprising a divalent, linear or branched, straight or cyclic, saturated or unsaturated hydrocarbon chain having from 2 to 20 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)- , -OC(=O)-, -N(Ci-Cg alkyl)-, NHC(=O)-, -N(Ci-Cg alkyl)C(=O)-, -S(=O)- or -S(=O)2- and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3 or 4) substituents;A divalent radical formed from an amino acid or peptide; and

[0303]

[0304] or a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester, carbamate, sulphate, phosphate and prodrug thereof.

[0305] According to some embodiments, the compound of formula I is a compound of structural Formula II

[0306]

[0307] According to some embodiments, the compound of formula I is a compound of structural Formula III

[0308] cargo

[0309]

[0310] linker

[0311]

[0312] According to some embodiments, the compound of formula I is a compound of structural Formula IV

[0313] cargo

[0314]

[0315] linker

[0316]

[0317] According to some embodiments, the compound of formula I is a compound of structural Formula Vcargo

[0318]

[0319]

[0320] According to some embodiments, the compound of formula I is a compound of structural Formula VI

[0321]

[0322] wherein R10is independently of one another — H, halogen, — CF3, —OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl, , or [(C=O)Or]s(Ci-C6)-alkyl.

[0323] According to some embodiments, the compound has R1, R2and R3each being (Ci-CuJ-alkyl, such as a linear or branched alkyl or cycloalkyl.

[0324] According to some embodiments, the compound has Ri being unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring.

[0325] According to some embodiments, the compound has R1and R2as not being connected to each other to form an unsubstituted cycloalkyl.

[0326] According to some embodiments, the compound has R1and R2being connected to form an unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring, and wherein R3and R4each are independently selected from alkyl or cycloalkyl.

[0327] According to some embodiments, the compound has Ri being a disubstituted phenyl where each of these substituents are independently selected from — H, halogen, — CF3,— OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl or [(C=O)Or]s(Ci-C6)-alkyl.According to some embodiments, the compound has R3being hydrogen.

[0328] According to some embodiments, the compound is selected from the group consisting of

[0329] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium iodide,

[0330] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-4-phenylpyridin-l-ium iodide,

[0331] 2,6-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0332] 3.5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0333] 3.5-dicyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0334] 3-cyclopropyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0335] 2-methyl-5-cyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0336] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)quinolin-l-ium iodide. 2.4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0337] 3.5-bis(4-methoxyphenyl)-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide,

[0338] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium saccharinate,

[0339] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium acesulfamate,

[0340] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium p-toluenesulfonate,

[0341] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium tetrafluoroborate,

[0342] 3.5-dicyclohexyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,

[0343] 3.5-dicyclopentyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0344] 3-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5- phenylpyridin-l-ium iodide,5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide,

[0345] 2-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,

[0346] 2,3,5-trimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0347] 3-chloro-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,

[0348] 3-cyclopentyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0349] 3-cyclohexyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0350] 5-cyclopropyl-2,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,

[0351] 2-cyclopropyl-3,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)

[0352] pyridin-l-ium iodide,

[0353] l-(3-(2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)acetamido) propyl)-3,5-diphenylpyridin-l-ium iodide,

[0354] l-(6-(((4E,6Z,9S,10E,12S,13R,14S)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-l(21),4,6,10,18-pentaen-19-yl)amino)hexyl)-3,5-diphenylpyridin-l-ium hexafluorophosphate(V) (Gamitrinib DPPy PF6-), l-(6-((9-(2-(methoxycarbonyl)phenyl)-3-oxo-3H-xanthen-6-yl)oxy)hexyl)-3,5-diphenylpyridin-l-ium iodide,

[0355] l-(10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)decyl)-3,5-diphenylpyridin-l-ium iodide,

[0356] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,5-diphenylpyridin-l-ium iodide,

[0357] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,4-diphenylpyridin-l-ium iodide,

[0358] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,3-diphenylpyridin-l-ium iodide,

[0359] 3-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,

[0360] 4-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide, and5-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide.

[0361] According to some embodiments, the compound has the cargo being an anticancer agent selected from the group consisting of Abemaciclib, Abiraterone, Acalabrutinib, Aclarubicin, Actinomycin D, Adagrasib, Adriamycin, Afatinib, Alectinib, Alitretinoin, All-trans-retinoic acid, Alpelisib, Altretamine, Amifostine, Aminolevulinic Acid, Amrubicin, Amsacrine, Anastrozole, Apalutamide, Ara C, Arsenic Trioxide, Asciminib, Avapritinib, Axitinib, Azacitidine, Belinostat, Belzutifan, Bendamustine, Bexarotene, Bicalutamide, Binimetinib, Bleomycin, Bortezomib, Bosutinib, Brigatinib, Buserelin, Busulfan, Cabazitaxel, Cabozantinib, Cabozantinib-S-Malate), Capecitabine, Capivasertib, Capmatinib, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cyproterone acetate, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin), Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dexamethasone, Diethylstilbestrol, Docetaxel, Doxorubicin, Duvelisib, Edotreotide, Eflornithine, Elacestrant, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, Epirubicin, Erdafitinib, Eribulin, Erlotinib, Estramustine, Etoposide, Everolimus, Exemestane, Fedratinib, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, Fostamatinib, Fotemustine, Fruquintinib, Fulvestrant, Futibatinib, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Goserelin, Histamine dihydrochloride, Histrelin, Hydrocortisone, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imetelstat, Imiquimod, Inavolisib, Infigratinib, Irinotecan, Ivosidenib, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Larotrectinib, Lazertinib, Lenalidomide, Lenvatinib, Letrozole, Leuprorelin, Lomustine, Lorlatinib, Lurbinectedin, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Methylnaltrexone Bromide, methylprednisolone, Midostaurin, Mifamurtide, Mitomycin, Mitotane, Mitoxantrone, Mobocertinib, Momelotinib, Nelarabine, Neratinib, Nilotinib, Nilutamide, Nintedanib, Niraparib, Nirogacestat, Octreotide, Olaparib, Olutasidenib, Omacetaxine, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib Citrate, Padeliporfin, Palbociclib, Pamidronate, Panobinostat, Pazopanib, Pemetrexed, Pemigatinib, Pentostatin, Pexidartinib, Pipobroman, Pirarubicin, Pirtobrutinib, Pixantrone, Polyestradiol Phosphate, Pomalidomide, Ponatinib, Porfimer, Pralatrexate, Pralsetinib, Prednisolone, Prednisone, Procarbazine, Quizartinib, Raltitrexed, Ranimustine, Regorafenib, Relugolix, Repotrectinib, Revumenib, Ribociclib, Ripretinib, Rolapitant, Romidepsin, Rucaparib, Ruxolitinib, Selinexor, Selpercatinib, Selumetinib, Sirolimus, Sonidegib, Sorafenib, Sotorasib, Streptozocin, Sunitinib, Talazoparib, Tamoxifen, Tazemetostat, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Tepotinib, Thalidomide, Thioguanine, Thiotepa, Tivozanib, Topotecan, Toremifene, Tovorafenib, Trabectedin, Trametinib, Treosulfan, Tretinoin, Triptorelin, Trofosfamide, Tucatinib, Umbralisib, Uridine Triacetate, Valrubicin, Vandetanib, Vemurafenib, Venetoclax, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorasidenib, Vorinostat, and Zanubrutinib.According to some embodiments, cargo is protein ligand moiety selected from modulators of mitochondrial targets.

[0362] According to some embodiments, cargo is inhibitor of the ion channels in mitochondria (Kv1.3, SK, NCLX) According to some embodiments, cargo is inhibitor of HSP90 in mitochondria.

[0363] According to some embodiments, cargo is fluorescent dye.

[0364] According to some embodiments, cargo is antioxidant.

[0365] Accordin to some embodiments, cargo is an inhibitor of cyclophilin D.

[0366] According to some embodiments, W comprises a cleavable group, which is selected from esters, carbamates, disulfide linkers, oxime linkers, hydrazine groups, diazolinkers, carbonyloxyethylsulfone groups, amino acid groups, and phenylacetamide groups.

[0367] According to some embodiments, W is selected from (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (C3-C6)cycloalkyl, aryl, heteroaryl, -OC(O)NR6-, -COO-, -OC(O)-, -CONR8-, -NHR8-, -SO-, -SO2NR8-, -CHR8-, -SO2-, -CO-, -S-, -O-, -CH2-, -OC(O)-CH2-C(O)O-, and -CH(OH)-CH(OH)-; wherein R8is -H, -F, -Cl, -Br, -OH, -(Ci-C6)-alkyl, or -OC(O)(Ci-C6)-alkyl, [(C=O)Or]saryl, or [(C=O)Or]s(Ci-C6)-alkyl.

[0368] According to some embodiments, R1is hydrogen.

[0369] According to some embodiments, R1is substituted or unsubstituted aryl.

[0370] According to some embodiments, R1is substituted or unsubstituted heterocyclyl.

[0371] According to some embodiments, R1is halogen.

[0372] According to some embodiments, R1is hydroxy.

[0373] According to some embodiments, R1is selected from HOfCi-CgJ-alkyloxy.

[0374] According to some embodiments, R1is selected from (Ci-C4)-perfluoroalkyl.

[0375] According to some embodiments, R1is O(CO)CCl3

[0376] According to some embodiments, R1is selected from (Ci-C6)-alkyl-S(O)n-.

[0377] According to some embodiments, R1is selected from phenyl-(CH2)r-S(O)n

[0378] According to some embodiments, R1is cyano.

[0379] According to some embodiments, R1is nitro.

[0380] According to some embodiments, R1is COOH.According to some embodiments, R1is selected from CO(Ci-Cs)-alkyl. According to some embodiments, R1is selected from COO(Ci-Cs)-alkyl.

[0381] According to some embodiments, R1is selected from CONR6R7.

[0382] According to some embodiments, R1is selected from NR6R7.

[0383] According to some embodiments, R1is selected from O(CO)NR6R7.

[0384] According to some embodiments, R1is azido.

[0385] According to some embodiments, R1is selected from NR6(CO)NR6R7.

[0386] According to some embodiments, R1is selected from (Ci-Cio)-alkyl.

[0387] According to some embodiments, R1is selected from (C2-Cio)-alkenyl.

[0388] According to some embodiments, R1is selected from (C2-Cio)-alkynyl.

[0389] According to some embodiments, R1is selected from O[(C=O)Or]s(Ci-C6)-alkyl. According to some embodiments, R1is selected from O[(C=O)Or]s(C2-C6)-alkenyl. According to some embodiments, R1is selected from O[(C=O)Or]saryl.

[0390] According to some embodiments, R1is selected from O[(C=O)Or]sheteroaryl. According to some embodiments, R1is selected from O(CH2)nheteroaryl.

[0391] According to some embodiments, R1is selected from O(CH2)naryl.

[0392] According to some embodiments, R2is hydrogen.

[0393] According to some embodiments, R2is substituted or unsubstituted aryl.

[0394] According to some embodiments, R2is substituted or unsubstituted heterocyclyl. According to some embodiments, R2is halogen.

[0395] According to some embodiments, R2is hydroxy.

[0396] According to some embodiments, R2is selected from HO(Ci-C6)-alkyloxy.

[0397] According to some embodiments, R2is selected from (Ci-C4)-perfluoroalkyl. According to some embodiments, R2is O(CO)CCI3

[0398] According to some embodiments, R2is selected from (Ci-C6)-alkyl-S(O)n-.

[0399] According to some embodiments, R2is selected from phenyl-(CH2)r-S(O)nAccording to some embodiments, R2is cyano.

[0400] According to some embodiments, R2is nitro.

[0401] According to some embodiments, R2is COOH.

[0402] According to some embodiments, R2is selected from CO(Ci-Cs)-alkyl.

[0403] According to some embodiments, R2is selected from COO(Ci-Cs)-alkyl.

[0404] According to some embodiments, R2is selected from CONR6R7.

[0405] According to some embodiments, R2is selected from NR6R7.

[0406] According to some embodiments, R2is selected from O(CO)NR6R7.

[0407] According to some embodiments, R2is azido.

[0408] According to some embodiments, R2is selected from NR6(CO)NR6R7.

[0409] According to some embodiments, R2is selected from (Ci-Cio)-alkyl.

[0410] According to some embodiments, R2is selected from (C2-Cio)-alkenyl.

[0411] According to some embodiments, R2is selected from (C2-Cio)-alkynyl.

[0412] According to some embodiments, R2is selected from O[(C=O)Or]s(Ci-C6)-alkyl. According to some embodiments, R2is selected from O[(C=O)Or]s(C2-C6)-alkenyl. According to some embodiments, R2is selected from O[(C=O)Or]saryl.

[0413] According to some embodiments, R2is selected from O[(C=O)Or]sheteroaryl. According to some embodiments, R2is selected from O(CH2)nheteroaryl.

[0414] According to some embodiments, R2is selected from O(CH2)naryl.

[0415] According to some embodiments, R3is hydrogen.

[0416] According to some embodiments, R3is substituted or unsubstituted aryl.

[0417] According to some embodiments, R3is substituted or unsubstituted heterocyclyl. According to some embodiments, R3is halogen.

[0418] According to some embodiments, R3is hydroxy.

[0419] According to some embodiments, R3is selected from HO(Ci-C6)-alkyloxy.

[0420] According to some embodiments, R3is selected from (Ci-C4)-perfluoroalkyl.According to some embodiments, R3is O(CO)CCl3

[0421] According to some embodiments, R3is selected from (Ci-C6)-alkyl-S(0)n-.

[0422] According to some embodiments, R3is selected from phenyl-(CH2)r-S(O)nAccording to some embodiments, R3is cyano.

[0423] According to some embodiments, R3is nitro.

[0424] According to some embodiments, R3is COOH.

[0425] According to some embodiments, R3is selected from CO(Ci-Cs)-alkyl.

[0426] According to some embodiments, R3is selected from COO(Ci-Cs)-alkyl.

[0427] According to some embodiments, R3is selected from CONR6R7.

[0428] According to some embodiments, R3is NR6R7.

[0429] According to some embodiments, R3is selected from O(CO)NR6R7.

[0430] According to some embodiments, R3is azido.

[0431] According to some embodiments, R3is selected from NR6(CO)NR6R7.

[0432] According to some embodiments, R3is selected from (Ci-Cio)-alkyl.

[0433] According to some embodiments, R3is selected from (C2-Cio)-alkenyl.

[0434] According to some embodiments, R3is selected from (C2-Cio)-alkynyl.

[0435] According to some embodiments, R3is selected from O[(C=O)Or]s(Ci-C6)-alkyl. According to some embodiments, R3is selected from O[(C=O)Or]s(C2-C6)-alkenyl. According to some embodiments, R3is selected from O[(C=O)Or]saryl.

[0436] According to some embodiments, R3is selected from O[(C=O)Or]sheteroaryl. According to some embodiments, R3is selected from O(CH2)nheteroaryl.

[0437] According to some embodiments, R3is selected from O(CH2)naryl.

[0438] According to some embodiments, R4is hydrogen.

[0439] According to some embodiments, R4is substituted or unsubstituted aryl.

[0440] According to some embodiments, R4is substituted or unsubstituted heterocyclyl. According to some embodiments, R4is halogen.According to some embodiments, R4is hydroxy.

[0441] According to some embodiments, R4is selected from HO(Ci-C6)-alkyloxy.

[0442] According to some embodiments, R4is selected from (Ci-C4)-perfluoroalkyl. According to some embodiments, R4is selected from O(CO)CCl3 According to some embodiments, R4is selected from (Ci-C6)-alkyl-S(O)n-.

[0443] According to some embodiments, R4is selected from phenyl-(CH2)r-S(O)nAccording to some embodiments, R4is cyano.

[0444] According to some embodiments, R4is nitro.

[0445] According to some embodiments, R4is COOH.

[0446] According to some embodiments, R4is selected from CO(Ci-Cs)-alkyl.

[0447] According to some embodiments, R4is selected from COO(Ci-Cs)-alkyl.

[0448] According to some embodiments, R4is selected from CONR6R7.

[0449] According to some embodiments, R4is selected from NR6R7.

[0450] According to some embodiments, R4is selected from O(CO)NR6R7.

[0451] According to some embodiments, R4is azido.

[0452] According to some embodiments, R4is selected from NR6(CO)NR6R7.

[0453] According to some embodiments, R4is selected from (Ci-Cio)-alkyl.

[0454] According to some embodiments, R4is selected from (C2-Cio)-alkenyl.

[0455] According to some embodiments, R4is selected from (C2-Cio)-alkynyl.

[0456] According to some embodiments, R4is selected from O[(C=O)Or]s(Ci-C6)-alkyl. According to some embodiments, R4is selected from O[(C=O)Or]s(C2-C6)-alkenyl. According to some embodiments, R4is selected from O[(C=O)Or]saryl.

[0457] According to some embodiments, R4is selected from O[(C=O)Or]sheteroaryl. According to some embodiments, R4is selected from O(CH2)nheteroaryl.

[0458] According to some embodiments, R4is selected from O(CH2)naryl.

[0459] According to some embodiments, R5is hydrogen.According to some embodiments, R5is substituted or unsubstituted aryl.

[0460] According to some embodiments, R5is substituted or unsubstituted heterocyclyl. According to some embodiments, R5is halogen.

[0461] According to some embodiments, R5is hydroxy.

[0462] According to some embodiments, R5is selected from HO(Ci-C6)-alkyloxy.

[0463] According to some embodiments, R5is selected from (Ci-C4)-perfluoroalkyl. According to some embodiments, R5is O(CO)CCl3

[0464] According to some embodiments, R5is selected from (Ci-C6)-alkyl-S(O)n-.

[0465] According to some embodiments, R5is selected from phenyl-(CH2)r-S(O)nAccording to some embodiments, R5is cyano.

[0466] According to some embodiments, R5is nitro.

[0467] According to some embodiments, R5is COOH.

[0468] According to some embodiments, R5is selected from CO(Ci-Cs)-alkyl.

[0469] According to some embodiments, R5is selected from COO(Ci-Cs)-alkyl.

[0470] According to some embodiments, R5is selected from CONR6R7.

[0471] According to some embodiments, R5is selected from NR6R7.

[0472] According to some embodiments, R5is selected from O(CO)NR6R7.

[0473] According to some embodiments, R5is azido.

[0474] According to some embodiments, R5is selected from NR6(CO)NR6R7.

[0475] According to some embodiments, R5is selected from (Ci-Cio)-alkyl.

[0476] According to some embodiments, R5is selected from (C2-Cio)-alkenyl.

[0477] According to some embodiments, R5is selected from (C2-Cio)-alkynyl.

[0478] According to some embodiments, R5is selected from O[(C=O)Or]s(Ci-C6)-alkyl. According to some embodiments, R5is selected from O[(C=O)Or]s(C2-C6)-alkenyl. According to some embodiments, R5is selected from O[(C=O)Or]saryl.

[0479] According to some embodiments, R5is selected from O[(C=O)Or]sheteroaryl.According to some embodiments, R5is selected from O(CH2)nheteroaryl.

[0480] According to some embodiments, R5is selected from O(CH2)naryl.

[0481] According to some embodiments, R2is phenyl.

[0482] According to some embodiments, R5is phenyl.

[0483] According to some embodiments, R1and R2are aryl.

[0484] According to some embodiments, R1and R2are phenyl.

[0485] According to some embodiments, R1and R2are thienyl.

[0486] According to some embodiments, R1and R2are cyclopropyl.

[0487] According to some embodiments, R1and R2are 4-methoxyphenyl.

[0488] According to some embodiments, R1is methyl and R2is phenyl.

[0489] According to some embodiments, R1is methyl and R2is cyclopropyl.

[0490] According to some embodiments, R1is methyl and R2is cyclopentyl.

[0491] According to some embodiments, R1is methyl and R2is cyclohexyl.

[0492] According to some embodiments, R1, R2and R3are methyl.

[0493] According to some embodiments, R1, R2are methyl and R3is cyclopropyl.

[0494] According to some embodiments, R1, R2are methyl and R3is cyclopentyl.

[0495] Methods and Compositions

[0496] Cargo Moiety

[0497] "Cargo" in the formulas disclosed herein is a moiety that is a modulator of mitochondrial function or a fluorescent dye. The cargo moiety typically does not accumulate in mitochondria when it is not conjugated to mitochondria-targeting moiety. Exemplary cargo moieties that can be incorporated into the disclosed compounds are modulators of mitochondrial therapeutic targets such as mitochondrial ion channels (Szabo and Szewczyk, Anna. Rev. Biophys. 2023, 52, 229-254) and TRAP1 (Kang and Kang, J. Med. Chem. 2022, 65, 16155-16172), antioxidants such as ubiquinone analogs, vitamin C analogs, vitamin E analogs, 2, 2,6,6-tetramethylpiperidine-V-oxyl etc. (Wang et al., ChemMedChem 2020, 15, 404-410), uncharged fluorescent dyes such as fluorescein esters, nile red, coumarin-cored dyes, inhibitors of cyclophilin D (Haleckova et al. Med. Res. Rev. 2022, 42, 1822-1855) etc.Nanoparticles

[0498] In certain aspects, the disclosed compounds can be incorporated into nanoparticles. Suitable nanoparticles include a core and one or more of the compounds disclosed herein. The disclosed compounds can be contained or embedded within the core. The disclosed compounds are preferably released from the core at a desired rate. The core is biodegradable and releases the disclosed compounds as the core is degraded or eroded. The targeting moieties preferably extend outwardly from the core so that they are available for interaction with the cellular components, which interactions will target the nanoparticles to the appropriate cells, such as apoptotic cells; organelles, such as mitochondria; or the like.

[0499] The core of the nanoparticle can be formed from any suitable component or components. Preferably, the core is formed from hydrophobic components such as hydrophobic polymers or hydrophobic portions or polymers or lipids. In certain examples, the core includes phospholipids which can form micelles having a hydrophobic core and a hydrophilic outer surface. The core can also or alternatively include block copolymers that have hydrophobic portions and hydrophilic portions that can self-assemble in an aqueous environment into particles having the hydrophobic core and a hydrophilic out surface. In certain examples, the core comprises one or more biodegradable polymers or a polymer having a biodegradable portion. Any suitable synthetic or natural biodegradable polymer can be used. Such polymers are recognizable and identifiable by one or ordinary skilled in the art. Non-limiting examples of synthetic, biodegradable polymers include: poly(amides) such as poly(amino acids) and polypeptides); poly(esters) such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid) (PLGA), and poly(caprolactone); poly(anhydrides); poly(orthoesters); poly(carbonates); and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), fibrin, fibrinogen, cellulose, starch, collagen, and hyaluronic acid, copolymers and mixtures thereof. The properties and release profiles of these and other suitable polymers are known or readily identifiable. Preferably, at least some of the polymers used to form the core are amphiphilic having hydrophobic portions and hydrophilic portions. The hydrophobic portions can form the core, while the hydrophilic regions can for a shell that helps the nanoparticle evade recognition by the immune system and enhances circulation halflife. Examples of amphiphilic polymers include block copolymers having a hydrophobic block and a hydrophilic block. In various examples, the core is formed from hydrophobic portions of a block copolymer, a hydrophobic polymer, or combinations thereof.

[0500] Any suitable hydrophilic polymer can form a hydrophilic block of a block copolymer. Examples of suitable hydrophilic polymers include polysaccharides, dextran, chitosan, hyaluronic acid, and the like. In embodiments, polyethylene glycol (PEG) is a hydrophilic polymer used to serve as the hydrophilic portion of a block copolymer. Nanoparticles, as described herein, can be of any suitable size. Generally, the nanoparticles are of a diametric dimension of less than about 999 nanometers, such as less than about 750 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, or less than about 200 nm. In addition, or alternatively, the nanoparticles can be of a diametric dimension of greaterthan about 5 nm. In embodiments, the nanoparticles are from about 30 nm to about 300 nm in diameter. In embodiments, the nanoparticles are separated according to size, such as from about 20 nm to about 40 nm, from about 40 nm to about 60 nm, from about 60 nm to about 80 nm, from about 80 nm to about 100 nm, or from about 100 nm to about 150 nm.

[0501] Nanoparticles, as described herein, can be synthesized or assembled via any suitable process. Preferably, the nanoparticles are assembled in a single step to minimize process variation. A single step process can include nanoprecipitation and self- assembly. The nanoparticles can be synthesized or assembled by dissolving or suspending hydrophobic components in an organic solvent, preferably a solvent that is miscible in an aqueous solvent used for precipitation. In certain examples, acetonitrile is used as the organic solvent, but any suitable solvent can be used. Hydrophilic components are dissolved in a suitable aqueous solvent, such as water, 4 wt% ethanol, or the like. The organic phase solution can be added drop wise to the aqueous phase solution to nanoprecipitate the hydrophobic components and allow self-assembly of the nanoparticle in the aqueous solvent.

[0502] A process for determining appropriate conditions for forming the nanoparticles can be as follows. Briefly, functionalized polymers and phospholipids may be co-dissolved in organic solvent mixtures (in embodiments, the phospholipids or functionalized phospholipids are dissolved in the aqueous solvent). This solution can be added drop wise into hot (e.g., 65°C) aqueous solvent (e.g., water, 4 wt-% ethanol, etc.), whereupon the solvents will evaporate, producing nanoparticles with a hydrophobic core coated with phospholipids. The phospholipids used at this stage may be a mixture of non- functionalized phospholipids and functionalized phospholipids (e.g., conjugated to targeting moieties) that can also include a hydrophilic polymer component, such as PEG. Once a set of conditions where a high (e.g., >75%) level of compound loading has been achieved, contrast agents or additional therapeutic agents can be included in the nanoprecipitation and self-assembly of the nanoparticles. The size of the nanoparticle produced can be varied by altering the ratio of hydrophobic core components to amphiphilic shell components. The choice of PEGylated lipids and bilayer forming phospholipids can affect resulting nanoparticle size. PEGylated lipids are known to form small micellar structures because of surface tension imposed by the PEG chains. NP size can also be controlled by changing the polymer length, by changing the mixing time, and by adjusting the ratio of organic to the phase. Prior experience with NPs from PLGA-b-PEG of different lengths suggests that NP size will increase from a minimum of about 20 nm for short polymers (e.g., PLGA3000-PEG750) to a maximum of about 150 nm for long polymers (e.g., PLGA1000,000-PEG 10,000). Thus, molecular weight of the polymer will serve to adjust the size.

[0503] NP surface charge can be controlled by mixing polymers with appropriately charged end groups. Additionally, the composition and surface chemistry can be controlled by mixing polymers with different hydrophilic polymer lengths, branched hydrophilic polymers, or by adding hydrophobic polymers. Once formed, the nanoparticles can be collected and washed via centrifugation, centrifugal ultrafiltration, or the like. Ifaggregation occurs, NPs can be purified by dialysis, can be purified by longer centrifugation at slower speeds, can be purified with the use surfactant, or the like.

[0504] Once collected, any remaining solvent can be removed and the particles can be dried, which should aid in minimizing any premature breakdown or release of components. The NPs can be freeze dried with the use of bulking agents such as mannitol, or otherwise prepared for storage prior to use.

[0505] Pharmaceutical Compositions

[0506] The compounds described herein can be provided in a pharmaceutical composition. Depending on the intended mode of administration, the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include a therapeutically effective amount of the compound described herein or derivatives thereof in combination with a pharmaceutically acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, or diluents. By pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.

[0507] As used herein, the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005. Examples of physiologically acceptable carriers include saline, glycerol, DMSO, buffers such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™ (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, NJ). To provide for the administration of such dosages for the desired therapeutic treatment, compositions disclosed herein can advantageously comprise between about 0.1% and 99%, and especially, 1 and 15% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent.

[0508] Compositions containing the compound described herein or derivatives thereof suitable for parenteral injection can comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions,suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like can also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0509] Solid dosage forms for oral administration of the compounds described herein or derivatives thereof include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents.

[0510] Solid compositions of a similar type can also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

[0511] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art. They can contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients. The disclosed compounds can also be incorporated into polymers, examples of which include poly (D-L lactide-co-glycolide) polymer for intracranial tumors; poly[bis(p-carboxyphenoxy) propane: sebacic acid] in a 20:80 molar ratio (as used in GLIADEL); chondroitin; chitin; and chitosan.Liquid dosage forms for oral administration of the compounds described herein or derivatives thereof include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0512] Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. Suspensions, in addition to the active compounds, can contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

[0513] Compositions of the compounds described herein or derivatives thereof for rectal administrations are optionally suppositories, which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of the compounds described herein or derivatives thereof include ointments, powders, sprays, and inhalants. The compounds described herein or derivatives thereof are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required. Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions.

[0514] The compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable salt refers to those salts of the compound described herein or derivatives thereof that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein. These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, laurylsulphonate salts, heksafluorofosfat, tetrafluoroborat, acesulfamat, and saharinat and the like. These can include cations based on the alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See S.M. Barge etal, J. Pharm. Sci. (1977) 66, 1, which is incorporated herein by reference in its entirety, at least, for compositions taught herein.)

[0515] Administration of the compounds and compositions described herein or pharmaceutically acceptable salts thereof to a subject can be carried out using therapeutically effective amounts of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder.

[0516] The effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein can be determined by one of ordinary skill in the art and includes exemplary dosage amounts for a mammal of from about 0.5 to about 200 mg / kg of body weight of active compound per day, which can be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.

[0517] Alternatively, the dosage amount can be from about 0.5 to about 150 mg / kg of body weight of active compound per day, about 0.5 to 100 mg / kg of body weight of active compound per day, about 0.5 to about 75 mg / kg of body weight of active compound per day, about 0.5 to about 50 mg / kg of body weight of active compound per day, about 0.5 to about 25 mg / kg of body weight of active compound per day, about 1 to about 20 mg / kg of body weight of active compound per day, about 1 to about 10 mg / kg of body weight of active compound per day, about 20 mg / kg of body weight of active compound per day, about 10 mg / kg of body weight of active compound per day, or about 5 mg / kg of body weight of active compound per day. The expression effective amount, when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other effect, for example an amount that results in enzyme inhibition.

[0518] Those of skill in the art will understand that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.

[0519] According to some embodiments, PHARM COMP claims

[0520] Medical uses

[0521] As stated above, a compound of the present invention is particularly useful as a medicament, e.g. as a medicament for the treatment or prevention of a disease or condition that is ameliorated by the inhibitionof mitochondrial ion channels (such as Kv1.3, SK, NCLX), inhibition of HSP90 in mitochondria, or by the action of the mitochondria-targeting antioxidants.

[0522] The present invention thus provides a compound of the present invention for use in medicine.

[0523] More specifically, the present invention provides a compound of the present invention, including but not limited to those specified in the examples, for use in the treatment or prevention of cancer types treatable by the compounds and compositions described herein include bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer. Further examples include cancer and / or tumors of the anus, bile duct, bone, bone marrow, bowel (including colon and rectum), eye, gall bladder, kidney, mouth, larynx, esophagus, stomach, testis, cervix, mesothelioma, neuroendocrine, penis, skin, spinal cord, thyroid, vagina, vulva, uterus, liver, muscle, blood cells (including lymphocytes and other immune system cells).

[0524] Preferred conditions also include cancer diseases and the like including breast, colon, and prostate tumors, melanoma (Artym and Petty, J. Gen. Physiol. 120, 29-37, 2002) smooth muscle, and skeletal muscle cancer, chronic lymphocytic leukemia (Teisseyre et al., Front Oncol, 9, 933, 2019), glioblastoma (Venturini et al., Neurosignals, 25, 26-38, 2017), and pancreatic ductal adenocarcinoma (Zaccagnino et al., Oncotarget, 8(24), 38276-38293, 2017).

[0525] Provided herein are methods of treating, preventing, or ameliorating cancer in a subject. The methods include administering to a subject an effective amount of one or more of the compounds or compositions described herein, or a pharmaceutically acceptable salt thereof. The compounds and compositions described herein or pharmaceutically acceptable salts thereof are useful for treating cancer in humans, e.g., pediatric and geriatric populations, and in animals, e.g., veterinary applications. The disclosed methods can optionally include identifying a patient who is or can be in need of treatment of a cancer. Examples of cancer types treatable by the compounds and compositions described herein include bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, and testicular cancer. Further examples include cancer and / or tumors of the anus, bile duct, bone, bone marrow, bowel (including colon and rectum), eye, gall bladder, kidney, mouth, larynx, esophagus, stomach, testis, cervix, mesothelioma, neuroendocrine, penis, skin, spinal cord, thyroid, vagina, vulva, uterus, liver, muscle, blood cells (including lymphocytes and other immune system cells). Specific cancers contemplated for treatment include carcinomas, Kaposi's sarcoma, melanoma, mesothelioma, soft tissue sarcoma, pancreatic cancer, lung cancer, leukemia (acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, and other), and lymphoma (Hodgkin's and non-Hodgkin's), and multiple myeloma. Treatment of breastcancer by administering the disclosed compounds is particularly preferred. Cancers that are preferably treated by the disclosed methods using the compounds disclosed herein are lung, breast, brain, ovarian, lymphoma, leukemia, head and neck, pancreatic, and cervical, colon and rectum, endometrial, esophagus, liver, penile, skin melanoma, skin-nonmelanoma, stomach, testicular, vaginal, uterine, vulvar, paranasal cancer, oropharyngeal and laryngeal cancers.

[0526] The methods of treatment or prevention described herein can further include treatment with one or more additional agents (e.g., an anti-cancer agent or ionizing radiation). The one or more additional agents and the compounds and compositions or pharmaceutically acceptable salts thereof as described herein can be administered in any order, including simultaneous administration, as well as temporally spaced order of up to several days apart. The methods can also include more than a single administration of the one or more additional agents and / or the compounds and compositions or pharmaceutically acceptable salts thereof as described herein.

[0527] The administration of the one or more additional agents and the compounds and compositions or pharmaceutically acceptable salts thereof as described herein can be by the same or different routes. When treating with one or more additional agents, the compounds and compositions or pharmaceutically acceptable salts thereof as described herein can be combined into a pharmaceutical composition that includes the one or more additional agents.

[0528] Another aspect of the present invention pertains to a pharmaceutical composition which comprises a compound of the present invention, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient and / or carrier. The pharmaceutical composition may be used in the treatment or prevention of any one of the diseases mentioned above.

[0529] As a general remark, the use of "comprising" and "comprises" as used herein, especially when defining the contents of a medicament or a pharmaceutical formulation is to be understood as also disclosing "consisting of" and "consists of" respectively etc. Thus, this also includes that the contents of the respective medicament or pharmaceutical formulation are then to be also understood to be limited to the exact contents preceded by this "comprising" or "comprises" etc.

[0530] Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.

[0531] In a preferred embodiment the pharmaceutical compositions are in oral form, either solid or liquid. Suitable dose forms for oral administration may be tablets, capsules, syrops or solutions and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.

[0532] The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants.

[0533] The mentioned formulations will be prepared using standard methods such as those described or referred to in the US Pharmacopoeia and similar reference texts.

[0534] As an immunosuppressive and anticancer drug, the compounds and compositions of the present invention are useful in the treatment of cancer including metastatic cancer and autoimmune diseases, the prevention of rejection of foreign organ transplants and / or related afflictions, diseases and illnesses. The compounds and compositions of this invention can be administered for the treatment of autoimmune diseases, the prevention of rejection of foreign organ transplants and / or related afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal. For example, administration, can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral. The term "parenteral" as used herein refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.

[0535] The compounds and compositions of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0536] The dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg / kg / day.

[0537] Process

[0538] In a further aspect the present invention provides a process of preparing a compound of the present invention.If not commercially available, the necessary starting materials for the procedures such as those described below may be made by procedures which are selected from standard organic chemistry techniques, techniques which are analogous to the synthesis of known structurally similar compounds, or techniques, which are analogous to the procedures described in the examples.

[0539] It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection.

[0540] Example of a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanol group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanol or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.

[0541] A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.

[0542] The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up. Methods for preparing the compounds of this invention are illustrated in the following schemes. Other synthetic protocols will be readily apparent to those skilled in the art.

[0543] EXAMPLES

[0544] The invention is illustrated but not limited by the following Examples in which unless otherwise stated:(i) evaporation was carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids after filtration;

[0545] (ii) operations were generally carried out at ambient temperature, that is typically between 18 and 26 °C and without exclusion of air unless otherwise stated, or unless skilled person would otherwise work under an inert atmosphere;

[0546] (iii) flash column chromatography was used to purify compounds and was performed on Merck Silica Gel 60 unless otherwise stated;

[0547] (iv) yields are given for illustration only and are not necessarily the maximum attainable;

[0548] (v) the structure of the end-products was generally confirmed by NMR and mass spectral techniques; proton NMR spectra is quoted and was determined using a Bruker Avance III 400 MHz spectrometer operating at field strength of 400 MHz. Chemical shifts are reported in part per million downfield from tetramethylsilane as an internal standard (6 scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; t, triplet; m, multiplet; br, broad;

[0549] (vi) mass spectra were obtained using an Exactive Plus Orbitrap mass spectrometer (Thermo Fisher Scientific, Waltham, Massachusetts, ZDA).

[0550] (vii) each intermediate was generally purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by mass spectrometry and NMR spectroscopy as appropriate.

[0551] General procedure for the synthesis of aryl pyridines

[0552] To a solution of a bromopyridine (2 mmol) in degassed dioxane / HjO 3:1 (10 mL) were added arylboronic acid (for monobromopyridine: 2 mmol, 1 eq; for dibromopyridines: 5 mmol, 2.5 eq), tetrakis(triphenylphosphine)palladium (0.02 mmol, 0.01 eq), K2CO3 (for monobromopyridines: 2.5 mmol, 1.25 eq; for dibromopyridines: 5 mmol, 2.5 eq) in a microwave vial (30 mL) under the atmosphere of argon, and the mixture was stirred for 15-60 min in a microwave reactor at 140 °C. The reaction mixture was filtered through Celite and washed quantitatively with ethylacetate. The mixture was then concentrated in vacuo, and purified by column chromatography, eluent hexane / EtOAc to get the corresponding substituted pyridine.

[0553] General procedure for the syntesis of 2- and / or 6-cyclopropylpyridines.

[0554] To a solution of a bromopyridine (2.69 mmol) in a degassed dioxane / HjO / KsPCU mixture (7.5 mL / 3.5 mL / 4.7g (3.5 eq) were added cyclopropylboronic acid (4 mmol, 1.5 eq), bis(tricyclohexylphosphine)palladium dichloride 0.05 eq), in a microwave vial (30 mL) under the atmosphere of argon, and the mixture was stirred for 15-60 min in a microwave reactor at 140 °C. The reaction mixture was filtered through Celite and washed quantitatively with ethylacetate. The mixture was then concentrated in vacuo, andpurified by column chromatography, eluent hexane / EtOAc to get the corresponding substituted pyridine.

[0555] General procedure for the syntesis of 3-, 4-and / or 5-cyclopropylpyridines.

[0556] To a solution of a bromopyridine (1-3 mmol) in a degassed dioxane / HjO / NajCOs (base added as a 2M aqueous solution, calculated relative to total volume of water) mixture (6 mL / 3.5 mL / 3-6 mmol) were added cyclopropylboronic acid (for monobromopyridines: 1.5 eq; for dibromopyridines: 3 eq), palladium(dppf)2dichloride 0.1 eq in a microwave vial (30 mL) under the atmosphere of argon, and the mixture was stirred for 15-70 min in a microwave reactor at 130 °C. The reaction mixture was filtered through Celite and washed quantitatively with ethylacetate. The mixture was then concentrated in vacuo, and purified by column chromatography, eluent hexane / EtOAc (6:1 - 1:1) to get the corresponding substituted pyridine.

[0557] General procedure for the synthesis of cyclopentyl- and cyclohexylpyridines.

[0558] To a solution of a bromopyridine (2 mmol) in degassed dioxane / l- O 3:1 (10 mL) were added 2-(cyclopent-l- en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane or 2-(cyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (for monobromopyridines: 2.2 mmol, 1.1 eq; for dibromopyridines: 5 mmol, 2.5 eq), tetrakis(triphenylphosphine)palladium (0.02 mmol, 0.01 eq), K2CO3 (for monobromopyridines: 2.5 mmol, 1.25 eq; for dibromopyridines: 3.5 equivalents; for 2-bromopyridines: 2 eq K3PO4) in a microwave vial (30 mL) under the atmosphere of argon, and the mixture was stirred for 15-60 min in a microwave reactor at 140 °C. The reaction mixture was filtered through Celite and washed quantitatively with EtOAc. The mixture was then concentrated in vacuo, and purified by column chromatography, eluent hexane / EtOAc to get the cycloalkenyl intermediate. The intermediate was dissolved in MeOH and hydrogenated at 1 atm H2(g) using 10% Pd / C (0.1 mass equivalents) at room temperature overnight. The reaction mixture was filtered through Celite and concentrated to get the corresponding cycloalkylpyridine.

[0559] Synthesis of Intermediate 2 from Intermediate 1.

[0560]

[0561] Intermediate 1 Intermediate 2

[0562] Intermediate 1 was prepared according to the published procedure (Parrasia et al., Pharmaceuticals 2021,

[0563] 14, 129).

[0564] Intermediate 2. 4-(4-(4-(3-iodopropyl)phenoxy)butoxy)-7H-furo[3,2-g]chromen-7-one. To a solution of intermediate 1 (2.06 g, 5 mmol) in DCM (50 mL) were added triphenylphosphine (1.85 g, 7 mmol, 1.4eq) and imidazole (1.14 g, 16.7 mmol, 3.3 eq). The resulting suspension was cooled to 0 °C while stirring, followed by addition of iodine (1.9 g, 7.5 mmol, 1.5 eq), and the reaction mixture was allowed to room temperature, until full conversion was confirmed by TLC. The reaction mixture was washed with a 0.5 M solution of sodium thiosulphate (3 x 50 mL). The aqueous phases were joined, and extracted with DCM (2 x 100 mL). The organic phases were joined, and washed with IM HCI(aq) (100 mL), brine (100 mL), dried over NajSC , filtered, and concentrated. The residue was purified by flash chromatography on silica, eluent EtOAc:hexane 1:2, to get the title compound as a white solid (2.35 g, 91% yield).TH NMR (400 MHz, Chloroform-d) 68.15 (dd, J = 9.8, 0.7 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J = 8.6 Hz, 2H), 6.96 (dd, J = 2.4, 1.0 Hz, 1H), 6.82 (d, J = 8.6 Hz, 2H), 6.25 (d, J = 9.8 Hz, 1H), 4.55 (t, J = 6.0 Hz, 2H), 4.05 (t, J = 5.7 Hz, 2H), 3.16 (t, J = 6.8 Hz, 2H), 2.67 (t, J = 7.3 Hz, 2H), 2.19-1.95 (m, 6H). NMR data is in accordance with the literature data (Parrasia et al., Pharmaceuticals 2021, 14, 129).

[0565] EXAMPLE 1

[0566]

[0567] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium iodide.

[0568] Step 1. 3,5-diphenylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines, using 3,5-dibromopyridine. NMR data is in accordance with the literature data (Gallon et al, Angew. Chem. Int. Ed. 2007, 46, 7251-7254).

[0569] Step 2. l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium iodide. To a heat-dried microwave vial (30 mL loading) under argon atmosphere were added Intermediate 2 (249 mg, 0.482 mmol), 3,5-diphenylpyridine (171 mg, 0.71 mmol, 1.47 eq), acetonitrile (8 mL), and the reaction mixture was stirred in a microwave reactor at 150 °C for 2 hours. The reaction mixture was then concentrated in vacuo to approximately 1 mL. The mixture had precipitated upon cooling, and was washed with 70 mL diethyl ether, redisolved in 2 mL acetonitrile and precipitated using diethylether, to get the title compound as a pale yellow-brownish solid (343 mg, 95 % yield).1HNMR (400 MHz, CDCI3) 69.44 (s, 2H), 8.50 (s, 1H), 8.09 (d, J = 9.8 Hz, 1H), 7.89 (d, J = 6.8 Hz, 5H), 7.59 - 7.56 (m, 1H), 7.52 (dt, J = 6.8, 4.6 Hz, 6H), 7.08 (s, 2H), 7.06 (s, 1H), 6.95 (d, J = 1.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 2H), 6.18 (d, J = 9.8 Hz, 1H), 5.33 (t, J = 7.2 Hz, 2H), 4.52 (t, J = 5.9 Hz, 2H), 3.92 (t, J = 5.7 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.60 - 2.28 (m, 2H), 2.13 - 1.80 (m, 4H).13C NMR (101 MHz, CDCI3) 6161.37, 158.38, 157.32, 152.75, 148.99, 145.00, 141.53, 140.46, 139.82, 139.47, 132.82, 131.97, 130.82, 129.95, 129.53, 127.92, 114.57, 113.24, 112.50, 106.72, 105.28, 93.89, 72.60, 67.32, 62.04, 33.71, 31.32, 27.01, 26.00. HRMS (ESI+): m / z calcd. For C4IH36NO5+[M+] 622.25880, found 622.25793 (-1.40 ppm). HPLC purity, 97.65 % at 254 nm (tR= 5.733 min).

[0570] EXAMPLE 2

[0571]

[0572] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-4-phenylpyridin-l-ium iodide . Step 1. 3,5-bis-(2-thienyl)-pyridine. Prepared according to the published procedure (Johnson et al., CrystEngComm 2019, 21, 3151-3157).

[0573] Step 2. l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-4-phenylpyridin-l-ium iodide.To a heat-dried microwave vial under argon atmosphere were Intermediate 2 (50 mg, 0.097 mmol), the above 3,5-bis-(2-thienyl)-pyridine (59 mg, 0.24 mmol, 2.5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 140 °C for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was recrystallized from acetonitrile to get the title compound as a yellow solid (21 mg, 28% yield).1H NMR (400 MHz, CDCI3) 69.46-9.39 (m, 2H), 8.25 (t, J = 1.7 Hz, 1H), 8.11 (d, J = 9.8 Hz, 1H), 8.06 (dd, J = 3.8, 1.1 Hz, 2H), 7.59 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 4.9 Hz, 2H), 7.20 (dd, J = 5.1, 3.7 Hz, 2H), 7.11 (s, 2H), 7.09 (s, 1H), 6.99-6.93 (m, 1H), 5.22 (t, J = 7.5 Hz, 2H), 4.54 (t, J = 5.9 Hz, 2H), 3.95 (t, J = 5.7 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.44 (p, J = 7.6 Hz, 2H), 2.14- 1.89 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.42, 158.43, 157.42, 152.80, 149.02, 145.02, 139.50, 137.97, 135.67, 135.11, 134.71, 131.78, 129.91, 129.83, 129.78, 129.55, 114.65, 113.29, 112.57,106.80, 105.29, 93.99, 72.64, 67.33, 61.77, 33.51, 31.28, 27.08, 26.06. HRMS (ESI+): m / z calcd. For C37H32NO5S2+[M+] 634.17164, found 634.17087 (-1.22 ppm). HPLC purity, 98.57 % at 254 nm (tR= 7.327 min).

[0574] EXAMPLE 3

[0575]

[0576] ,6-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide . To a heat-dried microwave vial were added Intermediate 2 (40 mg, 0.077 mmol, 1 eq) and 2,6- lutidine (124 mg, 1.16, 15 eq) in a microwave reactor at 168 °C for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by automatied flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as an orange oil (20 mg, 41% yield).

[0577] 3H NMR (400 MHz, CDCI3) 68.20 (t, J = 7.9 Hz, 1H), 8.14 (d, J = 9.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 5.5 Hz, 1H), 7.02 - 6.96 (m, 1H), 6.84 (d, J = 8.6 Hz, 2H), 6.21 (d, J = 9.8 Hz, 1H), 4.58 (dt, J = 17.0, 5.9 Hz, 4H), 4.07 (t, J = 5.8 Hz, 2H), 2.88 - 2.80 (m, 8H), 2.14 - 1.99 (m, 6H).13C NMR (101 MHz, CDCI3) 6 161.39, 158.41, 157.82, 155.49, 152.78, 149.04, 145.04, 144.47, 139.52, 131.30, 129.74, 128.77, 114.96, 113.30, 112.55, 106.77, 105.30, 93.94, 72.65, 67.49, 53.77, 31.80, 30.40, 27.05, 26.05, 22.33. HRMS (ESI+): m / z calcd. For C3IH32NO5+[ M+] 498.22750, found 498.22687 (-1.26 ppm). HPLC purity, 95.01 % at 254 nm (tR= 5.113 min).

[0578] EXAMPLE 4

[0579]

[0580] ,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide . To a heat-dried microwave vial were added Intermediate 2 (35 mg, 0.068 mmol), 3,5-lutidine (36 mg, 0.34 mmol, 5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 150 °C for 40 min. The reaction mixture was concentrated in vacuo and the residue was purified by automatied flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as an orange oil (35 mg, 82% yield).1H NMR (400 MHz, CDCI3) 69.00 (s, 2H), 8.10 (d, J = 9.7 Hz, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.11 (d, J = 5.8 Hz, 3H), 6.97 (s, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.16 (d, J = 9.7 Hz, 1H), 4.86 (t, J = 7.3 Hz, 2H), 4.56 (t, J = 5.3 Hz, 2H), 4.04 (d, J = 5.3 Hz, 2H), 2.75 (t, J = 7.2 Hz, 2H), 2.57 (s, 6H), 2.38 (d, J = 7.2 Hz, 2H), 2.15 - 1.94 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.43, 158.42, 157.48, 152.76, 149.03, 146.51, 145.03, 141.65, 139.56, 139.03, 131.78, 129.59, 114.71, 113.25, 112.45, 106.73, 105.30, 93.90, 72.65, 67.42, 61.12, 33.37, 31.36, 27.01, 26.09, 18.67. HRMS (ESI+): m / z calcd. For C31H32NC [M+] 498.22750, found 498.22705 (-0.90 ppm). HPLC purity, 98.82 % at 254 nm (tR= 5.157 min).

[0581] EXAMPLE 5

[0582]

[0583] 3,5-dicyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide.

[0584] Step 1. 3,5-dicyclopropylpyridine. Prepared according to the General procedure for the syntesis of 3-, 4- and / or 5-cyclopropylpyridines from 3,5-dibromopyridine.1H NMR (400 MHz, Chloroform-d) 60.57 - 0.81 (m, 4H), 0.87 - 1.07 (m, 4H), 1.85 (tt, J = 8.4, 5.1 Hz, 2H), 6.92 (t, J = 2.2 Hz, 1H), 8.18 (d, J = 2.2 Hz, 2H).

[0585] Step 2. 3,5-dicyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide . To a heat-dried microwave vial were added Intermediate 2 (52 mg, 0.1 mmol), 3,5-dicyclopropylpyridine (60 mg, 0.57 mmol, 5.7 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 150 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a yellow crispy foam (20 mg, 30% yield).1H NMR (400 MHz, CDCI3) 6 8.86 (d, J = 1.6 Hz, 2H), 8.11 (d, J = 9.8 Hz, 1H), 7.58 (dd, J = 10.2, 2.4 Hz, 1H), 7.49 (s, 1H), 7.10 (dd, J = 14.4, 10.7 Hz, 3H), 6.97 (dd, J = 2.4, 0.9 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.18 (d, J = 9.8 Hz, 1H), 4.99 - 4.89 (m, 2H), 4.61 - 4.49 (m, 2H), 4.03 (t, J = 5.8 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.44 - 2.24 (m, 2H), 2.22 - 1.95 (m, 6H), 1.31 - 1.17 (m, 4H), 1.06 - 0.95 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.44, 158.42, 157.43, 152.77, 149.03, 146.11, 145.02, 139.55, 139.06, 137.71, 131.95, 129.60, 114.67, 113.27, 112.48, 106.76, 105.30, 93.92, 72.65, 67.40, 61.15, 33.73, 31.25, 27.03, 26.09, 13.71, 11.54. HRMS (ESI+): m / z calcd. For C35H36NC [M+] 550.25880, found 550.25856 (-0.44 ppm). HPLC purity, 95.14 % at 254 nm (tR= 7.757 min).

[0586] EXAMPLE 6

[0587]

[0588] 3-cyclopropyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide .Step 1. 3-cyclopropyl-5-methylpyridine. Prepared according to the General procedure for the syntesis of 3- , 4-and / or 5-cyclopropylpyridines form 3-bromo-5-methylpyridine.

[0589] Step 2. 3-cyclopropyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl) propyl)pyridin-l-ium iodide . To a heat-dried microwave vial were added Intermediate 2 (51.8 mg, 0.1 mmol), the above 3-cyclopropyl-5-methylpyridine (66.5 mg, 0.5 mmol, 5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 150 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a brown oil (34 mg, 52% yield).

[0590] 3H NMR (400 MHz, CDCI3) 6 8.96 (d, J = 37.3 Hz, 2H), 8.10 (d, J = 9.8 Hz, 1H), 7.71 (s, 1H), 7.59 (d, J = 2.4 Hz, 1H), .T1 (s, 1H), 7.10 (s, 2H), 6.97 (dd, J = 2.3, 0.8 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.17 (d, J = 9.8 Hz, 1H), 4.94 - 4.85 (m, 2H), 4.55 (t, J = 5.9 Hz, 2H), 4.03 (t, J = 5.7 Hz, 2H), 2.78 - 2.69 (m, 2H), 2.55 (s, 3H), 2.42 - 2.30 (m, 2H), 2.16 (ddd, J = 13.5, 8.4, 5.1 Hz, 1H), 2.12 - 1.94 (m, 4H), 1.31 - 1.19 (m, 2H), 1.06 - 0.97 (m, 2H).13C NMR (101 MHz, CDCI3) 6 161.31, 158.29, 157.32, 152.63, 148.91, 146.10, 144.91, 141.74, 140.94, 139.60, 139.45, 138.85, 131.78, 129.47, 114.55, 113.13, 112.33, 106.61, 105.19, 93.76, 72.53, 67.29, 60.96, 33.45, 31.18, 26.90, 25.96, 18.65, 13.47, 11.53. HRMS (ESI+): m / z calcd. For C33H34NC [M+] 524.24315, found 524.24283 (-0.61 ppm). HPLC purity, 99.13 % at 254 nm (tR= 4.790 min).

[0591]

[0592] 2-methyl-5-cyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide .

[0593] Step 1. 5-cyclopropyl-2-methylpyridine. Prepared according to the General procedure for the syntesis of 3- , 4-and / or 5-cyclopropylpyridines form 5-bromo-2-methylpyridine.

[0594] Step 2. 2-methyl-5-cyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide. To a heat-dried microwave vial under argon atmosphere were added Intermediate 2 (51.8 mg, 0.1 mmol), the above 5-cyclopropyl-2-methylpyridine (66.5 mg, 0.5 mmol, 5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 150 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a reddish-brown oil (61 mg, 94% yield).3H NMR (400 MHz, DMSO-d6) 68.82 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 9.8 Hz, 1H), 8.13 (dd, J = 8.3, 1.9 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 4.1, 1.7 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.29 (d, J = 9.8 Hz, 1H), 4.59 (t, J = 5.6 Hz, 2H), 4.53 - 4.43 (m, 2H), 4.04 (t, J = 5.8 Hz, 2H), 2.72 (s, 3H), 2.69 - 2.62 (m, 2H), 2.19 - 2.09 (m, 3H), 2.03 - 1.89 (m, 4H), 1.20 - 1.11 (m, 2H), 0.95 - 0.88 (m, 2H).13C NMR (101 MHz, DMSO-d6) 6 160.14, 157.67, 156.94, 152.13, 151.56, 148.73, 145.96, 142.53, 142.45, 141.34, 139.49, 132.08, 129.36, 129.20, 114.37, 112.91, 112.29, 105.98, 105.69, 93.21, 72.30, 67.05, 57.00, 30.95, 30.89, 30.71, 26.21, 25.32, 18.90, 12.37, 10.41. HRMS (ESI+): m / z calcd. For C33H34NC [M+] 524.24315, found 524.24281 (-0.65 ppm). HPLC purity, 97.46 % at 254 nm (tR= 4.763 min).

[0595] EXAMPLE 8

[0596]

[0597] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)quinolin-l-ium iodide. To a heat- dried microwave vial were added Intermediate 2 (61.5 mg, 0.118 mmol), quinoline (76.7 mg, 0.59 mmol, 5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 145 °C for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a thick yellow-orange oil (69.5 mg, 91% yield).1H NMR (400 MHz, DMSO-dg) 6 9.55 (d, J = 5.3 Hz, 1H), 9.29 (d, J = 8.2 Hz, 1H), 8.59 (d, J = 8.9 Hz, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.28 (t, J = 7.7 Hz, 1H), 8.18 (dd, J = 6.2, 3.7 Hz, 2H), 8.07 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.35 (s, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 9.8 Hz, 1H), 5.09 (t, J = 7.3 Hz, 2H), 4.58 (d, J = 5.3 Hz, 2H), 4.03 (d, J = 5.4 Hz, 2H), 2.78 - 2.65 (m, 2H), 1. 1 (d, J = 6.7 Hz, 2H), 1.95 (s, 4H).13C NMR (101 MHz, DMSO- d6) 6 160.11, 157.65, 156.90, 152.11, 149.71, 148.72, 147.39, 145.95, 139.48, 137.45, 135.63, 132.14,130.74, 129.85, 129.73, 129.15, 122.16, 118.87, 114.37, 112.90, 112.28, 105.95, 105.68, 93.20, 72.29, 67.04, 57.15, 31.17, 30.90, 26.19, 25.30. HRMS (ESI+): m / z calcd. For C33H30NC [M+] 520.21185, found 520.21159 (-0.50 ppm). HPLC purity, 96.19 % at 254 nm (tR= 5.961 min).

[0598] EXAMPLE 9

[0599]

[0600] ,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide . To a heat-dried microwave vial were added Intermediate 2 (45 mg, 0.087 mmol), 2,4-lutidine (140 mg, 1.3 mmol, 15 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor at 155 °C for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a reddish-brown oil (61 mg, 94% yield).1H NMR (400 MHz, CDCI3) 6 9.34 (d, J = 6.4 Hz, 1H), 8.12 (d, J = 9.8 Hz, 1H), 7.69 (d, J = 6.2 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.79 (d, J = 8.5 Hz, 2H), 6.19 (d, J = 9.8 Hz, 1H), 4.82 - 4.69 (m, 2H), 4.56 (t, J = 5.8 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.76 (s, 3H), 2.59 (s, 3H), 2.30 - 2.16 (m, 2H), 2.16 - 1.95 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.40, 158.75, 158.40, 157.58, 153.18, 152.75, 149.02, 145.50, 145.02, 139.53, 131.72, 130.62, 129.62, 127.14, 114.80, 113.25, 112.48, 106.72, 105.30, 93.89, 72.63, 67.44, 57.03, 32.41, 31.36, 27.02, 26.06, 22.15, 20.71.

[0601] HRMS (ESI+): m / z calcd. For C31H32NC [M+] 498.22750, found 498.22700 (-1.00 ppm). HPLC purity, 97.27 % at 254 nm (tR= 4.697 min).

[0602] EXAMPLE 10

[0603]

[0604] 3,5-bis(4-methoxyphenyl)-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide .

[0605] Step 1. 3,5-bis-(4-methoxyphenyl)pyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 3,5-dibromopyridine. NMR data is in accordance with the literature data (Jacquemard et al., Eur. J. Med. Chem. 2005, 40, 1087-1095.

[0606] Step 2. 3,5-bis(4-methoxyphenyl)-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl) propyl)pyridin-l-ium iodide . To a solution of Intermediate 2 (45 mg, 0.087 mmol) in acetonitrile (2 mL) was added the above 3,5-bis-(4-methoxyphenyl)pyridine (76 mg , 0.261 mmol, 3eq) and the reaction mixture was stirred at 145 °C for 35 min in a microwave reactor. The resulting precipitate was collected and washed with acetonitrile (4 mL) to get the title compound as a pale yellow solid (74% yield, 52 mg).3H NMR (400 MHz, CDCI3) 69.30 (d, J = 1.4 Hz, 2H), 8.39 (s, 1H), 8.10 (d, J = 9.8 Hz, 1H), 7.92 - 7.80 (m, 4H), 7.58 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 8.8 Hz, 4H), 6.95 (dd, J = 2.3, 0.9 Hz, 1H), 6.19 (d, J = 9.8 Hz, 1H), 5.23 (t, J = 7.4 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 3.94 (t, J = 5.8 Hz, 2H), 3.82 (s, 6H), 2.79 (t, J = 7.5 Hz, 2H), 2.47 - 2.33 (m, 2H), 2.10 - 1.91 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.76, 161.38, 158.39, 157.34, 152.77, 149.01, 145.00, 140.97, 139.47, 138.85, 137.80, 132.01, 129.55, 129.30, 125.00, 115.35, 114.59, 113.27, 112.55, 106.76, 105.28, 93.94, 72.63, 67.34, 61.76, 55.65, 33.77, 31.32, 27.04, 26.02. HRMS (ESI+): m / z calcd. For [M+] C43H40NC 682.27993, found 682.27878 (-1.68 ppm). HPLC purity, 94.74 % at 254 nm (tR= 5.663 min).

[0607] EXAMPLE 11

[0608]

[0609] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium saccharinate . A solution of the compound of EXAMPLE 1 (69 mg, 0.092 mmol) in dichloromethane (20 mL) was washed with a 0.1 M solution of sodium saccharinate (2 x 10 mL, 2 x 15 mL), and water (30 mL), filtered and concentrated. The residue was purified by flash chromatography on silica, eluent 0- 10% MeOH in dichloromethane, to get the title compound as a white crispy foam (76 % yield, 56 mg).

[0610] 3H NMR (400 MHz, CDCI3) 69.29 (d, J = 1.6 Hz, 2H), 8.47 (t, J = 1.5 Hz, 1H), 8.10 (d, J = 9.8 Hz, 1H), 7.84 - 7.67 (m, 6H), 7.57 (d, J = 2.4 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.49 - 7.42 (m, 6H), 7.10 (s, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.94 (dd, J = 2.4, 0.9 Hz, 1H), 6.62 (d, J = 8.6 Hz, 2H), 6.20 (d, J = 9.8 Hz, 1H), 5.15 (t, J = 7.4 Hz, 2H), 4.51 (t, J = 6.0 Hz, 2H), 3.90 (t, J = 5.8 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H), 2.49 - 2.35 (m, 2H), 2.08 - 1.93 (m, 4H).13C NMR (101 MHz, CDCI3) 6 170.39, 161.38, 158.39, 157.25, 152.79, 149.01, 144.99, 144.93, 141.64, 141.06, 139.63, 139.45, 135.04, 133.09, 132.17, 131.89, 131.26, 130.59, 129.86, 129.52, 127.75, 123.31, 119.79, 114.54, 113.28, 112.59, 106.77, 105.27, 93.96, 72.62, 67.29, 62.46, 33.51, 31.53, 27.04, 26.00. HPLC purity, 95.58 % at 254 nm (tR= 5.433 min).

[0611] EXAMPLE 12

[0612]

[0613] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium acesulfamate . A solution of the compound of EXAMPLE 1 (80 mg, 0.107 mmol) in dichloromethane (20 mL) was washed with a 0.1M solution of potassium acesulfamate (2 x 10 mL, 2 x 15 mL), and water (30 mL), filtered and concentrated to get the title compound as a white crispy foam (92% yield, 77 mg).

[0614] 3H NMR (400 MHz, CDCI3) 6 9.19 (d, J = 1.5 Hz, 1H), 8.51 (s, 1H), 8.11 (d, J = 9.8 Hz, 1H), 7.76 (dd, J = 8.0, 1.3 Hz, 2H), 7.64 - 7.46 (m, 4H), 7.11 (s, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.68 (d, J= 8.6 Hz, 1H), 6.20 (d, J = 9.8 Hz, 1H), 5.44 (s, 1H), 5.05 (t, J = 7.5 Hz, 1H), 4.52 (t, J = 6.0 Hz, 1H), 3.94 (t, J = 5.8 Hz, 1H), 2.74 (t, J = 7.4 Hz, 1H), 2.50 - 2.32 (m, 1H), 2.11 - 1.91 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.39, 161.04, 158.41, 157.36, 152.80, 149.02, 145.00, 141.81, 140.98, 139.79, 139.46, 133.13, 132.05, 130.70, 129.95, 129.54, 127.78, 114.63, 113.29, 112.60, 106.79, 105.28, 102.47, 93.98, 72.63, 67.33, 62.50, 33.43, 31.59, 27.05, 26.03, 20.07. HPLC purity, 99.47 % at 254 nm (tR= 5.383 min).

[0615] EXAMPLE 13

[0616]

[0617] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium p- toluenesulfonate . Asolution of the compound of EXAMPLE 1 (70 mg, 0.093 mmol) in dichloromethane (20 mL) was washed with a 0.1 M solution of sodium tosylate (2 x 10 mL, 2 x 15 mL), followed by 30 mL water. The resulting solution was filtered, concentrated and purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a white crispy foam (54 % yield, 40 mg).3H NMR (400 MHz, CDCI3) 69.42 (d, J = 1.0 Hz, 2H), 8.40 (s, 1H), 8.09 (d, J = 9.8 Hz, 1H), 7.77 (dd, J = 10.6, 5.2 Hz, 6H), 7.56 (d, J = 2.3 Hz, 1H), 7.50 - 7.36 (m, 6H), 7.07 (s, 2H), 7.05 (s, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.93 (d, J = 1.6 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.17 (d, J = 9.8 Hz, 1H), 5.23 (t, J = 7.1 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 5.7 Hz, 2H), 2.70 (t, J = 7.5 Hz, 2H), 2.43 - 2.32 (m, 2H), 2.28 (d, J = 6.4 Hz, 3H), 2.08 - 1.88 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.32, 158.31, 157.10, 152.68, 148.95, 144.96, 141.30, 141.21, 139.44, 139.03, 132.99, 132.41, 130.44, 129.75, 129.43, 128.62, 127.69, 126.07, 114.36, 113.18, 112.43, 106.63, 105.24, 93.79, 72.54, 67.22, 62.20, 33.64, 31.42, 26.96, 25.93, 21.36. HRMS (ESI): m / z calcd for C41H36O5N [M]+622.2588; found 622.2573 (-2.44 ppm). HPLC purity, 98.73 % at 254 nm (tR= 5.400 min).

[0618] EXAMPLE 14

[0619]

[0620] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l-ium tetrafluoroborate . A solution of the compound of EXAMPLE 1 (67 mg, 0.089 mmol) in dichloromethane (20 mL) was washed with a 0.3 M solution of NaBF4solution (2 x 10 mL, 2 x 15 mL), and water (30 mL), then filtered. The resulting solution was concentrated to get the title compound as a white crispy foam (98% yield, 62 mg).3H NMR (400 MHz, CDCI3) 68.90 (d, J = 1.3 Hz, 2H), 8.47 (s, 1H), 8.07 (d, J = 9.8 Hz, 1H), 7.78 - 7.65 (m, 4H), 7.55 (d, J = 2.3 Hz, 1H), 7.54 - 7.41 (m, 6H), 7.05 (s, 1H), 7.02 (d, J = 8.5 Hz, 2H), 6.97 - 6.91 (m, 1H), 6.62 (d, J = 8.5 Hz, 2H), 6.15 (d, J = 9.8 Hz, 1H), 4.86 (t, J = 7.4 Hz, 2H), 4.49 (t, J = 6.0 Hz, 2H), 3.89 (t, J = 5.7 Hz, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.41 - 2.25 (m, 2H), 2.08 - 1.84 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.39, 158.36, 157.29, 152.71, 149.01, 145.01, 141.89, 140.38, 139.80, 139.52, 132.86, 132.05, 130.74, 129.94, 129.46, 127.66, 114.54, 113.21, 112.42, 106.66, 105.31, 93.80, 72.58, 67.29, 62.59, 33.43, 31.46, 26.97, 25.96.19F NMR (376 MHz, CDCk) 6 -150.68, -150.73. HRMS (ESI): m / z calcd for C41H36O5N [M]+622.2588; found 622.2573 (-2.38 ppm). HPLC purity, 98.59 % at 254 nm (tR= 5.380 min).

[0621] EXAMPLE 15

[0622]

[0623] 3,5-dicyclohexyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide .

[0624] Step 1. 3,5-dicyclohexylpyridine. Prepared according to the General procedure for the synthesis of cyclopentyl- and cyclohexylpyridines from 3,5-dibromopyridine.1H NMR (400 MHz, Chloroform-d) 6 1.19 - 1.32 (m, 2H), 1.35 - 1.50 (m, 8H), 1.73 - 1.82 (m, 2H), 1.82 - 1.95 (m, 8H), 2.50 (qd, J = 7.0, 2.8 Hz, 2H), 7.32 (t, J = 2.2 Hz, 1H), 8.28 (d, J = 2.1 Hz, 2H).Step 2. 3,5-dicyclohexyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide .To a solution of Intermediate 2 (21 mg, 0.041 mmol) in acetonitrile (2 mL) was added the above 3,5-dicyclohexylpyridine (60 mg , 0.247 mmol, 6.1 eq) and the reaction mixture was stirred at 110 °C overnight in a pressure tube in dark. The resulting solution was concentrated, dissolved in dichloromethane and concentrated to 0.5 mL, then precipitated by adding dietyl ether. The precipitate was collected and triturated with diethyl ether to get the title compound as a grey-brown solid (83 % yield, 26 mg).3H NMR (400 MHz, CDCI3) 68.94 (s, 2H), 8.12 (d, J = 9.7 Hz, 1H), 7.96 (s, 1H), 7.60 (s, 1H), 7.11 (s, 3H), 6.97 (s, 1H), 6.75 (d, J = 7.9 Hz, 2H), 6.19 (d, J = 9.7 Hz, 1H), 5.12 - 4.94 (m, 2H), 4.55 (d, J = 5.4 Hz, 2H), 4.03 (s, 2H), 2.78 (d, J = 7.7 Hz, 4H), 2.36 (s, 2H), 2.15 - 2.00 (m, 4H), 1.92 (dd, J = 24.7, 11.1 Hz, 8H), 1.78 (d, J = 11.9 Hz, 2H), 1.58 - 1.36 (m, 8H), 1.36 - 1.26 (m, 2H).13C NMR (101 MHz, CDCI3) 6 161.40, 158.41, 157.43, 152.78, 149.02, 148.79, 145.01, 141.65, 140.79, 139.51, 131.99, 129.60, 114.67, 113.26, 112.51, 106.75, 105.29, 93.92, 72.62, 67.40, 61.37, 41.93, 33.87, 33.74, 31.31, 27.04, 26.27, 26.06, 25.46. HRMS (ESI): m / z calcd for C41H48O5N [M]+634.3527; found 634.3510 (-2.66 ppm). HPLC purity, 94.19 % at 254 nm (tR= 6.792 min).

[0625] EXAMPLE 16

[0626]

[0627] 3,5-dicyclopentyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide .

[0628] Step 1. 3,5-dicyclopentylpyridine. Prepared according to the General procedure for the synthesis of cyclopentyl- and cyclohexylpyridines from 3,5-dibromopyridine.1H NMR (400 MHz, Chloroform-d) 6 1.51 - 1.66 (m, 4H), 1.66 - 1.78 (m, 4H), 1.78 - 1.94 (m, 4H), 2.02 - 2.16 (m, 4H), 2.97 (tt, J = 9.7, 7.5 Hz, 2H), 7.37 (t, J = 2.2 Hz, 1H), 8.31 (d, J = 2.2 Hz, 2H).

[0629] Step 2. 3,5-dicyclopentyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide . To a solution of Intermediate 2 (50 mg, 0.097 mmol) in acetonitrile (2 mL) was added the above 3,5-dicyclopentylpyridine (80 mg, 0.37 mmol, 3.8 eq) and the reaction mixture was stirred at 110 °C overnight in a pressure tube in dark. The resulting solution was concentrated to 0.3 mL, then precipitated by adding dietyl ether. The precipitate was collected and triturated with dichloromethane to get the title compound as a grey-brown solid (84 % yield, 60 mg).1H NMR (400MHz, CDCk) 69.00 (s, 2H), 8.11 (d, J = 9.7 Hz, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7. 1 (s, 1H), 7.11 (s, 2H), 6.97 (s, 1H), 6.74 (d, J = 8.1 Hz, 2H), 6.19 (d, J = 9.7 Hz, 1H), 5.11 - 4.88 (m, 2H), 4.55 (d, J = 5.5 Hz, 2H), 4.03 (s, 2H), 3.31 - 3.13 (m, 2H), 2.77 (d, J = 6.9 Hz, 2H), 2.37 (d, J = 6.7 Hz, 2H), 2.24 (s, 4H), 2.15 - 1.96 (m, 4H), 1.88 (s, 4H), 1.75 (d, J = 4.6 Hz, 4H), 1.64 (d, J = 8.7 Hz, 4H).13C NMR (101 M Hz, CDCI3) 6161.39, 158.40, 157.40, 152.76, 149.01, 147.71, 145.00, 141.92, 140.82, 139.51, 132.01, 129.59, 114.65, 113.24, 112.49, 106.73, 105.29, 93.89, 72.61, 67.39, 61.17, 43.19, 34.55, 33.85, 31.27, 27.03, 26.05, 25.51. HRMS (ESI): m / z calcd for C39H44O5N+[M]+606.3214; found 606.3199 (-2.44 ppm), HPLC purity, 97.74 % at 254 nm (tR= 5.720 min).

[0630] EXAMPLE 17

[0631]

[0632] 3-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l- ium iodide .

[0633] Step 1. 3-phenyl-5-methylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 3-bromo-5-methylpyridine.

[0634] Step 2. 3-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5- phenylpyridin-l-ium iodide. To a solution of Intermediate 2 (50 mg, 0.097 mmol) in acetonitrile (2 mL) was added the above 3-phenyl-5-methylpyridine (72 mg , 0.425 mmol, 4.4 eq) and the reaction mixture was stirred at 140 °C for lh in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated by adding dietyl ether, and the precipitate was dissolved in 0.5 mL dichloromethane, followed by precipitation with diethyl ether the title compound as a beige solid (98 % yield, 65 mg).1H NMR (400 MHz, CDCI3) 69.22 (d, J = 22.6 Hz, 2H), 8.29 (s, 1H), 8.10 (d, J = 9.8 Hz, 1H), 7.81 (d, J = 6.6 Hz, 2H), 7.67 - 7.42 (m, 4H), 7.09 (d, J = 5.8 Hz, 3H), 6.96 (s, 1H), 6.71 (d, J = 8.1 Hz, 2H), 6.17 (d, J = 9.8 Hz, 1H), 5.06 (t, J = 7.1 Hz, 2H), 4.54 (t, J = 5.5 Hz, 2H), 4.00 (d, J = 5.3 Hz, 2H), 2.77 (t, J = 7.1 Hz, 2H), 2.65 (s, 3H), 2.49 - 2.28 (m, 2H), 2.16 - 1.87 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.40, 158.40, 157.41, 152.75, 149.01, 145.01, 143.25, 142.52, 141.03, 139.63, 139.52, 132.78, 131.84, 130.69, 129.91, 129.55, 127.78, 114.64, 113.23, 112.47, 106.72, 105.29, 93.89, 72.62, 67.37, 65.97, 61.55, 33.51, 31.34, 27.01, 26.05, 18.98, 15.39. HRMS (ESI): m / z calcd for C36H34O5N [M]+560.2431; found 560.2421 (-1.82 ppm). HPLC purity, > 99.99% % at 254 nm (tR= 5.007 min).EXAMPLE 18

[0635]

[0636] 5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l- ium iodide .

[0637] Step 1. 2-phenyl-5-methylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 2-bromo-5-methylpyridine.

[0638] Step 2. 5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide . To a solution of Intermediate 2 (36 mg, 0.069 mmol) in acetonitrile (2 mL) was added the above 2-phenyl-5-methylpyridine (94 mg, 0.556 mmol, 5.7 eq) and the reaction mixture was stirred at 155 °C for lh in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated with dietyl ether, and the precipitate triturated with diethyl ether to get the title compound as a pale yellow solid (42 % yield, 20 mg).1H NMR (400 MHz, CDCU) 69.81 (s, 1H), 8.22 (d, J = 7.7 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.53 (t, J = 7.5 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.13 (s, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, 2H), 6.21 (d, J = 9.8 Hz, 1H), 4.81 - 4.63 (m, 2H), 4.56 (t, J = 5.9 Hz, 2H), 4.03 (t, J = 5.7 Hz, 2H), 2.71 (s, 3H), 2.57 (t, J = 7.3 Hz, 2H), 2.26 - 2.12 (m, 2H), 2.12 - 1.96 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.38, 158.41, 157.41, 152.79, 152.54, 149.02, 146.44, 145.78, 145.02, 139.48, 139.07, 131.52, 131.46, 130.99, 129.66, 129.36, 129.33, 128.82, 114.66, 113.30, 112.58, 106.78, 105.28, 93.98, 72.65, 67.43, 58.11, 33.16, 31.36, 27.07, 26.08, 18.61. HRMS (ESI): m / z calcd for C36H34O5N [M]+560.2431; found 560.2425 (-1.12 ppm). HPLC purity, 98.78 % at 254 nm (tR= 4.697 min).

[0639] EXAMPLE 19

[0640]

[0641] 2-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l- ium iodide .Step 1. 5-phenyl-2-methylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 5-bromo-2-methylpyridine.

[0642] Step 2. 2-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5- phenylpyridin-l-ium iodide . To a solution of Intermediate 2 (51 mg, 0.098 mmol) in acetonitrile (2 mL) was added the avove 5-phenyl-2-methylpyridine (74 mg , 0.44 mmol, 4.5 eq) and the reaction mixture was stirred at 155 °C for 1 h in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated by adding dietyl ether, and the precipitate triturated with diethyl ether to get the title compound as a pale beige solid (82 % yield, 55 mg).1H NMR (400 MHz, CDCU) 69.64 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 8.11 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 6.9 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 15.8, 8.2 Hz, 3H), 7.13 (d, J = 8.3 Hz, 2H), 7.10 (s, 1H), 6.97 (s, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.19 (d, J = 9.8 Hz, 1H), 4.98 (t, 2H), 4.55 (t, J = 5.7 Hz, 2H), 4.01 (t, J = 5.5 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.36 - 2.18 (m, 2H), 2.16 - 1.92 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.38, 158.39, 157.55, 152.75, 152.15, 149.01, 145.01, 143.42, 142.57, 139.50, 139.41, 132.38, 131.78, 130.53, 129.85, 129.60, 127.76, 114.76, 113.25, 112.50, 106.72, 105.29, 93.90, 72.62, 67.41, 65.97, 58.06, 32.65, 31.35, 27.03, 26.04, 20.57, 15.39. HRMS (ESI): m / z calcd for C36H34O5N [M]+560.2431; found 560.2420 (-2.02 ppm). HPLC purity, >99.99 % at 254 nm (tR= 4.973 min).

[0643] EXAMPLE 20

[0644]

[0645] 2,3,5-trimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide. To a solution of Intermediate 2 (40 mg, 0.077 mmol) in acetonitrile (2 mL) was added 2,3,5- trimethylpyridine (47 mg , 0.392 mmol, 5 eq) and the reaction mixture was stirred at 155 °C for lh in a microwave reactor. The resulting solution was concentrated to 0.5-1 mL, and triturated with dietylether to get the title compound as an off white solid (99 % yield, 49 mg).1H NMR (400 MHz, CDCI3) 69.29 (s, 1H), 8.11 (d, J = 9.8 Hz, 1H), 7.92 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.18 (d, J = 9.8 Hz, 1H), 4.90 - 4.67 (m, 2H), 4.56 (t, J = 5.7 Hz, 2H), 4.05 (t, J = 5.5 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 2.48 (s, 3H), 2.37 - 2.17 (m, 2H), 2.17 - 1.95 (m, 4H).13C NMR (101 MHz, CDCI3) 6161.35, 158.38, 157.53, 152.74, 150.33, 149.01, 146.67, 145.01, 143.57, 139.51, 138.07, 136.26, 131.84, 129.65, 114.73, 113.23, 112.47, 106.70, 105.30, 93.86, 72.63, 67.43, 65.95, 58.37, 32.44, 31.42, 27.01, 26.05, 20.41, 18.05, 17.00,15.38. HRMS (ESI): m / z calcd for C32H34O5N [M]+512.2431; found 512.2425 (-1.21 ppm). HPLC purity, 97.34 % at 254 nm (tR= 5.52 min).

[0646] EXAMPLE 21

[0647]

[0648] 3-chloro-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide . To a solution of Intermediate 2 (43 mg, 0.082 mmol) in acetonitrile (2 mL) was added 3- chloro-5-methylpyridine (73 mg , 0.57 mmol, 6.9 eq) and the reaction mixture was stirred at 155 °C for lh in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated with dietyl ether, and the precipitate triturated with dichloromethane and acetonitrile to get the title compound as a pale yellow crystalline solid (86 % yield, 46 mg).1H NMR (400 MHz, Chloroform-d) 6 1.93 - 2.18 (m, 4H), 2.33 - 2.56 (m, 2H), 2.65 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 4.04 (t, J = 5.5 Hz, 2H), 4.57 (t, J = 5.8 Hz, 2H), 4.96 (t, J = 7.6 Hz, 2H), 6.16 (d, J = 9.8 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H), 6.90 - 7.04 (m, 1H), 7.09 (s, 1H), 7.11 (d, J = 4.6 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 8.86 (s, 1H), 9.53 (s, 1H).

[0649] 13C NMR (101 MHz, DMSO-dg) 6 160.11, 157.66, 156.90, 152.12, 148.71, 145.94, 145.16, 143.50, 141.31, 139.75, 139.46, 133.19, 131.93, 129.13, 114.30, 112.90, 112.27, 105.96, 105.66, 93.19, 72.29, 67.05, 61.07, 31.71, 30.77, 26.20, 25.31, 17.75. HRMS (ESI): m / z calcd for C3oH2905NCI [M]+518.1729; found 518.1721 (1.50 ppm). HPLC purity, 98.86 % at 254 nm (tR= 4.537 min).

[0650] EXAMPLE 22

[0651]

[0652] 3-cyclopentyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide .Step 1. 3-cyclopentyl-5-methylpyridine. Prepared according to the General procedure for the synthesis of cyclopentyl- and cyclohexylpyridines from 3-bromo-5-rnethylpyridine.1H NMR (400 MHz, Chloroformed 6 1.24 (s, 1H), 1.32 - 1.49 (m, 4H), 1.72 - 1.81 (m, 1H), 1.81 - 1.93 (m, 4H), 2.31 (q, J = 0.7 Hz, 3H), 2.42 - 2.56 (m, 1H), 7.31 (tt, J = 2.2, 0.7 Hz, 1H), 8.23 - 8.26 (m, 1H), 8.27 (d, J = 1.1 Hz, 1H).

[0653] Step 2. 3-cyclopentyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide . To a solution of Intermediate 2 (43 mg, 0.082 mmol) in acetonitrile (2 mL) was added the above 3-cyclopentyl-5-methylpyridine (73 mg , 0.57 mmol, 6.9 eq) and the reaction mixture was stirred at 135 °C for 1 h in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated with dietyl ether, and the precipitate was redissolved in dichloromethane, precipitated with diethyl ether, then redissolved in acetonitrile and precipitated with diethyl ether, to get the title compound as a reddish-brown solid (86 % yield, 46 mg).1H NMR (400 MHz, CDCh) 69.10 (s, 1H), 8.98 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.11 (d, J = 9.3 Hz, 3H), 6.97 (s, 1H), 6.74 (d, J = 7.7 Hz, 2H), 6.17 (d, J = 9.6 Hz, 1H), 4.95 (s, 2H), 4.55 (s, 2H), 4.03 (s, 2H), 3.32 - 3.06 (m, 1H), 2.76 (s, 2H), 2.58 (s, 3H), 2.37 (s, 2H), 2.23 (s, 2H), 2.15 - 1.95 (m, 4H), 1.87 (s, 2H), 1.81 - 1.68 (m, 3H), 1.63 (s, 2H).13C NMR (101 MHz, CDCI3) 6 161.38, 158.38, 157.40, 152.73, 149.01, 147.57, 145.01, 144.22, 141.92, 140.61, 139.53, 139.09, 131.94, 129.57, 114.63, 113.21, 112.43, 106.69, 105.29, 93.84, 72.61, 67.39, 61.06, 42.99, 34.47, 33.60, 31.30, 27.00, 26.05, 25.51, 18.80. HRMS (ESI): m / z ealed for C35H38O5N [M]+552.2744; found 552.2734 (-1.86 ppm). HPLC purity, 97.60 % at 254 nm (tR= 5.147 min).

[0654] EXAMPLE 23

[0655]

[0656] 3-cyclohexyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide .

[0657] Step 1. 3-cyclopentyl-5-methylpyridine. Prepared according to the General procedure for the synthesis of cyclopentyl- and cyclohexylpyridines from 3-bromo-5-methylpyridine.1H NMR (400 MHz, Chloroformed 6 1.24 (s, 1H), 1.32 - 1.49 (m, 4H), 1.72 - 1.81 (m, 1H), 1.81 - 1.93 (m, 4H), 2.31 (q, J = 0.7 Hz, 3H), 2.42 - 2.56 (m, 1H), 7.31 (tt, J = 2.2, 0.7 Hz, 1H), 8.23 - 8.26 (m, 1H), 8.27 (d, J = 1.1 Hz, 1H).Step 2. 3-cyclohexyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide . To a solution of Intermediate 2 (43 mg, 0.083 mmol) in acetonitrile (2 mL) was added ESR-27 (93 mg , 0.53 mmol, 6.4 eq) and the reaction mixture was stirred at 140 °C for 1 h in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated with with dietyl ether, and the precipitate was triturated with diethyl ether to get the title compound as a pale beige solid (96 % yield, 55 mg).1H NMR (400 MHz, Chloroform-d) 6 1.28 (d, J = 17.9 Hz, 2H), 1.35 - 1.55 (m, 4H), 1.93 (d, J = 12.4 Hz, 4H), 2.01 - 2.23 (m, 4H), 2.29 - 2.50 (m, 2H), 2.59 (s, 3H), 2.76 (d, J = 9.9 Hz, 3H), 4.05 (d, J = 5.9 Hz, 2H), 4.56 (t, J = 5.5 Hz, 2H), 4.92 (t, J = 7.8 Hz, 2H), 6.18 (d, J = 9.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 2H), 6.97 (s, 1H), 7.11 (d, J = 7.8 Hz, 3H), 7.59 (s, 1H), 7.95 (s, 1H), 8.11 (d, J = 9.9 Hz, 1H), 8.79 (s, 1H), 9.10 (s, 1H).13C NMR (101 MHz, CDCI3) 6 161.40, 158.41, 157.45, 152.77, 149.02, 148.49, 145.01, 144.13, 142.13, 140.34, 139.53, 139.28, 131.88, 129.59, 114.68, 113.25, 112.48, 106.73, 105.30, 93.90, 72.63, 67.40, 61.22, 41.75, 33.68, 33.59, 31.34, 27.02, 26.25, 26.07, 25.47, 18.82. HRMS (ESI): m / z calcd for C36H40O5N [M]+566.2901; found 566.2891 (-1.77 ppm). HPLC purity, >99.99 % at 254 nm (tR= 5.333 min).

[0658] EXAMPLE 24

[0659]

[0660] 5-cyclopropyl-2,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide .

[0661] Step 1. 5-cyclopropyl-2,4-dimethylpyridine Prepared according to the General procedure for the syntesis of 3-, 4-and / or 5-cyclopropylpyridines from 5-bromo-2,4-dimethylpyridine.1H NMR (400 MHz, Chloroform-d) 60.60 - 0.78 (m, 2H), 0.90 - 1.03 (m, 2H), 1.70 - 1.88 (m, 1H), 2.37 (s, 3H), 2.46 (s, 3H), 6.92 (s, 1H), 8.11 (s, 1H).

[0662] Step 2. 5-cyclopropyl-2,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl) propyl)pyridin-l-ium iodide . To a solution of Intermediate 2 (42 mg, 0.081 mmol) in acetonitrile (2 mL) was added 2,4-dimethyl-5-cyclopropylpyridine (93 mg , 0.37 mmol, 4.6 eq) and the reaction mixture was stirred at 140 °C for lh in a microwave reactor. The resulting solution was concentrated to 0.5, precipitated with with dietylether, and the precipitate was triturated with diethyl ether to get the title compound as a white-pale beige solid (97 % yield, 52 mg).1H NMR (400 MHz, CDCI3) 68.91 (s, 1H), 8.12 (d, J = 9.8 Hz, 1H), 7.60 (d, J = 2.4 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.11 (s, 1H), 7.02 - 6.94 (m, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.19 (d, J = 9.8 Hz, 1H), 4.90 - 4.75 (m, 2H), 4.56 (t, J = 5.9 Hz, 2H), 4.04 (t,J = 5.7 Hz, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.69 (s, 3H), 2.62 (s, 3H), 2.19 (dt, J = 15.5, 7.7 Hz, 2H), 2.07 (tt, J = 13.1, 7.2 Hz, 4H), 1.88 (ddd, J = 13.6, 8.1, 5.8 Hz, 1H), 1.19 - 1.07 (m, 4H).13C NMR (101 MHz, CDCI3) 6 161.37, 158.78, 158.38, 157.51, 152.75, 150.32, 149.02, 145.01, 142.59, 141.54, 139.51, 131.97, 130.22, 129.63, 114.72, 113.25, 112.49, 106.71, 105.30, 93.87, 72.63, 67.43, 56.88, 32.68, 31.28, 27.03, 26.04, 20.19, 20.04, 11.74, 7.99. HRMS (ESI): m / z calcd. for C34H36O5N [M]+538.2588; found 538.2580 (-1.49 ppm). HPLC purity, 97.56 % at 254 nm (tR= 4.937 min).

[0663] EXAMPLE 25

[0664]

[0665] 2-cyclopropyl-3,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide .

[0666] Step 1. 3,5-dimethyl-2-cyclopropylpyridine. Prepared according to the General procedure for the syntesis of 2- and / or 6-cyclopropylpyridines from 3,5-dimethyl-2-bromopyridine.XH NMR (400 MHz, Chloroform-d) 60.92 (dt, J = 8.1, 3.1 Hz, 2H), 1.01 (dt, J = 5.7, 3.1 Hz, 2H), 2.04 (td, J = 8.5, 4.3 Hz, 1H), 2.23 (s, 3H), 2.38 (s, 3H), 7.19 (d, J = 2.1 Hz, 1H), 8.10 (s, 1H).

[0667] Step 2. 2-cyclopropyl-3,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl) propyl)pyridin-l-ium iodide . To a solution of Intermediate 2 (47.5 mg, 0.092 mmol) in acetonitrile (2 mL) was added the above3,5-dimethyl-2-cyclopropylpyridine (94 mg , 0.64 mmol, 7 eq) and the reaction mixture was stirred at 140 °C for 1 h in a microwave reactor. The resulting solution was concentrated to 0.5 mL, precipitated with dietyl ether, and the precipitate was triturated with diethyl ether to get the title compound as a pale beige solid (33 % yield, 22 mg).1H NMR (400 MHz, CDCI3) 6 9.35 (s, 1H), 8.12 (d, J = 9.8 Hz, 1H), 7.89 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.16 (d, J = 8.5 Hz, 2H), 7.12 (s, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 6.20 (d, J = 9.8 Hz, 1H), 5.14 - 5.00 (m, 2H), 4.56 (t, J = 5.9 Hz, 2H), 4.05 (t, J = 5.7 Hz, 2H), 2.81 (t, J = 7.1 Hz, 2H), 2.57 (s, 3H), 2.55 (s, 3H), 2.35 - 2.21 (m, 2H), 2.16 - 1.98 (m, 4H), 1.98 - 1.87 (m, 1H), 1.21 (q, J = 6.3 Hz, 2H), 0.89 (q, J = 6.0 Hz, 2H).13C NMR (101 MHz, CDCI3) 6 161.36, 158.40, 157.56, 152.77, 151.91, 149.02, 147.31, 145.02, 144.26, 140.01, 139.49, 137.04, 131.99, 129.74, 114.73, 113.26, 112.53, 106.74, 105.29, 93.92, 72.63, 67.49, 57.26, 33.40, 31.69, 27.03, 26.06, 20.24, 18.21, 11.56, 9.84. HRMS (ESI+): m / z calcd. For C34H36NC [M+] 538.25880, found 538.EXAMPLE 26

[0668]

[0669] l-(3-(2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)acetamido) propyl)-3,5-diphenylpyridin-l-ium iodide .

[0670] Step 1. tert-Butyl 2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)- yl)acetate To a solution of CGP-37157 (130 mg, 0.4 mmol) in freshly distilled THF (6.67 mL) under argon atmosphere was added NaH (48 mg, 2 mmol, 5 eq) as a suspension in freshly distilled THF (3.33 mL), and the solution was stirred at room temperature for 1 h, followed by the addition of tert-butyl 2- bromoacetate. The reaction mixture was stirred at room temperature for 2 h. 0.5 mL H2O was added to the reaction mixture which was then partially concentrated in vacuo. The resulting suspension was transferred to a separation funnel, along with H2O (25 mL) and EtOAc (25 mL). The aqueous phase was washed with EtOAc (25 mL), and the organic layers were joined, and washed with brine (50 mL) and dried over Na2SO4. The resulting suspension was filtered, concentrated and triturated with a minimum amount of diethyl ether, to get the title compound as a white solid (90 % yield, 157 mg).1H NMR (400 MHz, Chloroform-d) 6 1.52 (s, 9H), 3.09 (d, J = 12.4 Hz, 1H), 3.29 (d, J = 12.3 Hz, 1H), 4.08 (d, J = 17.0 Hz, 1H), 4.66 (d, J = 17.0 Hz, 1H), 6.26 (s, 1H), 6.61 (s, 1H), 7.29 (d, J = 1.3 Hz, 2H), 7.32 - 7.38 (m, 1H), 7.40 - 7.46 (m, 2H), 7.77 (d, J = 8.0 Hz, 1H).

[0671] Step 2. 2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)acetic acid. In a heat-dried flask under argon atmosphere, the above tert-butyl ester (144 mg, 0.33 mmol) was dissolved in 4 M solution of HCI in dioxane (3.3 mL) and the solution was stirred at 45 °C for 4 h, then the volatiles were completely removed in vacuo, to get the title compound as a white solid, used further without additional purification (94 % yield, 118 mg).1H NMR (400 MHz, Methanol-c / 4) 6 2.97 (d, J = 12.6 Hz, 1H), 3.25 (d, J = 3.6 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 4.49 (d, J = 17.3 Hz, 1H), 6.31 (s, 1H), 6.45 (d, J = 2.1 Hz, 1H), 7.26 - 7.33 (m, 2H), 7.33 - 7.36 (m, 1H), 7.36 - 7.45 (m, 2H), 7.74 (dd, J = 7.6, 1.8 Hz, 1H).Step 3. 2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)- / V-(3- chloropropyl)acetamide. In a heat-dried flask under argon atmosphere, to a solution of the above carboxyllic acid (46.6 mg, 0.122 mmol) in freshly distilled THF (1.2 mL) was added carbonyldiimidazole (24 mg, 0.146, 1.2 eq). The reaction mixture was stirred at room temperature for 30 min. To the stirring reaction mixture were added added 3-chloropropan-l-aminium chloride (31.6 mg, 0.244 mmol, 2 eq), triethylamine (49.4 mg, 0.488 mmol, 4 eq) dissolved in freshly distilled THF (1.2 mL, and the reaction mixture was left stirring at room temperature for 21 h. Additional 3-chloropropan-l-aminium chloride (31.6 mg, 0.244 mmol, 2 eq), triethylamine (49.4 mg, 0.488 mmol, 4 eq) dissolved in freshly distilled THF (1.2 mL) were added and the reaction mixture was left stirring for 4 h at room temperature. The rection mixture was then concentrated in vacuo, and adsorbed onto silica (200 mg), and purified by automated flash chromatography on silica, eluent hexane / EtOAc from 2:1 to 1.5:1, to get the title compound as a white solid (58 % yield, 32.3 mg).1H NMR (400 MHz, DMSO-c / g) 6 1.89 (q, J = 6.6 Hz, 2H), 3.17 (d, J = 15.8 Hz, 2H), 3.23 (d, J = 6.4 Hz, 2H), 3.66 (d, J = 6.6 Hz, 2H), 4.18 (d, J = 16.1 Hz, 1H), 4.50 (d, J = 16.1 Hz, 1H), 5.98 (s, 1H), 6.21 (s, 1H), 6.46 (d, J = 1.8 Hz, 1H), 7.47 - 7.51 (m, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.54 - 7.63 (m, 2H), 7.80 (dd, J = 7.5, 1.7 Hz, 1H), 8.22 (t, J = 5.5 Hz, 1H).

[0672] Step 4. 2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)-N-(3- iodopropyl)acetamide. To a solution of the above alkyl chloride (32.3 mg, 0.071 mmol) in acetone (2 mL) was added sodium iodide (106 mg, 0.71 mmol, 10 eq), and the reaction mixture was stirred at 70 °C overnight in a pressure tube. The rection mixture was then concentrated in vacuo, and adsorbed onto 200 mg silica, and purified by automated flash chromatography on silica, eluent hexane:EtOAc 2:1, to get the intermediate as a white solid, used without further purification (33 % yield, 13 mg).1H NMR (400 MHz, Chloroform-d) 62.10 (td, J = 6.8, 1.2 Hz, 2H), 3.10 (d, J = 12.3 Hz, 1H), 3.22 (t, J = 6.8 Hz, 2H), 3.30 (d, J = 12.3 Hz, 1H), 3.43 (q, J = 6.5 Hz, 2H), 4.05 (d, J = 14.9 Hz, 1H), 4.69 (d, J = 14.8 Hz, 1H), 6.00 (s, 1H), 6.58 (s, 1H), 6.61 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 7.5, 1.9 Hz, 1H), 7.39 - 7.45 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H).

[0673] Step 3. l-(3-(2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl) acetamido)propyl)-3,5-diphenylpyridin-l-ium iodide .

[0674] To a heat-dried microwave vial under argon atmosphere were added the above alkyl iodide (12.5 mg, 0.023 mmol), 3,5-diphenylpyridine (13 mg, 0.55 mmol, 2.5 eq), anhydrous acetonitrile (2 mL), and the reaction mixture was stirred in the microwave reactor for 2 h at 130 °C The reaction mixture was concentrated in vacuo. The impurities were separated from the product by flash chromatography onsilica, eluent 0-10% MeOH in dichloromethane, to get the title compound as an yellow solid (8 mg, 45% yield). HRMS (ESI+): m / z calcd. for C37H32CI2N3O2S+[M+] 652.15868, found 652.15743 (-1.92 ppm).

[0675] HPLC purity, 97.00 % at 254 nm (tR= 5.480 min).3H NMR (400 MHz, Chloroform-d) 6 2.50 - 2.69 (m, 2H), 2.78 (d, J = 12.5 Hz, 1H), 3.24 (d, J = 12.5 Hz, 1H), 3.49 - 3.64 (m, 2H), 4.36 (d, J = 15.9 Hz, 1H), 4.82 (d, J = 15.9 Hz, 1H), 5.26 - 5.38 (m, 1H), 5.39 - 5.54 (m, 1H), 6.25 (s, 1H), 6.54 (d, J = 2.4 Hz, 1H), 7.25 - 7.42 (m, 4H), 7.42 - 7.59 (m, 7H), 7.70 (dd, J = 7.9, 1.7 Hz, 1H), 7.87 - 8.03 (m, 4H), 8.43 (t, J = 5.7 Hz, 1H), 8.61 (t, J = 1.7 Hz, 1H), 9.71 (d, J = 1.8 Hz, 2H).13C NMR (101 MHz, CDCI3) 631.96, 32.51, 35.56, 43.29, 53.74, 59.54, 126.22, 126.87, 127.19, 127.93, 129.27, 129.71, 129.87, 130.42, 130.69, 133.00, 133.92, 134.17, 134.53, 135.83, 139.83, 140.54, 141.14, 141.77, 168.43, 169.02.

[0676] EXAMPLE 1

[0677]

[0678] l-(6-(((4E,6Z,9S,10E,12S,13 / ?,14S)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl- 3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-l(21),4,6,10,18-pentaen-19-yl)amino)hexyl)-3,5- diphenylpyridin-l-ium hexafluorophosphate(V) (Gamitrinib DPPy PF6).

[0679] Step 1. l-(6-ammoniohexyl)-3,5-diphenylpyridin-l-ium chloride. tert-Butyl (6-bromohexyl)carbamate (211 mg, 0.79 mmol), 3,5-diphenylpyridine (200 mg, 0.86 mmol, 1.1 eq), and anhydrous acetonitrile (2 mL) were added to a heat-dried pressure tube under Ar atmosphere, and the mixture was heated to 100 °C and stirred overnight. The reaction mixture was concentrated to 0.8 mL in vacuo, triturated with hexane (2 x 100 mL), and dried in vacuo. The resulting sticky white powder was dissolved in 4 M HCI in dioxane (2 mL) and stirred at 40 °C overnight, monitored by TLC. The reaction mixture was concentrated in vacuo, to get the title compound as an off-white solid (277 mg, 87% yield).1H NMR (400 MHz, DMSO) 69.58 (d, J = 1.5 Hz, 2H), 9.14 (s, 1H), 8.08 (dd, J = 8.0, 1.3 Hz, 7H), 7.72 - 7.56 (m, 6H), 4.79 (t, J = 7.5 Hz, 2H), 2.76 (dd, J = 13.4, 6.6 Hz, 2H), 2.09 (s, 2H), 1.67 - 1.52 (m, 2H), 1.41 (d, J = 2.9 Hz, 4H).13C NMR (101 MHz, DMSO) 6141.13, 139.81, 133.29, 130.21, 129.39, 127.91, 61.06, 38.51, 30.56, 26.54, 25.21, 24.99.Step 2. l-(6-(((4E,6Z,9S,10E,12S,13R,14S)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16- tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-l(21),4,6,10,18-pentaen-19- yl)amino)hexyl)-3,5-diphenylpyridin-l-ium hexafluorophosphate(V) (Gamitrinib DPPy PF6).

[0680] Geldanamycin (50 mg, 0.089 mmol), the above amine from Step 1 (107.6 mg, 0.267 mmol, 3 eq) and N,N- diisopropylethylamine (115 mg, 0.89 mmol, 10 eq) were dissolved in chloroform (8.3 mL) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to obtain 82 mg purple solid. The crude product was dissolved in DCM (3 mL), washed with 1 M KPFg (aq) (5 x 1.5 mL), and concentrated in vacuo. The resulting solid was redissolved in DCM, and filtered through a 200 nm HPLC filter, and dried in vacuo, to obtain the title compound as a dark purple solid (70 mg, 78 % yield). HRMS (ESI+): m / z calcd. For C5IH63N4O8+[M+] 859.4640, found 859.4629. HPLC purity, 96.54 % at 254 nm (tR= 4.087 min).

[0681] EXAMPLE 28

[0682]

[0683] l-(6-((9-(2-(methoxycarbonyl)phenyl)-3-oxo-3H-xanthen-6-yl)oxy)hexyl)-3,5-diphenylpyridin-l-ium iodide

[0684] Step 1. Methyl 2-(6-((6-chlorohexyl)oxy)-3-oxo-3H-xanthen-9-yl)benzoate. To a solution of fluorescein methyl ester (1 g, 2.9 mmol) in DMF (40 mL) was added l-bromo-6-chlorohexane (0.86 g, 640 uL, 4.34 mmol, 1.5 eq), caesium carbonate (1.42 g, 4.34 mmol, 1.5 eq). The reaction mixture was stirred at 50 °C overnight. The rection mixture was then concentrated in vacuo, 80 mL DCM and 100 mL H?O were added, and the aqueous layer was washed additionaly with DCM (2 x 80 mL). The organic phases were joined and washed with a saturated NaCI(aq) solution (100 mL), and dried with NajSO^s). The resulting solution was concentrated in vacuo, and purified by automatic flash chromatography on silica, eluent 0-7% MeOH in dichloromethane, to get the chloride intermediate as a dark orange oil, used without further purification (73 % yield, 0.989 g).1H NMR (400 MHz, Chloroform-d) 6 1.53 (q, J = 3.3 Hz, 4H), 1.84 (dt, J = 13.5, 6.8 Hz, 4H), 3.56 (t, J = 6.6 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 6.45 (d, J = 1.9 Hz, 1H), 6.54 (dd, J = 9.7, 1.9 Hz, 1H), 6.72 (dd, J = 8.9, 2.4 Hz, 1H), 6.84 (d, J = 9.7 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 7.31 (dd, J = 7.6, 1.3 Hz, 1H), 7.65 - 7.72 (m, 1H), 7.72 - 7.80 (m, 1H), 8.24 (dd, J= 7.7, 1.4 Hz, 1H).Step 2. methyl 2-(6-((6-iodohexyl)oxy)-3-oxo-3H-xanthen-9-yl)benzoate. To a solution of the above alkyl chloride (0.989 g, 2.12 mmol) in acetone (16 mL) was added sodium iodide (2.5 g, 16.9 mmol, 8 eq), and the reaction mixture was stirred at 100 °C for 30 min in a microwave reactor. To the reaction mixture was added 100 mL DCM to precipitate the inorganic salts present, and the clear solution was decanted to a round-bottom flask, followed by additional washing of the inorganic precipitate (2 x 20 mL) Upon partial concentration of the volatiles in vacuo, additional inorganic salts had precipitated, and the process was repeated. The resulting solution was concentrated in vacuo, and purified by automated flash chromatography on silica, eluent 0-7% MeOH in dichloromethane, to get title compound as a orange-red solid (59 % yield, 0.690 g).1H NMR (400 MHz, Chloroform-d) 6 1.50 (dt, J = 6.6, 3.1 Hz, 4H), 1.86 (q, J = 6.9 Hz, 4H), 3.21 (t, J = 7.0 Hz, 2H), 3.64 (s, 3H), 4.07 (t, J = 6.4 Hz, 2H), 6.46 (d, J = 1.9 Hz, 1H), 6.54 (dd, J = 9.7, 1.9 Hz, 1H), 6.72 (dd, J = 8.9, 2.4 Hz, 1H), 6.84 (d, J = 9.7 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 7.29 - 7.35 (m, 1H), 7.67 (td, J = 7.7, 1.4 Hz, 1H), 7.71 - 7.80 (m, 1H), 8.19 - 8.29 (m, 1H).

[0685] Step 3. l-(6-((9-(2-(methoxycarbonyl)phenyl)-3-oxo-3H-xanthen-6-yl)oxy)hexyl)-3,5-diphenylpyridin-l- ium iodide . Methyl 2-(6-((6-iodohexyl)oxy)-3-oxo-3H-xanthen-9-yl)benzoate (30 mg, 0.054 mmol) and 3,5-diphenylpyridine (50 mg, 0.216 mmol) were added into a 10 mL microwave vial under argon atmosphere, and dissolved in acetonitrile (2 mL). The reaction mixture was stirred in a microwave reactor at 135 °C for 1 h. The resulting mixture was concentrated to 0.5-1 mL, and precipitated with diethyl ether (25 mL). The precipitate was collected, redissolved in dichloromethane, and precipitated with diethyl ether, to get the title compound as a brown solid (35 mg, 82% yield).1H NMR (400 MHz, CDCI3) 69.58 (s, 2H), 8.57 (s, 1H), 8.24 (d, J = 7.7 Hz, 1H), 7.93 (d, J = 5.9 Hz, 4H), 7.74 (t, J = 7.2 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.52 (d, J = 7.0 Hz, 6H), 7.30 (s, 1H), 6.87 (d, J = 7.7 Hz, 2H), 6.84 (s, 1H), 6.70 (d, J = 8.7 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 5.32 (d, J = 16.2 Hz, 2H), 4.03 (s, 2H), 3.63 (d, J = 7.5 Hz, 3H), 2.15 (s, 2H), 1.94 (s, 2H), 1.80 (s, 2H), 1.57 (s, 2H - covered by H2O protons).13C NMR (101 MHz, CDCI3) 6165.71, 163.94, 154.52, 141.61, 140.54, 139.77, 134.66, 132.88, 132.77, 131.24, 130.87, 130.67, 130.34, 129.97, 129.85, 129.06, 127.96, 117.45, 114.82, 114.16, 100.99, 77.48, 77.16, 76.84, 68.80, 65.96, 62.24, 52.55, 32.36, 28.60, 25.68, 25.53. HRMS (ESI+): calcd. For C44H38NC [M+] 660.27445, found 660.27310 (-2.04 ppm). HPLC purity, 90.14 % at 254 nm (tR= 4.540 min).

[0686] EXAMPLE 29

[0687]

[0688] l-(10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)decyl)-3,5-diphenylpyridin-l-ium iodide. Step 1. Methyl 2-(6-((6-iodohexyl)oxy)-3-oxo-3H-xanthen-9-yl)benzoate. To a solution of idebenone (1 g, 2.96 mmol) in DCM (30 mL) were added triphenylphosphine (1.08 g, 4.14 mmol, 1.4 eq) and imidazole (664 mg, 9.76 mmol, 3.3 eq). The resulting suspension was cooled to 0 °C while stirring, followed by addition of iodine (1.12 g, 4.44 mmol, 1.5 eq), and the reaction mixture was allowed to room temperature, until reaction completion was observed on TLC. The reaction mixture was concentrated, and purified by flash chromatography on silica, eluent EtOAc:hexane 1:4, to get the title compound as an orange oil (74 % yield, 0.99 g).

[0689] Step 2. l-(10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)decyl)-3,5-diphenylpyridin-l- ium iodide . To a microwave vial were added the above intermediate alkyl iodide (60.5 mg, 0.135 mmol, 1 eq), 3,5-diphenylpyridine (74 mg, 0.32 mmol, 2.4 eq) and acetonitrile (2 mL), and the mixture was stirred for 1.5 h in a microwave reactor. The reaction mixture was concentrated in vacuo and purified by automated flash chromatography on silica, eluent 0-10% MeOH in dichloromethane, to get the title compound as a dark orange oil (58 mg, 63% yield).1H NMR (400 MHz, DMSO-dg) 61.15 - 1.49 (m, 14H), 1.92 (s, 3H), 2.08 (d, J = 9.3 Hz, 2H), 2.35 (d, J = 7.6 Hz, 2H), 3.87 (d, J = 1.4 Hz, 6H), 7.51 - 7.73 (m, 6H), 7.93 - 8.13 (m, 4H), 9.14 (t, J = 1.7 Hz, 1H), 9.47 (d, J = 1.8 Hz, 2H).13C NMR (101 MHz, DMSO) 6 11.66, 25.58, 25.66, 28.04, 28.42, 28.68, 28.75, 28.78, 29.09, 30.78, 60.73, 61.38, 127.85, 129.38, 130.21, 133.27, 138.23, 139.76, 139.83, 141.05, 141.86, 144.23, 144.29, 183.54, 184.01. HRMS (ESI+): calcd. For C36H42NCV [M+] 552.31084, found 552.31010 (-1.33 ppm). HPLC purity, 98.08 % at 254 nm (tR= 7.860 min).

[0690] EXAMPLE 30

[0691]

[0692] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,5-diphenylpyridin-l-ium iodide

[0693] Step 1. 2,5-diphenylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 2,5-dibromopyridine.1H NMR (400 MHz, CDCU) 68.94 (d, J = 1.8 Hz, 1H), 8.09-8.01 (m, 2H), 7.96 (dd, J = 8.2, 2.4 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.50 (t, J = 7.5 Hz, 4H), 7.47 - 7.39 (m, 2H).

[0694] Step 2. l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,5-diphenylpyridin-l- ium iodide. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 2,5-diphenylpyridine (112 mg; 0,485 mmol; 5 ekv) and the reaction mixture was stirred at 170 °C for 2h in a microwave reactor. The resulting solution was concentrated to 0.5 mL, then precipitated by adding dietyl ether. The procedure was repeated once with acetonitrile, and then with dichloromethane to get the title compound as a yellow solid (50 % yield, 30 mg).1H NMR (400 MHz, Chloroform-d) 6 1.99 - 1. 1 (m, 7H), 2.57 (t, J = 7.4 Hz, 2H), 4.00 (t, J = 5.8 Hz, 2H), 4.55 (t, J = 5.9 Hz, 2H), 4.89 - 5.12 (m, 2H), 6.20 (d, J = 9.8 Hz, 1H), 6.59 - 6.74 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 7.11 (s, 1H), 7.36 - 7.76 (m, 11H), 7.85 (d, J = 8.2 Hz, 1H), 7.95 - 8.09 (m, 2H), 8.13 (d, J = 9.8 Hz, 1H), 8.60 (dd, J = 8.3, 1.9 Hz, 1H), 9.77 (d, J = 2.0 Hz, 1H).13C NMR (101 MHz, CDCI3) 6 26.05, 27.07, 31.29, 33.27, 58.80, 67.41, 72.64, 93.95, 105.29, 106.76, 112.57, 113.28, 114.65, 128.10, 128.97, 129.28, 129.69, 129.93, 130.23, 130.73, 130.92, 131.52, 131.56, 132.48, 133.72, 133.81, 139.47, 140.55, 142.57, 144.15, 145.01, 149.02, 152.78, 153.24, 157.38, 158.39, 161.36. HRMS (ESI+): calcd. For C4IH36NO5+[M+] 622.25880, found 622.25808 (-1.16 ppm). HPLC purity, 94.49 % at 254 nm (tR= 5.347 min).EXAMPLE 31

[0695]

[0696] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,4-diphenylpyridin-l- ium iodide

[0697] Step 1. 2,4-diphenylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 2,4-dibromopyridine.1H NMR (400 MHz, CDCU) 68.74 (dd, J = 5.1, 0.7 Hz, 1H), 8.09 - 8.00 (m, 2H), 7.94 (dd, J = 1.7, 0.8 Hz, 1H), 7.76 - 7.66 (m, 2H), 7.56 - 7.40 (m, 7H).

[0698] Step 2. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 2,4- diphenylpyridine (112 mg; 0,485 mmol; 5eq) and the reaction mixture was stirred at 160 °C for lh in a microwave reactor. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane. The pure fractions were gathered, concentrated, and dissolved in 0.5 mL acetonitrile, then precipitated by adding dietyl ether. The procedure was repeated once with acetonitrile, and then with dichloromethane to get the title compound as a yellow solid (74 % yield, 45 mg).1H NMR (400 MHz, Chloroform-d) 6 1.93 - 2.26 (m, 6H), 2.59 (t, J = 7.3 Hz, 2H), 4.01 (t, J = 5.7 Hz, 2H), 4.56 (t, J = 5.9 Hz, 2H), 4.65 - 4.87 (m, 2H), 6.21 (d, J = 9.8 Hz, 1H), 6.62 - 6.74 (m, 2H), 6.87 - 7.04 (m, 3H), 7.11 (s, 1H), 7.47 - 7.66 (m, 9H), 7.78 - 7.86 (m, 2H), 7.88 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 8.31 (dd, J = 6.7, 2.3 Hz, 1H), 9.92 (d, J = 6.7 Hz, 1H).13C NMR (101 MHz, CDCI3) 626.03, 27.04, 31.33, 32.96, 57.64, 67.40, 72.63, 93.91, 105.28, 106.73, 112.55, 113.26, 114.65, 124.61, 126.56, 128.07, 128.79, 129.34, 129.69, 130.04, 131.32, 131.52, 131.56, 132.61, 133.62, 139.47, 145.01, 147.22, 149.00, 152.75, 155.10, 156.40, 157.38, 158.37, 161.34. HRMS (ESI+): calcd. For C4IH36NO5+[M+] 622.25880 , found 622.25823 (-0.92 ppm). HPLC purity, 97.97 % at 254 nm (tR= 5.363 min).EXAMPLE 32

[0699]

[0700] l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,3-diphenylpyridin-l- ium iodide

[0701] Step 1. 2,3-diphenylpyridine. Prepared according to the General procedure for the synthesis of arylpyridines from 2,3-dibromopyridine.1H NMR (400 MHz, CDCU) 68.70 (dd, J = 4.8, 1.7 Hz, 1H), 7.73 (dd, J = 7.7, 1.6 Hz, 1H), 7.41 - 7.01 (m, 11H).

[0702] Step 2. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 2,3- diphenylpyridine (112 mg; 0,485 mmol; 5 eq) and the reaction mixture was stirred at 160 °C for lh in a microwave reactor. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane to get the title compound as a yellow solid (61 % yield, 37 mgJTH NMR (400 MHz, Chloroform-d) 6 1.97 - 2.12 (m, 4H), 2.12 - 1. 1 (m, 2H), 2.56 (t, J = 7.3 Hz, 2H), 4.02 (t, J = 5.7 Hz, 2H), 4.55 (t, J = 6.0 Hz, 2H), 4.66 - 4.77 (m, 2H), 6.20 (d, J = 9.8 Hz, 1H), 6.63 - 6.71 (m, 2H), 6.85 - 6.93 (m, 2H), 6.97 (dd, J = 2.4, 1.0 Hz, 1H), 7.05 - 7.16 (m, 3H), 7.17 - 7.25 (m, 3H), 7.35 (d, J = 4.4 Hz, 4H), 7.38 - 7.47 (m, 1H), 7.60 (d, J = 2.4 Hz, 1H), 8.12 (dd, J = 9.8, 0.7 Hz, 1H), 8.25 (dd, J = 8.0, 6.2 Hz, 1H), 8.38 (dd, J = 8.0, 1.4 Hz, 1H), 9.85 (dd, J = 6.2, 1.4 Hz, 1H).13C NMR (101 MHz, CDCI3) 626.09, 27.11, 31.44, 33.23, 59.35, 67.46, 72.68, 93.98, 105.33, 106.79, 112.60, 113.31, 114.69, 127.72, 128.70, 129.08, 129.24, 129.39, 129.75, 129.79, 130.96, 131.57, 135.08, 139.51, 143.32, 145.05, 145.89, 146.24, 149.06, 152.82, 153.78, 157.41, 158.43, 161.39. HRMS (ESI+): calcd. For C4IH36NO5+[M+] 622.25880, found 622.25804 (-1.22 ppm). HPLC purity, 99.72 % at 254 nm (tR= 5.300 min).EXAMPLE 33

[0703]

[0704] 3-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5- phenylpyridin-l-ium iodide

[0705] Step 1.4-(5-phenylpyridin-3-yl)morpholine. Prepared according to the General procedure for the synthesis of arylpyridines from 4-(5-bromopyridin-3-yl)rnorpholine.1H NMR (400 MHz, CDCh) 6 8.36 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 2.8 Hz, 1H), 7.57 (dt, J = 3.2, 1.9 Hz, 2H), 7.51 - 7.44 (m, 2H), 7.41 (dt, J = 9.6, 4.3 Hz, 1H), 7.33 (dd, J = 2.6, 2.0 Hz, 1H), 3.91 (dd, J = 5.7, 4.0 Hz, 4H), 3.27 (dd, J = 5.7, 4.0 Hz, 4H).

[0706] Step 2. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 4- (5-phenylpyridin-3-yl)morpholine (116,4 mg; 0,485 mmol; 5 eq) and the reaction mixture was stirred at 120 °C for 2h in a microwave reactor. The resulting solution was dissolved in 0.5 mL acetonitrile, then precipitated by adding dietyl ether. The procedure was repeated three times, using acetonitrile, then dichloromethane, and then acetonitrile to get the title compound as a grey-brown solid (80 % yield, 49 mg).3H NMR (400 MHz, Chloroform-d) 61.90- 2.15 (m, 4H), 2.40 (q, J = 7.4, 6.9 Hz, 2H), 2.79 (t, J = 7.6 Hz, 2H), 3.61 (dd, J = 6.1, 3.7 Hz, 4H), 3.75 - 4.10 (m, 6H), 4.54 (t, J = 5.9 Hz, 2H), 5.06 (t, J = 7.5 Hz, 2H), 6.17 (d, J = 9.7 Hz, 1H), 6.62 - 6.81 (m, 2H), 6.96 (dd, J = 2.4, 1.0 Hz, 1H), 7.05 - 7.20 (m, 3H), 7.41 - 7.58 (m, 3H), 7.59 (d, J = 2.4 Hz, 1H), 7.66 (dt, J = 5.6, 1.9 Hz, 3H), 8.10 (d, J = 9.8 Hz, 1H), 8.25 (s, 1H), 9.35 (d, J = 2.3 Hz, 1H).13C NMR (101 MHz, CDCI3) 6 26.02, 27.00, 31.25, 33.97, 47.50, 61.76, 66.16, 67.37, 72.59, 93.85, 105.28, 106.69, 112.45, 113.21, 114.59, 123.99, 127.58, 129.56, 129.69, 129.80, 129.89, 130.48, 132.13, 133.92, 139.50, 141.55, 144.99, 148.99, 149.24, 152.72, 157.34, 158.36, 161.37. HRMS (ESI+): calcd. For C39H39N2O6+[M+] 631.28026, found 631.27945 (-1.29 ppm). HPLC purity, 99.58 % at 254 nm (tR= 5.057 min).EXAMPLE 34

[0707]

[0708] 4-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide

[0709] Step 1.4-(2-phenylpyridin-4-yl)morpholine. Prepared according to the General procedure for the synthesis of arylpyridines from 4-(2-bromopyridin-4-yl)rnorpholine.1H NMR (400 MHz, CDCh) 6 8.38 (d, J = 6.0 Hz, 1H), 7.92 - 7.78 (m, 2H), 7.46 - 7.36 (m, 3H), 7.06 (d, J = 2.5 Hz, 1H), 6.64 (dd, J = 6.0, 2.6 Hz, 1H), 3.96 - 3.76 (m, 4H), 3.47 - 3.28 (m, 4H).

[0710] Step 2. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 4- (2-phenylpyridin-4-yl)morpholine (116,4 mg; 0,485 mmol; 5 eq) and the reaction mixture was stirred at 160 °C for 2 h in a microwave reactor. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica, eluent 0-10% MeOH in dichloromethane to get the title compound as a grey-brown solid (40 % yield, 1 mg).1H NMR (400 MHz, Chloroform-d) 6 1.89 - 2.01 (m, 2H), 2.00 - 2.14 (m, 4H), 2.46 (t, J = 7.4 Hz, 2H), 3.71 (s, 4H), 3.87 (dd, J = 5.9, 3.9 Hz, 4H), 4.04 (t, J = 5.7 Hz, 2H), 4.11 - 4.22 (m, 2H), 4.56 (t, J = 6.0 Hz, 2H), 6.21 (d, J = 9.8 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H), 6.70 - 6.74 (m, 2H), 6.85 - 6.93 (m, 2H), 6.98 (dd, J = 2.4, 1.0 Hz, 1H), 7.11 (t, J = 0.8 Hz, 1H), 7.37 - 7.42 (m, 2H), 7.47 - 7.59 (m, 4H), 7.60 (d, J = 2.4 Hz, 1H), 8.13 (dd, J = 9.8, 0.7 Hz, 1H), 8.75 (d, J = 7.7 Hz, 1H).13C NMR (101 MHz, CDCh) 6 26.03, 27.03, 31.29, 32.43, 46.74, 54.80, 66.14, 67.44, 72.64, 93.89, 105.29, 106.73, 109.72, 109.77, 112.51, 113.28, 114.68, 128.60, 129.24, 129.43, 130.98, 131.64, 132.25, 139.52, 144.88, 145.02, 149.02, 152.74, 153.86, 155.92, 157.34, 158.38, 161.37. HRMS (ESI+): calcd. For C39H39N2O6+[M+] 631.28026 found 631.27944 (-1.30 ppm). HPLC purity, 98.07 % at 254 nm (tR= 5.057 min).EXAMPLE 35

[0711]

[0712] 5-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide

[0713] Step 1.4-(6-phenylpyridin-3-yl)morpholine. Prepared according to the General procedure for the synthesis of arylpyridines from 4-(6-bromopyridin-3-yl)rnorpholine.1H NMR (400 MHz, CDCh) 6 8.38 (d, J = in Hz, 1H), 7.96 - 7.89 (m, 2H), 7.64 (dd, J = 8.7, 0.6 Hz, 1H), 7.48 - 7.41 (m, 2H), 7.38 - 7.31 (m, 1H), 7.24 (d, J = 3.0 Hz, 1H), 4.04 - 3.78 (m, 4H), 3.33 - 3.13 (m, 4H).

[0714] Step 2. To a solution of Intermediate 2 (50 mg; 0,097 mmol) in acetonitrile (2 mL) was added the above 4- (6-phenylpyridin-3-yl)morpholine (116,4 mg; 0,485 mmol; 5 eq) and the reaction mixture was stirred at 160 °C for 2 h in a microwave reactor. The resulting solution was concentrated, dissolved in dichloromethane and concentrated to 0.5 mL, then precipitated by adding dietyl ether. The procedure was repeated using acetonitrile, to get the title compound as a yellow solid (83 % yield, 51 mg).1H NMR (400 MHz, Chloroform-d) 6 1.96 - 2.23 (m, 6H), 2.58 (t, J = 7.4 Hz, 2H), 3.63 (dd, J = 6.0, 3.7 Hz, 4H), 3.89 (dd, J = 6.1, 3.8 Hz, 4H), 4.02 (t, J = 5.7 Hz, 2H), 4.55 (t, J = 5.9 Hz, 2H), 4.72 - 4.89 (m, 2H), 6.20 (d, J = 9.8 Hz, 1H), 6.64 - 6.76 (m, 2H), 6.83 - 6.95 (m, 2H), 6.98 (dd, J = 2.4, 1.0 Hz, 1H), 7.10 (s, 1H), 7.30 (dt, J = 9.3, 1.8 Hz, 2H), 7.45 - 7.53 (m, 2H), 7.55 (dd, J = 8.2, 6.6 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 9.1, 2.8 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 9.38 (d, J = 2.8 Hz, 1H).13C NMR (101 MHz, CDCh) 6 26.00, 26.99, 31.08, 33.57, 47.52, 58.10, 66.15, 67.38, 72.60, 93.81, 105.26, 106.66, 112.43, 113.21, 114.50, 127.43, 128.96, 129.25, 129.51, 129.81, 130.86, 131.26, 131.50, 131.84, 139.49, 142.93, 144.98, 148.39, 148.98, 152.68, 157.22, 158.33, 161.33. HRMS (ESI+): calcd. For C39H39N2O6+[M+] 631.28026, found 631.27834 (-3.05 ppm). HPLC purity, 99.04 % at 254 nm (tR= 5.027 min).Biological data

[0715] The mitochondria-targeting ability of pyridinium cations was evaluated by assessing the capacity of their conjugates with a Kvl.3 inhibitor to reduce the viability of COLO-357 cells. These cells are known to overexpress the Kvl.3 ion channel in mitochondria, and inhibition of mitochondrial Kvl.3 by the benchmark triphenylphosphonium-conjugated inhibitor MTM has been shown to induce apoptosis (Leanza et al. Cancer Cell 2017, 31, 516-531). The benchmark triphenylphosphonium MTM displayes excellent activity (+++), whereas the unsubstitued pyridinium, 4-methyl substituted and 3,5-dimethyl substituted pyridinium cation displays no activity (o) or weak activity (+). Good actvity (++) and excellent activity (+++) were observed for di- and more substituted pyridinium cations with favorable substitution pattern involving alkyl, aryl and electron-donating substituents. Lipophilicity (logD74) of the permanent cations was determined experimentally and correlates well with the thermodynamic solubility, but does not correlate universally with efficient mitochondrial targeting. Importantly, the cations based on 3-(lH-tetrazol-5-yl)pyridine or 5- phenylthiazole are inactive despite having the lipophilicity in the range of the mitochondria-targeting triphenylphosphonium cation or 3,5-diphenylpyridinium cation.

[0716] Table 1. Profiling of mitochondrial targeting of permanent cations, and experimental determination of logD74and thermodynamic solubility of their conjugates with psoralene-based Kvl.3 inhibitors.

[0717]

[0718]

[0719]

[0720] aIC5o was determined by the resazurin-based assay after 72 h. Activity ranges: +++ IC50 < 1 pM; ++ 1 pM < IC50 < 2 pM; + 2 pM < IC50 < 5 pM; o IC50 > 5 pM.boctanol / PBS partition coeficient, determined by the shake-flask method (PBS, phosphate-buffered saline, pH 7.4).cThermodynamic solubility in phosphate buffer pH 7.4 determined by the shake-flask method.

[0721] The effect of Example 1 on the growth of non-transformed epithelial cells (hTERT-RPEl, immortalized with human telomerase) and a cell line derived from pancreatic carcinoma (COLO-357) was tested by high-content imaging in vitro using an incucyte system. High concentrations of the compound induced apoptosis and precluded the growth of both cell lines (Figure 1). This correlated with a change in mitochondrial morphology, as depicted in Figure 1, which shows a 3-D reconstruction obtained from a z-stack of confocal superresolution images of cells treated with MitoTracker Deep Red. Treatment with 5 pM Example 1 resulted in massive fragmentation of the mitochondria as compared to control conditions.Low concentrations of the compound, however, showed specificity for cancer cells. Apoptosis was determined as caspase cleavage in a live cell imaging system. The fluorescence values of the reporter (caspase activity) were normalized by the number of cells on the image (expressed as confluence) 48 hours after the addition of the compound.

Claims

1. CLAIMS1. Compound of formula (I):wherein:"cargo" is an antioxidant, ligand or a reporter;R1, R2, R3, R4and R5are independently selected from the group consisting of hydrogen, (Ci-Ci2)-alkyl, substituted or unsubstituted aryl, such as phenyl or naphtyl, and substituted or unsubstituted five or six membered heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S, such as a five or six membered aromatic heterocyclyl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S; halo, wherein halo is fluoro, chloro, bromo, or iodo; hydroxy, HO(Ci-Cg)-alkyloxy, (Ci-C4)-perfluoroalkyl, O(CO)CCl3, (Ci-C6)-alkyl-S(O)n-, phenyl-(CH2)r-S(O)n- , cyano, nitro, COOH, CO(Ci-C6)-alkyl, COO(Ci-C6)-alkyl, CONR6R7, NR6R7, O(CO)NR6R7, azido, NR6(CO)NR6R7, (Ci-Ci2)-alkyl, (C2-Cio)-alkenyl, (C2-Cio)-alkynyl, O[(C=O)Or]s(Ci-C6)-alkyl, O[(C=O)Or]s(C2- Cg)-alkenyl, O[(C=O)Or]saryl, O[(C=O)Or]sheteroaryl, O(CH2)nheteroaryl, O(CH2)naryl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;wherein the aryl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci- Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-C6)-alkyl-S(O)n-, 0(Co-C6)-alkyl-S(0)n-, phenyl, phenoxy, cycloalkyl, cyano, nitro, COOH, CO(Ci-Cg)-alkyl, COO(Ci-Cg)- alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;wherein the heterocyclyl, if substituted, is substituted with one or more (such as one or two) substituents selected from the group consisting of halo, wherein halo is fluoro, chloro, bromo, or iodo, hydroxy, (Ci-Cg)-alkyl, (Ci-C4)-perfluoroalkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Ci-Cg)-alkyloxy, (Ci-Cg)- alkyl-S(O)n-, 0(Co-C6)-alkyl-S(0)n-, phenyl, phenoxy, cycloalkyl, cyano, nitro, COOH, CO(Ci-Cg)-alkyl,C00(Ci-C6)-alkyl, CONR6R7, NR6R7, methylenedioxyl, OCF3, and fused benzo or pyridyl group, with n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;wherein R6and R7are independently selected from the group consisting of hydrogen, [(C=O)Or]saryl, [(C=O)Or]s(C2-C8)-alkenyl, [(C=O)Or]s(Ci-C8)-alkyl, (C=O)rS(O)n(Ci-C8)-alkyl, (C=O)rS(O)naryl, and heterocyclyl, with r and s at each occurrence being independently from each other 0 or 1, and n at each occurrence being 0, 1, 2 or 3, preferably n at each occurrence being 0 or 1;wherein R1and R2are optionally connected to form an unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring.W is a suitable functional group depending on the available site on the particular cargo of interest which is attached to the linker;Linker is selected from:-(C(R8)(R9))I-, wherein I is from 1 to 20, preferably from 1 to 10, more preferably 3 to 5; and R8and R9are independently of one another — H, halogen, -CF3,-OH, -(Ci-Cg)-alkyl, -OC(O)(Ci-Cg)- alkyl, [(C=O)Or]saryl, [(C=O)Or]sheteroaryl, or [(C=O)Or]s(Ci-C6)-alkyl;A non-peptidic polymeric linker, such as a non-peptidic polymeric linker selected from polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone as well as derivatives and copolymers thereof;A non-polymeric aliphatic linker, such as a non-polymeric aliphatic linker comprising a divalent, linear or branched, straight or cyclic, saturated or unsaturated hydrocarbon chain having from 2 to 20 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)-, -OC(=O)-, -N(CI-C6alkyl)-, NHC(=O)-, -N(CI-C6alkyl)C(=O)-, -S(=O)- or -S(=O)2- and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3 or 4) substituents;A divalent radical formed from an amino acid or peptide; andor a pharmaceutically acceptable salt, racemate, diastereomer, enantiomer, ester, carbamate, sulphate, phosphate and prodrug thereof.

2. The compound according to claim 1, having structural Formula II, wherein pyridinium cation is disubstituted, such that R1and R2are not hydrogen and R3, R4and R5are hydrogen.cargolinker3. The compound according to claim 1, having structural Formula III, wherein pyridinium cation is trisubstituted, such that R1, R2and R3are not hydrogen and R4and R5are hydrogen.

4. The compound according to claim 1, having structural Formula IV, wherein pyridinium cation is tetrasubstituted, such that R1, R2, R3and R4are not hydrogen and R5is hydrogen.

5. The compound according to claim 1, having structural Formula V, wherein pyridinium cation is pentasubstituted, such that none of R1, R2, R3, R4and R5are hydrogen6. The compound according to claim 2, wherein R1and R2each are independently selected from the group consisting of substituted or unsubtituted aryl and substituted or unsubstituted five or six membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of O, N and S.

7. The compound according to any one of claims 1, 2 and 6 having structural Formula VIwherein R10is independently of one another — H, halogen, — CF3, —OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl, , or [(C=O)Or]s(Ci-C6)-alkyl.

8. The compound according to claim 3, wherein R1, R2and R3each are (Ci-CuJ-alkyl, such as a linear or branched alkyl or cycloalkyl.

9. The compound according to claim 8, wherein Ri is unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring.

10. The compound according to any one of the preceding claims, wherein R1and R2are not connected to each other to form an unsubstituted cycloalkyl.

11. The compound according to claim 4, wherein R1and R2are connected to form an unsubstituted cycloalkyl having 3 to 12 carbons in a single ring, preferably from 3 to 7 carbons in a single ring, more preferably from 3 to 5 carbons in a single ring, and wherein R3and R4each are independently selected from alkyl or cycloalkyl.

12. The compound according to claim 3, wherein Ri is a disubstituted phenyl where each of these substituents are independently selected from — H, halogen, — CF3,— OH, -(Ci-Cg)-alkyl, cycloalkyl, aryl, heteroaryl, -OC(O)(Ci-Cs)-alkyl, [(C=O)Or]saryl or [(C=O)Or]s(Ci-C6)-alkyl.

13. The compound according to claim 1, wherein R3is hydrogen.

14. The compound according to any one of the preceding claims which is selected from the group consisting ofl-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-4-phenylpyridin-l-ium iodide,2,6-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,3.5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,3.5-dicyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,3-cyclopropyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,2-methyl-5-cyclopropyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4- yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)quinolin-l-ium iodide. 2.4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,3.5-bis(4-methoxyphenyl)-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) pyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium saccharinate,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium acesulfamate,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium p-toluenesulfonate,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-3,5-diphenylpyridin-l- ium tetrafluoroborate,3.5-dicyclohexyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l- ium iodide,3.5-dicyclopentyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,3-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2-phenylpyridin-l-ium iodide,2-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,2,3,5-trimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,3-chloro-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin- 1-ium iodide,3-cyclopentyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,3-cyclohexyl-5-methyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,5-cyclopropyl-2,4-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,2-cyclopropyl-3,5-dimethyl-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)pyridin-l-ium iodide,l-(3-(2-(7-chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydrobenzo[e][l,4]thiazepin-l(5H)-yl)acetamido) propyl)-3,5-diphenylpyridin-l-ium iodide,l-(6-(((4E,6Z,9S,10E,12S,13R,14S)-9-(carbamoyloxy)-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1]docosa-l(21),4,6,10,18-pentaen-19-yl)amino)hexyl)-3,5-diphenylpyridin-l-ium hexafluorophosphate(V) (Gamitrinib DPPy PF6-), l-(6-((9-(2-(methoxycarbonyl)phenyl)-3-oxo-3H-xanthen-6-yl)oxy)hexyl)-3,5-diphenylpyridin-l-ium iodide,l-(10-(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l-yl)decyl)-3,5-diphenylpyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,5-diphenylpyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,4-diphenylpyridin-l-ium iodide,l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2,3-diphenylpyridin-l-ium iodide,3-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-5-phenylpyridin-l-ium iodide,4-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide, and5-morpholino-l-(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl)-2- phenylpyridin-l-ium iodide.

15. The compound according to any one of the preceding claims, wherein cargo is an anticancer agent selected from the group consisting of Abemaciclib, Abiraterone, Acalabrutinib, Aclarubicin, Actinomycin D, Adagrasib, Adriamycin, Afatinib, Alectinib, Alitretinoin, All-trans-retinoic acid, Alpelisib, Altretamine, Amifostine, Aminolevulinic Acid, Amrubicin, Amsacrine, Anastrozole, Apalutamide, Ara C, Arsenic Trioxide, Asciminib, Avapritinib, Axitinib, Azacitidine, Belinostat, Belzutifan, Bendamustine, Bexarotene, Bicalutamide, Binimetinib, Bleomycin, Bortezomib, Bosutinib, Brigatinib, Buserelin, Busulfan, Cabazitaxel, Cabozantinib, Cabozantinib-S-Malate), Capecitabine, Capivasertib, Capmatinib, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cyproterone acetate, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin), Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dexamethasone, Diethylstilbestrol, Docetaxel, Doxorubicin, Duvelisib, Edotreotide, Eflornithine, Elacestrant, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, Epirubicin, Erdafitinib, Eribulin, Erlotinib, Estramustine, Etoposide, Everolimus, Exemestane, Fedratinib, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, Fostamatinib, Fotemustine, Fruquintinib, Fulvestrant, Futibatinib, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Goserelin, Histamine dihydrochloride, Histrelin, Hydrocortisone, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imetelstat, Imiquimod, Inavolisib, Infigratinib, Irinotecan, Ivosidenib, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Larotrectinib, Lazertinib, Lenalidomide, Lenvatinib, Letrozole, Leuprorelin, Lomustine, Lorlatinib, Lurbinectedin, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Methylnaltrexone Bromide, methylprednisolone, Midostaurin, Mifamurtide, Mitomycin, Mitotane, Mitoxantrone, Mobocertinib, Momelotinib, Nelarabine, Neratinib, Nilotinib, Nilutamide, Nintedanib, Niraparib, Nirogacestat, Octreotide, Olaparib, Olutasidenib, Omacetaxine, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib Citrate, Padeliporfin, Palbociclib, Pamidronate, Panobinostat, Pazopanib, Pemetrexed, Pemigatinib, Pentostatin, Pexidartinib, Pipobroman, Pirarubicin, Pirtobrutinib, Pixantrone, Polyestradiol Phosphate, Pomalidomide, Ponatinib, Porfimer, Pralatrexate, Pralsetinib, Prednisolone, Prednisone, Procarbazine, Quizartinib, Raltitrexed, Ranimustine, Regorafenib, Relugolix, Repotrectinib, Revumenib, Ribociclib, Ripretinib, Rolapitant, Romidepsin, Rucaparib, Ruxolitinib, Selinexor, Selpercatinib, Selumetinib, Sirolimus, Sonidegib, Sorafenib, Sotorasib, Streptozocin, Sunitinib, Talazoparib, Tamoxifen, Tazemetostat, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Tepotinib, Thalidomide, Thioguanine, Thiotepa, Tivozanib, Topotecan, Toremifene, Tovorafenib, Trabectedin, Trametinib, Treosulfan, Tretinoin, Triptorelin, Trofosfamide, Tucatinib, Umbralisib, Uridine Triacetate, Valrubicin, Vandetanib, Vemurafenib,Venetoclax, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorasidenib, Vorinostat, and Zanubrutinib.

16. The compound according to any one of claims 1 to 14, wherein cargo is a protein ligand moiety selected from modulators of mitochondrial targets.

17. The compound according to any one of claims 1 to 14 and 16, wherein cargo is an inhibitor of the ion channels in mitochondria (Kv1.3, SK, NCLX)18. The compound according to any one of claims 1 to 14 and 16 to 17, wherein cargo is inhibitor of HSP90 in mitochondria.

19. The compound according to any one of claims 1 to 14, wherein cargo is a reporter like fluorescent dye.

20. The compound according to any one of claims 1 to 14, wherein cargo is an antioxidant.

21. The compound according to any one of claims 1 to 14, wherein cargo is an inhibitor of cyclophilin D.

22. The compound according to any one of claims 1 to 21, which is an enantiomerically pure compound or an enantiomerically enriched compound.

23. The compound according to any one of claims 1 to 22, wherein W comprises a cleavable group, such as a cleavable group selected from esters, carbamates, disulfide linkers, oxime linkers, hydrazine groups, diazolinkers, carbonyloxyethylsulfone groups, amino acid groups, or phenylacetamide groups.

24. The compound according to any one of claims 1 to 23, wherein W is selected from the group consisting of (Ci-Cg)-alkyl, (C2-Cg)-alkenyl, (C2-Cg)-alkynyl, (Cs-Cgjcycloalkyl, aryl, heteroaryl, -OC(O)NR6-, -COO-, - OC(O)-, -CONR8-, -NHR8-, -SO-, -SO2NR8-, -CHR8-, -SO2-, -CO-, -S-, -O-, -CH2-, -OC(O)-CH2-C(O)O-, and - CH(OH)-CH(OH)-;wherein R8is -H, -F, -Cl, -Br, -OH, -(Ci-C6)-alkyl, or -OC(O)(Ci-C6)-alkyl, [(C=O)Or]saryl, or [(C=O)Or]s(Ci- C6)-alkyl.

25. The compound according to any one of the preceding claims, wherein the linker is -(C(R8)(R9))I-, wherein I is from 1 to 20, preferably from 1 to 10, more preferably 3 to 5; and R8and R9are independently of one another — H, halogen, -CF3,-OH, -(Ci-Cg)-alkyl, -OC(O)(Ci-Cg)-alkyl, [(C=O)Or]saryl, [(C=O)Or]sheteroaryl, or [(C=O)Or]s(Ci-C6)-alkyl.

26. The compound according to any one of claims 1 to 24, wherein the linker is a non-peptidic polymeric linker, such as a non-peptidic polymeric linker selected from polyalkylene oxides (e.g. polyethylene glycol, polypropylene glycol, and the like), polyvinyl alcohol, polyvinylpyrrolidone as well as derivatives and copolymers thereof.

27. The compound according to any one of claims 1 to 24, wherein the linker is a non-polymeric aliphatic linker, such as a non-polymeric aliphatic linker comprising a divalent, linear or branched, straight orcyclic, saturated or unsaturated hydrocarbon chain having from 2 to 20 carbon atoms, wherein the carbon atoms are optionally replaced by a group selected from -O-, -S-, -NH-, -C(=O)-, -OC(=O)-, -N(Ci- C6alkyl)-, NHC(=O)-, -N(Ci-Cg alkyl)C(=O)-, -S(=O)- or -S(=O)z- and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3 or 4) substituents.

28. The compound according to any one of claims 1 to 24, wherein the linker is a divalent radical formed from an amino acid or peptide.

29. The compound according to any one of claims 1 to 24, wherein the linker is30. The compound according to any one of the preceding claims for use in medicine.

31. The compound according to any one of the preceding claims for use in the treatment or prevention of a condition, the treatment of which is affected or facilitated by mitochondrial Kvl.3 inhibition, in a warm-blooded animal, such as a mammal (for example, rat, mouse, guinea pig, rabbit, sheep, horse, pig, cow, monkey, human), preferably human.

32. The compound for use according to claim 31, wherein the condition is a cancer.

33. The compound for use according to claim 32, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, smooth muscle cancer, skeletal muscle cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, cancer and / or tumors of the anus, bile duct cancer, bone cancer, bone marrow cancer, , eye cancer, gall bladder cancer, kidney cancer, mouth cancer, laryngeal cancer, esophagus cancer, stomach cancer, cervix cancer, mesothelioma cancer, neuroendocrine cancer, spinal cord, thyroid cancer, vaginal cancer, vulva cancer, uterus cancer, liver cancer, muscle cancer and blood cell cancer (including lymphomas and leukemias).

34. The compound for use according to claim 32 or 33, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, prostate cancer, melanoma, smooth muscle cancer, skeletal muscle cancer, chronic lymphocytic leukemia, glioblastoma, and pancreatic ductal adenocarcinoma.

35. Pharmaceutical composition comprising the compound as defined in any one of claims 1 to 29, or a pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable excipient and / or carrier.

36. The pharmaceutical composition according to claim 35, further comprising a (further) anticancer agent.

37. The pharmaceutical composition according to claim 36, wherein the anticancer agent is selected from the group consisting of Abemaciclib, Abiraterone, Acalabrutinib, Aclarubicin, Actinomycin D, Adagrasib, Adriamycin, Afatinib, Alectinib, Alitretinoin, All-trans-retinoic acid, Alpelisib, Altretamine, Amifostine, Aminolevulinic Acid, Amrubicin, Amsacrine, Anastrozole, Apalutamide, Ara C, Arsenic Trioxide, Asciminib, Avapritinib, Axitinib, Azacitidine, Belinostat, Belzutifan, Bendamustine, Bexarotene, Bicalutamide, Binimetinib, Bleomycin, Bortezomib, Bosutinib, Brigatinib, Buserelin, Busulfan, Cabazitaxel, Cabozantinib, Cabozantinib-S-Malate), Capecitabine, Capivasertib, Capmatinib, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Chlorambucil, Cisplatin, Cladribine, Clofarabine, Cobimetinib, Copanlisib, Crizotinib, Cyclophosphamide, Cyproterone acetate, Cytosine arabinoside, Dabrafenib, Dacarbazine, Dacomitinib, Dactinomycin), Darolutamide, Dasatinib, Daunorubicin, Decitabine, Degarelix, Dexamethasone, Diethylstilbestrol, Docetaxel, Doxorubicin, Duvelisib, Edotreotide, Eflornithine, Elacestrant, Enasidenib, Encorafenib, Entrectinib, Enzalutamide, Epirubicin, Erdafitinib, Eribulin, Erlotinib, Estramustine, Etoposide, Everolimus, Exemestane, Fedratinib, Floxuridine, Fludarabine, Fluorouracil, Fluoxymesterone, Flutamide, Fostamatinib, Fotemustine, Fruquintinib, Fulvestrant, Futibatinib, Gefitinib, Gemcitabine, Gilteritinib, Glasdegib, Goserelin, Histamine dihydrochloride, Histrelin, Hydrocortisone, Hydroxycarbamide, Hydroxyurea, Ibrutinib, Idarubicin, Idelalisib, Ifosfamide, Imatinib, Imetelstat, Imiquimod, Inavolisib, Infigratinib, Irinotecan, Ivosidenib, Ixabepilone, Ixazomib, Lanreotide, Lapatinib, Larotrectinib, Lazertinib, Lenalidomide, Lenvatinib, Letrozole, Leuprorelin, Lomustine, Lorlatinib, Lurbinectedin, Mechlorethamine, Medroxyprogesterone, Megestrol, Melphalan, Mercaptopurine, Methotrexate, Methylnaltrexone Bromide, methylprednisolone, Midostaurin, Mifamurtide, Mitomycin, Mitotane, Mitoxantrone, Mobocertinib, Momelotinib, Nelarabine, Neratinib, Nilotinib, Nilutamide, Nintedanib, Niraparib, Nirogacestat, Octreotide, Olaparib, Olutasidenib, Omacetaxine, Osimertinib, Oxaliplatin, Paclitaxel, Pacritinib Citrate, Padeliporfin, Palbociclib, Pamidronate, Panobinostat, Pazopanib, Pemetrexed, Pemigatinib, Pentostatin, Pexidartinib, Pipobroman, Pirarubicin, Pirtobrutinib, Pixantrone, Polyestradiol Phosphate, Pomalidomide, Ponatinib, Porfimer, Pralatrexate, Pralsetinib, Prednisolone, Prednisone, Procarbazine, Quizartinib, Raltitrexed, Ranimustine, Regorafenib, Relugolix, Repotrectinib, Revumenib, Ribociclib, Ripretinib, Rolapitant, Romidepsin, Rucaparib, Ruxolitinib, Selinexor, Selpercatinib, Selumetinib, Sirolimus, Sonidegib, Sorafenib, Sotorasib, Streptozocin, Sunitinib, Talazoparib, Tamoxifen, Tazemetostat, Temoporfin, Temozolomide, Temsirolimus, Teniposide, Tepotinib, Thalidomide, Thioguanine, Thiotepa, Tivozanib, Topotecan, Toremifene, Tovorafenib, Trabectedin, Trametinib, Treosulfan, Tretinoin, Triptorelin, Trofosfamide, Tucatinib, Umbralisib, Uridine Triacetate, Valrubicin, Vandetanib, Vemurafenib, Venetoclax, Vinblastine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorasidenib, Vorinostat, Zanubrutinib, Alemtuzumab, Amivantamab, Atezolizumab, Avelumab, Belantamab, Bevacizumab, Blinatumomab, Brentuximab, Caplacizumab, Cemiplimab, Cetuximab, Daratumumab, Denosumab, Dinutuximab,Dostarlimab, Durvalumab, Elotuzumab, Elranatamab, Emapalumab, Enfortumab, Epcoritamab, Gemtuzumab, Glofitamab, Ibritumomab, Inotuzumab, Ipilimumab, Isatuximab, Loncastuximab, Margetuximab, Mirvetuximab, Mogamulizumab, Mosunetuzumab, Moxetumomab, Naxitamab, Necitumumab, Nivolumab, Obinutuzumab, Odronextamab, Ofatumumab, Olaratumab, Panitumumab, Pembrolizumab, Pertuzumab, Polatuzumab, Racotumomab, Ramucirumab, Ravulizumab, Relatlimab, Retifanlimab, Rituximab, Sacituzumab, Siltuximab, Sugemalimab, Tafasitamab, Talquetamab, Tarlatamab, Teclistamab, Tislelizumab, Tocilizumab, Toripalimab, Trastuzumab, Tremelimumab, Zanidatamab, Zolbetuximab, Asparaginase, Calaspargase, Epoetin Alfa, Interferon Alfa-2b, Recombinant, lnterleukin-2, Ropeginterferon Alfa, Recombinant HPV bi, tetra or nonvalent vaccine, Nogapendekin Alfa Inbakicept, Granulocyte colony stimulating factor (G-CSF), lobenguane I 131, Lu 177-Dotatate, Radium 223 Dichloride, Idecabtagene Vicleucel, Lisocabtagene Maraleucel, Afamitresgene Autoleucel, Brexucabtagene Autoleucel, Ciltacabtagene Autoleucel, Obecabtagene Autoleucel, , Nadofaragene Firadenovec and Talimogene Laherparepvec.

38. The pharmaceutical composition according to any one of claims 35 to 37, which comprises nanoparticles having a core comprising one or more of the compounds as defined in claims 1 to 29.

39. The pharmaceutical composition according to claim 38, wherein said core is biodegradable.

40. The pharmaceutical composition according to any one of claims 35 to 37 for use in medicine.

41. The pharmaceutical composition according to any one of claims 35 to 37 for use in the treatment or prevention of a condition, the treatment of which is affected or facilitated by mitochondrial Kvl.3 inhibition, in a warm-blooded animal, such as a mammal (for example, rat, mouse, guinea pig, rabbit, sheep, horse, pig, cow, monkey, human), preferably human.

42. The pharmaceutical composition for use according to claim 41, wherein the condition is a cancer.

43. The pharmaceutical composition for use according to claim 42, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, genitourinary cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, smooth muscle cancer, skeletal muscle cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, cancer and / or tumors of the anus, bile duct cancer, bone cancer, bone marrow cancer, , eye cancer, gall bladder cancer, kidney cancer, mouth cancer, laryngeal cancer, esophagus cancer, stomach cancer, cervix cancer, mesothelioma cancer, neuroendocrine cancer, spinal cord, thyroid cancer, vaginal cancer, vulva cancer, uterus cancer, liver cancer, muscle cancer and blood cell cancer (including lymphomas and leukemias).

44. The pharmaceutical composition for use according to claim 42 or 43, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, prostate cancer, melanoma, smooth muscle cancer, skeletal muscle cancer, chronic lymphocytic leukemia, glioblastoma, and pancreatic ductal adenocarcinoma.

45. A method of inhibiting Kv1.3 channels in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of compound as defined in any one of claims 1 to 29.

46. The compound for use according to any one of claims 30 to 34, the pharmaceutical composition for use according to any one of claims 40 to 44, or the method of claim 45, wherein the warm-blooded animal is a mammal.

47. The compound for use of any one of claims 30 to 34, the pharmaceutical composition for use of any one of claims 40 to 44, or the method of claim 45, wherein the warm-blooded animal is a human.

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